The Impact of Delayed Radical Prostatectomy on Recurrence Outcomes After Initial Active Surveillance: Results from a Large Institutional Cohort.

BACKGROUND AND OBJECTIVE: Active surveillance (AS) of prostate cancer (PCa) involves regular monitoring for disease progression. The aim is to avoid unnecessary treatment while ensuring appropriate and timely treatment for those whose disease progresses. AS has emerged as the standard of care for low-grade (Gleason grade 1, GG 1) PCa. Opponents are concerned that initial undersampling and delay of definitive management for patients with GG 2 disease may lead to adverse outcomes. We sought to determine whether the timing for definitive management of GG 2 PCa, either upfront or after initial AS, affects recurrence outcomes after radical prostatectomy (RP). METHODS: Participants were diagnosed with cT1-2N0/xM0/x, prostate-specific antigen (PSA) <20 ng/ml, and GG 1-2 PCa between 2000 and 2020 and underwent immediate RP for GG 2 or AS followed by delayed RP on upgrading to GG 2. The outcome was recurrence-free survival (RFS) after surgery, with recurrence defined as either biochemical failure (2 PSA measurements ≥0.2 ng/ml) or a second treatment. Multivariable Cox proportional-hazards regression models were used to calculate associations between the timing for definitive RP and the risk of recurrence, adjusted for age at diagnosis, percentage of positive biopsy cores (PPC), PSA density, PSA before RP, year of diagnosis, surgical margins, genomic risk score, and prostate MRI findings. KEY FINDINGS: Of the 1259 men who met the inclusion criteria, 979 underwent immediate RP after diagnosis of GG 2, 190 underwent RP within 12 mo of upgrading to GG 2 on AS, and 90 men underwent RP >12 mo after upgrading to GG 2. The 5-yr RFS rates were 81% for the immediate RP group, 80% for the delayed RP ≤12 mo, and 70% for the delayed RP >12 mo group (univariate log-rank p = 0.03). Cox multivariable regression demonstrated no difference in RFS outcomes between immediate RP for GG 2 disease and delayed RP after upgrading on AS. PPC (hazard ratio [HR] per 10% increment 1.08, 95% confidence interval [CI] 1.02-1.15; p = 0.01) and PSA before RP (HR 1.06, 95% CI 1.03-1.09; p < 0.01) were significantly associated with the risk of recurrence. CONCLUSIONS AND CLINICAL IMPLICATIONS: PPC and PSA before RP, but not the timing of definitive surgery after upgrade to GG 2, were associated with the risk of PCa recurrence after RP on multivariable analysis. These findings support the safety of AS and delayed definitive therapy for a subset of patients with GG 2 disease. PATIENT SUMMARY: In a large group of 1259 patients with low-grade prostate cancer, we found that delaying surgical treatment after an initial period of active surveillance resulted in no differences in prostate cancer recurrence. Our results support the safety of active surveillance for low-grade prostate cancer.

Effect of a Home-based Walking Intervention on Cardiopulmonary Fitness and Quality of Life Among Men with Prostate Cancer on Active Surveillance: The Active Surveillance Exercise Randomized Controlled Trial.

BACKGROUND: Active surveillance (AS) is standard care for most men with low-risk prostate cancer (PC); yet, many men on AS eventually undergo curative therapy. Interventions to lower the risk of cancer progression and fear of recurrence among men on AS for PC are needed. OBJECTIVE: To determine the effect of aerobic exercise on cardiorespiratory fitness, body size, and quality of life (QOL) among men on AS for PC. DESIGN, SETTING, AND PARTICIPANTS: We conducted a 1:1 randomized controlled trial among 51 men with low-risk PC who elected AS. Participants were enrolled at the University of California, San Francisco. INTERVENTION: The 16-wk intervention included a home-based walking program with a nonlinear exercise prescription tailored to baseline fitness level, heart rate monitor, and weekly phone call with an exercise physiologist. Controls received printed materials. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cardiorespiratory fitness was measured using VO2peak; secondary outcomes included change in body size, anxiety, and QOL. Analyses were based on intention to treat. RESULTS AND LIMITATIONS: Between 2016 and 2021, we randomized 51 men to intervention (n = 26) or control (n = 25). Follow-up was 88% (45/51), 85% (22/26) in the intervention and 92% (23/25) in the control group. At 16 wk, the intervention group had a higher mean VO2peak than the control group (31.9 ± 4.7 vs 27.2 ± 4.8 ml/kg/min; group × time effect p value: <0.001). Additionally, the intervention group reported less fear of PC recurrence and urinary obstruction/irritation, while controls reported more of these two QOL measures, from 0 to 16 wk (p = 0.04 and 0.03, respectively). Two participants discontinued the intervention, including one due to knee pain related to the study. CONCLUSIONS: A home-based walking program improved VO2peak and reduced urinary obstruction/irritation and fear of recurrence among men on AS for PC. PATIENT SUMMARY: Moderate to vigorous aerobic exercise improves fitness and quality of life among men on active surveillance for prostate cancer.

Primary Whole-gland Ablation for the Treatment of Clinically Localized Prostate Cancer: A Focal Therapy Society Best Practice Statement.

CONTEXT: Whole-gland ablation is a feasible and effective minimally invasive treatment for localized prostate cancer (PCa). Previous systematic reviews supported evidence for favorable functional outcomes, but oncological outcomes were inconclusive owing to limited follow-up. OBJECTIVE: To evaluate the real-world data on the mid- to long-term oncological and functional outcomes of whole-gland cryoablation and high-intensity focused ultrasound (HIFU) in patients with clinically localized PCa, and to provide expert recommendations and commentary on these findings. EVIDENCE ACQUISITION: We performed a systematic review of PubMed, Embase, and Cochrane Library publications through February 2022 according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. As endpoints, baseline clinical characteristics, and oncological and functional outcomes were assessed. To estimate the pooled prevalence of oncological, functional, and toxicity outcomes, and to quantify and explain the heterogeneity, random-effect meta-analyses and meta-regression analyses were performed. EVIDENCE SYNTHESIS: Twenty-nine studies were identified, including 14 on cryoablation and 15 on HIFU with a median follow-up of 72 mo. Most of the studies were retrospective (n = 23), with IDEAL (idea, development, exploration, assessment, and long-term study) stage 2b (n = 20) being most common. Biochemical recurrence-free survival, cancer-specific survival, overall survival, recurrence-free survival, and metastasis-free survival rates at 10 yr were 58%, 96%, 63%, 71-79%, and 84%, respectively. Erectile function was preserved in 37% of cases, and overall pad-free continence was achieved in 96% of cases, with a 1-yr rate of 97.4-98.8%. The rates of stricture, urinary retention, urinary tract infection, rectourethral fistula, and sepsis were observed to be 11%, 9.5%, 8%, 0.7%, and 0.8%, respectively. CONCLUSIONS: The mid- to long-term real-world data, and the safety profiles of cryoablation and HIFU are sound to support and be offered as primary treatment for appropriate patients with localized PCa. When compared with other existing treatment modalities for PCa, these ablative therapies provide nearly equivalent intermediate- to long-term oncological and toxicity outcomes, as well as excellent pad-free continence rates in the primary setting. This real-world clinical evidence provides long-term oncological and functional outcomes that enhance shared decision-making when balancing risks and expected outcomes that reflect patient preferences and values. PATIENT SUMMARY: Cryoablation and high-intensity focused ultrasound are minimally invasive treatments available to selectively treat localized prostate cancer, considering their nearly comparable intermediate- to long term cancer control and preservation of urinary continence to other radical treatments in the primary setting. However, a well-informed decision should be made based on one's values and preferences.

Stability of Prognostic Estimation Using the CAPRA Score Incorporating Imaging-based vs Physical Exam-based Staging.

PURPOSE: Although official T-staging criteria for prostate cancer are based on digital rectal examination findings, providers increasingly rely on transrectal US and MRI to define pragmatic clinical stage to guide management. We assessed the impact of incorporating imaging findings into T-staging on performance of a well-validated prognostic instrument. MATERIALS AND METHODS: Patients who underwent radical prostatectomy for prostate cancer diagnosed between 2000 and 2019 with stage ≤cT3a on both digital rectal examination and imaging (transrectal US/MRI) were included. The University of California, San Francisco CAPRA (Cancer of the Prostate Risk Assessment) score was computed 2 ways: (1) incorporating digital rectal examination-based T stage and (2) incorporating imaging-based T stage. We assessed for risk changes across the 2 methods and associations of CAPRA (by both methods) with biochemical recurrence, using unadjusted and adjusted Cox proportional hazards models. Model discrimination and net benefit were assessed with time-dependent area under the curve and decision curve analysis, respectively. RESULTS: Of 2,222 men included, 377 (17%) increased in CAPRA score with imaging-based staging (P < .01). Digital rectal examination-based (HR 1.54; 95% CI 1.48-1.61) and imaging-based (HR 1.52; 95% CI 1.46-1.58) CAPRA scores were comparably accurate for predicting recurrence with similar discrimination and decision curve analyses. On multivariable Cox regression, positive digital rectal examination at diagnosis (HR 1.29; 95% CI 1.09-1.53) and imaging-based clinical T3/4 disease (HR 1.72; 95% CI 1.43-2.07) were independently associated with biochemical recurrence. CONCLUSIONS: The CAPRA score remains accurate whether determined using imaging-based staging or digital rectal examination-based staging, with relatively minor discrepancies and similar associations with biochemical recurrence. Staging information from either modality can be used in the CAPRA score calculation and still reliably predict risk of biochemical recurrence.

Limited Relevance of the Very Low Risk Prostate Cancer Classification in the Modern Era: Results from a Large Institutional Active Surveillance Cohort.

Although the American Urological Association recently dropped the very low-risk (VLR) subcategory for low-risk prostate cancer (PCa) and the European Association of Urology does not substratify low-risk PCa, the National Comprehensive Cancer Network (NCCN) guidelines still maintain this stratum, which is based on the number of positive biopsy cores, tumor extent in each core, and prostate-specific antigen density. This subdivision may be less applicable in the modern era in which imaging-targeted prostate biopsies are common practice. In our large institutional active surveillance cohort of patients diagnosed from 2000 to 2020 (n = 1276), the number of patients meeting NCCN VLR criteria decreased significantly in recent years, with no patient meeting VLR criteria after 2018. By contrast, the multivariable Cancer of the Prostate Risk Assessment (CAPRA) score effectively substratified patients over the same period and was predictive of upgrading on repeat biopsy to Gleason grade group ≥2 on multivariable Cox proportional-hazards regression modeling (hazard ratio 1.21, 95% confidence interval 1.05-1.39; p < 0.01), independent of age, genomic test results, and magnetic resonance imaging findings. These findings suggest that the NCCN VLR criteria are less applicable in the targeted biopsy era, and that the CAPRA score or similar instruments are better contemporary risk stratification tools for men on active surveillance. PATIENT SUMMARY: We investigated whether the National Comprehensive Cancer Network classification of very low risk (VLR) for prostate cancer is relevant in the modern era. We found that in a large group of patients on active surveillance, no man diagnosed after 2018 satisfied the VLR criteria. However, the Cancer of the Prostate Risk Assessment (CAPRA) score discriminated patients by cancer risk at diagnosis and was predictive of outcomes on active surveillance, and thus may be a more relevant classification scheme in the modern era.

Improving multiparametric MR-transrectal ultrasound guided fusion prostate biopsies with hyperpolarized 13 C pyruvate metabolic imaging: A technical development study.

PURPOSE: To develop techniques and establish a workflow using hyperpolarized carbon-13 (13 C) MRI and the pyruvate-to-lactate conversion rate (kPL ) biomarker to guide MR-transrectal ultrasound fusion prostate biopsies. METHODS: The integrated multiparametric MRI (mpMRI) exam consisted of a 1-min hyperpolarized 13 C-pyruvate EPI acquisition added to a conventional prostate mpMRI exam. Maps of kPL values were calculated, uploaded to a picture archiving and communication system and targeting platform, and displayed as color overlays on T2 -weighted anatomic images. Abdominal radiologists identified 13 C research biopsy targets based on the general recommendation of focal lesions with kPL >0.02(s-1 ), and created a targeting report for each study. Urologists conducted transrectal ultrasound-guided MR fusion biopsies, including the standard 1 H-mpMRI targets as well as 12-14 core systematic biopsies informed by the research 13 C-kPL targets. All biopsy results were included in the final pathology report and calculated toward clinical risk. RESULTS: This study demonstrated the safety and technical feasibility of integrating hyperpolarized 13 C metabolic targeting into routine 1 H-mpMRI and transrectal ultrasound fusion biopsy workflows, evaluated via 5 men (median age 71 years, prostate-specific antigen 8.4 ng/mL, Cancer of the Prostate Risk Assessment score 2) on active surveillance undergoing integrated scan and subsequent biopsies. No adverse event was reported. Median turnaround time was less than 3 days from scan to 13 C-kPL targeting, and scan-to-biopsy time was 2 weeks. Median number of 13 C targets was 1 (range: 1-2) per patient, measuring 1.0 cm (range: 0.6-1.9) in diameter, with a median kPL of 0.0319 s-1 (range: 0.0198-0.0410). CONCLUSIONS: This proof-of-concept work demonstrated the safety and feasibility of integrating hyperpolarized 13 C MR biomarkers to the standard mpMRI workflow to guide MR-transrectal ultrasound fusion biopsies.

Patient engagement in a mobile health intervention to improve preparedness for prostate biopsy.

OBJECTIVE: We designed and implemented a peri-procedural text message (SMS) program for patients undergoing transrectal prostate biopsy and aimed to evaluate predictors of patient enrollment and engagement with the SMS program. METHODS: We designed an SMS-based program with 8 messages containing web-based modules with educational content and reminders confirming MRI for fusion biopsy, antibiotic adherence, enema use, and anticoagulation cessation. Data on patient demographics, enrollment, and engagement with modules were collected from June 1, 2018 to February 28, 2021. Engagement was defined as a patient clicking a link delivered via SMS to access modules. We made multivariable models to identify predictors of patient enrollment and engagement. RESULTS: Of the 1,760 prostate biopsies between June 2018 and March 2021, 1,383 (78.6%) were enrolled in SMS, 182 (10.3%) in email, 106 (6.0%) in both, and 240 (13.6%) were not enrolled. Of 1418 patients enrolled, 1,270 (89.6%) engaged with at least one module. African American patients had 50% lower odds of being enrolled (OR = 0.50, 95% CI 0.28-0.96; P = 0.03), but once enrolled there were no differences in engagement. Patients for whom English was not listed as their primary language had 60% lower odds of engagement (OR = 0.40, 95% CI 0.17-1.00, P = .04) and patients who were single or divorced had a 40% lower odds of engagement (OR = 0.60, 95% CI 0.41-0.91, P = 0.01). CONCLUSIONS: A cohort of older men undergoing prostate biopsy were able to engage with a text message-based education and reminder program. Future efforts must address barriers to enrollment for Black or African American men and improve accessibility to non-English speaking patients.

Medium Term Outcomes of Focal Cryoablation for Intermediate and High Risk Prostate Cancer: MRI and PSA are Not Predictive of Residual or Recurrent Disease.

OBJECTIVE: To understand oncologic outcomes of focal cryoablation for prostate cancer and efficacy MRI and PSA to predict residual disease and recurrence. METHODS: We retrospectively analyzed patients who underwent focal cryotherapy at a single institution. Inclusion criteria included clinically localized biopsy-proven cancer that was clearly visible on MRI or ultrasound. The primary outcomes were failure-free survival (FFS) defined as no transition to radical, whole-gland or systemic therapy and biochemical recurrence (Phoenix PSA nadir +2 increases), and secondary outcomes included changes in the Gleason grade group (GG) and MRI findings. RESULTS: 75 patients completed post cryotherapy biopsy with a median follow-up of 1.89 [IQR 1.19-2.77] years. Failure free survival was met by 96.2% of patients at 2 year follow up and of those who did not meet this outcome, 3 had metastasis, 1 had a salvage prostatectomy and 5 underwent radiation. On the treated side of the prostate, 7 (9.5%) of patients had residual ≥GG2 disease compared to 7 (9.5%) patients on the untreated side. Out of the 12 patients who had residual ≥GG2 disease at follow up biopsy (either on treated or untreated side of the prostate), 11 (91.7%) had PI-RADS 1-3 on follow up MRI. Using a multivariate cox proportional hazards model, Phoenix criteria for recurrence (PSA nadir +2) was not predictive for FFS. CONCLUSIONS: Focal cryotherapy is effective for treating focal lesions of prostate cancer, but patients require continued surveillance. MRI and PSA are not reflective of residual disease on follow up biopsy.

The Natural History of Untreated Biopsy Grade Group Progression and Delayed Definitive Treatment for Men on Active Surveillance for Early-Stage Prostate Cancer.

PURPOSE: For men with clinically localized prostate cancer outcomes of continuing active surveillance (AS) after biopsy progression are not well understood. We aim to determine the impact of continuing AS and delayed definitive treatment after biopsy progression on oncologic outcomes. MATERIALS AND METHODS: Participants in our prospective AS cohort (1990-2018) diagnosed with grade group (GG) 1, localized prostate cancer, with prostate specific antigen <20 who were subsequently upgraded to ≥GG2, and underwent further surveillance (biopsy/imaging/prostate specific antigen) were identified. Patients were stratified by post-progression followup into 3 groups: continue AS untreated, pursue early radical prostatectomy (RP) ≤6 months, or undergo late RP within 6 months to 5 years of progression. Patients receiving other treatments were excluded. We compared characteristics between groups and examined the associations of early vs late RP with risk of adverse pathology (AP) at RP and recurrence-free survival (RFS) after RP. RESULTS: Of 531 patients with biopsy progression and further surveillance 214 (40%) remained untreated, 192 (36%) pursued early RP and 125 (24%) underwent late RP. Among patients who underwent early vs late RP, there was no difference in GG (p=0.15) or AP (55% vs 53%, p=0.74) rate at RP, or 3-year RFS (80% vs 87%, log-rank p=0.64) after RP. In multivariable models, only Cancer of Prostate Risk Assessment post-surgical score was associated with risk of RFS (HR=1.42 per point, 95% CI 1.24-1.64). CONCLUSIONS: Among patients continuing AS after biopsy progression, 60% underwent surgery within 5 years. Delayed surgery after progression was not associated with higher risk of AP or RFS. This suggests select patients may be able to safely delay treatment after progression.

US lesion visibility predicts clinically significant upgrade of prostate cancer by systematic biopsy.

PURPOSE: To identify predictors of when systematic biopsy leads to a higher overall prostate cancer grade compared to targeted biopsy. METHODS AND MATERIALS: 918 consecutive patients who underwent prostate MRI followed by MRI/US fusion biopsy and systematic biopsies from January 2015 to November 2019 at a single academic medical center were retrospectively identified. The outcome was upgrade of PCa by systematic biopsy, defined as cases when systematic biopsy led to a Gleason Grade (GG) ≥ 2 and greater than the maximum GG detected by targeted biopsy. Generalized linear regression and conditional logistic regression were used to analyze predictors of upgrade. RESULTS: At the gland level, the presence of an US-visible lesion was associated with decreased upgrade (OR 0.64, 95% CI 0.44-0.93, p = 0.02). At the sextant level, upgrade was more likely to occur through the biopsy of sextants with MRI-visible lesions (OR 2.58, 95% CI 1.87-3.63, p < 0.001), US-visible lesions (OR 1.83, 95% CI 1.14-2.93, p = 0.01), and ipsilateral lesions (OR 3.89, 95% CI 2.36-6.42, p < 0.001). CONCLUSION: Systematic biopsy is less valuable in patients with an US-visible lesion, and more likely to detect upgrades in sextants with imaging abnormalities. An approach that takes additional samples from regions with imaging abnormalities may provide analogous information to systematic biopsy.

Characteristics of Cancer Progression on Serial Biopsy in Men on Active Surveillance for Early-stage Prostate Cancer: Implications for Focal Therapy.

BACKGROUND: Active surveillance (AS) is a safe and accepted option for managing men with low-risk prostate cancer. Nevertheless, some patients lack confidence in or access to AS. Focal therapy (FT) is a possible alternative to radical treatment for such patients. OBJECTIVE: We evaluated dominant tumor (DT) progression across serial biopsies to determine whether men on AS could be reasonable candidates for FT. DESIGN, SETTING, AND PARTICIPANTS: Men enrolled in AS at University of California, San Francisco between 1996 and 2017 with low/intermediate risk were included. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Changes in biopsy grade, volume, and focality of the DT over time were assessed. Focality (good or poor for FT) was defined by the number of cores, laterality, and contiguity of prostate sites containing tumor (based on pathology reports). Candidates (either for targeted/quadrant ablation or for hemigland ablation) were defined based on good focality, grade group (GG) ≤2, and low-volume disease. Patients were classified as favorable (GG ≤ 2 with good focality and concordant multiparametric magnetic resonance imaging [mpMRI]) or unfavorable (poor focality or high-volume disease or discordant mpMRI) for FT at surveillance biopsies. RESULTS AND LIMITATIONS: A total of 1057 men met the inclusion criteria. The median number of biopsies per patient was three (interquartile range 2-4), and 196 patients (18.5%) underwent five or more biopsies. At confirmatory biopsy, 43% remained candidates for FT (67% for targeted/quadrant ablation and 33% for hemigland ablation) and 20% had a negative biopsy. Of the candidates for FT at initial biopsy, 11% had less favorable characteristics at confirmatory biopsy. Among candidates for FT based on both initial and confirmatory biopsies, 70% remained favorable for hemigland ablation at subsequent biopsies. Limitations include retrospective design and mpMRI information only at surveillance biopsy. CONCLUSIONS: Serial biopsy findings in men with early-stage cancer on AS show that tumor location remains relatively stable and significant changes in grade and/or volume occur largely in the DT. Combined diagnostic and confirmatory biopsy findings help better select patients for FT than the use of the diagnostic biopsy alone. PATIENT SUMMARY: In a large cohort of patients on active surveillance for prostate cancer, we evaluated changes across serial biopsies to identify potential candidates for focal therapy (FT). Our findings showed that the dominant tumor remained stable over time and the majority of men were favorable candidates for FT.

Diagnostic Accuracy and Prognostic Value of Serial Prostate Multiparametric Magnetic Resonance Imaging in Men on Active Surveillance for Prostate Cancer.

BACKGROUND: Multiparametric magnetic resonance imaging (MRI) is increasingly utilized to improve the detection of clinically significant prostate cancer. Evidence for serial MRI in men on active surveillance (AS) is lacking. OBJECTIVE: To evaluate the role of MRI in detecting Gleason grade group (GG) ≥2 disease in confirmatory and subsequent surveillance biopsies for men on AS. DESIGN, SETTING, AND PARTICIPANTS: This was a single-center study of men with low-risk prostate cancer enrolled in an AS cohort between 2006 and 2018. All men were diagnosed by systematic biopsy and underwent MRI prior to confirmatory ("MRI1") and subsequent surveillance ("MRI2") biopsies. MRI lesions were scored with Prostate Imaging Reporting and Data System (PI-RADS) version 2. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was biopsy upgrade to GG ≥ 2 prostate cancer, and the secondary outcome was definitive treatment. Test characteristics for PI-RADS score were calculated. Multivariable logistic and Cox proportional hazard regression models were used to determine the associations between PI-RADS score change and outcomes, on a per-examination basis. RESULTS AND LIMITATIONS: Of 125 men with a median follow-up of 78 mo, 38% experienced an increase in PI-RADS scores. The sensitivity and positive predictive value of PI-RADS ≥3 for GG ≥ 2 disease improved from MRI1 to MRI2 (from 85% to 91% and from 26% to 49%, respectively). An increase in PI-RADS scores from MRI1 to MRI2 was associated with GG ≥ 2 (odds ratio [OR] 4.8, 95% confidence interval [CI] 1.7-13.2) compared with PI-RADS 1-3 on both MRI scans. Men with PI-RADS 4-5 lesions on both MRI scans had a higher likelihood of GG ≥ 2 than patients with PI-RADS 1-3 lesions on both (OR 3.3, 95% CI 1.3-8.6). Importantly, any increase in PI-RADS scores was independently associated with definitive treatment (hazard ratio 3.9, 95% CI 1.3-11.9). This study was limited by its retrospective, single-center design. CONCLUSIONS: The prognostic value of MRI improves with serial examination and provides additional risk stratification. Validation in other cohorts is needed. PATIENT SUMMARY: We looked at the role of serial prostate magnetic resonance imaging in men with low-risk prostate cancer on active surveillance at the University of California, San Francisco. We found that both consistently visible and increasingly suspicious lesions were associated with biopsy upgrade and definitive treatment.

Salvage High-Dose-Rate Brachytherapy for Recurrent Prostate Cancer After Definitive Radiation.

PURPOSE: Salvage high-dose-rate brachytherapy (sHDRBT) for locally recurrent prostate cancer after definitive radiation is associated with biochemical control in approximately half of patients at 3 to 5 years. Given potential toxicity, patient selection is critical. We present our institutional experience with sHDRBT and validate a recursive partitioning machines model for biochemical control. MATERIALS AND METHODS: We performed a retrospective analysis of 129 patients who underwent whole-gland sHDRBT between 1998 and 2016. We evaluated clinical factors associated with biochemical control as well as toxicity. RESULTS: At diagnosis the median prostate-specific antigen (PSA) was 7.77 ng/mL. A majority of patients had T1-2 (73%) and Gleason 6-7 (82%) disease; 71% received external beam radiation therapy (RT) alone, and 22% received permanent prostate implants. The median disease-free interval (DFI) was 56 months, and median presalvage PSA was 4.95 ng/mL. At sHDRBT, 46% had T3 disease and 51% had Gleason 8 to 10 disease. At a median of 68 months after sHDRBT, 3- and 5-year disease-free survival were 85% (95% CI, 79-91) and 71% (95% CI, 62-79), respectively. Median PSA nadir was 0.18 ng/mL, achieved a median of 10 months after sHDRBT. Patients with ≥35%+ cores and a DFI <4.1 years had worse biochemical control (19% vs 50%, P = .02). Local failure (with or without regional/distant failure) was seen in 11% of patients (14/129), and 14 patients (11%) developed acute urinary obstruction requiring Foley placement and 19 patients (15%) developed strictures requiring dilation. CONCLUSIONS: sHDRBT is a reasonable option for patients with locally recurrent prostate cancer after definitive RT. Those with <35%+ cores or an initial DFI of ≥4.1 years may be more likely to achieve long-term disease control after sHDRBT.

Clinical Utility of 4Kscore®, ExosomeDx™ and Magnetic Resonance Imaging for the Early Detection of High Grade Prostate Cancer.

PURPOSE: We aimed to evaluate 4Kscore® and ExosomeDx™ with multiparametric magnetic resonance imaging in the detection of high grade prostate cancer and number of biopsies avoided. MATERIAL AND METHODS: Patients had 1 liquid biomarker test with or without multiparametric magnetic resonance imaging. High grade prostate cancer was defined as Gleason grade group 2 or greater. The overall number of avoided biopsies (with Gleason grade 1 or less), and number of missed Gleason grade 2 or greater cancer among the biopsied patients, were determined. RESULTS: Of the 783 patients in the overall cohort 419 (53.5%) underwent biopsy. 4Kscore and ExosomeDx scores higher than the manufacturers' cut point were associated with PI-RADS™ scores 3 to 5 and Gleason grade 2 or greater prostate cancer. Limiting biopsy to the men with liquid biomarker scores above the manufacturers' cut point would have resulted avoiding 29.5% to 39.9% unnecessary biopsies overall, while missing 4.0% to 4.8% Gleason grade 2 or greater prostate cancer in the biopsy group. Screening algorithms with up-front liquid biomarker testing followed by multiparametric magnetic resonance imaging if the biomarker is above the manufacturers' cut point, then followed by biopsy if the multiparametric magnetic resonance imaging is positive or if 4Kscore 20 or greater or ExosomeDx 19 or greater would have missed 4.8% to 5.6% of Gleason grade 2 or greater prostate cancer in the biopsy group while avoiding 39.4% to 43.0% biopsies and 29.5% to 39.9% multiparametric magnetic resonance imaging overall. Similar algorithms with up-front multiparametric magnetic resonance imaging followed by liquid biomarker testing for negative multiparametric magnetic resonance imaging would have missed 2.4% of Gleason grade 2 or greater prostate cancer in the biopsy group but only avoided 17.2% 19.3% biopsies overall. CONCLUSIONS: Screening algorithms with up-front liquid biomarker testing followed by multiparametric magnetic resonance imaging and biopsy at certain biomarker thresholds could reduce unnecessary biopsies, multiparametric magnetic resonance imaging and overdetection of Gleason grade 1 prostate cancer.

How Often Does Magnetic Resonance Imaging Detect Prostate Cancer Missed by Transrectal Ultrasound?

BACKGROUND: Lesion-targeted prostate biopsy based on multiparametric magnetic resonance imaging (mpMRI) has been shown to be superior to systematic transrectal ultrasound (TRUS) biopsy (SBx) alone in men at risk for prostate cancer (PCa). However, the incremental benefit of MRI-targeted biopsy (MBx) beyond SBx with ultrasound-targeted biopsy (UBx) is less clear. OBJECTIVE: We performed a three-way comparison of UBx versus MBx versus SBx for PCa detection. DESIGN, SETTING, AND PARTICIPANTS: A prospective, single-center cohort study was conducted on consecutive patients with PCa suspicion or low-risk PCa on active surveillance (AS). All men had at least one lesion (Prostate Imaging Reporting and Data System [PI-RADS] ≥3) on pre-biopsy mpMRI. UBx, MBx, and SBx were performed during the same encounter, and the urologists were blinded to MRI results and targeting until both SBx and UBx were completed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The ability of each biopsy type to identify the highest grade group (GG) was determined, and UBx and MBx were compared using a paired t test. RESULTS AND LIMITATIONS: We prospectively enrolled 201 consecutive men undergoing targeted prostate biopsy: 72 (36%) were biopsy-naïve, 34 (17%) had a prior negative SBx, and 95 (47%) were on AS. Median age and prostate-specific antigen were 66 yr (interquartile range [IQR] 62-71) and 6.8 ng/ml (IQR 4.9-9.8), respectively. Suspicious hypoechoic lesions were reported on TRUS in 69%. Among the 169 men with PCa, SBx detected the highest GG or was equivalent to UBx/MBx in 136 (80%) men. UBx detected the highest GG or was equivalent to MBx in 19 (11%) men, and MBx alone detected the highest GG in 14 (8%) men. There was no significant difference between UBx and MBx in direct comparison (p = 0.08). Limitations include that patients were not randomized, our population was heterogeneous, and TRUS expertise at a tertiary care academic center might not reflect routine practice. CONCLUSIONS: In the setting of high expertise and experience with both ultrasound and MRI, MBx offers only a modest benefit over SBx and UBx. PATIENT SUMMARY: At a highly experienced academic medical center, we examined the detection rates of prostate cancer among men undergoing prostate biopsy using three techniques: transrectal ultrasound lesion-targeted biopsy, magnetic resonance imaging-targeted biopsy, and systematic biopsy. We identified a few more cases of aggressive prostate cancer with magnetic resonance imaging-targeted biopsy, but a large majority was found by ultrasound alone.

Long-Term Results of NRG Oncology/RTOG 0321: A Phase II Trial of Combined High Dose Rate Brachytherapy and External Beam Radiation Therapy for Adenocarcinoma of the Prostate.

PURPOSE: To report the long-term outcome of patients with prostate cancer treated with external beam radiation therapy and high dose rate (HDR) brachytherapy from a prospective multi-institutional trial conducted by NRG Oncology/RTOG. METHODS AND MATERIALS: Patients with clinically localized (T1c-T3b) prostate cancer without prior history of transurethral resection of prostate or hip prosthesis were eligible for this study. All patients were treated with a combination of 45 Gy in 25 fractions from external beam radiation therapy and one HDR implant delivering 19 Gy in 2 fractions. Adverse events (AE) were collected using Common Toxicity Criteria for Adverse Events, version 3. Cumulative incidence was used to estimate time to severe late gastrointestinal (GI)/genitourinary (GU) toxicity, biochemical failure, disease-specific mortality, local failure, and distant failure. Overall survival was estimated using the Kaplan-Meier method. RESULTS: One hundred and twenty-nine patients were enrolled from July 2004 to May 2006. AE data was available for 115 patients. Patients were National Comprehensive Cancer Network (NCCN) intermediate to very high risk. The median age was 68, T1c-T2c 91%, T3a-T3b 9%, PSA ≤10 70%, PSA >10 to ≤20 30%, GS 6 10%, GS 7 72%, and GS 8 to 10 18%. Forty-three percent of patients received hormonal therapy. At a median follow-up time of 10 years, there were 6 (5%) patients with grade 3 GI and GU treatment-related AEs, and no late grade 4 to 5 GI and GU AEs. At 5 and 10 years, the rate of late grade 3 gastrointestinal and genitourinary AEs was 4% and 5%, respectively. Five- and 10-year overall survival rates were 95% and 76%. Biochemical failure rates per Phoenix definition at 5 and 10 years were 14% and 23%. The 10-year rate of disease-specific mortality was 6%. At 5 and 10 years, the rates of distant failure were 4% and 8%, respectively. The rates of local failure at 5 and 10 years were 2% at both time points. CONCLUSIONS: Combined modality treatment using HDR prostate brachytherapy leads to excellent long-term clinical outcomes in this prospective multi-institutional trial.

Multiparametric Magnetic Resonance Imaging Alone is Insufficient to Detect Grade Reclassification in Active Surveillance for Prostate Cancer.

Multiparametric magnetic resonance imaging (mpMRI) has improved the detection of clinically significant prostate cancer. It remains unclear, however, whether mpMRI can safely replace confirmatory or surveillance biopsies in men with low-risk disease managed with active surveillance (AS). Overall, 166 men were upgraded at a median of 29 mo (interquartile range 13-54). The overall negative predictive value (NPV) of mpMRI was 79.5% and ranged from 74.4% to 84.6% for all AS biopsies up to the fourth surveillance biopsy. In men with prostate-specific antigen density ≥0.15 ng/ml/cm3, the overall NPV of mpMRI was 65.5% and ranged from 57.1% to 73.3% across serial mpMRI scans. These findings support the hypothesis that mpMRI is helpful but insufficient to rule out pathological reclassification, especially at confirmatory biopsy or in the presence of other risk factors. PATIENT SUMMARY: Multiparametric magnetic resonance imaging (mpMRI) alone misses a considerable percentage of clinically significant prostate cancers (Gleason grade group ≥2) in men on active surveillance for low-risk prostate cancer. We conclude that mpMRI alone cannot safely replace surveillance prostate biopsies, particularly at confirmatory biopsy or in the presence of other risk factors.

Risk Factors for Biopsy Reclassification over Time in Men on Active Surveillance for Early Stage Prostate Cancer.

PURPOSE: Few validated clinical tools currently exist to standardize the frequency of biopsies for men on active surveillance for low risk prostate cancer. We determined predictors of biopsy reclassification at specific time points after enrollment on active surveillance. MATERIALS AND METHODS: We identified men with clinically low risk prostate cancer prospectively enrolled on active surveillance at the University of California, San Francisco between 2000 and 2016. Biopsy reclassification was defined as Gleason Grade Group 2 or greater on subsequent biopsy. Multivariable Cox proportional hazards regression models were used to identify factors associated with risk of biopsy reclassification at first surveillance biopsy and 1 to 3, 3 to 5 and 5 to 10 years after enrollment, adjusting for clinicodemographic factors, PI-RADS® (Prostate Imaging Reporting and Data System) score and genomic testing. RESULTS: A total of 1,031 men were included in the study. On multivariable analysis biopsy reclassification was associated with prostate specific antigen density 0.15 or greater (HR 3.37, 95% CI 1.83-6.21), percentage biopsy cores positive (HR 1.27, 95% CI 1.05-1.54) and high genomic score (HR 2.81, 95% CI 1.21-6.52) at first surveillance biopsy and also at 1 to 3 years, after adjustment. Prostate specific antigen density 0.15 or greater (HR 2.36, 95% CI 1.56-3.56) and prostate specific antigen kinetics (HR 2.19, 95% CI 1.43-3.34) were associated with reclassification at 3 to 5 years. A PI-RADS 4-5 score was not associated with biopsy reclassification at any time point. CONCLUSIONS: High genomic score, prostate specific antigen kinetics and prostate specific antigen density 0.15 or greater were associated with reclassification within 3 years of commencing active surveillance, and prostate specific antigen kinetics and prostate specific antigen density 0.15 or greater remained associated with reclassification at 5 years after diagnosis.

MRI-Based Prostate-Specific Antigen Density Predicts Gleason Score Upgrade in an Active Surveillance Cohort.

OBJECTIVE. Elevated prostate-specific antigen density (PSAD) based on transrectal ultrasound (TRUS) measurements has been shown to be strongly associated with clinically significant disease and to predict progression on active surveillance (AS) for men with disease that is at a low stage or grade. We hypothesized that elevated MRI PSAD is similarly associated with increased risk of progression on subsequent biopsy. MATERIALS AND METHODS. In this retrospective study, men with Gleason score of 3+3 on diagnostic TRUS-guided biopsy who were managed with AS, had undergone MRI, and had at least one additional biopsy were included. MRI PSAD was calculated using prostate volume on MRI and prostate-specific antigen level temporally closest to the MRI. Multivariable logistics regression models were used to evaluate the association between MRI PSAD and predictors of upgrade on serial biopsy. RESULTS. A total of 166 patients were identified, of whom 74 (44.6%) were upgraded to a Gleason score of 7 or higher on subsequent biopsy. Lesions with Prostate Imaging Reporting and Data System (PI-RADS) scores of 4 and 5 more commonly had MRI PSAD of 0.15 ng/mL2 or higher (51.93% vs 22.22%, p = 0.01) than lesions with PI-RADS scores of 1-3. Median MRI PSAD was significantly higher in the upgraded group compared with the group that was not upgraded (0.15 ng/mL2 vs 0.11 ng/mL2, p = 0.01). MRI PSAD was significantly associated with increased odds of upgrading on subsequent biopsy (log transformation; odds ratio, 1.9 [95% CI, 1.2-2.8]; p = 0.01) after adjusting for age and length of follow-up. CONCLUSION. MRI PSAD was significantly associated with Gleason score upgrading on subsequent biopsy for men initially diagnosed with Gleason 3+3 disease. Although this result is intuitive, to our knowledge it has not been previously shown. As MRI utilization increases, MRI PSAD can aid in risk stratification for men managed with AS.

Differences in negative predictive value of prostate MRI based in men with suspected or known cancer.

OBJECTIVE: To compare the negative predictive value (NPV) of multiparametric MRI for Gleason score (GS) ≥ 3+4 cancer and evaluate predictors of these tumors in men with suspected disease and under active surveillance (AS). MATERIALS AND METHODS: This retrospective study included 38 men with suspected prostate cancer and 38 under AS with scans assigned PI-RADS v2 scores 1 or 2 between May 2016 and September 2017. Biopsy results were no cancer, GS = 3+3, or GS ≥ 3+4. Pre-MRI PSA, gland volume, and PSA density were recorded. Chi-square, equality of proportions, and logistic regressions were used to analyze the data. RESULTS: Intermediate to high-grade cancer was found in 12.8% (95% CI = 2.3-23.3) and 35.9% (95% CI = 20.8-50.9) of men with suspected cancer, and under AS (p = 0.02), respectively. The NPV for GS ≥ 3+4 were 87.2% (suspected cancer; 76.7-97.7) and 64.1% (AS; 49.0-79.2). In neither group PSA significantly predicted cancer grade (p = 0.75 and 0.63). Although it did not reach conventional statistical significance, PSA density was a good predictor of cancer grade in men with suspected disease (p = 0.06), but not under AS (p = 0.62). CONCLUSION: The NPV of multiparametric MRI for GS ≥ 3+4 is higher in men with suspected prostate cancer than in men under AS. PSA density ≤ 0.15 improved the prediction of intermediate to high-grade disease in patients without known cancer.

OBJETIVO: Comparar o valor preditivo negativo (VPN) da RM multiparamétrica da próstata para o diagnóstico de tumores escore de Gleason (EG) ≥ 3+4 e avaliar os preditores desses tumores em homens com suspeita de doença e nos sob vigilância ativa (VA). MATERIAIS E MÉTODOS: Este estudo retrospectivo incluiu 38 homens com suspeita de câncer de próstata e 38 em VA com RM, aos quais foram atribuídos escores PI-RADS v2 1 ou 2 entre maio de 2016 e setembro de 2017. Os resultados da biópsia foram ausência de câncer, câncer EG = 3+3 ou câncer EG ≥ 3+4. PSA pré-RM, volume da glândula e densidade de PSA foram anotados. Qui-quadrado, igualdade de proporções e regressões logísticas foram utilizados para analisar os dados. RESULTADOS: Câncer de grau intermediário a alto grau foi encontrado em 12,8% (IC 95% = 2,3­23,3) e 35,9% (IC 95% = 20,8­50,9) dos homens com suspeita de câncer e nos sob VA (p = 0,02), respectivamente. O VPN para GS ≥ 3+4 foi 87,2% (suspeita de câncer; IC 95% = 76,7­97,7) e 64,1% (VA; IC 95% = 49,0­79,2). Em nenhum dos grupos o PSA previu significativamente o grau de câncer (p = 0,75 e 0,63. Embora não tenha alcançado o limiar de significância estatística usual, a densidade de PSA foi um bom preditor de grau de câncer em homens com suspeita de doença (p = 0,06), mas não sob VA (p = 0,62). CONCLUSÃO: O VPN da RM multiparamétrica para GS ≥ 3+4 é maior em homens com suspeita de câncer de próstata do que em homens sob VA. Uma densidade de PSA ≤ 0,15 melhorou a previsão de doença de grau intermediário a alto grau em pacientes sem diagnóstico prévio de câncer.