Screening history and risk of death from prostate cancer: a nested case-control study within the screening arm of the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC).

PURPOSE: We assessed the risk of death from prostate cancer (PCa) in relation to men's screening histories, i.e., screening attendance among men who were offered screening. METHODS: Men in the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) screening arm were invited to up to three screening rounds with the serum prostate-specific antigen (PSA) test at 4-year intervals during 1996-2007. Case subjects (n = 330) were men who died from PCa. Each case was matched to five controls (n = 1544) among the men who were free of PCa. Screening history was defined as (1) never/ever attended screening prior to the case diagnosis; (2) attended at the first screening round; and (3) recency of screening, calculated as the time from last screening attendance to the date of case diagnosis. The association between screening history and the risk of death from PCa was estimated by odds ratios (OR) with 95% confidence intervals (CI) using conditional logistic regression. RESULTS: Having ever attended screening versus never attended was associated with a reduced risk of PCa death (OR 0.60, 95% CI 0.45-0.81) and a similar association was found for those attended (versus not attended) the first screening round (OR 0.67, 95% CI 0.51-0.87). The effect by time since last screen for the risk of PCa death was significantly lower 2-7 years since last screen. CONCLUSION: Among men invited to screening, subjects who attended any PSA screening during the previous 19 years had a 40% reduction in PCa mortality compared to non-screened men.

Which men benefit from prostate cancer screening? Prostate cancer mortality by subgroup in the European Randomised Study of Screening for Prostate Cancer.

OBJECTIVE: To evaluate whether a subgroup of men can be identified that would benefit more from screening than others. MATERIALS AND METHODS: This retrospective cohort study was based on three European Randomised Study of Screening for Prostate Cancer (ERSPC) centres, Finland, the Netherlands and Sweden. We identified 126 827 men aged 55-69 years in the study who were followed for maximum of 16 years after randomisation. The primary outcome was prostate cancer (PCa) mortality. We analysed three age groups 55-59, 60-64 and 65-69 years and PCa cases within four European Association of Urology (EAU) risk groups: low, intermediate, high risk, and advanced disease. RESULTS: The hazard ratio (HR) for PCa mortality in the screening arm relative to the control arm for men aged 55-59 years was 0.96 (95% confidence interval [CI] 0.75-1.24) in Finland, 0.70 (95% CI 0.44-1.12) in the Netherlands and 0.42 (95% CI 0.24-0.73) in Sweden. The HR for men aged 60-64 years was 1.03 (95% CI 0.77-1.37) in Finland, 0.76 (95% CI 0.50-1.16) in the Netherlands and 0.97 (95% CI 0.64-1.48) in Sweden. The HR for men aged 65-69 years was 0.80 (95% CI 0.62-1.03) in Finland and 0.57 (95% CI 0.38-0.83) in the Netherlands, and this age group was absent in Sweden. In the EAU risk group analysis, PCa mortality rates were materially lower for men with advanced disease at diagnosis in all three countries: 0.67 (95% CI 0.56-0.82) in Finland, 0.28 (95% CI 0.18-0.44) in the Netherlands, and 0.48 (95% CI 0.30-0.78) in Sweden. CONCLUSION: We were unable to unequivocally identify the optimal age group for screening, as mortality reduction differed among centres and age groups. Instead, the screening effect appears to depend on screening duration, and the number and frequency of screening rounds. PCa mortality reduction by screening is largely attributable to stage shift.

Expected impact of MRI-targeted biopsy interreader variability among uropathologists on ProScreen prostate cancer screening trial: a pre-trial validation study.

PURPOSE: Prostate cancer (PCa) histology, particularly the Gleason score, is an independent prognostic predictor in PCa. Little is known about the inter-reader variability in grading of targeted prostate biopsy based on magnetic resonance imaging (MRI). The aim of this study was to assess inter-reader variability in Gleason grading of MRI-targeted biopsy among uropathologists and its potential impact on a population-based randomized PCa screening trial (ProScreen). METHODS: From June 2014 to May 2018, 100 men with clinically suspected PCa were retrospectively selected. All men underwent prostate MRI and 86 underwent targeted prostate of the prostate. Six pathologists individually reviewed the pathology slides of the prostate biopsies. The five-tier ISUP (The International Society of Urological Pathology) grade grouping (GG) system was used. Fleiss' weighted kappa (κ) and Model-based kappa for associations were computed to estimate the combined agreement between individual pathologists. RESULTS: GG reporting of targeted prostate was highly consistent among the trial pathologists. Inter-reader agreement for cancer (GG1-5) vs. benign was excellent (Model-based kappa 0.90, Fleiss' kappa κ = 0.90) and for clinically significant prostate cancer (csPCa) (GG2-5 vs. GG0 vs. GG1), it was good (Model-based kappa 0.70, Fleiss' kappa κ 0.67). CONCLUSIONS: Inter-reader agreement in grading of MRI-targeted biopsy was good to excellent, while it was fair to moderate for MRI in the same cohort, as previously shown. Importantly, there was wide consensus by pathologists in assigning the contemporary GG on MRI-targeted biopsy suggesting high reproducibility of pathology reporting in the ProScreen trial.

Prostate Cancer Screening With PSA, Kallikrein Panel, and MRI: The ProScreen Randomized Trial.

Importance: Prostate-specific antigen (PSA) screening has potential to reduce prostate cancer mortality but frequently detects prostate cancer that is not clinically important. Objective: To describe rates of low-grade (grade group 1) and high-grade (grade groups 2-5) prostate cancer identified among men invited to participate in a prostate cancer screening protocol consisting of a PSA test, a 4-kallikrein panel, and a magnetic resonance imaging (MRI) scan. Design, Setting, and Participants: The ProScreen trial is a clinical trial conducted in Helsinki and Tampere, Finland, that randomized 61 193 men aged 50 through 63 years who were free of prostate cancer in a 1:3 ratio to either be invited or not be invited to undergo screening for prostate cancer between February 2018 and July 2020. Interventions: Participating men randomized to the intervention underwent PSA testing. Those with a PSA level of 3.0 ng/mL or higher underwent additional testing for high-grade prostate cancer with a 4-kallikrein panel risk score. Those with a kallikrein panel score of 7.5% or higher underwent an MRI of the prostate gland, followed by targeted biopsies for those with abnormal prostate gland MRI findings. Final data collection occurred through June 31, 2023. Main Outcomes and Measures: In descriptive exploratory analyses, the cumulative incidence of low-grade and high-grade prostate cancer after the first screening round were compared between the group invited to undergo prostate cancer screening and the control group. Results: Of 60 745 eligible men (mean [SD] age, 57.2 [4.0] years), 15 201 were randomized to be invited and 45 544 were randomized not to be invited to undergo prostate cancer screening. Of 15 201 eligible males invited to undergo screening, 7744 (51%) participated. Among them, 32 low-grade prostate cancers (cumulative incidence, 0.41%) and 128 high-grade prostate cancers (cumulative incidence, 1.65%) were detected, with 1 cancer grade group result missing. Among the 7457 invited men (49%) who refused participation, 7 low-grade prostate cancers (cumulative incidence, 0.1%) and 44 high-grade prostate cancers (cumulative incidence, 0.6%) were detected, with 7 cancer grade groups missing. For the entire invited screening group, 39 low-grade prostate cancers (cumulative incidence, 0.26%) and 172 high-grade prostate cancers (cumulative incidence, 1.13%) were detected. During a median follow-up of 3.2 years, in the group not invited to undergo screening, 65 low-grade prostate cancers (cumulative incidence, 0.14%) and 282 high-grade prostate cancers (cumulative incidence, 0.62%) were detected. The risk difference for the entire group randomized to the screening invitation vs the control group was 0.11% (95% CI, 0.03%-0.20%) for low-grade and 0.51% (95% CI, 0.33%-0.70%) for high-grade cancer. Conclusions and Relevance: In this preliminary descriptive report from an ongoing randomized clinical trial, 1 additional high-grade cancer per 196 men and 1 low-grade cancer per 909 men were detected among those randomized to be invited to undergo a single prostate cancer screening intervention compared with those not invited to undergo screening. These preliminary findings from a single round of screening should be interpreted cautiously, pending results of the study's primary mortality outcome. Trial Registration: ClinicalTrials.gov Identifier: NCT03423303.

Prostate cancer incidence in men with prostate-specific antigen below 3 ng/mL: The Finnish Randomized Study of Screening for Prostate Cancer.

Prostate-specific antigen (PSA)-based screening for prostate cancer (PCa) can reduce PCa mortality, but also involves overdetection of low-risk disease with potential adverse effects. We evaluated PCa incidence among men with PSA below 3 ng/mL and no PCa diagnosis at the first screening round of the Finnish Randomized Study of Screening for PCa. Follow-up started at the first screening attendance and ended at PCa diagnosis, emigration, death or the common closing date (December 2016), whichever came first. Cox regression analysis was used to estimate hazard ratios and their confidence intervals (CI). Among men with PSA <3 ng/mL, cumulative PCa incidence was 9.1% after 17.6 years median follow-up. Cumulative incidence was 3.6% among men with baseline PSA 0 to 0.99 ng/mL, 11.5% in those with PSA 1.0 to 1.99 ng/mL and 25.7% among men with PSA 2 to 2.99 ng/mL (hazard ratio 9.0, 95% CI: 7.9-10.2 for the latter). The differences by PSA level were most striking for low-risk disease based on Gleason score and EAU risk group. PSA values <1 ng/mL indicate a very low 20-year risk, while at PSA 2 to 2.99 ng/mL risks are materially higher, with 4- to 5-fold risk for aggressive disease. Using risk-stratification and appropriate rescreening intervals will reduce screening intensity and overdetection. Using cumulative incidence of clinically significant PCa (csPCa) as the criterion, rescreening intervals could range from approximately 3 years for men with initial PSA 2 to 2.99 ng/mL, 6 years for men with PSA 1 to 1.99 ng/mL to 10 years for men with PSA <1 ng/mL.

Antidiabetic drugs, glycemic control and risk of benign prostatic hyperplasia.

BACKGROUND: Diabetes has been associated with an increased risk of benign prostatic hyperplasia (BPH). However, the role of antidiabetic drugs as a BPH risk factor is unclear. The objective of our study was to examine the risk of BPH by antidiabetic drug use and glycemic control in a large population-based cohort of Finnish men. METHODS: A total of 74,754 men in the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) free of BPH at baseline in 1996-1999 were linked to the national medication reimbursement database for information on physician-prescribed antidiabetic drug purchases. Information on recorded BPH procedures and diagnoses was obtained from the National Care Register for Health Care, and for a subgroup of 17,739 men, information on blood glucose levels (BGLs) from the Fimlab Laboratories database. Cox regression with antidiabetic drug use and BGL as time-dependent variables was used to analyze the risks for starting BPH medication, recorded BPH diagnosis, and undergoing BPH surgery. The analysis was adjusted for age, use of statins, antihypertensive medication, and nonsteroidal anti-inflammatory drugs. RESULTS: Of the subjects, 14,012 men (18.7%) used antidiabetic medication. Of the subgroup with fasting blood glucose data available, 7487 (42.2%) had diabetic level. The risks for BPH diagnosis (HR: 1.08, 95% CI: 1.03-1.13) and surgery (HR: 1.16, 95% CI: 1.09-1.24) were slightly elevated among antidiabetic drug users compared to nonusers. The association was strongest for insulin use. Similarly, risk of BPH surgery was increased in men with diabetic blood glucose compared to normoglycemic men. The risk association was attenuated by use of antidiabetic drugs. CONCLUSIONS: Diabetic BGL and antidiabetic medication use, especially insulin, are associated with an elevated risk of BPH surgery compared to nondiabetic men. These findings support the roles of insulin use and untreated hyperglycemia as possible BPH risk factors.

Testosterone replacement therapy is not associated with increased prostate cancer incidence, prostate cancer-specific, or cardiovascular disease-specific mortality in Finnish men.

BACKGROUND: Concerns have been expressed over the safety of testosterone replacement therapy (TRT) in men with late-onset hypogonadism (LOH). Previous studies have shown controversial results regarding the association of TRT with the risk of cardiovascular events or prostate cancer (PCa) incidence, aggressiveness, and mortality. This study explores the overall risk of PCa and risk by tumor grade and stage, as well as mortality from PCa and cardiovascular disease (CVD), among men treated with TRT compared to men without LOH and TRT use. MATERIALS AND METHODS: The study included 78,615 men of age 55-67 years at baseline from the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). Follow-up started at randomization and ended at death, emigration, or a common closing date January 1st, 2017. Cox proportional hazards regression model with time-dependent variables and adjustment for age, trial arm, use of other medications, and Charlson comorbidity index was used. Comprehensive information on TRT purchases during 1995-2015 was obtained from the Finnish National Prescription Database. PCa cases were identified from the Finnish Cancer Registry and causes of death obtained from Statistics Finland. RESULTS: Over the course of 18 years of follow-up, 2919 men were on TRT, and 285 PCa cases were diagnosed among them. TRT users did not exhibit a higher incidence or mortality rate of PCa compared to non-users. On the contrary, men using TRT had lower PCa mortality than non-users (HR = 0.52; 95% CI 0.3-0.91). Additionally, TRT users had slightly lower CVD and all-cause mortality compared to non-users (HR = 0.87; 95% CI 0.75-1.01 and HR = 0.93; 95% CI 0.87-1.0, respectively). No time- or dose-dependency of TRT use was evident in any of the analyses. CONCLUSION: Men using TRT were not associated to increased risk for PCa and did not experience increased PCa- or CVD-specific mortality compared to non-users. Further studies considering blood testosterone levels are warranted.

Anti-epileptic drugs and prostate cancer-specific mortality compared to non-users of anti-epileptic drugs in the Finnish Randomized Study of Screening for Prostate Cancer.

BACKGROUND: Drugs with histone deacetylase inhibitory (HDACi) properties have shown to decrease prostate cancer (PCa) cell growth in vitro. METHODS: A cohort of 9261 PCa cases from the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) was used to evaluate prostate cancer-specific mortality in men using anti-epileptic drugs (AEDs). A national subscription database was used to obtain information on medication use. Cox regression with AED use as a time-dependent variable was used to analyse prostate cancer mortality in men using AEDs compared to non-users, and in men using HDACi AEDs compared to users of other AEDs. The analysis was adjusted for age, screening trial arm, PCa risk group, primary treatment of PCa, Charlson co-morbidity score and concomitant use of other drugs. RESULTS: The use of AEDs, in general, was associated with an increased risk of PCa death. The use of HDACi AEDs was not significantly associated with decreased PCa mortality compared to use of other AEDs (HR 0.61, 95% CI 0.31-1.23). CONCLUSIONS: AED usage is associated with elevated PCa mortality compared to non-users, likely reflecting the differences between men with epilepsy and those without. No benefit was observed from HDACi drugs compared to other AEDs.

Population-based randomized trial of screening for clinically significant prostate cancer ProScreen: a pilot study.

OBJECTIVES: To evaluate the feasibility of a population-based screening trial using prostate-specific antigen (PSA), a kallikrein panel and multiparametric magnetic resonance imaging (MRI) aimed at minimizing overdiagnosis, while retaining mortality benefit. PATIENTS AND METHODS: Feasibility of the screening algorithm was evaluated in terms of participation, screening test results and cancer detection. A random sample of 400 men aged 65 years was identified from the population registry and invited for screening with three stepwise tests (PSA, kallikrein panel and MRI). Men with PSA levels ≥3 ng/mL were further tested with the kallikrein panel, and those with positive findings (risk >7.5%) were referred for prostate MRI. Men with positive MRI (Prostate Imaging Reporting and Data System [PI-RADS] score 3-5) had targeted biopsies only. Men with negative MRI, but PSA density ≥0.15 underwent systematic biopsies. RESULTS: Of the 399 men invited, 158 (40%) participated and 27 had PSA levels ≥3 ng/mL (7% of the invited and 17% of the participants). Of these, 22 had a positive kallikrein panel (6% of the invited and 81% of the PSA-positive men). Finally, 10 men (3% of the invited and 45% of 4Kscore [kallikrein panel]-positive) had a suspicious MRI finding (PI-RADS score ≥3) and five were diagnosed with a clinically significant prostate cancer (Gleason Grade Group [GG] ≥2) at fusion biopsy (3% of the participants), with two GG 1 cases (1%). Additional testing (kallikrein panel and MRI) after PSA reduced biopsies by 56%. CONCLUSION: The findings constitute proof of principle for our screening protocol, as we achieved a substantial detection rate for clinically significant cancer with few clinically insignificant cases. Participation, however, was suboptimal.

Antiepileptic drugs and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer.

Antiepileptic drugs (AEDs) with histone deacetylase (HDAC) inhibitor properties decrease prostate cancer (PCa) cell proliferation in vitro. A population-based cohort of 78 615 men was used to evaluate the risk of PCa among users of AEDs. Study population was linked to the Finnish national prescription database to obtain information on individual medication reimbursements in 1996 to 2015. Cox regression with antiepileptic medication use as a time-dependent variable was used to analyze PCa risk overall, and low, medium and high-risk PCa separately. The analysis was adjusted for age, screening trial arm, and other drugs in use, including statins, antidiabetic drugs, antihypertensive drugs, aspirin, and nonsteroidal anti-inflammatory drugs. Compared to the nonusers of AEDs, overall PCa risk was decreased among AED users (hazard ratio [HR] = 0.86, 95% confidence interval [CI] = 0.76-0.96). A similar PCa risk decrease was observed among users of HDACi AEDs (HR = 0.87, 95% CI = 0.76-1.01), but no risk difference was found when comparing HDACi AED users to users of other AEDs (HR = 0.98, 95% CI = 0.76-1.27). Our study showed a decrease in overall PCa risk among men using AEDs compared to nonusers. The risk associations were similar for HDAC inhibitors as for AEDs in general.

Number of screening rounds attended and incidence of high-risk prostate cancer in the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC).

BACKGROUND: The European Randomized Study of Screening for Prostate Cancer has shown a 20% reduction in prostate cancer (PC) mortality by prostate-specific antigen-based screening. In addition, screening has been shown to reduce the risk of advanced PC. The objective of the current study was to analyze the impact of screening participation on the incidence of PC by risk group. METHODS: The participants in the screening arm of the Finnish trial (31,867 men) were classified according to screening attendance in a time-dependent fashion. Initially, all men in the screening arm were regarded as nonattenders until the first screening attendance; they then remained in the once-screened group until the second screen and similarly for the possible third round. The control arm formed the reference group. Follow-up started at randomization and ended at the time of diagnosis of PC, emigration, or the end of 2015. PC cases were divided into risk groups according to European Association of Urology definitions. RESULTS: The incidence of low-risk PC increased with the number of screens, whereas no clear relation with participation was noted in the intermediate-risk and high-risk cases. For patients with advanced PC, attending screening at least twice was associated with a lower risk. CONCLUSIONS: Screening reduces the risk of advanced PC after only 2 screening cycles. A single screen demonstrated no benefit in terms of PC incidence. Repeated screening is necessary to achieve screening advantages.

Radical Prostatectomy or Watchful Waiting in Prostate Cancer - 29-Year Follow-up.

BACKGROUND: Radical prostatectomy reduces mortality among men with clinically detected localized prostate cancer, but evidence from randomized trials with long-term follow-up is sparse. METHODS: We randomly assigned 695 men with localized prostate cancer to watchful waiting or radical prostatectomy from October 1989 through February 1999 and collected follow-up data through 2017. Cumulative incidence and relative risks with 95% confidence intervals for death from any cause, death from prostate cancer, and metastasis were estimated in intention-to-treat and per-protocol analyses, and numbers of years of life gained were estimated. We evaluated the prognostic value of histopathological measures with a Cox proportional-hazards model. RESULTS: By December 31, 2017, a total of 261 of the 347 men in the radical-prostatectomy group and 292 of the 348 men in the watchful-waiting group had died; 71 deaths in the radical-prostatectomy group and 110 in the watchful-waiting group were due to prostate cancer (relative risk, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001; absolute difference in risk, 11.7 percentage points; 95% CI, 5.2 to 18.2). The number needed to treat to avert one death from any cause was 8.4. At 23 years, a mean of 2.9 extra years of life were gained with radical prostatectomy. Among the men who underwent radical prostatectomy, extracapsular extension was associated with a risk of death from prostate cancer that was 5 times as high as that among men without extracapsular extension, and a Gleason score higher than 7 was associated with a risk that was 10 times as high as that with a score of 6 or lower (scores range from 2 to 10, with higher scores indicating more aggressive cancer). CONCLUSIONS: Men with clinically detected, localized prostate cancer and a long life expectancy benefited from radical prostatectomy, with a mean of 2.9 years of life gained. A high Gleason score and the presence of extracapsular extension in the radical prostatectomy specimens were highly predictive of death from prostate cancer. (Funded by the Swedish Cancer Society and others.).

Estimating the rate of overdiagnosis with prostate cancer screening: evidence from the Finnish component of the European Randomized Study of Screening for Prostate Cancer.

PURPOSE: Screening for prostate cancer may have limited impact on decreasing prostate cancer-related mortality. A major disadvantage is overdiagnosis, whereby lesions are identified that would not have become evident during the man's lifetime if screening had not taken place. The present study aims to estimate the rate of overdiagnosis using Finnish data from the European randomized trial of prostate cancer screening. METHODS: We used data from 80,149 men randomized to a screening or a control group, distinguishing four birth cohorts. We used the "catch-up method" to identify when the difference in the cumulative incidence of prostate cancer between the screening and control groups had stabilized, implying that the screening has no further effect. We define the overdiagnosis rate to be the relative excess cumulative incidence in the screened group at that point. As an independent method, we also examined the diagnosis rates of T1c tumors as an indicator of early tumors detected by PSA. RESULTS: The estimates of overdiagnosis rates from the catch-up method using the full period of available follow-up ranged between cohorts from 2.3% to 15.4%, and the T1c analysis gave very similar results. CONCLUSION: Some overdiagnosis has occurred, but there is uncertainty about its extent. A long follow-up is required to demonstrate the full impact of screening. We evaluated the overdiagnosis rates at a population level, associated with being offered screening, taking account of contamination (screening among the controls). The overall evaluation of screening should incorporate mortality benefit, cost-effectiveness, and quality of life.

Health-Related Quality of Life and Survival in Prostate Cancer Patients in a Real-World Setting.

OBJECTIVE: To analyze the health-related quality of life (HRQoL) and survival of real-world prostate cancer (PC) patients and to calculate quality-adjusted life-years (QALYs) experienced under different treatment strategies. MATERIALS AND METHODS: PC patients undergoing active surveillance (n = 226), radiation treatment (n = 280), surgery (n = 299), or hormonal treatment (n = 62) responded to the generic 15-dimensional (15D) HRQoL questionnaire at the time of the diagnosis and were followed up 3, 6, 12, and 24 months later. QALYs experienced during the follow-up were calculated for each treatment group, and variables associated with survival were analyzed using Cox proportional hazards models. RESULTS: HRQoL was stable during the first 2 years after diagnosis in all other treatment groups, except in patients treated with hormonal therapy. The overall survival within 6.5-year follow-up time was 84.4%. The number of QALYs experienced during the 2-year follow-up was similar in patients in active surveillance (1.790), surgery (1.784), and radiation groups (1.767), but significantly lower in the hormonal therapy group (1.665). CONCLUSIONS: Patients receiving hormonal treatment had significantly impaired HRQoL and survival compared with other treatments. Although the number of QALYs experienced was similar in the 3 other treatment lines, there were marked differences between treatment lines on some 15D dimensions.

Bias-corrected estimates of effects of PSA screening decisions on the risk of prostate cancer diagnosis and death: Analysis of the Finnish randomized study of screening for prostate cancer.

More information is needed about effects of prostate-specific antigen (PSA) screening for informed decision making. The objective of our study is to evaluate the effects of an implemented screening decision on the risk of prostate cancer (PC) diagnosis and PC death. In a randomized trial, 31,867 Finnish men aged 55-67 years were allocated to the screening arm and 48,282 to the control arm during 1996-1999. Two to three screening rounds were offered to the screening arm with a PSA cut-off of 4.0 ng/ml. A counterfactual exclusion method was used to adjust for the effects of screening noncompliance and PSA contamination on risk of PC death and PC incidence by prognostic group at 15 years of follow up. After correcting for noncompliance and contamination, PSA screening led to 32.4 (95% CI 26.4, 38.6) more PC diagnoses per 1,000 men after 15 years and 1.4 (95% CI 0.0, 2.8) fewer PC deaths compared to the control arm. The corresponding results of an intention-to-screen analysis were 16.5 (95% CI 12.3, 20.7) and 0.8 (95% CI 0.5, 2.0), respectively. These results can be used for patient counseling in informed decision making about PC screening. A limitation of the study was the lack of comprehensive data on contamination.

Clonal heterogeneity influences drug responsiveness in renal cancer assessed by ex vivo drug testing of multiple patient-derived cancer cells.

Renal cell cancer (RCC) has become a prototype example of the extensive intratumor heterogeneity and clonal evolution of human cancers. However, there is little direct evidence on how the genetic heterogeneity impacts on drug response profiles of the cancer cells. Our goal was to determine how genomic clonal evolution impacts drug responses. Finding from our study could help to define the challenge that clonal evolution poses on cancer therapy. We established multiple patient-derived cells (PDCs) from different tumor regions of four RCC patients, verified their clonal relationship to each other and to the uncultured tumor tissue by genome sequencing. Furthermore, comprehensive drug-sensitivity testing with 460 oncological drugs was performed on all PDC clones. The PDCs retained many cancer-specific copy number alterations and mutations in driver genes such as VHL, PBRM1, PIK3C2A, KMD5C and TSC2 genes. The drug testing highlighted vulnerability in the PDCs toward approved RCC drugs, such as the mTOR-inhibitor temsirolimus, but also novel sensitivities were uncovered. The individual PDC clones from different tumor regions in a patient showed distinct drug-response profiles, suggesting that genomic heterogeneity contributes to the variability in drug responses. Studies of multiple PDCs from a patient with cancer are informative for elucidating cancer heterogeneity and for the determination on how the genomic evolution is manifested in cancer drug responsiveness. This approach could facilitate tailoring of drugs and drug combinations to individual patients.

The association of financial difficulties and out-of-pocket payments with health-related quality of life among breast, prostate and colorectal cancer patients.

Objectives: Financial difficulties experienced by cancer patients may affect their health-related quality of life (HRQoL). This study assessed the direct economic burden that out-of-pocket (OOP) payments cause and explored how they and financial difficulties are associated with HRQoL. Methods: This is a cross-sectional registry and survey study of 1978 cancer patients having either prostate (630), breast (840) or colorectal cancer (508) treated in Finland. The patients were divided into five groups according to the stage of their disease: primary treatment, rehabilitation, remission, metastatic disease and palliative care. The cost data and OOP payments were retrieved from primary and secondary healthcare registries, the Social Insurance Institution of Finland, and a patient questionnaire. HRQoL was measured by 15D, EQ-5D-3L and by EORTC-QLQ-C30. Financial difficulties were evaluated based on patients' self-assessment in the EORTC-QLQ-C30 four-level question about financial difficulties. A path analysis was used to explore the relationship between clinical and demographic factors, HRQoL, OOP payments and financial difficulties. Results: The highest OOP payments were caused by outpatient medication. Total costs and OOP payments were highest in the palliative care group in which the OOP payments consisted mostly of outpatient medication and public sector specialist care. Private sector health care was an important item of OOP payments in the early stages of cancer. Financial difficulties increased together with OOP payments. HRQoL deteriorated the more a person had financial difficulties. In the path analysis, financial difficulties had a major negative direct and total effect on the HRQoL. Factors that attenuated financial difficulties were age, cohabiting and higher education and factors that increased them were OOP payments, total costs of healthcare use, and unemployment. Conclusions: High OOP payments are related to financial difficulties, which have a negative effect on HRQoL. Outpatient medication was a major driver of OOP payments. Among palliative patients, the economic burden was highest and associated with impaired HRQoL.

Evolving Clinical Picture of Renal Cell Carcinoma: A Population-Based Study from Helsinki.

BACKGROUND: There is a lack of detailed population-based data for renal cell carcinoma (RCC). OBJECTIVES: The study aimed to examine the contemporary changes in the clinical picture and treatment of RCC. METHODS: A total of 1,719 consecutive patients living in the Helsinki metropolitan area with a solid or cystic renal mass (Bosniak 3-4) ≥10 mm were identified. Data from medical records was evaluated for clinical characteristics and treatments in the periods I (2006-2008), II (2009-2011), III (2012-2014), and IV (2015-2016). RESULTS: The proportions of patients with comorbidities (Charlson index ≥2) and frailty (Eastern Co-operative Oncology Group classification ≥2) increased significantly during the study period. The percentage of clinical stage I patients, cystic tumors and use of needle biopsies increased significantly. Use of observation increased from 9% (I) to 32% (IV; p < 0.001). First-line oncological treatments within 6 months were given to 47% of 262 patients with metastases and -cytoreductive nephrectomy (CN) was delivered to 54% of those patients. CONCLUSIONS: The size of renal tumors continued to decrease, while the percentage of patients with significant comorbidity or frailty increased. Active surveillance emerged as the initial strategy. Tyrosine kinase inhibitors with CN remained the primary option in patients with metastatic RCC.

Fasting blood glucose, glycaemic control and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer.

BACKGROUND: Diabetic men have lowered overall risk of prostate cancer (PCa), but the role of hyperglycaemia is unclear. In this cohort study, we estimated PCa risk among men with diabetic fasting blood glucose level. METHODS: Participants of the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) were linked to laboratory database for information on glucose measurements since 1978. The data were available for 17,860 men. Based on the average yearly level, the men were categorised as normoglycaemic, prediabetic, or diabetic. Median follow-up was 14.7 years. Multivariable-adjusted Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for prostate cancer overall and separately by Gleason grade and metastatic stage. RESULTS: In total 1,663 PCa cases were diagnosed. Compared to normoglycaemic men, those men with diabetic blood glucose level had increased risk of PCa (HR 1.52; 95% CI 1.31-1.75). The risk increase was observed for all tumour grades, and persisted for a decade afterwards. Antidiabetic drug use removed the risk association. Limitations include absence of information on lifestyle factors and limited information on BMI. CONCLUSIONS: Untreated diabetic fasting blood glucose level may be a prostate cancer risk factor.

Health-related quality of life in different states of breast cancer - comparing different instruments.

BACKGROUND: The prognosis of breast cancer has improved significantly during the last few decades increasing the interest in health-related quality of life (HRQoL). The aim of this study was to compare the HRQoL scores produced by different instruments and to shed light on their validity in various states of breast cancer by studying the association of cancer-related symptoms with HRQoL. MATERIAL AND METHODS: An observational, cross-sectional study of breast cancer patients treated in the Helsinki and Uusimaa Hospital District from September 2009 to April 2011. A total of 840 patients completed three HRQoL questionnaires: the EQ-5D-3L (including VAS), 15D and EORTC QLQ-30 and a questionnaire concerning sociodemographic factors. Patients were divided into five mutually exclusive groups: primary treatment (n = 118), recovery (6-18 months from diagnosis) (n = 150), remission (>18 months) (n = 382), metastatic disease (n = 176) and palliative care (n = 14). The association of HRQoL with sociodemographic and clinical factors and cancer-related symptoms, screened by the EORTC QLQ-30, was studied by multivariate modeling using stepwise linear regression analysis. RESULTS: HRQoL scores were the best at the time closest to diagnosis and deteriorated with disease progression. The EQ-5D had a pronounced ceiling effect with 40.8% of the respondents scoring 1 (perfect health) compared to 6% for the 15D and 5.6% for VAS. In regression analyses, pain, fatigue and financial difficulties were the most important predictors of lower HRQoL. The 15D showed better discriminatory power and content validity. The EORTC QLQ-C30 functioning deteriorated in advanced states of the disease with physical, social and role functioning being the most affected. Insomnia, fatigue and pain were the most commonly reported symptoms in all groups. CONCLUSIONS: Different HRQoL instruments produce notably different HRQoL scores. The EQ-5D has a pronounced ceiling effect. Pain and fatigue are the most common symptoms associated with poor HRQoL in all disease states.