Balancing the harms and benefits of early detection of prostate cancer

Background: The benefits of prostate cancer screening on an individual level remain unevaluated.Methods: Between 1993 and 1999, a total of 43,987 men, aged 55-74 years, were included in the intervention arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC) section in the Netherlands, Sweden, and Finland. A total of 42,503 men, aged 55-74 years, were included in a clinical population in Northern Ireland. Serum prostate-specific antigen (PSA) &lt;20.0 ng/mL was measured in all men at study entry. All men were followed for prostate cancer incidence and causes of death until December 31, 2006.Results: The adjusted absolute difference in prostate cancer specific mortality between the intervention population and the clinical population increased with increasing PSA level at study entry, ie, 0.05 per 10,000 person-years for men who had a serum PSA level of 0.0-1.9 ng/mL and 8.8 per 10,000 person-years for men who had a serum PSA level of 10-19.9 ng/mL. To evaluate the risks of early detection, the number needed to investigate (NNI) and number needed to treat (NNT) to save 1 death from prostate cancer were calculated. Both NNI and NNT were higher for those who had lower PSA levels at study entry. The NNI was 24,642 men for patients who had a serum PSA level of 0.0-1.9 ng/mL and was 133 men for patients who had a serum PSA level of 10-19.9 ng/mL; the NNT was 724 men for patients who had a serum PSA level of 0.0-1.9 ng/mL and was 60 men for patients with a serum PSA level of 10-19.9 ng/mL.Conclusions: For men with a low serum PSA level, the benefits of aggressive investigation and treatment may be limited because they are associated with a large increase in cumulative incidence and potential overtreatment.<br/

Pair-matched patient-reported quality of life and early oncological control following focal irreversible electroporation versus robot-assisted radical prostatectomy

Purpose: The design, conduct and completion of randomized trials for curative prostate cancer (PCa) treatments are challenging. To evaluate the effect of robot-assisted radical prostatectomy (RARP) versus focal irreversible electroporation (IRE) on patient-reported quality of life (QoL) and early oncological control using propensity-scored matching. Methods: Patients with T1c–cT2b significant PCa (hig

Evolution of European prostate cancer screening protocols and summary of ongoing trials

Population-based organised repeated screening for prostate cancer has been found to reduce disease-specific mortality, but with substantial overdiagnosis leading to overtreatment. Although only very few countries have implemented a screening programme on a national level, individual prostate-specific antigen (PSA) testing is common. This opportunistic testing may have little favourable impact, while stressing the side-effects. The classic early detection protocols as were state-of-the-art in the 1990s applied a PSA and digital rectal examination threshold for sextant systematic prostate biopsy, with a fixed interval for re-testing, and limited indication for expectant management. In the three decades since these trials were started, different important improvements have become available in the cascade of screening, indication for biopsy, and treatment. The main developed aspects include: better identification of individuals at risk (using early/baseline PSA, family history, and/or genetic profile), individualised re-testing interval, optimised and individualised starting and stopping age, with gradual invitation at a fixed age rather than invitation of a wider range of age groups, risk stratification for biopsy (using PSA density, risk calculator, magnetic resonance imaging, serum and urine biomarkers, or combinations/sequences), targeted biopsy, transperineal biopsy approach, active surveillance for low-risk prostate cancer, and improved staging of disease. All these developments are suggested to decrease the side-effects of screening, while at least maintaining the advantages, but Level 1 evidence is lacking. The knowledge gained and new developments on early detection are being tested in different prospective screening trials throughout Europe. In addition, the European Union-funded PRostate cancer Awareness and Initiative for Screening in the European Union (PRAISE-U) project will compare and evaluate different screening pilots throughout Europe. Implementation and sustainability will also be addressed. Modern screening approaches may reduce the burden of the second most frequent cause of cancer-related death in European males, while minimising side-effects. Also, less efficacious opportunistic early detection may be indirectly reduced.</p

Evolution of European prostate cancer screening protocols and summary of ongoing trials

Population-based organised repeated screening for prostate cancer has been found to reduce disease-specific mortality, but with substantial overdiagnosis leading to overtreatment. Although only very few countries have implemented a screening programme on a national level, individual prostate-specific antigen (PSA) testing is common. This opportunistic testing may have little favourable impact, while stressing the side-effects. The classic early detection protocols as were state-of-the-art in the 1990s applied a PSA and digital rectal examination threshold for sextant systematic prostate biopsy, with a fixed interval for re-testing, and limited indication for expectant management. In the three decades since these trials were started, different important improvements have become available in the cascade of screening, indication for biopsy, and treatment. The main developed aspects include: better identification of individuals at risk (using early/baseline PSA, family history, and/or genetic profile), individualised re-testing interval, optimised and individualised starting and stopping age, with gradual invitation at a fixed age rather than invitation of a wider range of age groups, risk stratification for biopsy (using PSA density, risk calculator, magnetic resonance imaging, serum and urine biomarkers, or combinations/sequences), targeted biopsy, transperineal biopsy approach, active surveillance for low-risk prostate cancer, and improved staging of disease. All these developments are suggested to decrease the side-effects of screening, while at least maintaining the advantages, but Level 1 evidence is lacking. The knowledge gained and new developments on early detection are being tested in different prospective screening trials throughout Europe. In addition, the European Union-funded PRostate cancer Awareness and Initiative for Screening in the European Union (PRAISE-U) project will compare and evaluate different screening pilots throughout Europe. Implementation and sustainability will also be addressed. Modern screening approaches may reduce the burden of the second most frequent cause of cancer-related death in European males, while minimising side-effects. Also, less efficacious opportunistic early detection may be indirectly reduced.</p

A Personalized, Risk-Based Approach to Active Surveillance for Prostate Cancer with Takeaways from Broader Oncology Practices:A Mixed Methods Review

Background/Objectives: To summarize the current state of knowledge regarding personalized, risk-based approaches in active surveillance (AS) for prostate cancer (PCa) and to explore the lessons learned from AS practices in other types of cancer. Methods: This mixed methods review combined a systematic review and a narrative review. The systematic review was conducted according to the Preferred Reporting Items for Systematic rviews and Meta-Analyses (PRISMA) guidelines, with searches performed in the Medline, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and Google Scholar databases. Only studies evaluating personalized, risk-based AS programs for PCa were included. The narrative review focused on AS approaches in other solid tumors (thyroid, breast, kidney, and bladder cancer) to contextualize the findings and highlight lessons learned.Results: After screening 3137 articles, 9 were suitable for inclusion, describing the following four unique risk-based AS tools: PRIAS, Johns Hopkins, Canary PASS, and STRATCANS. These models were developed using data from men with low-risk (Grade Group 1) disease, with little to no magnetic resonance imaging (MRI) data. They used patient information such as (repeated) prostate-specific antigen (PSA) measurements and biopsy results to predict the risk of upgrading at the next biopsy or at radical prostatectomy, or to assign a patient to a pre-defined risk category with a corresponding pre-defined follow-up (FU) regimen. Performance was moderate across models, with the area under the curve/concordance index values ranging from 0.58 to 0.85 and calibration was generally good. The PRIAS, Canary PASS, and STRATCANS models demonstrated the benefits of less burdensome biopsies, clinic visits, and MRIs during FU when used, compared to current one-size-fits-all practices. Although little is known about risk-based AS in thyroid, breast, kidney, and bladder cancer, learning from their current practices could further refine patient selection, streamline monitoring protocols, and address adoption barriers, improving AS’s overall effectiveness in PCa management. Conclusions: Personalized, risk-based AS models allow for a reduction in the FU burden for men at low risk of progression while maintaining sensitive FU visits for those at higher risk. The comparatively limited evidence and practice of risk-based AS in other cancer types highlight the advanced state of AS in PCa.</p

Early Cost-Effectiveness Analysis of Using Whole-Genome Sequencing for Patients With Castration-Resistant Prostate Cancer

Objectives: This study aims to assess the potential cost-effectiveness of using whole-genome sequencing (WGS)-guided systemic therapy in metastatic castrate-resistant prostate cancer compared with the European Association of Urology guideline recommended diagnostics from a Dutch societal perspective. Methods: A decision analytic model combining a decision tree and partitioned survival models was developed to link diagnostic results with subsequent biomarker-guided treatments. Two diagnostic strategies, WGS and guideline-recommended practice—the genomic testing for breast cancer gene 1/2 (BRCA1/2) and deficient mismatch repair, were simulated to compare the health outcome and cost. Treatment effectiveness was estimated through survival analysis using published trial data. Sensitivity and scenario analyses were conducted to examine result robustness and to identify conditions under which WGS may be cost-effective. Results: WGS identified an additional 21% of patients eligible for personalized therapy (PD-1/PDL-1 inhibitors and olaparib), resulting in an incremental increase in cost (€14 260) and quality-adjusted life years (QALY = 0.05). These results yielded an incremental cost-effectiveness ratio of €289 625 per QALY gained. WGS would become cost-effective if the cost of biomarker-guided therapies decreases by 62% and when identifying a proportion of 23% more patients with actional targets. Conclusions: Our findings suggest that future treatments with improved efficacy and reduced cost could potentially make the WGS strategy cost-effective. Its unaccounted potential value to identify prognostic biomarkers, diagnostic alternatives, and patient heterogeneity should be addressed in future research and considered for optimal implementation. New reimbursement options are needed considering the high prices of biomarker-guided therapies that drive the incremental cost-effectiveness ratio.</p

Synchronous and metachronous urothelial carcinoma of the upper urinary tract and the bladder: Are they clonally related? A systematic review

Purpose: Following radical nephroureterectomy for upper urinary tract urothelial carcinoma (UTUC), intravesical recurrence (IVR) is found in 22% to 47% of patients. Patients with a primary urothelial carcinoma of the bladder (UCB) have an increased risk of a future UTUC (1%–5%). Paired UTUC and UCB might represent clonally related tumors due to intraluminal seeding of tumor cells or might be separate entities of urothelial carcinoma caused by field cancerization. We systematically reviewed all the relevant literature to address the possible clonal relation of UTUC and paired UCB. Materials and Methods: MEDLINE, EMBASE, and COCHRANE databases were systematically searched for relevant citations published between January 2000 and July 2019. This study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Of 5038 citations identified, 86 full papers were screened, and 9 studies met the inclusion criteria. Results: The populations studied and the molecular techniques used to assess clonality of UTUC and paired UCB differed largely over time. Eight studies reported on primary UTUC and meta- or synchronous IVR without a history of UCB. A total of 118 tumors

Evolution of European prostate cancer screening protocols and summary of ongoing trials

Population-based organised repeated screening for prostate cancer has been found to reduce disease-specific mortality, but with substantial overdiagnosis leading to overtreatment. Although only very few countries have implemented a screening programme on a national level, individual prostate-specific antigen (PSA) testing is common. This opportunistic testing may have little favourable impact, while stressing the side-effects. The classic early detection protocols as were state-of-the-art in the 1990s applied a PSA and digital rectal examination threshold for sextant systematic prostate biopsy, with a fixed interval for re-testing, and limited indication for expectant management. In the three decades since these trials were started, different important improvements have become available in the cascade of screening, indication for biopsy, and treatment. The main developed aspects include: better identification of individuals at risk (using early/baseline PSA, family history, and/or genetic profile), individualised re-testing interval, optimised and individualised starting and stopping age, with gradual invitation at a fixed age rather than invitation of a wider range of age groups, risk stratification for biopsy (using PSA density, risk calculator, magnetic resonance imaging, serum and urine biomarkers, or combinations/sequences), targeted biopsy, transperineal biopsy approach, active surveillance for low-risk prostate cancer, and improved staging of disease. All these developments are suggested to decrease the side-effects of screening, while at least maintaining the advantages, but Level 1 evidence is lacking. The knowledge gained and new developments on early detection are being tested in different prospective screening trials throughout Europe. In addition, the European Union-funded PRostate cancer Awareness and Initiative for Screening in the European Union (PRAISE-U) project will compare and evaluate different screening pilots throughout Europe. Implementation and sustainability will also be addressed. Modern screening approaches may reduce the burden of the second most frequent cause of cancer-related death in European males, while minimising side-effects. Also, less efficacious opportunistic early detection may be indirectly reduced

Feasibility of Diffuse Reflection Spectroscopy for Intraoperative Margin Assessment During Prostatectomy

Background and objective: A positive surgical margin (PSM) occurs in up to 32% of patients undergoing robot-assisted radical prostatectomy (RARP). Diffuse reflectance spectroscopy (DRS), which measures tissue composition according to its optical properties, can potentially be used for real-time PSM detection during RARP. Our objective was to assess the feasibility of DRS in distinguishing prostate cancer from benign tissue in RARP specimens. Methods: In a single-center prospective study, DRS measurements were taken ex vivo for RARP specimens from 59 patients with biopsy-proven prostate carcinoma. Discriminating features from the DRS spectra were used to create a machine learning–based classification algorithm. The data were split patient-wise into training (70%) and testing (30%) sets, with ten iterations to ensure algorithm robustness. The average sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve (AUC) from ten classification iterations were calculated. Key findings and limitations: We collected 542 DRS measurements, of which 53% were tumor and 47% were healthy-tissue measurements. Twenty discriminating features from the DRS spectra were used as the input for a support vector machine model. This model achieved average sensitivity of 89%, specificity of 82%, accuracy of 85%, and AUC of 0.91 for the test set. Limitations include the binary label input for classification. Conclusions and clinical implications: DRS can potentially discriminate prostate cancer from benign tissue. Before implementing the technique in clinical practice, further research is needed to assess its performance on heterogeneous tissue volumes and measurements from the prostate surface. Patient summary: We looked at the ability of a technique called diffuse reflectance spectroscopy to guide surgeons in discriminating prostate cancer tissue from benign prostate tissue in real time during prostate cancer surgery. Our study showed promising results in an experimental setting. Future research will focus on bringing this technique to clinical practice.</p

Beyond Gleason grading:MRI radiomics to differentiate cribriform growth from non-cribriform growth in prostate cancer men

ObjectiveTo differentiate cribriform (GP4Crib+) from non-cribriform growth and Gleason 3 patterns (GP4Crib-/GP3) using MRI.MethodsTwo hundred and ninety-one operated prostate cancer men with pre-treatment MRI and whole-mount prostate histology were retrospectively included. T2-weighted, apparent diffusion coefficient (ADC) and fractional blood volume maps from 1.5/3T MRI systems were used. 592 histological GP3, GP4Crib- and GP4Crib+ regions were segmented on whole-mount specimens and manually co-registered to MRI sequences/maps. Radiomics features were extracted, and an erosion process was applied to minimize the impact of delineation uncertainties. A logistic regression model was developed to differentiate GP4Crib+ from GP3/GP4Crib- in the 465 remaining regions. The differences in balanced accuracy between the model and baseline (where all regions are labeled as GP3/GP4Crib-) and 95% confidence intervals (CI) for all metrics were assessed using bootstrapping.ResultsThe logistic regression model, using the 90th percentile ADC feature with a negative coefficient, showed a balanced accuracy of 0.65 (95% CI: 0.48-0.79), receiver operating characteristic area under the curve (AUC) of 0.75 (95% CI: 0.54-0.92), a precision-recall AUC of 0.35 (95% CI: 0.14-0.68).ConclusionThe radiomics MRI-based model, trained on Gleason sub-patterns segmented on whole-mount specimen, was able to differentiate GP4Crib+ from GP3/GP4Crib- patterns with moderate accuracy. The most dominant feature was the 90th percentile ADC. This exploratory study highlights 90th percentile ADC as a potential biomarker for cribriform growth differentiation, providing insights into future MRI-based risk assessment strategies