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.).

Protocol of a randomised, controlled trial comparing immediate curative therapy with conservative treatment in men aged ≥75 years with non-metastatic high-risk prostate cancer (SPCG 19/GRand-P).

BACKGROUND: Older men (aged ≥75 years) with high risk, non-metastatic prostate cancer (PCa) are increasingly treated with curative therapy (surgery or radiotherapy). However, it is unclear if curative therapy prolongs life and improves health-related quality of life (HRQoL) in this age group compared to conservative therapy, which has evolved considerably during the last decade. STUDY DESIGN: The Scandinavian Prostate Cancer Group (SPCG) 19/Norwegian Get-Randomized Research Group-Prostate (GRand-P) is a randomised, two-armed, controlled, multicentre, phase III trial carried out at study centres in Norway, Denmark, Finland, and Sweden. ENDPOINTS: The primary endpoints are overall survival and HRQoL (burden of disease scale, European Organisation for the Research and Treatment of Cancer [EORTC] Elderly Cancer patients). Secondary endpoints are PCa-specific survival, metastasis-free survival, role-functioning scale (EORTC quality of life questionnaire 30-item core), urinary irritative/obstructive scale (26-item Expanded Prostate Cancer Index Composite [EPIC-26]), bowel scale (EPIC-26), intervention-free survival, PCa morbidity, use of secondary and tertiary systemic therapies, mean quality-adjusted life-years (QALYs), and mean total healthcare costs. PATIENTS AND METHODS: A total of 980 men (aged ≥75 years) with non-metastatic, high-risk PCa will initially be screened with Geriatric 8 (G8) health status screening tool and Mini-COG© brief cognitive test. Participants identified by G8 as 'fit' or 'frail' will be randomised (ratio 1:1) to either immediate curative therapy (radiotherapy or prostatectomy) or conservative therapy (endocrine therapy or observation). Participants who are unable or unwilling to participate in randomisation will be enrolled in a separate observation group. Randomised patients will be followed for 10 years. TRIAL REGISTRATION: Ethics approval has been granted in Norway (457593), Denmark (H-22051998), Finland (R23043) and Sweden (Dnr 2023-05296-01). The trial is registered on Clinicaltrials.org (NCT05448547).

Tailoring biopsy strategy in the MRI-fusion prostate biopsy era: systematic, targeted or neither?

BACKGROUND: Magnetic  resonance imaging (MRI) followed by targeted biopsy (TBx) is utilized for prostate cancer (PCa) detection. However, the value of adding systematic biopsies (SBx) to targeted biopsy procedures (combined biopsy; CBx) in men with suspicious MRI findings has not been determined. METHODS: We analysed biopsy outcomes in 429 men with MRI lesions in the prospective multicenter STHLM3MRI pilot study, planned for prostate biopsy. Participants underwent 1.5T biparametric MRI without contrast enhancement, reported according to the PI-RADS v2, and with TBx plus SBx if the MRI lesion score was ≥ 3. The endpoints were clinically nonsignificant (nsPCa) and clinically significant PCa (csPCa), defined as ISUP grade groups 1 and ≥ 2, respectively. RESULTS: The median age was 65 years (59-70), and the median PSA 6.0 ng/ml (4.1-9.0). The detection rates of csPCa when using TBx or SBx combined were 18%, 46%, and 85% in men with PIRADS scores of 3 (n = 195), 4 (n = 121), and 5 (n = 113), respectively. This combined strategy detected csPCa in more men than TBx alone (43.6% vs 39.2%, p < 0.02), with similar detection of nsPCa (19.3% vs 17.7%, p = 0.2). In men with equivocal lesions (PI-RADS 3), the detection rates for csPCa were similar for the combined strategy and for TBx alone (17.9% and 15.4%, p = 0.06). However, there was an increase in the detection of nsPCa when using the combined strategy (21.0% vs 15.4%, p < 0.02). Men with equivocal lesions and a PSA density < 0.1 ng/ml2 or a Stockholm 3 test < 0.11 had a low risk of harboring csPCa. CONCLUSIONS: Supplementing targeted with systematic biopsies enhances clinically significant cancer detection. However, in men with equivocal lesions, this combination has potential for detecting nonsignificant disease. A subgroup of men with equivocal MRI findings may be identified as having a low risk for significant cancer and spared unnecessary biopsies.

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.

Diagnosis of prostate cancer with magnetic resonance imaging in men treated with 5-alpha-reductase inhibitors.

PURPOSE: The primary aim of this study was to evaluate if exposure to 5-alpha-reductase inhibitors (5-ARIs) modifies the effect of MRI for the diagnosis of clinically significant Prostate Cancer (csPCa) (ISUP Gleason grade ≥ 2). METHODS: This study is a multicenter cohort study including patients undergoing prostate biopsy and MRI at 24 institutions between 2013 and 2022. Multivariable analysis predicting csPCa with an interaction term between 5-ARIs and PIRADS score was performed. Sensitivity, specificity, and negative (NPV) and positive (PPV) predictive values of MRI were compared in treated and untreated patients. RESULTS: 705 patients (9%) were treated with 5-ARIs [median age 69 years, Interquartile range (IQR): 65, 73; median PSA 6.3 ng/ml, IQR 4.0, 9.0; median prostate volume 53 ml, IQR 40, 72] and 6913 were 5-ARIs naïve (age 66 years, IQR 60, 71; PSA 6.5 ng/ml, IQR 4.8, 9.0; prostate volume 50 ml, IQR 37, 65). MRI showed PIRADS 1-2, 3, 4, and 5 lesions in 141 (20%), 158 (22%), 258 (37%), and 148 (21%) patients treated with 5-ARIs, and 878 (13%), 1764 (25%), 2948 (43%), and 1323 (19%) of untreated patients (p < 0.0001). No difference was found in csPCa detection rates, but diagnosis of high-grade PCa (ISUP GG ≥ 3) was higher in treated patients (23% vs 19%, p = 0.013). We did not find any evidence of interaction between PIRADS score and 5-ARIs exposure in predicting csPCa. Sensitivity, specificity, PPV, and NPV of PIRADS ≥ 3 were 94%, 29%, 46%, and 88% in treated patients and 96%, 18%, 43%, and 88% in untreated patients, respectively. CONCLUSIONS: Exposure to 5-ARIs does not affect the association of PIRADS score with csPCa. Higher rates of high-grade PCa were detected in treated patients, but most were clearly visible on MRI as PIRADS 4 and 5 lesions. TRIAL REGISTRATION: The present study was registered at ClinicalTrials.gov number: NCT05078359.

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.

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.

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.

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

OBJECTIVE: This study aimed to assess the cost-effectiveness of magnetic resonance imaging (MRI) with combinations of targeted biopsy (TBx) and systematic biopsy (SBx) for early prostate cancer detection in Sweden. METHODS: A cost-utility analysis was conducted from a lifetime societal perspective using a microsimulation model. Five strategies included no screening and quadrennial screening for men aged 55 to 69 years using SBx alone, TBx on positive MRI (MRI + TBx), combined TBx/SBx on positive MRI (MRI + TBx/SBx), and SBx on negative MRI with TBx/SBx on positive MRI (MRI - SBx, MRI + TBx/SBx). Test characteristics were based on a recent Cochrane review. We predicted the number of biopsies, costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios. RESULTS: The screening strategies were classified in Sweden as high costs per QALY gained compared with no screening. Using MRI + TBx and MRI + TBx/SBx reduced the number of biopsy episodes across a lifetime by approximately 40% compared with SBx alone. Both strategies showed strong dominance over SBx alone and MRI - SBx, MRI + TBx. Compared with MRI + TBx, the MRI + TBx/SBx strategy had an incremental cost-effectiveness ratio of more than €200 000 per QALY gained, which was classified in Sweden as a very high cost. These predictions were robust in the probabilistic sensitivity analysis. Limitations included generalizability of the model assumptions and uncertainty regarding the health-state values and study heterogeneity from the Cochrane review. CONCLUSIONS: MRI + TBx and MRI + TBx/SBx showed strong dominance over alternative screening strategies. MRI + TBx resulted in similar or marginally lower gains in QALYs and lower costs than MRI + TBx/SBx. MRI + TBx was considered the optimal choice among the screening strategies.

The economic burden of prostate cancer - a Swedish prevalence-based register study.

BACKGROUND: Incidence and prevalence of prostate cancer in Sweden have increased markedly due to prostate-specific antigen (PSA) testing. Moreover, new diagnostic tests and treatment technologies are expected to further increase the overall costs. Our aims were (i) to estimate the societal costs for existing testing, diagnosis, management and treatment of prostate cancer, and (ii) to provide reference values for future cost-effectiveness analyses of prostate cancer screening and treatment. METHODS: Taking a societal perspective, this study aimed to investigate the annual cost of prostate cancer in Sweden using a prevalence-based cost-of-illness approach. Resource utilisation and related costs within Stockholm Region during 2016 were quantified using data from the Stockholm PSA and Biopsy Register and other health and population registers. Costs included: (i) direct medical costs for health care utilisation at primary care, hospitals, palliative care and prescribed drugs; (ii) informal care; and (iii) indirect costs due to morbidity and premature mortality. The resource utilisation was valued using unit costs for direct medical costs and the human capital method for informal care and indirect costs. Costs for the Stockholm region were extrapolated to Sweden based on cancer prevalence and the average costs by age and resource type. RESULTS: The societal costs due to prostate cancer in Stockholm in 2016 were estimated to be €64 million Euro (€Mn), of which the direct medical costs, informal care and productivity losses represented 62, 28 and 10% of the total costs, respectively. The total annual costs extrapolated to Sweden were calculated to be €281 Mn. The average direct medical cost, average costs for informal care and productivity losses per prevalent case were €1510, €828 and €271, respectively. These estimates were sensitive to assumptions related to the proportion of primary care visits associated with PSA testing and the valuation method for informal care. CONCLUSION: The societal costs due to prostate cancer were substantial and constitute a considerable burden to Swedish society. Data from this study are relevant for future cost-effectiveness evaluations of prostate cancer screening and treatment.

Effects of replacing PSA with Stockholm3 for diagnosis of clinically significant prostate cancer in a healthcare system - the Stavanger experience.

OBJECTIVE: To describe early experience of replacing PSA with Stockholm3 for detection of prostate cancer in primary care. DESIGN AND METHODS: Longitudinal observations, comparing outcome measures before and after the implementation of Stockholm3. SETTING: Stavanger region in Norway with about 370,000 inhabitants, 304 general practitioners (GPs) in 97 primary care clinics, and one hospital. INTERVENTION: GPs were instructed to use Stockholm3 instead of PSA as standard procedure for diagnosis of prostate cancer. MAIN OUTCOME MEASURES: Proportion of GP clinics that had ordered a Stockholm3 test. Number of men referred to needle biopsy. Distribution of clinically significant prostate cancer (csPC) (Gleason Score ≥7) and clinically non-significant prostate cancer (cnsPC) (Gleason Score 6), in needle biopsies. Estimation of direct healthcare costs. RESULTS: Stockholm3 was rapidly implemented as 91% (88/97) of the clinics started to use the test within 14 weeks. After including 4784 tested men, the percentage who would have been referred for prostate needle biopsy was 29.0% (1387/4784) if based on PSA level ≥3ng/ml, and 20.8% (995/4784) if based on Stockholm3 Risk Score (p < 0.000001). The proportion of positive biopsies with csPC increased from 42% (98/233) before to 65% (185/285) after the implementation. Correspondingly, the proportion of cnsPC decreased from 58% (135/233) before to 35% (100/285) after the implementation (p < 0.0017). Direct healthcare costs were estimated to be reduced by 23-28% per tested man. CONCLUSION: Replacing PSA with Stockholm3 for early detection of prostate cancer in primary care is feasible. Implementation of Stockholm3 resulted in reduced number of referrals for needle-biopsy and a higher proportion of clinically significant prostate cancer findings in performed biopsies. Direct healthcare costs decreased. KEY POINTS A change from PSA to Stockholm3 for the diagnosis of prostate cancer in primary care in the Stavanger region in Norway is described and assessed. •Implementation of a new blood-based test for prostate cancer detection in primary care was feasible. A majority of GP clinics started to use the test within three months. •Implementation of the Stockholm3 test was followed by: -a 28% reduction in number of men referred for urological prostate cancer work-up -an increase in the proportion of clinically significant cancer in performed prostate biopsies from 42 to 65% -an estimated reduction in direct health care costs between 23 and 28%.

Is there any association between prostate-specific antigen screening frequency and uptake of active surveillance in men with low or very low risk prostate cancer?

BACKGROUND: Patient-related factors such as concern about cancer are believed to influence both men's decisions to undergo prostate specific antigen (PSA) testing and to have definitive treatment if diagnosed with low risk prostate cancer (PCa). The potential link between screening frequency and choice of active surveillance (AS) for low risk disease has not been studied previously. Our aim was to investigate whether there is any association between PCa screening frequency or previous negative prostate biopsy and uptake of AS among men with low risk PCa. METHODS: This register-based study included all men ≤75 years from Stockholm who were diagnosed with low risk PCa from 2008 to 2014 (n = 4336). Pre-diagnostic PSA testing and biopsy histories were obtained from the Stockholm PSA and Biopsy Register, a population-based register for the Stockholm country. The association between previous screening/biopsy history and AS uptake (based on primary treatment recorded in the National Prostate Cancer Register) was examined using multivariable logistic regression. RESULTS: Forty seven percent of men with low risk PCa underwent AS. Uptake was associated with older age, very low risk disease, more recent diagnosis and absence of family history. None of the screening/biopsy measures (testing frequency, mean interval, PSA velocity, highest pre-diagnostic PSA or prior negative biopsy) were associated with uptake of AS among men with low risk PCa. Generalisability to settings with different policies and practices may be limited. CONCLUSION: We found no evidence that screening frequency and negative biopsy influence uptake of AS among Swedish men with low risk PCa. Further research is required to determine factors that still present barriers for men taking up AS.

Effects of increasing the PSA cutoff to perform additional biomarker tests before prostate biopsy.

BACKGROUND: Multi-step testing might enhance performance of the prostate cancer diagnostic pipeline. Using PSA >1 ng/ml for first-line risk stratification and the Stockholm 3 Model (S3M) blood-test >10% risk of Gleason Score > 7 prostate cancer to inform biopsy decisions has been suggested. We aimed to determine the effects of changing the PSA cutoff to perform reflex testing with S3M and the subsequent S3M cutoff to recommend prostate biopsy while maintaining the sensitivity to detect Gleason Score ≥ 7 prostate cancer. METHODS: We used data from the prospective, population-based, paired, diagnostic Stockholm 3 (STHLM3) study with participants invited by date of birth from the Swedish Population Register during 2012-2014. All participants underwent testing with PSA and S3M (a combination of plasma protein biomarkers [PSA, free PSA, intact PSA, hK2, MSMB, MIC1], genetic polymorphisms, and clinical variables [age, family, history, previous prostate biopsy, prostate exam]). Of 47,688 men in the STHLM3 main study, we used data from 3133 men with S3M >10% and prostate biopsy data. Logistic regression models were used to calculate prostate cancer detection rates and proportion saved biopsies. RESULTS: 44.2%, 62.5% and 67.9% of the participants had PSA <1, <1.5 and <1.7 ng/ml, respectively. Increasing the PSA cut-off for additional work-up from 1 ng/ml to 1.5 ng/ml would thus save 18.3% of the performed tests, 4.9% of the biopsies and 1.3% (10/765) of Gleason Grade ≥ 7 cancers would be un-detected. By lowering the S3M cutoff to recommend biopsy, sensitivity to high-grade prostate cancer can be restored, to the cost of increasing the number of performed biopsies modestly. CONCLUSION: The sensitivity to detect prostate cancer can be maintained when using different PSA cutoffs to perform additional testing. Biomarker cut-offs have implications on number of tests and prostate biopsies performed. A PSA cutoff of 1.5 ng/ml to perform additional testing such as the S3M test might be considered. TRIAL REGISTRATION: ISRCTN84445406 .

Associations between circulating carotenoids, genomic instability and the risk of high-grade prostate cancer.

BACKGROUND: Carotenoids are a class of nutrients with antioxidant properties that have been purported to protect against cancer. However, the reported associations between carotenoids and prostate cancer have been heterogeneous and lacking data on interactions with nucleotide sequence variations and genomic biomarkers. OBJECTIVE: To examine the associations between carotenoid levels and the risk of high-grade prostate cancer, also considering antioxidant-related genes and tumor instability. METHODS: We measured plasma levels of carotenoids and genotyped 20 single nucleotide polymorphisms (SNP) in SOD1, SOD2, SOD3, XRCC1, and OGG1 among 559 men with non-metastatic prostate cancer undergoing radical prostatectomy. We performed copy number analysis in a subset of these men (n = 67) to study tumor instability assessed as Fraction of the Genome Altered (FGA). We examined associations between carotenoids, genotypes, tumor instability and risk of high-grade prostate cancer (Gleason grade ≥ 4 + 3) using logistic and linear regression. RESULTS: Circulating carotenoid levels were inversely associated with the risk of high-grade prostate cancer; odds ratios (OR) and 95% confidence intervals (CI) comparing highest versus lowest quartiles were: 0.34 (95% CI: 0.18-0.66) for α-carotene, 0.31 (95% CI: 0.15-0.63) for ß-carotene, 0.55 (0.28-1.08) for lycopene and 0.37 (0.18-0.75) for total carotenoids. SNPs rs25489 in XRCC1, rs699473 in SOD3 and rs1052133 in OGG1 modified these associations for α-carotene, ß-carotene and lycopene, respectively (P ≤ 0.05). The proportion of men with a high degree of FGA increased with Gleason Score (P < 0.001). Among men with Gleason score ≤ 3 + 4, higher lycopene levels were associated with lower FGA (P = 0.04). CONCLUSION: Circulating carotenoids at diagnosis, particularly among men carrying specific somatic variations, were inversely associated with risk of high-grade prostate cancer. In exploratory analyses, higher lycopene level was associated with less genomic instability among men with low-grade disease which is novel and supports the hypothesis that lycopene may inhibit progression of prostate cancer early in its natural history.

Prostate cancer screening in men aged 50-69 years (STHLM3): a prospective population-based diagnostic study.

BACKGROUND: The prostate-specific antigen (PSA) test is used to screen for prostate cancer but has a high false-positive rate that translates into unnecessary prostate biopsies and overdiagnosis of low-risk prostate cancers. We aimed to develop and validate a model to identify high-risk prostate cancer (with a Gleason score of at least 7) with better test characteristics than that provided by PSA screening alone. METHODS: The Stockholm 3 (STHLM3) study is a prospective, population-based, paired, screen-positive, diagnostic study of men without prostate cancer aged 50-69 years randomly invited by date of birth from the Swedish Population Register kept by the Swedish Tax Agency. Men with prostate cancer at enrolment were excluded from the study. The predefined STHLM3 model (a combination of plasma protein biomarkers [PSA, free PSA, intact PSA, hK2, MSMB, MIC1], genetic polymorphisms [232 SNPs], and clinical variables [age, family, history, previous prostate biopsy, prostate exam]), and PSA concentration were both tested in all participants enrolled. The primary aim was to increase the specificity compared with PSA without decreasing the sensitivity to diagnose high-risk prostate cancer. The primary outcomes were number of detected high-risk cancers (sensitivity) and the number of performed prostate biopsies (specificity). The STHLM3 training cohort was used to train the STHLM3 model, which was prospectively tested in the STHLM3 validation cohort. Logistic regression was used to test for associations between biomarkers and clinical variables and prostate cancer with a Gleason score of at least 7. This study is registered with ISCRTN.com, number ISRCTN84445406. FINDINGS: The STHLM3 model performed significantly better than PSA alone for detection of cancers with a Gleason score of at least 7 (p<0·0001), the area under the curve was 0·56 (95% CI 0·55-0·60) with PSA alone and 0·74 (95% CI 0·72-0·75) with the STHLM3 model. All variables used in the STHLM3 model were significantly associated with prostate cancers with a Gleason score of at least 7 (p<0·05) in a multiple logistic regression model. At the same level of sensitivity as the PSA test using a cutoff of ≥3 ng/mL to diagnose high risk prostate cancer, use of the STHLM3 model could reduce the number of biopsies by 32% (95% CI 24-39) and could avoid 44% (35-54) of benign biopsies. INTERPRETATION: The STHLM3 model could reduce unnecessary biopsies without compromising the ability to diagnose prostate cancer with a Gleason score of at least 7, and could be a step towards personalised risk-based prostate cancer diagnostic programmes. FUNDING: Stockholm County Council (Stockholms Läns Landsting).

Rapid increase in multidrug-resistant enteric bacilli blood stream infection after prostate biopsy - A 10-year population-based cohort study.

BACKGROUND: Bloodstream infection following a transrectal prostate biopsy is a well-known and feared complication. Previous studies have shown an increase in multi-resistant bacterial infections as a consequence of higher usage of antibiotics in investigated populations. Our aim was to analyze bacterial resistance patterns in positive blood cultures, after prostate biopsies in Stockholm, Sweden, where the use of antibiotics has been low and decreasing during the last 10 years. METHODS: From the three pathology laboratories in Stockholm, reports of prostate examinations were retrieved (n = 56,076) from 2003 to 2012. By linking men to the National Patient Register all but prostate core biopsies were excluded (n = 12,024). Prostate biopsies in men younger than 30 years of age were excluded (n = 5) leaving 44,047 biopsies for analysis. From laboratory information systems data regarding blood cultures were retrieved. Proportions of blood cultures within 30 days by year were calculated. Crude and adjusted logistic regression models were used to estimate ORs. RESULTS: In total, 44,047 prostate biopsies were performed in 32,916 men over 10 years. On 620 occasions a blood culture was drawn within 30 days of the biopsy; 266 of these were positive. The proportions with positive blood cultures in 2003 and 2012 were 0.38 and 1.14%, respectively. The proportion of multidrug-resistant bacteria increased significantly during the study. In the crude and the adjusted analysis, the year of biopsy and Charlson Comorbidity Index were associated with the risk of having a positive blood culture. CONCLUSION: Multidrug-resistant enteric bacilli are becoming a problem in Sweden, despite low antimicrobial use. Men need to be informed about the increasing risks of infectious complications of transrectal prostate biopsy. One out of 50 men undergoing a prostate biopsy will develop symptoms suggestive of a bloodstream infection after the biopsy and one in 100 men will have a positive blood culture.

[Prostate cancer - diagnostics and screening]. / Prostatacancer ­ utredning, klinisk diagnostik och screening.

Prostate-specific antigen (PSA) based screening is controversial, even though randomised trials show that screening can reduce prostate cancer mortality. The main reason is that screening leads to overdiagnosis of indolent cancers that would never have surfaced clinically in the absence of screening. Recently, several large studies have shown that magnetic resonance imaging (MRI) improves prostate cancer diagnostics. With MRI, up to half of all men with elevated PSA values can be spared a biopsy. When a biopsy is needed, the needles can be directed towards the suspicious area in the prostate, which increases the detection of clinically significant tumors. In Sweden, regional programmes with organised prostate cancer testing were introduced in 2020. These programmes aim to make prostate cancer testing more standardized, efficient, and equitable. In the future, biomarkers and AI-based systems will likely be important to further improve prostate cancer diagnostics.

Spatio-temporal variation in prostate cancer testing in Stockholm: A population-based study.

Prostate cancer screening using prostate-specific antigen (PSA) testing is controversial but remains prevalent in many countries. There is little information in Sweden or elsewhere on the spatial variation in PSA testing. This study aims to describe the spatio-temporal variation in PSA testing prior to a prostate cancer diagnosis in the Stockholm region at the municipality and small area levels. A population-based register study comprised men aged 40 years and over living in the Stockholm region during 2007-2016. For Stockholm in 2016, we reported the proportion of men who had a PSA test for the preceding one, two, five and ten years by ten-year age groups. The age-standardised proportion of men having a PSA test was reported for municipalities by calendar years. We used spatial smoothing for calculating the age-standardised proportion of men having a PSA test in a small area for each calendar year. In 2016, 74.0% and 77.8% of men aged 60-69 and 70-79 years respectively had taken a PSA test in the previous ten years. The municipalities of Danderyd and Ekerö showed high proportions of PSA testing. A marked heterogeneity in such proportions within each municipality was observed. The odds ratio for having a PSA test for those born in Sweden was 2.22 (95% CI 2.00-2.52). Opportunistic PSA testing is widespread with three quarters of men in their sixties and seventies having had a test in the preceding decade. We found evidence for marked geographical heterogeneity, where more affluent and metropolitan areas had higher levels of testing. Variations in PSA testing was associated with socio-economic position and demographic factors including education, income and country of birth.