Biomarker vs MRI-Enhanced Strategies for Prostate Cancer Screening: The STHLM3-MRI Randomized Clinical Trial.

Importance: Prostate cancer guidelines often recommend obtaining magnetic resonance imaging (MRI) before a biopsy, yet MRI access is limited. To date, no randomized clinical trial has compared the use of novel biomarkers for risk estimation vs MRI-based diagnostic approaches for prostate cancer screening. Objective: To evaluate biomarker-based risk estimation (Stockholm3 risk scores or prostate-specific antigen [PSA] levels) with systematic biopsies vs an MRI-enhanced strategy (PSA levels and MRI with systematic and targeted biopsy) for the detection of clinically significant prostate cancer in a screening setting. Design, Setting, and Participants: This open-label randomized clinical trial conducted in Stockholm, Sweden, between April 4, 2018, and December 10, 2020, recruited men aged 50 to 74 years with no history of prostate cancer. Participants underwent blood sampling for PSA and Stockholm3 tests to estimate their risk of clinically significant prostate cancer (Gleason score ≥3 + 4). After the blood tests were performed, participants were randomly assigned in a 2:3 ratio to receive a Stockholm3 test with systematic biopsy (biomarker group) or a PSA test followed by MRI with systematic and targeted biopsy (MRI-enhanced group). Data were analyzed from September 1 to November 5, 2023. Interventions: In the biomarker group, men with a Stockholm3 risk score of 0.15 or higher underwent systematic biopsies. In the MRI-enhanced group, men with a PSA level of 3 ng/mL or higher had an MRI and those with a Prostate Imaging-Reporting and Data System (PI-RADS) score of 3 or higher (range: 1-5, with higher scores indicating a higher likelihood of clinically significant prostate cancer) underwent targeted and systematic biopsies. Main Outcomes and Measures: Primary outcome was detection of clinically significant prostate cancer (Gleason score ≥3 + 4). Secondary outcomes included detection of clinically insignificant cancer (Gleason score ≤6) and the number of biopsy procedures performed. Results: Of 12 743 male participants (median [IQR] age, 61 [55-67] years), 5134 were assigned to the biomarker group and 7609 to the MRI-enhanced group. In the biomarker group, 8.0% of men (413) had Stockholm3 risk scores of 0.15 or higher and were referred for systematic biopsies. In the MRI-enhanced group, 12.2% of men (929) had a PSA level of 3 ng/mL or higher and were referred for MRI with biopsies if they had a PI-RADS score of 3 or higher. Detection rates of clinically significant prostate cancer were comparable between the 2 groups: 2.3% in the biomarker group and 2.5% in the MRI-enhanced group (relative proportion, 0.92; 95% CI, 0.73-1.15). More biopsies were performed in the biomarker group than in the MRI-enhanced group (326 of 5134 [6.3%] vs 338 of 7609 [4.4%]; relative proportion, 1.43 [95% CI, 1.23-1.66]), and more indolent prostate cancers were detected (61 [1.2%] vs 41 [0.5%]; relative proportion, 2.21 [95% CI, 1.49-3.27]). Conclusions and Relevance: Findings of this randomized clinical trial indicate that combining a Stockholm3 test with systematic biopsies is comparable with MRI-based screening with PSA levels and systematic and targeted biopsies for detection of clinically significant prostate cancer, but this approach resulted in more biopsies as well as detection of a greater number of indolent cancers. In regions where access to MRI is lacking, the Stockholm3 test can aid in selecting patients for systematic prostate biopsy. Trial Registration: ClinicalTrials.gov Identifier: NCT03377881.

The Capio Prostate Cancer Center Model for Prostate Cancer Diagnostics-Real-world Evidence from 2018 to 2022.

Background: The Capio Prostate Cancer Center (Capio PCC) in Stockholm, Sweden, adopts a comprehensive diagnostic approach, utilizing prostate-specific antigen (PSA), Stockholm3, and magnetic resonance imaging (MRI) for prostate cancer risk assessment, followed by targeted and systematic biopsies for high-risk cases. Objective: This study aims to elucidate the clinical process and real-world outcomes of the Capio PCC model for prostate cancer diagnosis at Capio S:t Göran Hospital. Design setting and participants: Between 2018 and 2022, a cohort of 12 406 men aged 45-75 yr underwent prostate cancer testing, adhering to Capio PCC's structured diagnostic protocol. Outcome measurements and statistical analysis: We provide a comprehensive description of the Capio PCC model and present results from its implementation, including assessments of PSA, Stockholm3, MRI scans, and biopsies. A comparative analysis is conducted between the diagnostic outcomes obtained at Capio PCC and those obtained at other regions in Sweden. Results and limitations: The median participant age was 61 yr (interquartile range [IQR]: 55-67), with PSA levels at 1.6 ng/ml (IQR: 0.8-3.3) and Stockholm3 scores at 4 (IQR: 3-11). Among 1064 men (8.6%) undergoing biopsies, 611 (57% of biopsied) were diagnosed with International Society of Urological Pathology grade ≥ 2 cancer. Notably, employing a Stockholm3 ≥ 15 cutoff for biopsy, in lieu of PSA ≥ 3 ng/ml, reduced biopsy recommendations by 43%. For men with PSA levels between 1.5 and 2.9 ng/ml, 360 (12%) exhibited Stockholm3 scores of ≥ 15, with 72 (56% of biopsied) diagnosed with clinically significant prostate cancer. A comparative analysis with national Swedish prostate cancer detection data indicated that the Capio PCC model (vs Sweden) revealed a distribution of 14% (vs 25%) low-risk, 59% (vs 42%) intermediate-risk, and 26% (vs 30%) high-risk and advanced cancers. Conclusions: This study underscores the effectiveness of the protocol-driven diagnostic process at Capio PCC, enabling earlier detection of intermediate-risk prostate cancer and reducing the need for MRI assessments compared with standard prostate cancer care in Sweden. Patient summary: At the Capio Prostate Cancer Center, a novel diagnostic approach incorporating prostate-specific antigen, Stockholm3, magnetic resonance imaging, and targeted biopsies has been implemented to enhance prostate cancer testing and diagnosis in Stockholm, Sweden.

Repeated Prostate Cancer Screening Using Prostate-Specific Antigen Testing and Magnetic Resonance Imaging: A Secondary Analysis of the STHLM3-MRI Randomized Clinical Trial.

Importance: Magnetic resonance imaging (MRI) has been proposed to enhance the benefit-to-harm ratio of prostate cancer screening, but data on repeated screening outcomes are lacking. Objective: To describe outcomes of prostate-specific antigen (PSA)-based screening with MRI and prostate biopsies at repeat screening. Design, Setting, and Participants: This secondary analysis examined the population-based, screen-by-invitation STHLM3-MRI randomized clinical trial, which recruited Swedish men aged 50 to 74 years. Men were eligible for repeat screening at 2 to 3 years if they had PSA levels of 1.5 ng/mL or greater at trial inclusion, were randomized to the MRI-targeted group (including screening using biomarkers and MRI), and were not diagnosed with prostate cancer after the first screening round. Repeat screening was performed between November 10, 2021, and February 20, 2023. Data analysis was performed between May and August 2023. Intervention: Participants underwent blood sampling, including PSA testing. A biparametric MRI scan was performed if PSA levels were 3 ng/mL or greater, and men with lesions with a Prostate Imaging-Reporting and Data System (PI-RADS) score of 3 or greater were referred for targeted and systematic biopsies. Main Outcomes and Measures: The primary outcome was clinically significant prostate cancer (Gleason score of ≥3 + 4). Secondary outcomes included the proportion of men with clinically insignificant cancer (Gleason score of 6), the number of elevated PSA tests, MRI scans, and biopsy procedures. Results: Of 7609 men from the first screening round, 2078 (27.3%) were eligible for and were invited for rescreening. Among the invitees, 1500 (72.2%) participated. Their median age was 67 (IQR, 61-72) years. Of 1094 men with PSA levels between 1.5 and 2.9 ng/mL in the first screening round, 326 (29.8%) had levels of 3 ng/mL or greater in the second round. Overall, 667 men (44.5%) had PSA levels of 3 ng/mL or greater: 617 underwent MRI (92.5%), revealing 51 (7.6%) with equivocal lesions (PI-RADS score of 3) and 33 (4.9%) with suspicious lesions (PI-RADS score of ≥4). Only 10 of 383 men (2.6%) with a prior negative MRI result had a lesion with a PI-RADS score of 4 or greater. Among the 1500 rescreened men, 48 (3.2%) had a Gleason score of 3 + 4 or greater, including 19 (1.3%) with a score of 4 + 3 or greater and 11 (0.7%) with a score of 6. Conclusions and Relevance: In this secondary analysis of the STHLM3-MRI randomized clinical trial, cancer detection during the second screening round in biennial PSA and MRI-based prostate cancer screening was limited, and the detection of low-grade tumors remained low. A substantial proportion of men exhibited elevated PSA levels during rescreening, and a considerable portion of MRI scans performed lacked lesions suggestive of cancer. Future studies should explore strategies to reduce MRI-related resource use. Trial Registration: ClinicalTrials.gov Identifier: NCT03377881.

Manual prostate MRI segmentation by readers with different experience: a study of the learning progress.

OBJECTIVE: To evaluate the learning progress of less experienced readers in prostate MRI segmentation. MATERIALS AND METHODS: One hundred bi-parametric prostate MRI scans were retrospectively selected from the Göteborg Prostate Cancer Screening 2 Trial (single center). Nine readers with varying degrees of segmentation experience were involved: one expert radiologist, two experienced radiology residents, two inexperienced radiology residents, and four novices. The task was to segment the whole prostate gland. The expert's segmentations were used as reference. For all other readers except three novices, the 100 MRI scans were divided into five rounds (cases 1-10, 11-25, 26-50, 51-76, 76-100). Three novices segmented only 50 cases (three rounds). After each round, a one-on-one feedback session between the expert and the reader was held, with feedback on systematic errors and potential improvements for the next round. Dice similarity coefficient (DSC) > 0.8 was considered accurate. RESULTS: Using DSC > 0.8 as the threshold, the novices had a total of 194 accurate segmentations out of 250 (77.6%). The residents had a total of 397/400 (99.2%) accurate segmentations. In round 1, the novices had 19/40 (47.5%) accurate segmentations, in round 2 41/60 (68.3%), and in round 3 84/100 (84.0%) indicating learning progress. CONCLUSIONS: Radiology residents, regardless of prior experience, showed high segmentation accuracy. Novices showed larger interindividual variation and lower segmentation accuracy than radiology residents. To prepare datasets for artificial intelligence (AI) development, employing radiology residents seems safe and provides a good balance between cost-effectiveness and segmentation accuracy. Employing novices should only be considered on an individual basis. CLINICAL RELEVANCE STATEMENT: Employing radiology residents for prostate MRI segmentation seems safe and can potentially reduce the workload of expert radiologists. Employing novices should only be considered on an individual basis. KEY POINTS: • Using less experienced readers for prostate MRI segmentation is cost-effective but may reduce quality. • Radiology residents provided high accuracy segmentations while novices showed large inter-reader variability. • To prepare datasets for AI development, employing radiology residents seems safe and might provide a good balance between cost-effectiveness and segmentation accuracy while novices should only be employed on an individual basis.

Prostate Age Gap: An MRI Surrogate Marker of Aging for Prostate Cancer Detection.

BACKGROUND: Aging is the most important risk factor for prostate cancer (PC). Imaging techniques can be useful to measure age-related changes associated with the transition to diverse pathological states. However, biomarkers of aging from prostate magnetic resonance imaging (MRI) remain to be explored. PURPOSE: To develop an aging biomarker from prostate MRI and to examine its relationship with clinically significant PC (csPC, Gleason score ≥7) risk occurrence. STUDY TYPE: Retrospective. POPULATION: Four hundred and sixty-eight (65.97 ± 6.91 years) biopsied males, contributing 7243 prostate MRI slices. A deep learning (DL) model was trained on 3223 MRI slices from 81 low-grade PC (Gleason score ≤6) and 131 negative patients, defined as non-csPC. The model was tested on 90 negative, 52 low-grade (142 non-csPC), and 114 csPC patients. FIELD STRENGTH/SEQUENCE: 3-T, axial T2-weighted spin sequence. ASSESSMENT: Chronological age was defined as the age of the participant at the time of the visit. Prostate-specific antigen (PSA), prostate volume, Gleason, and Prostate Imaging-Reporting and Data System (PI-RADS) scores were also obtained. Manually annotated prostate masks were used to crop the MRI slices, and a DL model was trained with those from non-csPC patients to estimate the age of the patients. Following, we obtained the prostate age gap (PAG) on previously unseen csPC and non-csPC cropped MRI exams. PAG was defined as the estimated model age minus the patient's age. Finally, the relationship between PAG and csPC risk occurrence was assessed through an adjusted multivariate logistic regression by PSA levels, age, prostate volume, and PI-RADS ≥ 3 score. STATISTICAL TESTS: T-test, Mann-Whitney U test, permutation test, receiver operating characteristics (ROC), area under the curve (AUC), and odds ratio (OR). A P value <0.05 was considered statistically significant. RESULTS: After adjusting, there was a significant difference in the odds of csPC (OR = 3.78, 95% confidence interval [CI]: 2.32-6.16). Further, PAG showed a significantly larger bootstrapped AUC to discriminate between csPC and non-csPC than that of adjusted PI-RADS ≥ 3 (AUC = 0.981, 95% CI: 0.975-0.987). DATA CONCLUSION: PAG may be associated with the risk of csPC and could outperform other PC risk factors. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 3.

[Improved prostate cancer diagnostics with a structured pathway including ¼Stockholm 3« test, MRI and targeted perineal biopsies]. / Strukturerad kedja vid test för prostatacancer kortar ledtider.

The Prostate Cancer Center at Capio S:t Göran hospital is located in Stockholm and offers testing for prostate cancer. The pathway applies task shifting from doctors to nurses and new and innovative test methods, and leverages digitalization opportunities to enable a cost-efficient pathway with high specificity and sensitivity. In this article, we describe our experiences of the Capio S:t Göran Model.

Prostate Cancer IRE Study (PRIS): A Randomized Controlled Trial Comparing Focal Therapy to Radical Treatment in Localized Prostate Cancer.

The aim of focal treatments (FTs) in prostate cancer (PCa) is to treat lesions while preserving surrounding benign tissue and anatomic structures. Irreversible electroporation (IRE) is a nonthermal technique that uses high-voltage electric pulses to increase membrane permeability and induce membrane disruption in cells, which potentially causes less damage to the surrounding tissue in comparison to other ablative techniques. We summarize the study protocol for the Prostate Cancer IRE Study (PRIS), which involves two parallel randomized controlled trials comparing IRE with (1) robot-assisted radical prostatectomy (RARP) or (2) radiotherapy in men with newly diagnosed intermediate-risk PCa (NCT05513443). To reduce the number of patients for inclusion and the study duration, the primary outcomes are functional outcomes: urinary incontinence in study 1 and irritative urinary symptoms in study 2. Providing evidence of the lower impact of IRE on functional outcomes will lay a foundation for the design of future multicenter studies with an oncological outcome as the primary endpoint. Erectile function, quality of life, treatment failure, adverse events, and cost effectiveness will be evaluated as secondary objectives. Patients diagnosed with Gleason score 3 + 4 or 4 + 3 PCa from a single lesion visible on magnetic resonance imaging (MRI) without any Gleason grade 4 or higher in systematic biopsies outside of the target (unifocal significant disease), aged ≥40 yr, with no established extraprostatic extension on multiparametric MRI, a lesion volume of <1.5 cm3, prostate-specific antigen <20 ng/ml, and stage ≤T2b are eligible for inclusion. The study plan is to recruit 184 men.

Effect of digital-enabled multidisciplinary therapy conferences on efficiency and quality of the decision making in prostate cancer care.

OBJECTIVES: To investigate the impact on efficiency and quality of preprostatectomy multidisciplinary therapy conferences (MDT) at Karolinska University Hospital related to the use of a digital solution compared with standard of care. Further, to explore whether gains in MDT efficiency and quality impact oncological or functional patient outcomes. METHODS: We conducted a prospective, observational study of preoperative prostate cancer MDT at Karolinska between February 2017 and March 2021, including 1329 patients. We compared efficiency and quality of the standard MDT and the MDT using the digital solution IntelliSpace Precision Medicine Multidisciplinary Team Orchestrator (ISPM) based on the previously used MDT-MODe approach. Clinical and patient-reported functional outcomes were derived from the medical records and the Swedish National Prostate Cancer Register. RESULTS: While ISPM was used during the MDT meeting, the time spent per patient was reduced by 24% (p<0.001) and most of the MDT-MODe items were scored significantly higher. There was a reduction in pelvic lymph-node dissection procedures in the ISPM cohort (p=0.001) and an increased proportion of unilateral nerve-sparing procedures (p=0.005), while all other outcome-related measures were not significantly different between the two patient groups. DISCUSSION AND CONCLUSION: To increase the value of the MDT, all data relevant for treatment decision need to be purposefully presented and compiled, which also enables secondary use of the data.The use of a digital solution during preoperative MDTs for prostate cancer decision making at Karolinska University Hospital improved the efficiency and quality of this multidisciplinary team meeting without impacting patient outcomes.

Characteristics of Patients in SPCG-15-A Randomized Trial Comparing Radical Prostatectomy with Primary Radiotherapy plus Androgen Deprivation Therapy in Men with Locally Advanced Prostate Cancer.

Background: There is no high-grade evidence for surgery as primary treatment for locally advanced prostate cancer. The SPCG-15 study is the first randomized trial comparing surgical treatment with radiotherapy. Objective: To describe the baseline characteristics of the first 600 randomized men in the SPCG-15 study. The study will compare mortality and functional outcomes. Design setting and participants: This study is a Scandinavian prospective, open, multicenter phase III randomized clinical trial aiming to randomize 1200 men. Intervention: Radical prostatectomy with or without consecutive radiotherapy (experimental) and radiotherapy with neoadjuvant androgen deprivation therapy (standard of care). Outcome measurements and statistical analysis: Cause-specific survival, metastasis-free survival, overall survival, and patient-reported bowel function, sexual health, and lower urinary tract symptoms were measured. Results and limitations: The distribution of characteristics was similar in the two study arms. The median age was 67 yr (range 45-75 yr). Among the operated men, 36% had pT3a stage of disease and 39% had pT3b stage. International Society of Urological Pathology grades 2, 3, 4, and 5 were prevalent in 21%, 35%, 7%, and 27%, respectively. Half of the men (51%) in the surgery arm had no positive lymph nodes. The main limitation is the pragmatic design comparing the best available practice at each study site leading to heterogeneity of treatment regimens within the study arms. Conclusions: We have proved that randomization between surgery and radiotherapy for locally advanced prostate cancer is feasible. The characteristics of the study population demonstrate a high prevalence of advanced disease, well-balanced comparison groups, and a demography mirroring the Scandinavian population of men with prostate cancer at large. Patient summary: This study, which has recruited >600 men, compares radiotherapy with surgery for prostate cancer, and an analysis at the time of randomization indicates that the study will be informative and generalizable to most men with locally advanced but not metastasized prostate cancer.

Cost-Effectiveness of the Stockholm3 Test and Magnetic Resonance Imaging in Prostate Cancer Screening: A Microsimulation Study.

BACKGROUND: Stockholm3 is a risk model that combines the prostate-specific antigen (PSA) test, other plasma protein biomarkers, single nucleotide polymorphisms, and clinical variables. The STHLM3-MRI study (NCT03377881) found that the Stockholm3 test with magnetic resonance imaging (MRI) and combined targeted and systematic biopsies maintained the sensitivity for clinically significant cancers, and reduced the number of benign biopsies and clinically insignificant cancers. OBJECTIVE: To assess the cost-effectiveness of MRI-based screening for prostate cancer using either Stockholm3 as a reflex test or PSA alone. DESIGN, SETTING, AND PARTICIPANTS: A cost-utility analysis was performed from a lifetime societal perspective using a microsimulation model for men aged 55-69 yr in Sweden. Test characteristics were estimated from the STHLM3-MRI study. INTERVENTION: No screening and three quadrennial screening strategies, including either PSA ≥3 ng/ml or Stockholm3 with reflex test thresholds of PSA ≥1.5 or 2 ng/ml as criteria for referral to MRI, were performed, and those who were MRI positive had combined targeted and systematic biopsies. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Predictions included the number of tests, cancer incidence and mortality, costs, and quality-adjusted life-years. Uncertainties in key parameters were assessed using sensitivity analyses. RESULTS AND LIMITATIONS: Compared with no screening, the screening strategies were predicted to reduce prostate cancer deaths by 7-9% across a lifetime. The use of Stockholm3 with PSA ≥2 ng/ml resulted in a 60% reduction in MRI compared with screening using PSA. This Stockholm3 strategy was cost-effective with a probability of 70% at a cost-effectiveness threshold of €47 218 (500 000 Swedish Kronor). As a potential limitation, the economic perspective was specific to Sweden. CONCLUSIONS: Screening with the Stockholm3 test at a reflex threshold of PSA ≥2 ng/ml and MRI was predicted to be cost-effective in Sweden. PATIENT SUMMARY: The Stockholm3 test with image-based screening may reduce screening-related harms and costs, while maintaining the health benefits from early detection of prostate cancer.

Prostate cancer screening using a combination of risk-prediction, MRI, and targeted prostate biopsies (STHLM3-MRI): a prospective, population-based, randomised, open-label, non-inferiority trial.

BACKGROUND: Screening for prostate cancer using prostate-specific antigen (PSA) reduces prostate cancer mortality but can lead to adverse outcomes. We aimed to compare a traditional screening approach with a diagnostic strategy of blood-based risk prediction combined with MRI-targeted biopsies. METHODS: We did a prospective, population-based, randomised, open-label, non-inferiority trial (STHLM3-MRI) in Stockholm county, Sweden. Men aged 50-74 years were randomly selected by Statistics Sweden and invited by mail to participate in screening; those with an elevated risk of prostate cancer, defined as either a PSA of 3 ng/mL or higher or a Stockholm3 score of 0·11 or higher were eligible for randomisation. Men with a previous prostate cancer diagnosis, who had undergone a prostate biopsy within 60 days before the invitation to participate, with a contraindication for MRI, or with severe illness were excluded. Eligible participants were randomly assigned (2:3) using computer-generated blocks of five, stratified by clinically significant prostate cancer risk, to receive either systematic prostate biopsies (standard group) or biparametric MRI followed by MRI-targeted and systematic biopsy in MRI-positive participants (experimental group). The primary outcome was the detection of clinically significant prostate cancer at prostate biopsy, defined as a Gleason score of 3 + 4 or higher. We used a margin of 0·78 to assess non-inferiority for the primary outcome. Key secondary outcome measures included the proportion of men with clinically insignificant prostate cancer (defined as a Gleason score of 3 + 3), and the number of any prostate MRI and biopsy procedures done. We did two comparisons: Stockholm3 (using scores of 0·11 and 0·15 as cutoffs) versus PSA in the experimental group (paired analyses) and PSA plus standard biopsy versus Stockholm3 plus MRI-targeted and systematic biopsy (unpaired, randomised analyses). All analyses were intention to treat. This study is registered with ClinicalTrials.gov, NCT03377881. FINDINGS: Between Feb 5, 2018, and March 4, 2020, 49 118 men were invited to participate, of whom 12 750 were enrolled and provided blood specimens, and 2293 with elevated risk were randomly assigned to the experimental group (n=1372) or the standard group (n=921). The area under the receiver-operating characteristic curve for detection of clinically significant prostate cancer was 0·76 (95% CI 0·72-0·80) for Stockholm3 and 0·60 (0·54-0·65) for PSA. In the experimental group, a Stockholm3 of 0·11 or higher was non-inferior to a PSA of 3 ng/mL or higher for detection of clinically significant prostate cancer (227 vs 192; relative proportion [RP] 1·18 [95% CI 1·09-1·28], p<0·0001 for non-inferiority), and also detected a similar number of low-grade prostate cancers (50 vs 41; 1·22 [0·96-1·55], p=0·053 for superiority) and was associated with more MRIs and biopsies. Compared with PSA of 3 ng/mL or higher, a Stockholm3 of 0·15 or higher provided identical sensitivity to detect clinically significant cancer, and led to fewer MRI procedures (545 vs 846; 0·64 [0·55-0·82]) and fewer biopsy procedures (311 vs 338; 0·92 (0·86-1·03). Compared with screening using PSA and systematic biopsies, a Stockholm3 of 0·11 or higher combined with MRI-targeted and systematic biopsies was associated with higher detection of clinically significant cancers (227 [3·0%] men tested vs 106 [2·1%] men tested; RP 1·44 [95% CI 1·15-1·81]), lower detection of low-grade cancers (50 [0·7%] vs 73 [1·4%]; 0·46 [0·32-0·66]), and led to fewer biopsy procedures. Patients randomly assigned to the experimental group had a lower incidence of prescription of antibiotics for infection (25 [1·8%] of 1372 vs 41 [4·4%] of 921; p=0·0002) and a lower incidence of admission to hospital (16 [1·2%] vs 31 [3·4%]; p=0·0003) than those in the standard group. INTERPRETATION: The Stockholm3 test can inform risk stratification before MRI and targeted biopsies in prostate cancer screening. Combining the Stockholm3 test with an MRI-targeted biopsy approach for prostate cancer screening decreases overdetection while maintaining the ability to detect clinically significant cancer. FUNDING: The Swedish Cancer Society, the Swedish Research Council, and Stockholm City Council.

MRI-Targeted or Standard Biopsy in Prostate Cancer Screening.

BACKGROUND: High rates of overdiagnosis are a critical barrier to organized prostate cancer screening. Magnetic resonance imaging (MRI) with targeted biopsy has shown the potential to address this challenge, but the implications of its use in the context of organized prostate cancer screening are unknown. METHODS: We conducted a population-based noninferiority trial of prostate cancer screening in which men 50 to 74 years of age from the general population were invited by mail to participate; participants with prostate-specific antigen (PSA) levels of 3 ng per milliliter or higher were randomly assigned, in a 2:3 ratio, to undergo a standard biopsy (standard biopsy group) or to undergo MRI, with targeted and standard biopsy if the MRI results suggested prostate cancer (experimental biopsy group). The primary outcome was the proportion of men in the intention-to-treat population in whom clinically significant cancer (Gleason score ≥7) was diagnosed. A key secondary outcome was the detection of clinically insignificant cancers (Gleason score 6). RESULTS: Of 12,750 men enrolled, 1532 had PSA levels of 3 ng per milliliter or higher and were randomly assigned to undergo biopsy: 603 were assigned to the standard biopsy group and 929 to the experimental biopsy group. In the intention-to-treat analysis, clinically significant cancer was diagnosed in 192 men (21%) in the experimental biopsy group, as compared with 106 men (18%) in the standard biopsy group (difference, 3 percentage points; 95% confidence interval [CI], -1 to 7; P<0.001 for noninferiority). The percentage of clinically insignificant cancers was lower in the experimental biopsy group than in the standard biopsy group (4% [41 participants] vs. 12% [73 participants]; difference, -8 percentage points; 95% CI, -11 to -5). CONCLUSIONS: MRI with targeted and standard biopsy in men with MRI results suggestive of prostate cancer was noninferior to standard biopsy for detecting clinically significant prostate cancer in a population-based screening-by-invitation trial and resulted in less detection of clinically insignificant cancer. (Funded by the Swedish Research Council and others; STHLM3-MRI ClinicalTrials.gov number, NCT03377881.).

Mapping prostatic microscopic anisotropy using linear and spherical b-tensor encoding: A preliminary study.

PURPOSE: Tensor-valued diffusion encoding provides more specific information than conventional diffusion-weighted imaging (DWI), but has mainly been applied in neuroimaging studies. This study aimed to assess its potential for the imaging of prostate cancer (PCa). METHODS: Seventeen patients with histologically proven PCa were enrolled. DWI of the prostate was performed with linear and spherical tensor encoding using a maximal b-value of 1.5 ms/µm2 and a voxel size of 3 × 3 × 4 mm3 . The gamma-distribution model was used to estimate the mean diffusivity (MD), the isotropic kurtosis (MKI ), and the anisotropic kurtosis (MKA ). Regions of interest were placed in MR-defined cancerous tissues, as well as in apparently healthy tissues in the peripheral and transitional zones (PZs and TZs). RESULTS: DWI with linear and spherical encoding yielded different image contrasts at high b-values, which enabled the estimation of MKA and MKI . Compared with healthy tissue (PZs and TZs combined) the cancers displayed a significantly lower MD (P < .05), higher MKI (P < 10-5 ), and lower MKA (P < .05). Compared with the TZ, tissue in the PZ showed lower MD (P < 10-3 ) and higher MKA (P < 10-3 ). No significant differences were found between cancers of different Gleason scores, possibly because of the limited sample size. CONCLUSION: Tensor-valued diffusion encoding enabled mapping of MKA and MKI in the prostate. The elevated MKI in PCa compared with normal tissues suggests an elevated heterogeneity in the cancers. Increased in-plane resolution could improve tumor delineation in future studies.

Predictors of adverse pathology on radical prostatectomy specimen in men initially enrolled in active surveillance for low-risk prostate cancer.

PURPOSE: To evaluate clinical variables, including magnetic resonance imaging (MRI) predictive of adverse pathology (AP) at radical prostatectomy (RP) in men initially enrolled in active surveillance (AS). METHODS: A population-based cohort study of men diagnosed with low-risk prostate cancer (PCa), in Stockholm County, Sweden, during 2008-2017 enrolled in AS their intended primary treatment followed by RP. AP was defined as ISUP grade group ≥ 3 and/or pT-stage ≥ T3. Association between clinical variables at diagnosis and time to AP was evaluated using Cox regression and multivariate logistic regression to evaluate the association between AP and clinical variables at last biopsy before RP. RESULTS: In a cohort of 6021 patients with low-risk PCa, 3116 were selected for AS and 216 underwent RP. Follow-up was 10 years, with a median time on AS of 23 months. 37.7% of patients had AP at RP. Clinical T-stage [Hazard ratio (HR): 1.81, 95% confidence interval (CI) 1.04-3.18] and PSA (HR: 1.31, 95% CI 1.17-1.46) at diagnosis and age [Odds Ratio (OR): 1.09, 95% CI 1.02-1.18), PSA (OR: 1.22, 95% CI 1.07-1.41), and PI-RADS (OR 1.66, 95% CI 1.11-2.55)] at last re-biopsy were significantly associated with AP. CONCLUSION: PI-RADS score is significantly associated with AP at RP and support current guidelines recommending MRI before enrollment in AS. Furthermore, age, cT-stage, and PSA are significantly associated with AP.

Incorporating Magnetic Resonance Imaging and Biomarkers in Active Surveillance Protocols - Results From the Prospective Stockholm3 Active Surveillance Trial (STHLM3AS).

BACKGROUND: Active surveillance (AS) for men with low-risk prostate cancer (PC) can lead to patient morbidity and healthcare overutilization. The aim of this study was to evaluate an AS protocol using the Stockholm3 test and magnetic resonance imaging (MRI) to reduce biopsy intensity. METHODS: We conducted a prospective multicenter study of 280 invited men from a contemporary screening study (STHLM3), with Gleason Score (GS) 3 + 3 PC on a current AS protocol. Patients underwent prostate-MRI and blood sampling for analysis of the Stockholm3 test including protein biomarkers, genetic variants, and clinical variables to predict risk of GS ≥3 + 4 PC followed by systematic biopsies and targeted biopsies (for Prostate Imaging Reporting and Data System version 2 ≥3 lesions) in all men. Primary outcomes were reclassification to GS ≥3 + 4 PC and clinically significant PC (csPCa), including unfavorable intermediate risk PC or higher based on National Comprehensive Cancer Network guidelines. RESULTS: Adding MRI-targeted biopsies to systematic biopsies increased sensitivity of GS ≥3 + 4 PC compared with systematic biopsies alone (relative sensitivity [RS] = 1.52, 95% confidence interval [CI] = 1.28 to 1.85). Performing biopsies in only MRI positive increased sensitivity of GS ≥3 + 4 PC (RS = 1.30, 95% CI = 1.04 to 1.67) and reduced number of biopsy procedures by 49.3% while missing 7.2% GS ≥3 + 4 PC and 1.4% csPCa. Excluding men with negative Stockholm3 test reduced the number of MRI investigations at follow-up by 22.5% and biopsies by 56.8% while missing 6.9% GS ≥3 + 4 PC and 1.3% csPCa. CONCLUSION: Including MRI and targeted/systematic biopsies in the follow-up for men on AS increased sensitivity of PC reclassification. Incorporation of risk prediction models including biomarkers may reduce the need for MRI use in men with low-risk PC.

Effect of information on prostate biopsy history on biopsy outcomes in the era of MRI-targeted biopsies.

PURPOSE: To describe the predictive value of information on previous benign biopsy for the outcome of MRI-targeted biopsies. METHODS: An exploratory analysis was conducted using data from a prospective, multicenter, paired diagnostic study of 532 men undergoing diagnostics for prostate cancer during 2016-2017. All men underwent 1.5 T MRI; systematic prostate biopsies; and MRI-targeted biopsies to MRI lesions with Prostate Imaging Reporting and Data System version 2, PI-RADS ≥ 3. The main outcome was numbers of detected prostate cancer characterized by grade group (GG) where GG ≥ 2 defined clinically significant cancer (csPCa). RESULTS: Men with previous biopsies had significantly more often negative MRI (26% vs. 17%, p < 0.05) compared to men without previous biopsies. Men with previous biopsies showed higher rates of benign biopsies (41% vs. 26%, p < 0.05) and lower rates of GG2 (17% vs. 30%, p < 0.05) and GG ≥ 3 (5% vs. 10%, p < 0.05) cancer. Biopsy-naïve men had higher proportions of highly suspicious MRI lesions (PIRADS 5; p < 0.05) and a higher proportion of significant cancer in those lesions (p = 0.05). In multivariate regression analysis, a previous benign prostate biopsy was associated with less than half the odds of csPCa (OR 0.38; 95% CI 0.20-0.71). CONCLUSION: In this large prospective multicenter trial, we showed that men with a previous prostate biopsy had higher proportions of MRIs without lesions and lower proportion of highly suspicious lesions than biopsy-naïve men. Further, biopsy-naïve men showed higher detection of clinically significant cancer when using MRI-targeted biopsies. Also, in the era of MRI-targeted biopsy strategies, biopsy history should be carefully considered in biopsy decisions. TRIAL REGISTRATION: NCT02788825 (ClinicalTrials.gov). Date of registration June 2, 2016.

The value of a first MRI and targeted biopsies after several years of active surveillance for low-risk prostate cancer - results from the SAMS trial.

OBJECTIVE: To assess the value of a first MRI examination and image-fusion-guided biopsies in men with low-risk prostate cancer who have been on active surveillance (AS) for several years with no signs of progression. PATIENTS AND METHODS: All 45 participants from two centers who had not previously had an MRI were included. They had been on AS for T1c Gleason score 6 prostate cancer for 2.6 to 6.7 years and had 2 to 5 sets of systematic biopsies with a total of 1640 cores. All underwent a bi-parametric MRI, PI-RADS ≥ 3 lesions were targeted with image-fusion-guided biopsies. Primary outcome measure: detection of Gleason score ≥7 cancer. RESULTS: Twenty-five of the 45 men (56%) had a total of 30 suspicious MRI lesions. The lesion with the highest score was a PI-RADS 3 in 18, a PI-RADS 4 in 5 and PI-RADS 5 in 3 men. Targeted biopsies from the 30 lesions detected Gleason score 7 cancer in 6 men. Of these six cancers, four were located in the apical and one in the anterior/apical part of the prostate. A Gleason score 7 cancer was detected in 3 of 5 men with PSA density >0.15 ng/ml/cm3. CONCLUSIONS: Even after several years of AS with stable PSA values and many sets of systematic biopsies, a first MRI and targeted biopsies lead to the detection of Gleason score 7 (ISUP 2 and ISUP 3) cancer in a significant proportion of men, particularly among those with a high PSA density.

A Unified Prostate Cancer Risk Prediction Model Combining the Stockholm3 Test and Magnetic Resonance Imaging.

BACKGROUND: Risk prediction models and magnetic resonance imaging (MRI) of the prostate can reduce unnecessary biopsies and overdiagnosis of low-risk prostate cancer. However, it is unclear how these tools should be used in concert. OBJECTIVE: To develop a unified risk prediction model (S3M-MRI) that combines the Stockholm3 score (based on protein and genetic markers and clinical variables) and Prostate Imaging-Reporting and Data System v.2 scores modified for MRI without contrast (modPI-RADS). DESIGN, SETTING, AND PARTICIPANTS: We used data for 532 men from the prospective multicentre STHLM3-MRI diagnostic study to construct S3M-MRI. We compared S3M-MRI to Stockholm3 and modPI-RADS alone with respect to model discrimination, calibration, and net benefit. We also compared clinical outcomes for five diagnostic strategies according to the use of combinations of the three models. RESULTS AND LIMITATIONS: The area under the receiver operating characteristic curve (AUC) was 0.88 (95% confidence interval [CI] 0.85-0.91) for S3M-MRI, which was significantly higher (p=0.04) than for Stockholm3 (0.86, 95% CI 0.83-0.89) and modPI-RADS (0.83, 95% CI 0.79-0.87). S3M-MRI had a higher net benefit on decision curve analysis for clinically relevant probability thresholds for biopsy recommendation in comparison to Stockholm3 and modPI-RADS. However, for different diagnostic strategies, sequential use of Stockholm3 followed by MRI only for Stockholm3-positive men resulted in a similar number of unnecessary biopsies (64 vs 69) and diagnosed International Society of Urological Pathology (ISUP) grade group 1 cancers (56 vs 51) at similar sensitivity for ISUP grade group ≥2 cancers, while avoiding 38% of MRI scans. Limitations include the ethnically homogeneous study population. CONCLUSIONS: The unified S3M-MRI model was superior to the Stockholm3 model and modPI-RADS alone. However, the S3M-MRI improvement was marginal compared to sequential use of Stockholm3 followed by MRI, and resulted in 60% more MRI scans. PATIENT SUMMARY: A new risk prediction model combining clinical variables, genetic and protein biomarkers, and results from prostate magnetic resonance imaging improved the clinical outcome performance of prostate cancer diagnostics.

PCASTt/SPCG-17-a randomised trial of active surveillance in prostate cancer: rationale and design.

INTRODUCTION: Overtreatment of localised prostate cancer is substantial despite increased use of active surveillance. No randomised trials help define how to monitor patients or when to initiate treatment with curative intent. METHODS AND ANALYSIS: A randomised, multicentre, intervention trial designed to evaluate the safety of an MRI-based active surveillance protocol, with standardised triggers for repeated biopsies and radical treatment. The aim is to reduce overtreatment of prostate cancer. 2000 men will be randomly allocated to either surveillance according to current practice or to standardised triggers at centres in Sweden, Norway, Finland and the UK. Men diagnosed in the past 12 months with prostate cancer, ≤T2a, prostate-specific antigen (PSA) <15 ng/mL, PSA density ≤0.2 ng/mL/cc, any International Society of Urological Pathology (ISUP) grade 1 are eligible. Men with ISUP grade 2 in <30% of cores on systematic biopsy and <10 mm cancer in one core on systematic or targeted biopsy are also eligible. Men diagnosed on systematic biopsy should have an MRI and targeted biopsies against Prostate Imaging and Reporting Data System V.2 3-5 lesions before inclusion. Identical follow-up in the two study arms: biannual PSA testing, yearly clinical examination and MRI every second year. In the experimental arm, standardised triggers based on MRI and PSA density elicit repeated biopsies. MRI and histopathological progression trigger radical treatment. Primary outcome measure is progression-free survival. Secondary outcome measures are cumulative incidence of metastatic disease, treatments with curative intent, pT3-4 at radical prostatectomy, switch to watchful waiting, prostate cancer mortality and quality of life. Inclusion started in October 2016 and in October 2018; 275 patients have been enrolled. ETHICS AND DISSEMINATION: Ethical approval was obtained in each participating country. Results for the primary and secondary outcome measures will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02914873.