Relationship Between Baseline Prostate-specific Antigen on Cancer Detection and Prostate Cancer Death: Long-term Follow-up from the European Randomized Study of Screening for Prostate Cancer.

BACKGROUND: The European Association of Urology guidelines recommend a risk-based strategy for prostate cancer screening based on the first prostate-specific antigen (PSA) level and age. OBJECTIVE: To analyze the impact of the first PSA level on prostate cancer (PCa) detection and PCa-specific mortality (PCSM) in a population-based screening trial (repeat screening every 2-4 yr). DESIGN, SETTING, AND PARTICIPANTS: We evaluated 25589 men aged 55-59 yr, 16898 men aged 60-64 yr, and 12936 men aged 65-69 yr who attended at least one screening visit in the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial (screening arm: repeat PSA testing every 2-4 yr and biopsy in cases with elevated PSA; control arm: no active screening offered) during 16-yr follow-up (FU). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We assessed the actuarial probability for any PCa and for clinically significant (cs)PCa (Gleason ≥7). Cox proportional-hazards regression was performed to assess whether the association between baseline PSA and PCSM was comparable for all age groups. A Lorenz curve was computed to assess the association between baseline PSA and PCSM for men aged 60-61 yr. RESULTS AND LIMITATIONS: The overall actuarial probability at 16 yr ranged from 12% to 16% for any PCa and from 3.7% to 5.7% for csPCa across the age groups. The actuarial probability of csPCa at 16 yr ranged from 1.2-1.5% for men with PSA <1.0 ng/ml to 13.3-13.8% for men with PSA ≥3.0 ng/ml. The association between baseline PSA and PCSM differed marginally among the three age groups. A Lorenz curve for men aged 60-61 yr showed that 92% of lethal PCa cases occurred among those with PSA above the median (1.21 ng/ml). In addition, for men initially screened at age 60-61 yr with baseline PSA <2 ng/ml, further continuation of screening is unlikely to be beneficial after the age of 68-70 yr if PSA is still <2 ng/ml. No case of PCSM emerged in the subsequent 8 yr (up to age 76-78 yr). A limitation is that these results may not be generalizable to an opportunistic screening setting or to contemporary clinical practice. CONCLUSIONS: In all age groups, baseline PSA can guide decisions on the repeat screening interval. Baseline PSA of <1.0 ng/ml for men aged 55-69 yr is a strong indicator to delay or stop further screening. PATIENT SUMMARY: In prostate cancer screening, the patient's baseline PSA (prostate-specific antigen) level can be used to guide decisions on when to repeat screening. The PSA test when used according to current knowledge is valuable in helping to reduce the burden of prostate cancer.

A 16-yr Follow-up of the European Randomized study of Screening for Prostate Cancer.

BACKGROUND: The European Randomized study of Screening for Prostate Cancer (ERSPC) has previously demonstrated that prostate-specific antigen (PSA) screening decreases prostate cancer (PCa) mortality. OBJECTIVE: To determine whether PSA screening decreases PCa mortality for up to 16yr and to assess results following adjustment for nonparticipation and the number of screening rounds attended. DESIGN, SETTING, AND PARTICIPANTS: This multicentre population-based randomised screening trial was conducted in eight European countries. Report includes 182160 men, followed up until 2014 (maximum of 16yr), with a predefined core age group of 162389 men (55-69yr), selected from population registry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcome was PCa mortality, also assessed with adjustment for nonparticipation and the number of screening rounds attended. RESULTS AND LIMITATIONS: The rate ratio of PCa mortality was 0.80 (95% confidence interval [CI] 0.72-0.89, p<0.001) at 16yr. The difference in absolute PCa mortality increased from 0.14% at 13yr to 0.18% at 16yr. The number of men needed to be invited for screening to prevent one PCa death was 570 at 16yr compared with 742 at 13yr. The number needed to diagnose was reduced to 18 from 26 at 13yr. Men with PCa detected during the first round had a higher prevalence of PSA >20ng/ml (9.9% compared with 4.1% in the second round, p<0.001) and higher PCa mortality (hazard ratio=1.86, p<0.001) than those detected subsequently. CONCLUSIONS: Findings corroborate earlier results that PSA screening significantly reduces PCa mortality, showing larger absolute benefit with longer follow-up and a reduction in excess incidence. Repeated screening may be important to reduce PCa mortality on a population level. PATIENT SUMMARY: In this report, we looked at the outcomes from prostate cancer in a large European population. We found that repeated screening reduces the risk of dying from prostate cancer.

Results of Prostate Cancer Screening in a Unique Cohort at 19yr of Follow-up.

We assessed the effect of screening in the European Randomized study of Screening for Prostate Cancer (ERSPC) Rotterdam pilot 1 study cohort with men randomized in 1991-1992. A total of 1134 men were randomized on a 1:1 basis to a screening (S) and control (C) arm after prostate-specific antigen (PSA) testing (PSA ≥10.0ng/ml was excluded from randomization). Further PSA testing was offered to all men in the S-arm with 4-yr intervals starting at age 55yr and screened up to the age of 74yr. Overall, a PSA level of ≥3.0ng/ml triggered biopsy. At time of analysis, 63% of men had died. Overall relative risk of metastatic (M+) disease and prostate cancer (PCa) death was 0.46 (95% confidence interval [CI]: 0.19-1.11) and 0.48 (95% CI: 0.17-1.36), respectively, in favor of screening. This ERSPC Rotterdam pilot 1 study cohort, screened in a period without noteworthy contamination, shows that PSA-based screening could result in considerable reductions of M+ disease and mortality which if confirmed in larger datasets should trigger further discussion on pros/cons of PCa screening. PATIENT SUMMARY: In a cohort with 19yr of follow-up, we found indications for a more substantial reduction in metastatic disease and cancer-specific mortality in favor of prostate cancer screening than previously reported. If confirmed in larger cohorts, these findings should be considered in the ongoing discussion on harms and benefits of prostate cancer screening.

Characteristics of Prostate Cancer Found at Fifth Screening in the European Randomized Study of Screening for Prostate Cancer Rotterdam: Can We Selectively Detect High-grade Prostate Cancer with Upfront Multivariable Risk Stratification and Magnetic Resonance Imaging?

BACKGROUND: The harm of screening (unnecessary biopsies and overdiagnosis) generally outweighs the benefit of reducing prostate cancer (PCa) mortality in men aged ≥70 yr. Patient selection for biopsy using risk stratification and magnetic resonance imaging (MRI) may improve this benefit-to-harm ratio. OBJECTIVE: To assess the potential of a risk-based strategy including MRI to selectively identify men aged ≥70 yr with high-grade PCa. DESIGN, SETTING, AND PARTICIPANTS: Three hundred and thirty-seven men with prostate-specific antigen ≥3.0 ng/ml at a fifth screening (71-75 yr) in the European Randomized study of Screening for Prostate Cancer Rotterdam were biopsied. One hundred and seventy-nine men received six-core transrectal ultrasound biopsy (TRUS-Bx), while 158 men received MRI, 12-core TRUS-Bx, and fusion TBx in case of Prostate Imaging Reporting and Data System ≥3 lesions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the overall, low-grade (Gleason Score 3+3) and high-grade (Gleason Score ≥ 3+4) PCa rate. Secondary outcome was the low- and high-grade PCa rate detected by six-core TRUS-Bx, 12-core TRUS-Bx, and MRI ± TBx. Tertiary outcome was the reduction of biopsies and low-grade PCa detection by upfront risk stratification with the Rotterdam Prostate Cancer Risk Calculator 4. RESULTS AND LIMITATIONS: Fifty-five percent of men were previously biopsied. The overall, low-grade, and high-grade PCa rates in biopsy naïve men were 48%, 27%, and 22%, respectively. In previously biopsied men these PCa rates were 25%, 20%, and 5%. Sextant TRUS-Bx, 12-core TRUS-Bx, and MRI ± TBx had a similar high-grade PCa rate (11%, 12%, and 11%) but a significantly different low-grade PCa rate (17%, 28%, and 7%). Rotterdam Prostate Cancer Risk Calculator 4-based stratification combined with 12-core TRUS-Bx ± MRI-TBx would have avoided 65% of biopsies and 68% of low-grade PCa while detecting an equal percentage of high-grade PCa (83%) compared with a TRUS-Bx all men approach (79%). CONCLUSIONS: After four repeated screens and ≥1 previous biopsies in half of men, a significant proportion of men aged ≥70 yr still harbor high-grade PCa. Upfront risk stratification and the combination of MRI and TRUS-Bx would have avoided two-thirds of biopsies and low-grade PCa diagnoses in our cohort, while maintaining the high-grade PCa detection of a TRUS-Bx all men approach. Further studies are needed to verify these results. PATIENT SUMMARY: Prostate cancer screening reduces mortality but is accompanied by unnecessary biopsies and overdiagnosis of nonaggressive tumors, especially in repeatedly screened elderly men. To tackle these drawbacks screening should consist of an upfront risk-assessment followed by magnetic resonance imaging and transrectal ultrasound-guided biopsy.

Testosterone treatment is not associated with increased risk of prostate cancer or worsening of lower urinary tract symptoms: prostate health outcomes in the Registry of Hypogonadism in Men.

OBJECTIVES: To evaluate the effects of testosterone-replacement therapy (TRT) on prostate health indicators in hypogonadal men, including rates of prostate cancer diagnoses, changes in prostate-specific antigen (PSA) levels and lower urinary tract symptoms (LUTS) over time. PATIENTS AND METHODS: The Registry of Hypogonadism in Men (RHYME) is a multi-national patient registry of treated and untreated, newly-diagnosed hypogonadal men (n = 999). Follow-up assessments were performed at 3-6, 12, 24, and 36 months. Baseline and follow-up data collection included medical history, physical examination, blood sampling, and patient questionnaires. Prostate biopsies underwent blinded independent adjudication for the presence and severity of prostate cancer; PSA and testosterone levels were measured via local and central laboratory assays; and LUTS severity was assessed via the International Prostate Symptom Score (IPSS). Incidence rates per 100 000 person-years were calculated. Longitudinal mixed models were used to assess effects of testosterone on PSA levels and IPSS. RESULTS: Of the 999 men with clinically diagnosed hypogonadism (HG), 750 (75%) initiated TRT, contributing 23 900 person-months of exposure. The mean testosterone levels increased from 8.3 to 15.4 nmol/L in treated men, compared to only a slight increase from 9.4 to 11.3 nmol/L in untreated men. In all, 55 biopsies were performed for suspected prostate cancer, and 12 non-cancer related biopsies were performed for other reasons. Overall, the proportion of positive biopsies was nearly identical in men on TRT (37.5%) compared to those not on TRT (37.0%) over the course of the study. There were no differences in PSA levels, total IPSS, or the IPSS obstructive sub-scale score by TRT status. Lower IPSS irritative sub-scale scores were reported in treated compared to untreated men. CONCLUSIONS: Results support prostate safety of TRT in newly diagnosed men with HG.

What explains the differences between centres in the European screening trial? A simulation study.

BACKGROUND: The European Randomised study of Screening for Prostate Cancer (ERSPC) is a multicentre, randomised screening trial on men aged 55-69 years at baseline without known prostate cancer (PrCa) at randomisation to an intervention arm invited to screening or to a control arm. The ERSPC has shown a significant 21% reduction in PrCa mortality at 13 years of follow-up. The effect of screening appears to vary across centres, for which several explanations are possible. We set to assess if the apparent differences in PrCa mortality reduction between the centres can be explained by differences in screening protocols. METHODS: We examined the centre differences by developing a simulation model and estimated how alternative screening protocols would have affected PrCa mortality. RESULTS: Our results showed outcomes similar to those observed, when the results by centres were reproduced by simulating the screening regimens with PSA threshold of 3 versus 4ng/ml, or screening interval of two versus four years. The findings suggest that the differences are only marginally attributable to the different screening protocols. CONCLUSION: The small screening impact in Finland was not explained by the differences in the screening protocols. A possible reason for it was the contamination of and the unexpectedly low PrCa mortality in the Finnish control arm.

Absolute Effect of Prostate Cancer Screening: Balance of Benefits and Harms by Center within the European Randomized Study of Prostate Cancer Screening.

PURPOSE: The balance of benefits and harms in prostate cancer screening has not been sufficiently characterized. We related indicators of mortality reduction and overdetection by center within the European Randomized Study of Prostate Cancer Screening (ERSPC). EXPERIMENTAL DESIGN: We analyzed the absolute mortality reduction expressed as number needed to invite (NNI = 1/absolute risk reduction; indicating how many men had to be randomized to screening arm to avert a prostate cancer death) for screening and the absolute excess of prostate cancer detection as number needed for overdetection (NNO = 1/absolute excess incidence; indicating the number of men invited per additional prostate cancer case), and compared their relationship across the seven ERSPC centers. RESULTS: Both absolute mortality reduction (NNI) and absolute overdetection (NNO) varied widely between the centers: NNI, 200-7,000 and NNO, 16-69. Extent of overdiagnosis and mortality reduction was closely associated [correlation coefficient, r = 0.76; weighted linear regression coefficient, ß = 33; 95% confidence interval (CI), 5-62; R(2) = 0.72]. For an averted prostate cancer death at 13 years of follow-up, 12 to 36 excess cases had to be detected in various centers. CONCLUSIONS: The differences between the ERSPC centers likely reflect variations in prostate cancer incidence and mortality, as well as in screening protocol and performance. The strong interrelation between the benefits and harms suggests that efforts to maximize the mortality effect are bound to increase overdiagnosis and might be improved by focusing on high-risk populations. The optimal balance between screening intensity and risk of overdiagnosis remains unclear.

[Early detection of prostate cancer--recommendations after 13 years of follow-up in the European randomised study]. / Vroege opsporing van prostaatkanker--aanbevelingen na 13 jaar follow-up in de Europese gerandomiseerde studie.

The recent publication of updated results from the European randomised study of screening for prostate cancer (ERSPC) with a median 13-year follow-up confirms significant relative and absolute reductions in prostate cancer mortality. In spite of existing guidelines, Dutch men and professionals remain uncertain about the use of PSA testing. The data now available will be helpful in reaching informed decisions. In men aged 55-69 years, the relative mortality reduction remained similar at 21%; the absolute reduction increased from 0.9 to 1.28 fewer deaths/1000 men screened. This translates into much improved figures needing to be invited for screening and diagnosed, at 781 and 27 (1410 and 48 in 2009). As expected, overall mortality does not differ between the arms of the study. The main downside of PSA-driven screening remains the diagnosis of non-life-threatening cancers (overdiagnosis) by screening, at a frequency of about 40%, which can be reduced by use of the Prostate Cancer Risk Calculator. Current data support the present guideline which recommends informed decision-making, taking into account the advantages and potential damage caused by PSA testing.

Metastatic Prostate Cancer Incidence and Prostate-specific Antigen Testing: New Insights from the European Randomized Study of Screening for Prostate Cancer.

BACKGROUND: The European Randomized Study of Screening for Prostate Cancer (ERSPC) has shown a 21% reduction in prostate cancer (PCa) mortality and a 1.6-fold increase in PCa incidence with prostate-specific antigen (PSA)-based screening (at 13 yr of follow-up). We evaluated PCa incidence by risk category at diagnosis across the study arms to assess the potential impact on PCa mortality. DESIGN, SETTING, AND PARTICIPANTS: Information on arm, centre, T and M stage, Gleason score, serum PSA at diagnosis, age at randomisation, follow-up time, and vital status were extracted from the ERSPC database. Four risk categories at diagnosis were defined: 1, low; 2, intermediate; 3, high; 4, metastatic disease. PSA (≤100 or >100 ng/ml) was used as the indicator of metastasis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Incidence rate ratios (IRRs) for screening versus control arm by risk category at diagnosis and follow-up time were calculated using Poisson regression analysis for seven centres. Follow-up was truncated at 13 yr. Missing data were imputed using chained equations. The analyses were carried out on an intention-to-treat basis. RESULTS AND LIMITATIONS: In the screening arm, 7408 PCa cases were diagnosed and 6107 in the control arm. The proportion of missing stage, Gleason score, or PSA value was comparable in the two arms (8% vs 10%), but differed among centres. The IRRs were elevated in the screening arm for the low-risk (IRR: 2.14; 95% CI, 2.03-2.25) and intermediate-risk (IRR: 1.24; 95% CI, 1.16-1.34) categories at diagnosis, equal to unity for the high-risk category at diagnosis (IRR: 1.00; 95% CI, 0.89-1.13), and reduced for metastatic disease at diagnosis (IRR: 0.60; 95% CI, 0.52-0.70). The IRR of metastatic disease had temporal pattern similar to mortality, shifted forwards an average of almost 3 yr, although the mortality reduction was smaller. CONCLUSIONS: The results confirm a reduction in metastatic disease at diagnosis in the screening arm, preceding mortality reduction by almost 3 yr. PATIENT SUMMARY: The findings of this study indicate that the decrease in metastatic disease at diagnosis is the major determinant of the prostate cancer mortality reduction in the European Randomized study of Screening for Prostate Cancer.

Do Treatment Differences between Arms Affect the Main Outcome of ERSPC Rotterdam?

PURPOSE: We assessed differences in treatment between the screening and control arms of ERSPC Rotterdam and studied whether possible treatment differences could explain the positive study outcome. MATERIALS AND METHODS: In ERSPC Rotterdam men 55 to 74 years old were randomized to a screening arm of 21,210 and a control arm of 21,166. Treatment after diagnosis was at the discretion of the care provider chosen by the patient. Initial treatment was compared in 4 risk groups. The relation between prostate cancer incidence and prostate cancer mortality was assessed by risk group by correlating the incidence RR and the mortality RR. A direct relation would have supported a stage shift as the main cause of changes in prostate cancer mortality. RESULTS: Initial treatment differed between the arms in the low, intermediate and high risk groups but not in the metastatic group. The RRs of prostate cancer incidence and mortality per risk group were related 1:1 (regression line slope 1.00, 95% CI 0.30-1.74). Of changes in prostate cancer mortality 94% could be explained by changes in prostate cancer incidence. This made treatment differences unlikely as the reason for the observed decrease in prostate cancer mortality. CONCLUSIONS: Differences in treatment between the ERSPC Rotterdam screening and control arms were unlikely to explain the differences in prostate cancer mortality. Results are instead consistent with a decrease in prostate cancer mortality as the result of a favorable stage through screening.

Differences in Treatment and Outcome After Treatment with Curative Intent in the Screening and Control Arms of the ERSPC Rotterdam.

UNLABELLED: Screening for prostate cancer (PCa) results in a favorable stage shift. However, even if screening did not result in a clinically apparent lower stage or grade, it might still lead to less disease recurrence after treatment with curative intent (radical prostatectomy [RP] and radiation therapy [RT]) because the tumor had less time to develop outside the prostate. The outcome after treatment could also differ because of variations in treatment quality (eg, radiation dosage/adjuvant hormonal therapy). To test these hypotheses, we compared differences in the treatment quality of the screening and control arms of the European Randomized Study of Screening for Prostate Cancer (ERSPC) Rotterdam and disease-free survival (DFS) after curative treatment in PCa patients with similar stage and grade. A total of 2595 men were initially treated with RP or RT. In the control arm, RT was more often combined with hormonal therapy; treatment dosage was often ≥69Gy. This most likely resulted from changes over time in treatment that coincided with the later detection in the control arm. DFS was higher in the screening arm in all risk groups. After correction for lead time, these differences were minimal, however. We concluded that treatment quality differed between the screening and control arms of the ERSPC Rotterdam. RT quality was especially superior in the control arm with higher dosages and more often RT in combination with hormonal therapy. Despite these differences favoring the control arm, DFS differences were minimal. PATIENT SUMMARY: We looked at differences in prostate cancer (PCa) treatment and outcome after PCa treatment in men diagnosed after screening and men diagnosed after normal clinical practice. Treatment differed with superior treatment given to men diagnosed in normal clinical practice. We propose a likely explanation for this apparently counterintuitive finding (progressive insight combined with, on average, a later detection of tumors in unscreened men). Although unscreened men received better treatment, this advantage seemed to be outweighed by the advantage associated with the earlier detection, on average, of the tumor in screened men. TRIAL REGISTRATION: ISRCTN49127736.

A longitudinal study on the impact of active surveillance for prostate cancer on anxiety and distress levels.

OBJECTIVE: Patients with potentially indolent prostate cancer (PC) can be managed with active surveillance (AS). Our objective was to analyse how anxiety and distress develop in men with untreated PC and whether highly anxious men quit AS. METHODS: One hundred and fifty Dutch patients who opted for AS in the Prostate cancer Research International: Active Surveillance Study were invited to participate in an additional prospective, longitudinal quality of life (QoL) study within 6 months after diagnosis. Participants completed questionnaires with validated measures on anxiety and distress at inclusion (t = 0), 9 (t = 9) and 18 (t = 18) months after diagnosis. We assessed changes in scores on depression (Center for Epidemiologic Studies Depression (CES-D) scale), generic anxiety (State-Trait Anxiety Inventory (STAI-6)), PC-specific anxiety (Memorial Anxiety Scale for Prostate Cancer (MAX-PC)) and decisional conflict (Decisional Conflict Scale (DCS)) about patients' treatment choice between t = 0, t = 9 and t = 18 using repeated measures analysis. RESULTS: Response rates for patients still on AS at t = 0, t = 9 and t = 18 assessments were 86%, 90% and 96%, respectively. Nine patients (7%, 9/129) between t = 0 and t = 9 and 33 of 108 patients (31%) between t = 9 and t = 18 stopped AS, mostly (86%) because of protocol-based reasons. CES-D, total MAX-PC and DCS scores did not change significantly (p > 0.05) when comparing t = 18 with t = 9 and t = 0 scores, but generic anxiety (STAI-6; p = 0.033) and fear of disease progression (sub-score of the MAX-PC; p = 0.007) decreased significantly. These differences, however, were clinically modest (0.089 SD and 0.281 SD). Overall, six of 129 men (5%) discontinued AS because of anxiety and distress. CONCLUSIONS: When men with low-risk PC are managed with AS, fear of disease progression and general anxiety decreased, and only few may discontinue AS because of anxiety and distress. This suggests that negative QoL effects are limited in men with favourable clinical characteristics who opted for AS. (Registered trial number, NTR1718) .

Prevention and early detection of prostate cancer.

Prostate cancer is a common malignancy in men and the worldwide burden of this disease is rising. Lifestyle modifications such as smoking cessation, exercise, and weight control offer opportunities to reduce the risk of developing prostate cancer. Early detection of prostate cancer by prostate-specific antigen (PSA) screening is controversial, but changes in the PSA threshold, frequency of screening, and the use of other biomarkers have the potential to minimise the overdiagnosis associated with PSA screening. Several new biomarkers for individuals with raised PSA concentrations or those diagnosed with prostate cancer are likely to identify individuals who can be spared aggressive treatment. Several pharmacological agents such as 5α-reductase inhibitors and aspirin could prevent development of prostate cancer. In this Review, we discuss the present evidence and research questions regarding prevention, early detection of prostate cancer, and management of men either at high risk of prostate cancer or diagnosed with low-grade prostate cancer.

Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up.

BACKGROUND: The European Randomised study of Screening for Prostate Cancer (ERSPC) has shown significant reductions in prostate cancer mortality after 9 years and 11 years of follow-up, but screening is controversial because of adverse events such as overdiagnosis. We provide updated results of mortality from prostate cancer with follow-up to 2010, with analyses truncated at 9, 11, and 13 years. METHODS: ERSPC is a multicentre, randomised trial with a predefined centralised database, analysis plan, and core age group (55-69 years), which assesses prostate-specific antigen (PSA) testing in eight European countries. Eligible men aged 50-74 years were identified from population registries and randomly assigned by computer generated random numbers to screening or no intervention (control). Investigators were masked to group allocation. The primary outcome was prostate cancer mortality in the core age group. Analysis was by intention to treat. We did a secondary analysis that corrected for selection bias due to non-participation. Only incidence and no mortality data at 9 years' follow-up are reported for the French centres. This study is registered with Current Controlled Trials, number ISRCTN49127736. FINDINGS: With data truncated at 13 years of follow-up, 7408 prostate cancer cases were diagnosed in the intervention group and 6107 cases in the control group. The rate ratio of prostate cancer incidence between the intervention and control groups was 1·91 (95% CI 1·83-1·99) after 9 years (1·64 [1·58-1·69] including France), 1·66 (1·60-1·73) after 11 years, and 1·57 (1·51-1·62) after 13 years. The rate ratio of prostate cancer mortality was 0·85 (0·70-1·03) after 9 years, 0·78 (0·66-0·91) after 11 years, and 0·79 (0·69-0·91) at 13 years. The absolute risk reduction of death from prostate cancer at 13 years was 0·11 per 1000 person-years or 1·28 per 1000 men randomised, which is equivalent to one prostate cancer death averted per 781 (95% CI 490-1929) men invited for screening or one per 27 (17-66) additional prostate cancer detected. After adjustment for non-participation, the rate ratio of prostate cancer mortality in men screened was 0·73 (95% CI 0·61-0·88). INTERPRETATION: In this update the ERSPC confirms a substantial reduction in prostate cancer mortality attributable to testing of PSA, with a substantially increased absolute effect at 13 years compared with findings after 9 and 11 years. Despite our findings, further quantification of harms and their reduction are still considered a prerequisite for the introduction of populated-based screening. FUNDING: Each centre had its own funding responsibility.

Prostate cancer antigen 3: diagnostic outcomes in men presenting with urinary prostate cancer antigen 3 scores ≥100.

OBJECTIVE: To describe the results of 3 rounds of diagnostic testing and linkage to the Dutch Cancer Registry for men with an initial prostate cancer antigen 3 (PCA3) score ≥100. METHODS: Within an earlier reported comparative study of PCA3 vs prostate-specific antigen in a prescreened population, 90 men with a PCA3 score ≥100 were identified and underwent biopsy, 28 prostate cancers (PCs) were found, 62 men remained at risk of a diagnosis of PC. All men were offered repeat testing; 6 PCs were found in 20 men at rebiopsy. Men with at least 1 negative biopsy (n = 56) were invited to undergo magnetic resonance imaging (MRI) studies and MRI-guided biopsies if indicated. Linkage to the Dutch Cancer Registry after 2.8 years of follow-up was performed for men with negative biopsies. RESULTS: Of the 56 men at risk, 28 agreed to participate in further testing. They were offered MRI studies; only 7 men agreed, and in 2, suspicious lesions were found and biopsies carried out. Only 1 PC was diagnosed and classified as T1c, Gleason 3 + 3 = 6. The overall findings of 3 rounds of testing and of linkage to the cancer registry show that eventually 35 PCs were detected in 90 men with PCA3 scores ≥100 (positive predictive value 38.9%). CONCLUSION: Finding no PC despite extended diagnostic efforts in many men with initial PCA3 scores ≥100 is unexpected and might be clinically relevant.

Long-term tolerability and efficacy of degarelix: 5-year results from a phase III extension trial with a 1-arm crossover from leuprolide to degarelix.

OBJECTIVE: To demonstrate the safety and efficacy of up to 5 years of degarelix treatment and the effects of crossing over from leuprolide to degarelix in the extension phase of a phase III pivotal 1-year trial. METHODS: Patients receiving degarelix who completed the 1-year trial continued on 80 mg (n = 125) or 160 mg (n = 126) maintenance doses. Patients who received leuprolide were rerandomized to degarelix 240/80 mg (n = 69) or 240/160 mg (n = 65). Safety and tolerability were assessed (primary end point), as well as testosterone and prostate-specific antigen levels and prostate-specific antigen progression-free survival (secondary end points). RESULTS: Adverse event frequency was similar between both the groups. Adverse events included initial injection site reactions, hot flushes, and increased weight. Testosterone and prostate-specific antigen values during the extension study were similar to those seen during the 1-year trial in patients who continued on degarelix or crossed over from leuprolide. The prostate-specific antigen progression-free survival hazard rate was decreased significantly after the crossover in the leuprolide to degarelix group (from 0.20 to 0.09; P = .002), whereas in patients who continued on degarelix, the rate did not change significantly. In patients with baseline prostate-specific antigen >20 ng/mL, the same hazard rate change pattern was observed on crossover (from 0.38 to 0.19; P = .019). CONCLUSION: Degarelix was well tolerated; no safety concerns were identified. The significant prostate-specific antigen progression-free survival benefit established for degarelix over leuprolide during year 1 remained consistent at 5 years.

Prospective study of diagnostic accuracy comparing prostate cancer detection by transrectal ultrasound-guided biopsy versus magnetic resonance (MR) imaging with subsequent MR-guided biopsy in men without previous prostate biopsies.

BACKGROUND: The current diagnosis of prostate cancer (PCa) uses transrectal ultrasound-guided biopsy (TRUSGB). TRUSGB leads to sampling errors causing delayed diagnosis, overdetection of indolent PCa, and misclassification. Advances in multiparametric magnetic resonance imaging (mpMRI) suggest that imaging and selective magnetic resonance (MR)-guided biopsy (MRGB) may be superior to TRUSGB. OBJECTIVE: To compare the diagnostic efficacy of the magnetic resonance imaging (MRI) pathway with TRUSGB. DESIGN, SETTING, AND PARTICIPANTS: A total of 223 consecutive biopsy-naive men referred to a urologist with elevated prostate-specific antigen participated in a single-institution, prospective, investigator-blinded, diagnostic study from July 2012 through January 2013. INTERVENTION: All participants had mpMRI and TRUSGB. Men with equivocal or suspicious lesions on mpMRI also underwent MRGB. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was PCa detection. Secondary outcomes were histopathologic details of biopsy and radical prostatectomy specimens, adverse events, and MRI reader performance. Sensitivity, specificity, negative predictive values (NPVs), and positive predictive values were estimated and basic statistics presented by number (percentage) or median (interquartile range). RESULTS AND LIMITATIONS: Of 223 men, 142 (63.7%) had PCa. TRUSGB detected 126 cases of PCa in 223 men (56.5%) including 47 (37.3%) classed as low risk. MRGB detected 99 cases of PCa in 142 men (69.7%) with equivocal or suspicious mpMRI, of which 6 (6.1%) were low risk. The MRGB pathway reduced the need for biopsy by 51%, decreased the diagnosis of low-risk PCa by 89.4%, and increased the detection of intermediate/high-risk PCa by 17.7%. The estimated NPVs of TRUSGB and MRGB for intermediate/high-risk disease were 71.9% and 96.9%, respectively. The main limitation is the lack of long follow-up. CONCLUSIONS: We found that mpMRI/MRGB reduces the detection of low-risk PCa and reduces the number of men requiring biopsy while improving the overall rate of detection of intermediate/high-risk PCa. PATIENT SUMMARY: We compared the results of standard prostate biopsies with a magnetic resonance (MR) image-based targeted biopsy diagnostic pathway in men with elevated prostate-specific antigen. Our results suggest patient benefits of the MR pathway. Follow-up of negative investigations is required.

Screening for prostate cancer: current status of ERSPC and screening-related issues.

The "European Randomized Study of Screening for Prostate Cancer" (ERSPC) was initiated in 1993 and up to 1998 six other European countries were joined. The main goal is to establish the effect of Prostate Specific Antigen (PSA)-based screening on prostate cancer (PCa) mortality with morbidity as secondary end point. At present, with 11 and 12 years of follow-up significant relative reductions of 21 % and 31 % relating to both end points have been reported. The diagnosis of non-life threatening PCA (over diagnosis) is estimated to be in the range of 50 % and represents the main "harm", which prevents the introduction of population-based screening. As a result, the prevention of over diagnosis is now given top research priority. PSA as a screening test has poor performance characteristics including a low specificity. With the cut-off value of 3.0 ng/ml chosen within ERSPC, about 25 % of men aged 55--69 test positively, 75 % have "negative" test results, which do not definitely exclude the presence of PCa. Research to establish empirical schemes of follow-up based on PSA levels and other parameters are ongoing worldwide. In the meantime, we are, by approximation, capable to identify over diagnosed PCa detected by screening. Active surveillance can be applied to avoid side effects and expenses of treatment and is, among others, based on the grade of differentiation determined on biopsies. The assignment of the most favorable "Gleason score 6" is a crucial decision element. Unfortunately, biopsy pathology underestimates the true degree of PC aggressiveness by 25--30 % which establishes the need of careful follow-up.