The value of micro-ultrasound for prostate cancer screening: A retrospective real-world feasibility study

OPTIMAL PREDICTORS OF PROSTATE CANCER ON REPEAT PROSTATE BIOPSY: A PROSPECTIVE STUDY OF 1,051 MEN

Combined Use of Prostate-specific Antigen Density and Magnetic Resonance Imaging for Prostate Biopsy Decision Planning: A Retrospective Multi-institutional Study Using the Prostate Magnetic Resonance Imaging Outcome Database (PROMOD)

Overview of Performance Indicators of Prostate Cancer Screening Trials

Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

PD40-02 RE-EXAMINING PSA DENSITY: DEFINING THE OPTIMAL PSA RANGE AND PATIENTS FOR USING PSA DENSITY TO PREDICT PROSTATE CANCER USING EXTENDED TEMPLATE BIOPSY

Re-examining Prostate-specific Antigen (PSA) Density: Defining the Optimal PSA Range and Patients for Using PSA Density to Predict Prostate Cancer Using Extended Template Biopsy

Prostate Specific Antigen and Human Glandular Kallikrein 2 in Early Detection of Prostate Cancer

<p dir="ltr">The landscape of prostate cancer diagnostics and management continues to evolve, driven by efforts to balance early detection, minimize overdiagnosis, and enhance clinical outcomes. This thesis aims to examine critical aspects of this field, encompassing the relationship between lower urinary tract symptoms (LUTS) and prostate cancer, the validation of risk calculators, the integration of magnetic resonance imaging (MRI) in diagnostic pathways, and the implications of biopsy strategies.</p><p dir="ltr">The association between LUTS and prostate cancer was assessed in Study I, which is a population-based study involving men aged 50-69 years. Using data from the STHLM3 screening cohort, we compared International Prostate Symptom Score (IPSS) and biopsy outcomes and thereby the risk of prostate cancer. Among 45,595 men, 75% reported no or mild LUTS, and only 3% experienced severe symptoms. Also, men with high-risk prostate cancer (ISUP grade group ≥3 or cT ≥3) did not have higher IPSS values than those with benign biopsies. In multivariate logistic regression analysis, adjusting for age, PSA, prostate volume and clinical T-stage, there was no significant association between LUTS and prostate cancer risk. These findings challenge the assumption that prostate cancer commonly presents with worsening urinary symptoms, suggesting that reliance on LUTS for cancer suspicion may lead to unnecessary testing and overdiagnosis. Clinicians should instead focus on validated biomarkers and imaging tools for early detection.</p><p dir="ltr">The accurate prediction of prostate cancer risk is essential to optimize diagnostic and therapeutic decision-making. In Study II, we evaluated the Rotterdam Prostate Cancer Risk Calculator (RPCRC) and the Prostate Biopsy Collaborative Group Risk Calculator (PBCG-RC). We again used available data from the STHLM3 trial, identifying 5,841 men with PSA 23 ng/ml who underwent systematic biopsies. We assessed the performance of both RCs in predicting clinically significant prostate cancer (ISUP grade group ≥2) by calculating the risk for all men and comparing to biopsy outcome.</p><p dir="ltr">Both risk calculators exhibited good discriminatory ability, with area under the curve (AUC) values of 0.74 for the RPCRC and 0.70 for the PBCG-RC. The PBCG- RC demonstrated adequate calibration and clinical utility in its current form, offering a net benefit in decision curve analyses. In contrast, the RPCRC underestimated the risk of csPCa and showed no clinical benefit before recalibration. Recalibration of the RPCRC improved its performance, narrowing the differences between the two calculators. This study underscores the necessity of external validation and recalibration of risk prediction tools to ensure their reliability and applicability in various clinical settings.</p><p dir="ltr">The adoption of MRI before prostate biopsy has reshaped the field of prostate cancer diagnostics. MRI facilitates the detection of significant cancer by enabling targeted biopsies of suspicious lesions. In Study III we explored the implications of omitting systematic biopsies completely. Using data from the STHLM3-MRI screening trial, we included 395 men with either elevated PSA (>3 ng/ml) or Stockholm3 test (>11%) who had had a positive MRI (PI-RADS ≥3) followed by combined targeted and systematic biopsies. In total, 13% had ISUP grade group 1, and 58% had ISUP grade group ≥2 cancer. Omitting systematic biopsies decreased detection rates for both ISUP grade group 1 (risk ratio (RR) 0.83) and ISUP grade group ≥2 (RR 0.85) tumors. For every case of ISUP grade group 1 averted, there were 3.8 of missed ISUP grade group ≥2 and 1.1 ISUP grade group >3 cancer. Furthermore, omitting systematic biopsies increased the rate of misclassification at radical prostatectomy, with a higher proportion of men being upgraded following targeted-only biopsies compared to those receiving combined biopsies (31% vs. 19%, p <0.05). Assessing another strategy using PSA density >0.05 ng/ml2 as a threshold for biopsy yielded similar reductions in ISUP grade group 1 detection while improving the detection rates for clinically significant cancers. These findings highlight the need for future research to further improve biopsy strategies that would maximize cancer detection while minimizing overdiagnosis and misclassification.</p><p dir="ltr">In Study IV, we conducted a longitudinal, population-based study examining trends in prostate cancer diagnostics in the Stockholm region from 2010 to 2023. Using data from the Stockholm PSA and Biopsy Register, we included all men aged 40 years and older without a prior prostate cancer diagnosis. We analyzed how the use of PSA testing, MRI, and prostate biopsies evolved over time, particularly in the context of MRI being incorporated into the diagnostic pathway. We also examined changes in the distribution of ISUP grade groups on biopsy.</p><p dir="ltr">PSA testing remained common and stable throughout the study period, with 59% of all men - and over 75% of men aged 60 and above - being tested at least once. Following an elevated PSA, MRI usage increased markedly from 3% to 30%, while biopsy rates declined from 23% to 16% (RR 0.66; 95% CI: 0.64- 0.69)). By 2023, 83% of men undergoing biopsy had had a pre-biopsy MRI. Additionally, we observed a reduction in the proportion of benign biopsies and ISUP grade group 1 cancers, alongside a substantial increase in detection of ISUP grade group >2 cancers. These findings offer real-world evidence of improved diagnostic precision following the integration of MRI into routine clinical practice.</p><p dir="ltr">This thesis aims to give an overview in the rapidly evolving field of prostate cancer diagnostics. The four outlined studies discuss various aspects of patient selection, risk prediction and diagnostic strategies. In summary, they highlight the need for a more precise, evidence-based approach to improve clinical outcomes and reduce unnecessary interventions.</p><h3>List of scientific papers</h3><p dir="ltr">I. <b>Chandra Engel J,</b> Palsdottir T, Aly M, Egevad L, Grönberg H, Eklund M, Nordström T. Lower urinary tract symptoms (LUTS) are not associated with an increased risk of prostate cancer in men 50-69 years with PSA ≥3 ng/ml. Scand J Urol. 2020 Feb;54(1):1-6. <a href="https://doi.org/10.1080/21681805.2019.1703806" rel="noreferrer" target="_blank">https://doi.org/10.1080/21681805.2019.1703806</a></p><p dir="ltr">II. <b>Chandra Engel J,</b> Palsdottir T, Ankerst D, Remmers S, Mortezavi A, Chellappa V, Egevad L, Grönberg H, Eklund M, Nordström T. External Validation of the Prostate Biopsy Collaborative Group Risk Calculator and the Rotterdam Prostate Cancer Risk Calculator in a Swedish Population-based Screening Cohort. Eur Urol Open Sci. 2022 May 19;41:1-7. <a href="https://doi.org/10.1016/j.euros.2022.04.010" rel="noreferrer" target="_blank">https://doi.org/10.1016/j.euros.2022.04.010</a></p><p dir="ltr">III. <b>Chandra Engel J,</b> Eklund M, Jäderling F, Palsdottir T, Falagario U, Discacciati A, Nordström T. Diagnostic Effects of Omitting Systematic Biopsies in Prostate Cancer Screening. Eur Urol Oncol. 2024 Oct 22:S2588-9311(24)00229-3. <a href="https://doi.org/10.1016/j.euo.2024.10.002" rel="noreferrer" target="_blank">https://doi.org/10.1016/j.euo.2024.10.002</a></p><p dir="ltr">IV. <b>Chandra Engel J,</b> Rai B, Eklund M, Jäderling F, Clements M, Nordström T. Trends and patterns in prostate cancer diagnostics during the era of MRI implementation - real world evidence from a population-based study in the Stockholm Region, Sweden 2010- 2023. [Manuscript]</p>

<p dir="ltr">The landscape of prostate cancer diagnostics and management continues to evolve, driven by efforts to balance early detection, minimize overdiagnosis, and enhance clinical outcomes. This thesis aims to examine critical aspects of this field, encompassing the relationship between lower urinary tract symptoms (LUTS) and prostate cancer, the validation of risk calculators, the integration of magnetic resonance imaging (MRI) in diagnostic pathways, and the implications of biopsy strategies.</p><p dir="ltr">The association between LUTS and prostate cancer was assessed in Study I, which is a population-based study involving men aged 50-69 years. Using data from the STHLM3 screening cohort, we compared International Prostate Symptom Score (IPSS) and biopsy outcomes and thereby the risk of prostate cancer. Among 45,595 men, 75% reported no or mild LUTS, and only 3% experienced severe symptoms. Also, men with high-risk prostate cancer (ISUP grade group ≥3 or cT ≥3) did not have higher IPSS values than those with benign biopsies. In multivariate logistic regression analysis, adjusting for age, PSA, prostate volume and clinical T-stage, there was no significant association between LUTS and prostate cancer risk. These findings challenge the assumption that prostate cancer commonly presents with worsening urinary symptoms, suggesting that reliance on LUTS for cancer suspicion may lead to unnecessary testing and overdiagnosis. Clinicians should instead focus on validated biomarkers and imaging tools for early detection.</p><p dir="ltr">The accurate prediction of prostate cancer risk is essential to optimize diagnostic and therapeutic decision-making. In Study II, we evaluated the Rotterdam Prostate Cancer Risk Calculator (RPCRC) and the Prostate Biopsy Collaborative Group Risk Calculator (PBCG-RC). We again used available data from the STHLM3 trial, identifying 5,841 men with PSA 23 ng/ml who underwent systematic biopsies. We assessed the performance of both RCs in predicting clinically significant prostate cancer (ISUP grade group ≥2) by calculating the risk for all men and comparing to biopsy outcome.</p><p dir="ltr">Both risk calculators exhibited good discriminatory ability, with area under the curve (AUC) values of 0.74 for the RPCRC and 0.70 for the PBCG-RC. The PBCG- RC demonstrated adequate calibration and clinical utility in its current form, offering a net benefit in decision curve analyses. In contrast, the RPCRC underestimated the risk of csPCa and showed no clinical benefit before recalibration. Recalibration of the RPCRC improved its performance, narrowing the differences between the two calculators. This study underscores the necessity of external validation and recalibration of risk prediction tools to ensure their reliability and applicability in various clinical settings.</p><p dir="ltr">The adoption of MRI before prostate biopsy has reshaped the field of prostate cancer diagnostics. MRI facilitates the detection of significant cancer by enabling targeted biopsies of suspicious lesions. In Study III we explored the implications of omitting systematic biopsies completely. Using data from the STHLM3-MRI screening trial, we included 395 men with either elevated PSA (>3 ng/ml) or Stockholm3 test (>11%) who had had a positive MRI (PI-RADS ≥3) followed by combined targeted and systematic biopsies. In total, 13% had ISUP grade group 1, and 58% had ISUP grade group ≥2 cancer. Omitting systematic biopsies decreased detection rates for both ISUP grade group 1 (risk ratio (RR) 0.83) and ISUP grade group ≥2 (RR 0.85) tumors. For every case of ISUP grade group 1 averted, there were 3.8 of missed ISUP grade group ≥2 and 1.1 ISUP grade group >3 cancer. Furthermore, omitting systematic biopsies increased the rate of misclassification at radical prostatectomy, with a higher proportion of men being upgraded following targeted-only biopsies compared to those receiving combined biopsies (31% vs. 19%, p <0.05). Assessing another strategy using PSA density >0.05 ng/ml2 as a threshold for biopsy yielded similar reductions in ISUP grade group 1 detection while improving the detection rates for clinically significant cancers. These findings highlight the need for future research to further improve biopsy strategies that would maximize cancer detection while minimizing overdiagnosis and misclassification.</p><p dir="ltr">In Study IV, we conducted a longitudinal, population-based study examining trends in prostate cancer diagnostics in the Stockholm region from 2010 to 2023. Using data from the Stockholm PSA and Biopsy Register, we included all men aged 40 years and older without a prior prostate cancer diagnosis. We analyzed how the use of PSA testing, MRI, and prostate biopsies evolved over time, particularly in the context of MRI being incorporated into the diagnostic pathway. We also examined changes in the distribution of ISUP grade groups on biopsy.</p><p dir="ltr">PSA testing remained common and stable throughout the study period, with 59% of all men - and over 75% of men aged 60 and above - being tested at least once. Following an elevated PSA, MRI usage increased markedly from 3% to 30%, while biopsy rates declined from 23% to 16% (RR 0.66; 95% CI: 0.64- 0.69)). By 2023, 83% of men undergoing biopsy had had a pre-biopsy MRI. Additionally, we observed a reduction in the proportion of benign biopsies and ISUP grade group 1 cancers, alongside a substantial increase in detection of ISUP grade group >2 cancers. These findings offer real-world evidence of improved diagnostic precision following the integration of MRI into routine clinical practice.</p><p dir="ltr">This thesis aims to give an overview in the rapidly evolving field of prostate cancer diagnostics. The four outlined studies discuss various aspects of patient selection, risk prediction and diagnostic strategies. In summary, they highlight the need for a more precise, evidence-based approach to improve clinical outcomes and reduce unnecessary interventions.</p><h3>List of scientific papers</h3><p dir="ltr">I. <b>Chandra Engel J,</b> Palsdottir T, Aly M, Egevad L, Grönberg H, Eklund M, Nordström T. Lower urinary tract symptoms (LUTS) are not associated with an increased risk of prostate cancer in men 50-69 years with PSA ≥3 ng/ml. Scand J Urol. 2020 Feb;54(1):1-6. <a href="https://doi.org/10.1080/21681805.2019.1703806" rel="noreferrer" target="_blank">https://doi.org/10.1080/21681805.2019.1703806</a></p><p dir="ltr">II. <b>Chandra Engel J,</b> Palsdottir T, Ankerst D, Remmers S, Mortezavi A, Chellappa V, Egevad L, Grönberg H, Eklund M, Nordström T. External Validation of the Prostate Biopsy Collaborative Group Risk Calculator and the Rotterdam Prostate Cancer Risk Calculator in a Swedish Population-based Screening Cohort. Eur Urol Open Sci. 2022 May 19;41:1-7. <a href="https://doi.org/10.1016/j.euros.2022.04.010" rel="noreferrer" target="_blank">https://doi.org/10.1016/j.euros.2022.04.010</a></p><p dir="ltr">III. <b>Chandra Engel J,</b> Eklund M, Jäderling F, Palsdottir T, Falagario U, Discacciati A, Nordström T. Diagnostic Effects of Omitting Systematic Biopsies in Prostate Cancer Screening. Eur Urol Oncol. 2024 Oct 22:S2588-9311(24)00229-3. <a href="https://doi.org/10.1016/j.euo.2024.10.002" rel="noreferrer" target="_blank">https://doi.org/10.1016/j.euo.2024.10.002</a></p><p dir="ltr">IV. <b>Chandra Engel J,</b> Rai B, Eklund M, Jäderling F, Clements M, Nordström T. Trends and patterns in prostate cancer diagnostics during the era of MRI implementation - real world evidence from a population-based study in the Stockholm Region, Sweden 2010- 2023. [Manuscript]</p>

The Impact of Recent Screening Recommendations on Prostate Cancer Screening in a Large Health Care System

To evaluate the diagnostic accuracy and imaging findings of an abbreviated biparametric MRI (bpMRI) protocol for prostate cancer (PCa) screening. In this single-centre, prospective study, men aged 50-75 years were randomly selected for invitation to screening through participating general practices. Participants underwent screening with abbreviated bpMRI (axial T2-weighted and b2000 diffusion-weighted sequences) and PSA testing between October 2019 and December 2020. Screening MRIs were independently reported by two radiologists as either positive or negative by screening criteria, with a third radiologist if there was disagreement. Positive MRI or raised PSA density (PSAd) (≥ 0.12 ng/mL2) triggered standard-of-care NHS PCa assessment. Outcomes of the NHS assessment were collated as a composite reference standard and included multiparametric MRI ± biopsy, and a 2-year healthcare record follow-up. Diagnostic accuracy was evaluated using positive predictive value (PPV). Among 303 men who completed screening (median age 62 years [IQR 56, 68]), 16% (48/303) had a positive screening MRI, and an additional 5% (16/303) had raised PSAd alone. Of 61 men referred to secondary care, 48% (29/61) had clinically significant PCa, with 2 (3%, 2/61) additional diagnoses during 2-year follow-up. Of 31 men with clinically significant PCa, 87% (27/31) had a positive screening MRI and 42% (13/31) had raised PSAd. The PPV of the screening MRI was 59% (27/46, 95% CI: 44, 72). Abbreviated bpMRI may have value in PCa screening independently of PSA testing. However, prospective multicentre evaluation is needed to assess the feasibility and cost-effectiveness of MRI-based screening at a national level. Question MRI may reduce over- and under-diagnosis from prostate-specific antigen (PSA) testing in PCa screening, but its use is limited by long scan times, cost, and availability. Findings Abbreviated bpMRI identified more men with clinically significant cancer than PSAd (≥ 0.12 ng/mL2), with a PPV of 59% (95% CI: 44, 72). Clinical relevance Prostate MRI may improve cancer detection independently of PSA testing, with abbreviated protocols enhancing feasibility and scalability. While MRI may offer an opportunity for early diagnosis, further prospective, multicentre evaluation is needed to explore its potential role in screening settings.

Prostate-specific Antigen Density as a Selection Tool Before Magnetic Resonance Imaging in Prostate Cancer Screening: An Analysis from the STHLM3MRI Randomized Clinical Trial.

Is Prostate-Specific Antigen Velocity Selective for Clinically Significant Prostate Cancer in Screening? European Randomized Study of Screening for Prostate Cancer (Rotterdam)

70 Background: PSA density (PSAD) is an important predictor of prostate cancer (PCa). We assessed whether the predictive accuracy of PSAD varied based on the range of PSA or whether the patient had a previous negative prostate biopsy (PB). Methods: We assessed a prospective cohort of men who were referred for a PB due to suspicion of PCa at 26 different sites across USA. The area under the receiver operating characteristic curve (AUC) was used to assess the added predictive accuracy of PSAD versus PSA across 3 different PSA ranges ( < 4, 4 – 10, > 10 ng/mL) and in men with or without a prior negative PB for the detection of any and significant (Gleason ≥ 7) PCa. Results: Of the 1,290 men, 585 (45%) and 284 (22%) had any and significant PCa, respectively. PSAD was significantly more predictive than PSA for detecting any PCa in the PSA ranges of 4 – 10 (AUC 0.70 vs 0.53, P < 0.00001) and > 10 (AUC 0.84 vs 0.65, P < 0.00001) ng/mL. Similarly, for significant PCa, PSAD was more predictive than PSA in the PSA ranges of 4 – 10 (AUC 0.72 vs 0.57, P < 0.00001) and > 10 (AUC 0.82 vs 0.68, P = 0.0001) ng/mL. Furthermore, PSAD was significantly more predictive than PSA in detecting PCa in men that had a prior negative PB (AUC 0.69 vs 0.56, P = 0.0001 for any PCa and AUC 0.81 vs 0.70, P = 0.0042 for significant PCa), and those that didn’t (AUC 0.72 vs 0.67, P = 0.0001 for any PCa and AUC 0.77 vs 0.73, P = 0.0026 for significant PCa). However the difference between the AUC of PSAD and PSA (ΔAUC) was a lot more pronounced in men that had a prior negative PB (ΔAUC = 0.13 for any PCa and ΔAUC = 0.11 for significant PCa) as opposed to those that didn’t (ΔAUC = 0.05 for any PCa and ΔAUC = 0.04 for significant PCa), suggesting that PSAD is a much better predictor than PSA alone in men who have undergone a previous PB. Conclusions: As PSA increases, the predictive accuracy of PSAD over PSA appears to improve for the detection of any PCa and significant PCa. Additionally, PSAD has a more pronounced predictive value over PSA in detecting any and significant PCa in men who have undergone a prior negativePB. We support the use of PSAD testing to avoid unnecessary biopsies in men who have elevated PSA secondary to an enlarged prostate.

At present, increased early detection of prostate cancer appears to be the most feasible way to reduce cancer-related mortality. As a result significant efforts have been made to identify more men with curable cancer. This article reviews the role of serum prostate-specific antigen in an early detection or screening strategy and describes efforts to enhance the specificity of prostate-specific antigen testing.