Results from 22 years of Followup in the Göteborg Randomized Population-Based Prostate Cancer Screening Trial.

PURPOSE: Our goal was to analyze results from 22 years of followup in the Göteborg randomized prostate cancer (PC) screening trial. MATERIALS AND METHODS: In December 1994, 20,000 men born 1930-1944 were randomly extracted from the Swedish population register and were randomized (1:1) into either a screening group (SG) or to a control group (CG). Men in the SG were repeatedly invited for biennial prostate specific antigen testing up to an average age of 69 years. Main endpoints were PC incidence and mortality (intention-to-screen principle). RESULTS: After 22 years, 1,528 men in the SG and 1,124 men in the CG had been diagnosed with PC. In total, 112 PC deaths occurred in the SG and 158 in the CG. Compared with the CG, the SG showed a PC incidence rate ratio (RR) of 1.42 (95% CI, 1.31-1.53) and a PC mortality RR of 0.71 (95% CI, 0.55-0.91). The 22-year cumulative PC mortality rate was 1.55% (95% CI, 1.29-1.86) in the SG and 2.13% (95% CI, 1.83-2.49) in the CG. Correction for nonattendance (Cuzick method) yielded a RR of PC mortality of 0.59 (95% CI, 0.43-0.80). Number needed to invite and number needed to diagnose was estimated to 221 and 9, respectively. PC death risk was increased in the following groups: nontesting men, men entering the program after age 60 and men with >10 years of followup after screening termination. CONCLUSIONS: Prostate specific antigen-based screening substantially decreases PC mortality. However, not attending, starting after age 60 and stopping at age 70 seem to be major pitfalls regarding PC death risk.

Intervention-related Deaths in the European Randomized Study of Screening for Prostate Cancer.

BACKGROUND: Identification of intervention-related deaths is important for an accurate assessment of the ratio of benefit to harm in screening trials. OBJECTIVE: To investigate intervention-related deaths by study arm in the European Randomized Study of Prostate Cancer Screening (ERSPC). DESIGN SETTING AND PARTICIPANTS: ERSPC is a multicenter trial initiated in the 1990s to investigate whether screening on the basis of prostate-specific antigen (PSA) can decrease prostate cancer mortality. The present study included men in the core age group (55-69 yr: screening group n = 112 553, control group n = 128 681) with 16-yr follow-up. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Causes of death among men with prostate cancer in ERSPC were predominantly evaluated by independent national committees via review of medical records according to a predefined algorithm. Intervention-related deaths were defined as deaths caused by complications during the screening procedure, treatment, or follow-up. Descriptive statistics were used for the results. RESULTS AND LIMITATIONS: In total, 34 deaths were determined to be intervention-related, of which 21 were in the screening arm and 13 in the control arm. The overall risk of intervention-related death was 1.41 (95% confidence interval 0.99-1.99) per 10 000 randomized men for both arms combined and varied among centers from 0 to 7.0 per 10 000 randomized men. A limitation of this study is that differences in procedures among centers decreased the comparability of the results. CONCLUSIONS: Intervention-related deaths were rare in ERSPC. Monitoring of intervention-related deaths in screening trials is important for assessment of harms. PATIENT SUMMARY: We investigated deaths due to screening or treatment to assess harm in a trial of prostate cancer screening. Few such deaths were identified.

Eighteen-year follow-up of the Göteborg Randomized Population-based Prostate Cancer Screening Trial: effect of sociodemographic variables on participation, prostate cancer incidence and mortality.

OBJECTIVE: This study examined whether previously reported results, indicating that prostate-specific antigen (PSA) screening can reduce prostate cancer (PC) mortality regardless of sociodemographic inequality, could be corroborated in an 18 year follow-up. MATERIALS AND METHODS: In 1994, 20,000 men aged 50-64 years were randomized from the Göteborg population register to PSA screening or control (1:1) (study ID: ISRCTN54449243). Men in the screening group (n = 9950) were invited for biennial PSA testing up to the median age of 69 years. Prostate biopsy was recommended for men with PSA ≥2.5 ng/ml. Last follow-up was on 31 December 2012. RESULTS: In the screening group, 77% (7647/9950) attended at least once. After 18 years, 1396 men in the screening group and 962 controls had been diagnosed with PC [hazard ratio 1.51, 95% confidence interval (CI) 1.39-1.64]. Cumulative PC mortality was 0.98% (95% CI 0.78-1.22%) in the screening group versus 1.50% (95% CI 1.26-1.79%) in controls, an absolute reduction of 0.52% (95% CI 0.17-0.87%). The rate ratio (RR) for PC death was 0.65 (95% CI 0.49-0.87). To prevent one death from PC, the number needed to invite was 231 and the number needed to diagnose was 10. Systematic PSA screening demonstrated greater benefit in PC mortality for men who started screening at age 55-59 years (RR 0.47, 95% CI 0.29-0.78) and men with low education (RR 0.49, 95% CI 0.31-0.78). CONCLUSIONS: These data corroborate previous findings that systematic PSA screening reduces PC mortality and suggest that systematic screening may reduce sociodemographic inequality in PC mortality.

Role of Magnetic Resonance Imaging in Prostate Cancer Screening: A Pilot Study Within the Göteborg Randomised Screening Trial.

BACKGROUND: Magnetic resonance imaging (MRI) and targeted biopsies (TB) have shown potential to more accurately detect significant prostate cancer compared with prostate-specific antigen (PSA) and systematic biopsies (SB). OBJECTIVE: To compare sequential screening (PSA+MRI) with conventional PSA screening. DESIGN, SETTING, AND PARTICIPANTS: Of 384 attendees in the 10th screening round of the Göteborg randomised screening trial, 124 men, median age 69.5 yr, had a PSA of ≥ 1.8 ng/ml and underwent a prebiopsy MRI. Men with suspicious lesions on MRI and/or PSA ≥ 3.0ng/ml were referred for biopsy. SB was performed blinded to MRI results and TB was performed in men with tumour-suspicious findings on MRI. Three screening strategies were compared (PSA ≥ 3.0+SB; PSA ≥ 3.0+MRI+TB and PSA ≥ 1.8+MRI+TB). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cancer detection rates, sensitivity, and specificity were calculated per screening strategy and compared using McNemar's test. RESULTS AND LIMITATIONS: In total, 28 cases of prostate cancer were detected, of which 20 were diagnosed in biopsy-naïve men. Both PSA ≥ 3.0+MRI and PSA ≥ 1.8+MRI significantly increased specificity compared with PSA ≥ 3.0+SB (0.92 and 0.79 vs 0.52; p<0.002 for both), while sensitivity was significantly higher for PSA ≥ 1.8+MRI compared with PSA ≥ 3.0+MRI (0.73 vs 0.46, p=0.008). The detection rate of significant cancer was higher with PSA ≥ 1.8+MRI compared with PSA ≥ 3.0+SB (5.9% vs 4.0%), while the detection rate of insignificant cancer was lowered by PSA ≥ 3.0+MRI (0.3% vs 1.2%). The primary limitation of this study is the small sample of men. CONCLUSION: A screening strategy with a lowered PSA cut-off followed by TB in MRI-positive men seems to increase the detection of significant cancers while improving specificity. If replicated, these results may contribute to a paradigm shift in future screening. PATIENT SUMMARY: Major concerns in prostate-specific antigen screening are overdiagnosis and underdiagnosis. We evaluated whether prostate magnetic resonance imaging could improve the balance of benefits to harm in prostate cancer screening screening, and we found a promising potential of using magnetic resonance imaging in addition to prostate-specific antigen.

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.

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.

Effects of surgeon variability on oncologic and functional outcomes in a population-based setting.

BACKGROUND: Oncologic and functional outcomes after radical prostatectomy (RP) can vary between surgeons to a greater extent than is expected by chance. We sought to examine the effects of surgeon variation on functional and oncologic outcomes for patients undergoing RP for prostate cancer in a European center. METHODS: The study comprised 1,280 men who underwent open retropubic RP performed by one of nine surgeons at an academic institution in Sweden between 2001 and 2008. Potency and continence outcomes were measured preoperatively and 18 months postoperatively by patient-administered questionnaires. Biochemical recurrence (BCR) was defined as a prostate-specific antigen (PSA) value > 0.2 ng/mL with at least one confirmatory rise. Multivariable random effect models were used to evaluate heterogeneity between surgeons, adjusting for case mix (age, PSA, pathological stage and grade), year of surgery, and surgical experience. RESULTS: Of 679 men potent at baseline, 647 provided data at 18 months with 122 (19%) reporting potency. We found no evidence for heterogeneity of potency outcomes between surgeons (P = 1). The continence rate for patients at 18 months was 85%, with 836 of the 979 patients who provided data reporting continence. There was statistically significant heterogeneity between surgeons (P = 0.001). We did not find evidence of an association between surgeons' adjusted probabilities of functional recovery and 5-year probability of freedom from BCR. CONCLUSIONS: Our data support previous studies regarding a large heterogeneity among surgeons in continence outcomes for patients undergoing RP. This indicates that some patients are receiving sub-optimal care. Quality assurance measures involving performance feedback, should be considered. When surgeons are aware of their outcomes, they can improve them to provide better care to patients.

The absence of voiding symptoms in men with a prostate-specific antigen (PSA) concentration of ≥3.0 ng/mL is an independent risk factor for prostate cancer: results from the Gothenburg Randomized Screening Trial.

UNLABELLED: What's known on the subject? and What does the study add? There are only a few studies and no consensus concerning the relationship between LUTS and prostate cancer. This paper focuses on 2353 men with an elevated PSA level within the Gothenburg Randomized Screening Trial who underwent biopsy and answered questions regarding LUTS. The main conclusion was that the absence of voiding symptoms is an independent risk factor for prostate cancer detection. OBJECTIVE: To investigate whether men with obstructive voiding symptoms are at increased risk for being diagnosed with prostate cancer within the Gothenburg randomized population-based prostate cancer screening trial. SUBJECTS AND METHODS: In 1995, 20 000 men born between 1930 and 1944 were randomly selected from the population register and randomized to either a screening group (10 000), invited for total prostate-specific antigen (tPSA) testing every second year until they reached an upper age-limit pending between 67 and 71 years, or to a control group not invited (10 000). Men with a PSA concentration of ≥3.0 ng/mL were offered further examination with prostate biopsies. Immediately before the physician's examination a self-administered, study-specific questionnaire was completed including one question concerning obstructive voiding symptoms. Multivariate logistic regression modelling was used to estimate odds ratios (ORs) for associations of age, tPSA, free/total PSA (f/tPSA) ratio, prostate volume and the presence of voiding symptoms in prostate cancer risk. A P < 0.05 was considered statistically significant. RESULTS: Between 1995 and 2010 there were 2590 men who had an elevated PSA concentration (≥3.0 ng/mL) at least once during the study. Of these, 2353 men (91%) accepted further clinical examination with transrectal ultrasonography (TRUS) and prostate biopsies. In all, 633/2353 men had prostate cancer (27%) on biopsy and 1720/2353 men (73%) had a benign pathology. Men with prostate cancer reported a lower frequency of voiding symptoms (24% vs 31%, P < 0.001), independent of age and locally advanced tumours (T2b-T4). In the multivariate logistic regression model increasing age and tPSA were positively associated with prostate cancer while prostate volume, f/tPSA ratio and the presence of voiding symptoms were all inversely associated with the risk of detecting prostate cancer in a screening setting. This inverse association of voiding symptoms and prostate cancer detection was restricted to men with large prostates (>37.8 mL); 15% in men with voiding symptoms vs 22% in asymptomatic men (P < 0.001). CONCLUSION: The presence of voiding symptoms should not be a decision tool for deciding which men with an elevated PSA concentration should be offered biopsies of the prostate.

Prostate-cancer mortality at 11 years of follow-up.

BACKGROUND: Several trials evaluating the effect of prostate-specific antigen (PSA) testing on prostate-cancer mortality have shown conflicting results. We updated prostate-cancer mortality in the European Randomized Study of Screening for Prostate Cancer with 2 additional years of follow-up. METHODS: The study involved 182,160 men between the ages of 50 and 74 years at entry, with a predefined core age group of 162,388 men 55 to 69 years of age. The trial was conducted in eight European countries. Men who were randomly assigned to the screening group were offered PSA-based screening, whereas those in the control group were not offered such screening. The primary outcome was mortality from prostate cancer. RESULTS: After a median follow-up of 11 years in the core age group, the relative reduction in the risk of death from prostate cancer in the screening group was 21% (rate ratio, 0.79; 95% confidence interval [CI], 0.68 to 0.91; P=0.001), and 29% after adjustment for noncompliance. The absolute reduction in mortality in the screening group was 0.10 deaths per 1000 person-years or 1.07 deaths per 1000 men who underwent randomization. The rate ratio for death from prostate cancer during follow-up years 10 and 11 was 0.62 (95% CI, 0.45 to 0.85; P=0.003). To prevent one death from prostate cancer at 11 years of follow-up, 1055 men would need to be invited for screening and 37 cancers would need to be detected. There was no significant between-group difference in all-cause mortality. CONCLUSIONS: Analyses after 2 additional years of follow-up consolidated our previous finding that PSA-based screening significantly reduced mortality from prostate cancer but did not affect all-cause mortality. (Current Controlled Trials number, ISRCTN49127736.).

No excess mortality after prostate biopsy: results from the European Randomized Study of Screening for Prostate Cancer.

OBJECTIVE: • To assess possible excess mortality associated with prostate biopsy among screening participants of the European Randomized Study of Screening for Prostate Cancer (ERSPC). PATIENTS AND METHODS: • From three centres in the ERSPC (Finland, The Netherlands and Sweden) 50,194 screened men aged 50.2-78.4 years were prospectively followed. A cohort of 12,959 first-time screening-positive men (i.e. with biopsy indication) was compared with another cohort of 37,235 first-time screening-negative men. • Overall mortality rates (i.e. other cause than prostate cancer mortality) were calculated and the 120-day and 1-year cumulative mortality were calculated by the Kaplan-Meier method, with a log-rank test for statistical significance. • Incidence rate ratios (RR) and statistical significance were evaluated using Poisson regression analyses, adjusting for age, total PSA level, screening centre and whether a biopsy indication was present, or whether a biopsy was actually performed or not. RESULTS: • There was no statistically significant difference in cumulative 120-day other cause mortality between the two groups of men: 0.24% (95% CI, 0.17-0.34) for screening-positive men vs 0.24% (95% CI, 0.20-0.30) for screening-negative men (P= 0.96). This implied no excess mortality for screening-positive men. • Screening-positive men who were not biopsied (n= 1238) had a more than fourfold risk of other cause mortality during the first 120 days compared to screening-negative men: RR, 4.52 (95% CI, 2.63-7.74) (P < 0.001), adjusted for age, whereas men who were actually biopsied (n= 11,721) had half the risk: RR, 0.41 (95% CI, 0.23-0.73) (P= 0.002), adjusted for age. • Only 14/31 (45%) of the screening-positive men who died within 120 days were biopsied and none died as an obvious complication to the biopsy. CONCLUSION: • Prostate biopsy is not associated with excess mortality and fatal complications appear to be very rare.

The excess burden of side-effects from treatment in men allocated to screening for prostate cancer. The Göteborg randomised population-based prostate cancer screening trial.

BACKGROUND: The number of men needed to treat to prevent one death is rather high in prostate cancer screening. How this affects the burden of treatment-related side-effects is unclear. The aim of this study was to evaluate the treatment related morbidity following radical prostatectomy in men participating in the Göteborg randomised population-based prostate cancer screening trial. METHODS: In 1995, 20,000 men aged 50-64 years were randomly allocated (1:1) to biennial PSA-screening or to a control group not invited. A subset of prostate cancer patients undergoing radical prostatectomy between 2001 and 2008 responded to questionnaires preoperatively and at 18 months postoperatively. The primary endpoint was patient-reported frequencies of erectile dysfunction as measured by the validated International Index of Erectile Function-5 questionnaire and urinary incontinence as assessed by use of pads. Analyses were made according to intention to screen. FINDINGS: After 14 years of follow-up, a total of 1849 men were detected with prostate cancer (1138 screened versus 711 controls, excluding 7 cancers detected at autopsy in the control group). Overall, 1047 received treatment with curative intent and radical prostatectomy was performed in 829 cases (79.2%). In this study, 294 of these men participated (205 screened and 89 controls). Of preoperatively potent men 79.1% (91/115) in the screening-group and 90.7% (49/54) in the control-group became impotent or sexually inactive 18 months postoperatively, whereas 14.3% (29/203) of screened men and 20.5% (18/88) of controls were considered postoperatively incontinent (regular use of pads). Extrapolated data yields that 120/10,000 more men become impotent and 25/10,000 more men will have the need of pads among men invited to regular PSA screening. The 'cost' per life saved at the same follow-up of screening is four men impotent and less than one man incontinent. INTERPRETATION: Despite the relatively high risk of erectile dysfunction and incontinence following radical prostatectomy for prostate cancer, the excess burden of permanent side-effects after population-based screening can be regarded as relatively low, when related to the number of men saved from prostate cancer death. These data can be useful when calculating the harms and benefits of screening. However, the outcome on a population-level may differ from the benefit for the individual.

Prostate specific antigen velocity does not aid prostate cancer detection in men with prior negative biopsy.

PURPOSE: Prostate specific antigen velocity has been proposed as a marker to aid in prostate cancer detection. We determined whether prostate specific antigen velocity could predict repeat biopsy results in men with persistently increased prostate specific antigen after initial negative biopsy. MATERIALS AND METHODS: We identified 1,837 men who participated in the Göteborg or Rotterdam section of the European Randomized Screening study of Prostate Cancer and who underwent 1 or more subsequent prostate biopsies after an initial negative finding. We evaluated whether prostate specific antigen velocity improved predictive accuracy beyond that of prostate specific antigen alone. RESULTS: Of the 2,579 repeat biopsies 363 (14%) were positive for prostate cancer, of which 44 (1.7%) were high grade (Gleason score 7 or greater). Prostate specific antigen velocity was statistically associated with cancer risk but had low predictive accuracy (AUC 0.55, p <0.001). There was some evidence that prostate specific antigen velocity improved AUC compared to prostate specific antigen for high grade cancer. However, the small increase in risk associated with high prostate specific antigen velocity (from 1.7% to 2.8% as velocity increased from 0 to 1 ng/ml per year) had questionable clinical relevance. CONCLUSIONS: Men with prior negative biopsy are at lower risk for prostate cancer at subsequent biopsies with high grade disease particularly rare. We found little evidence to support prostate specific antigen velocity to aid in decisions about repeat biopsy for prostate cancer.

Post-radical prostatectomy inguinal hernia: a simple surgical intervention can substantially reduce the incidence--results from a prospective randomized trial.

PURPOSE: After radical retropubic prostatectomy a postoperative inguinal hernia develops in 15% to 20% of patients. We investigated whether a simple prophylactic procedure during radical retropubic prostatectomy would reduce this incidence. MATERIALS AND METHODS: A total of 294 consecutive patients scheduled for radical retropubic prostatectomy at our clinic were prospectively included in the study. Patients with a present inguinal hernia or a previous inguinal hernia surgery were not included in the analysis. The subjects were randomized for side of prophylactic intervention (left or right). At radical retropubic prostatectomy a nonresorbable figure-of-8 suture was placed lateral to the internal ring of the inguinal canal and the spermatic cord on either side according to outcome of the randomization. Patients were followed at regular followup visits at the clinic. At the end of the study all patients were invited for a final interview and examination by an independent examiner who was unaware of the side of intervention. RESULTS: Of the patients 86% (254) showed up for the final examination. The cumulative inguinal hernia incidence was 3.5% on the intervention side and 9.1% on the control side (log rank Mantel-Cox p = 0.011). There were no serious adverse events, and no increase in postoperative discomfort in the groin and testicular region on the intervention side. The procedure added 5 to 10 minutes to the duration of surgery. CONCLUSIONS: The prophylactic procedure was simple and safe to perform, and it decreased the risk of postoperative inguinal hernia formation by 62%. We believe it should be considered for patients undergoing radical retropubic prostatectomy.

Mortality results from the Göteborg randomised population-based prostate-cancer screening trial.

BACKGROUND: Prostate cancer is one of the leading causes of death from malignant disease among men in the developed world. One strategy to decrease the risk of death from this disease is screening with prostate-specific antigen (PSA); however, the extent of benefit and harm with such screening is under continuous debate. METHODS: In December, 1994, 20,000 men born between 1930 and 1944, randomly sampled from the population register, were randomised by computer in a 1:1 ratio to either a screening group invited for PSA testing every 2 years (n=10,000) or to a control group not invited (n=10,000). Men in the screening group were invited up to the upper age limit (median 69, range 67-71 years) and only men with raised PSA concentrations were offered additional tests such as digital rectal examination and prostate biopsies. The primary endpoint was prostate-cancer specific mortality, analysed according to the intention-to-screen principle. The study is ongoing, with men who have not reached the upper age limit invited for PSA testing. This is the first planned report on cumulative prostate-cancer incidence and mortality calculated up to Dec 31, 2008. This study is registered as an International Standard Randomised Controlled Trial ISRCTN54449243. FINDINGS: In each group, 48 men were excluded from the analysis because of death or emigration before the randomisation date, or prevalent prostate cancer. In men randomised to screening, 7578 (76%) of 9952 attended at least once. During a median follow-up of 14 years, 1138 men in the screening group and 718 in the control group were diagnosed with prostate cancer, resulting in a cumulative prostate-cancer incidence of 12.7% in the screening group and 8.2% in the control group (hazard ratio 1.64; 95% CI 1.50-1.80; p<0.0001). The absolute cumulative risk reduction of death from prostate cancer at 14 years was 0.40% (95% CI 0.17-0.64), from 0.90% in the control group to 0.50% in the screening group. The rate ratio for death from prostate cancer was 0.56 (95% CI 0.39-0.82; p=0.002) in the screening compared with the control group. The rate ratio of death from prostate cancer for attendees compared with the control group was 0.44 (95% CI 0.28-0.68; p=0.0002). Overall, 293 (95% CI 177-799) men needed to be invited for screening and 12 to be diagnosed to prevent one prostate cancer death. INTERPRETATION: This study shows that prostate cancer mortality was reduced almost by half over 14 years. However, the risk of over-diagnosis is substantial and the number needed to treat is at least as high as in breast-cancer screening programmes. The benefit of prostate-cancer screening compares favourably to other cancer screening programs. FUNDING: The Swedish Cancer Society, the Swedish Research Council, and the National Cancer Institute.

Impact of recent screening on predicting the outcome of prostate cancer biopsy in men with elevated prostate-specific antigen: data from the European Randomized Study of Prostate Cancer Screening in Gothenburg, Sweden.

BACKGROUND: Risk models to predict prostate cancer on biopsy, whether they include only prostate-specific antigen (PSA) or other markers, are intended for use in all men of screening age. However, the association between PSA and cancer probably depends on a man's recent screening history. METHODS: The authors examined the effect of prior screening on the ability to predict the risk of prostate cancer by using a previously reported, 4-kallikrein panel that included total PSA, free PSA, intact PSA, and human kallikrein-related peptidase 2 (hK2). The study cohort comprised 1241 men in Gothenburg, Sweden who underwent biopsy for elevated PSA during their second or later visit for the European Randomized Study of Screening for Prostate Cancer. The predictive accuracy of the 4-kallikrein panel was calculated. RESULTS: Total PSA was not predictive of prostate cancer. The previously published 4-kallikrein model increased predictive accuracy compared with total PSA and age alone (area under the curve [AUC], 0.66 vs 0.51; P < .001) but was poorly calibrated and missed many cancers. A model that was developed with recently screened men provided important improvements in discrimination (AUC, 0.67 vs 0.56; P < .001). Using this model reduced the number of biopsies by 413 per 1000 men with elevated PSA, missed 60 of 216 low-grade cancers (Gleason score < or =6), but missed only 1 of 43 high-grade cancers. CONCLUSIONS: Previous participation in PSA screening dramatically changed the performance of statistical models that were designed to predict biopsy outcome. A 4-kallikrein panel was able to predict prostate cancer in men who had a recent screening history and provided independent confirmation that multiple kallikrein forms contribute important diagnostic information for men with elevated PSA. Cancer

Is delayed radical prostatectomy in men with low-risk screen-detected prostate cancer associated with a higher risk of unfavorable outcomes?

BACKGROUND: Strategies of active surveillance (AS) of low-risk screen-detected prostate cancer have emerged, because the balance between survival outcomes and quality of life issues when radically treating these malignancies is disputable. Delay before radical treatment caused by active surveillance may be associated with an impaired chance of curability. METHODS: Men diagnosed with low-risk (T1c/T2; prostate-specific antigen [PSA] = <10.0; PSA density, <0.2 ng/mL; Gleason score, 3 + 3=6; 1-2 positive biopsies) prostate cancer in the Swedish section of the European Randomized Study of Screening for Prostate Cancer who received radical prostatectomy (RP) were studied. One group received immediate RP, whereas another group received delayed RP after an initial period of expectant management. These groups were compared regarding histopathological and biochemical outcomes, correcting for baseline differences. RESULTS: Mean follow-up after diagnosis was 5.7 years (standard deviation [SD], 3.2). The immediate RP group (n = 158) received RP a mean of 0.5 (SD, 0.2) years after diagnosis; the delayed RP group (n = 69) received RP after 2.6 (SD, 2.0) years (P < .001). After adjustment for small baseline dissimilarities, no differences in RP frequencies of Gleason score >6 (odds ratio [OR], 1.54; P = .221), capsular penetration (OR, 2.45; P = .091), positive margins (OR, 1.34; P = .445), RP tumor volume (difference, 0.099; P = .155), or biochemical progression rates (P = .185, P = .689) were found between groups, although all data were in favor of immediate RP. CONCLUSIONS: With limited patient numbers available for analysis, differences in intermediate outcomes between immediate RP and delayed RP were nonsignificant. The delayed RP group may be subject to a selection bias. Prospective evaluation of active surveillance protocols is essential.

Living with a prostate cancer diagnosis: a qualitative 2-year follow-up.

AIM: Previous research has identified how newly diagnosed prostate cancer affects men's daily lives, including daily activities and existential issues. The aim of this qualitative study was to provide information if and how prostate cancer affects men's daily lives 2 years after the diagnosis. METHODS: A second follow-up interview with men who were diagnosed with localized or advanced prostate cancer approximately 18-24 months earlier. Twenty-two men aged 50-85 years participated, data were analyzed by hermeneutical interpretation with Gadamer's approach. RESULTS: The men feel healthy, but prostate cancer affects their daily lives. They experience every day fatigue associated with several changes in life due to age. Three equivalent fusions which influenced the men are: 'Age is claiming its due', 'Living with uncertainty', and 'Strengthen self-esteem'. The unifying fusion is identified as 'Balancing a changed life situation.' CONCLUSIONS: There is need for knowledge and guidance for men with prostate cancer on how to adapt to new life situation decreasing uncertainty and increasing welfare. Men found a sense of pride, despite physical changes, in appreciating independence and close relationships. Value of life was readjusted. The findings indicate harmony in living, enjoying being frank as well as rating the 'little' things.

Risk of dying from prostate cancer in men randomized to screening: differences between attendees and nonattendees.

BACKGROUND: Although the true benefits and disadvantages of prostate cancer screening are still not known, the analysis of fatal cases is important for increasing knowledge of the effects of prostate cancer screening on mortality. Who dies from prostate cancer despite participation in a population-based prostate-specific antigen (PSA) screening program? METHODS: From the Goteborg branch of the European Randomized study of Screening for Prostate Cancer, 10,000 men randomly assigned to active PSA-screening every second year formed the basis of the present study. Prostate cancer mortality was attributed to whether the men were attendees in the screening program (attending at least once) or nonattendees. RESULTS: Thirty-nine men died from prostate cancer during the first 13 years. Both overall (34% vs 13 %; P<.0001) and cancer-specific mortality (0.8% vs 0.3 %; P<.005) were found to be significantly higher among nonattendees compared with attendees. Furthermore, the majority of deaths (12 of 18) among screening attendees were in men diagnosed at first screening (prevalent cases). Only 6 deaths (including 3 interval cases) were noted among men complying with the biennial screening program. CONCLUSIONS: Nonattendees in prostate cancer screening constitute a high-risk group for both death from prostate cancer and death from other causes comparable to that described in other cancer screening programs.