Franz Recker

Screening and Prostate-Cancer Mortality in a Randomized European Study

BACKGROUND The European Randomized Study of Screening for Prostate Cancer was initiated in the early 1990s to evaluate the effect of screening with prostate-specific-antigen (PSA) testing on death rates from prostate cancer. METHODS We identified 182,000 men between the ages of 50 and 74 years through registries in seven European countries for inclusion in our study. The men were randomly assigned to a group that was offered PSA screening at an average of once every 4 years or to a control group that did not receive such screening. The predefined core age group for this study included 162,243 men between the ages of 55 and 69 years. The primary outcome was the rate of death from prostate cancer. Mortality follow-up was identical for the two study groups and ended on December 31, 2006. RESULTS In the screening group, 82% of men accepted at least one offer of screening. During a median follow-up of 9 years, the cumulative incidence of prostate cancer was 8.2% in the screening group and 4.8% in the control group. The rate ratio for death from prostate cancer in the screening group, as compared with the control group, was 0.80 (95% confidence interval [CI], 0.65 to 0.98; adjusted P=0.04). The absolute risk difference was 0.71 death per 1000 men. This means that 1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent one death from prostate cancer. The analysis of men who were actually screened during the first round (excluding subjects with noncompliance) provided a rate ratio for death from prostate cancer of 0.73 (95% CI, 0.56 to 0.90). CONCLUSIONS PSA-based screening reduced the rate of death from prostate cancer by 20% but was associated with a high risk of overdiagnosis. (Current Controlled Trials number, ISRCTN49127736.)

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.).

Prostate Cancer Mortality Reduction by Prostate-Specific Antigen-Based Screening Adjusted for Nonattendance and Contamination in the European Randomised Study of Screening for Prostate Cancer (ERSPC)

BACKGROUND Prostate-specific antigen (PSA) based screening for prostate cancer (PCa) has been shown to reduce prostate specific mortality by 20% in an intention to screen (ITS) analysis in a randomised trial (European Randomised Study of Screening for Prostate Cancer [ERSPC]). This effect may be diluted by nonattendance in men randomised to the screening arm and contamination in men randomised to the control arm. OBJECTIVE To assess the magnitude of the PCa-specific mortality reduction after adjustment for nonattendance and contamination. DESIGN, SETTING, AND PARTICIPANTS We analysed the occurrence of PCa deaths during an average follow-up of 9 yr in 162,243 men 55-69 yr of age randomised in seven participating centres of the ERSPC. Centres were also grouped according to the type of randomisation (ie, before or after informed written consent). INTERVENTION Nonattendance was defined as nonattending the initial screening round in ERSPC. The estimate of contamination was based on PSA use in controls in ERSPC Rotterdam. MEASUREMENTS Relative risks (RRs) with 95% confidence intervals (CIs) were compared between an ITS analysis and analyses adjusting for nonattendance and contamination using a statistical method developed for this purpose. RESULTS AND LIMITATIONS In the ITS analysis, the RR of PCa death in men allocated to the intervention arm relative to the control arm was 0.80 (95% CI, 0.68-0.96). Adjustment for nonattendance resulted in a RR of 0.73 (95% CI, 0.58-0.93), and additional adjustment for contamination using two different estimates led to estimated reductions of 0.69 (95% CI, 0.51-0.92) to 0.71 (95% CI, 0.55-0.93), respectively. Contamination data were obtained through extrapolation of single-centre data. No heterogeneity was found between the groups of centres. CONCLUSIONS PSA screening reduces the risk of dying of PCa by up to 31% in men actually screened. This benefit should be weighed against a degree of overdiagnosis and overtreatment inherent in PCa screening.

Screening for prostate cancer decreases the risk of developing metastatic disease: Findings from the European Randomized Study of Screening for Prostate Cancer (ERSPC)

BACKGROUND Metastatic disease is a major morbidity of prostate cancer (PCa). Its prevention is an important goal. OBJECTIVE To assess the effect of screening for PCa on the incidence of metastatic disease in a randomized trial. DESIGN, SETTING, AND PARTICIPANTS Data were available for 76,813 men aged 55-69 yr coming from four centers of the European Randomized Study of Screening for Prostate Cancer (ERSPC). The presence of metastatic disease was evaluated by imaging or by prostate-specific antigen (PSA) values >100 ng/ml at diagnosis and during follow-up. INTERVENTION Regular screening based on serum PSA measurements was offered to 36270 men randomized to the screening arm, while no screening was provided to the 40543 men in the control arm. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The Nelson-Aalen technique and Poisson regression were used to calculate cumulative incidence and rate ratios of M+ disease. RESULTS AND LIMITATIONS After a median follow-up of 12 yr, 666 men with M+ PCa were detected, 256 in the screening arm and 410 in the control arm, resulting in cumulative incidence of 0.67% and 0.86% per 1000 men, respectively (p<0.001). This finding translated into a relative reduction of 30% (hazard ratio [HR]: 0.70; 95% confidence interval [CI], 0.60-0.82; p=0.001) in the intention-to-screen analysis and a 42% (p=0.0001) reduction for men who were actually screened. An absolute risk reduction of metastatic disease of 3.1 per 1000 men randomized (0.31%) was found. A large discrepancy was seen when comparing the rates of M+ detected at diagnosis and all M+ cases that emerged during the total follow-up period, a 50% reduction (HR: 0.50; 95% CI, 0.41-0.62) versus the 30% reduction. The main limitation is incomplete explanation of the lack of an effect of screening during follow-up. CONCLUSIONS PSA screening significantly reduces the risk of developing metastatic PCa. However, despite earlier diagnosis with screening, certain men still progress and develop metastases. The ERSPC trial is registered under number ISRCTN49127736.

Human glandular kallikrein as a tool to improve discrimination of poorly differentiated and non-organ-confined prostate cancer compared with prostate-specific antigen

OBJECTIVES Human glandular kallikrein (hK2) possesses 80% structure identity with prostate-specific antigen (PSA) and is secreted by identical prostate epithelial cells. Although increasing with pathologic stage, PSA is not clinically sufficient to predict histologic grade and pathologic stage of prostate cancer (PCa) in individual cases. To address this issue, serum hK2 in various PCa grades was investigated. METHODS Sera from 122 consecutive patients with PCa, graded as well-differentiated (G1, n = 35); moderately differentiated (G2, n = 61), and poorly differentiated (G3, n = 26) PCa, was studied. In patients who underwent radical prostatectomy (n = 42), 24 had organ-confined (pT2a-b) and 18 extracapsular (pT3a or greater) disease. hK2 was measured by an indirect immunofluorometric assay with a functional sensitivity of 0.03 ng/mL. Total PSA (tPSA), free PSA (fPSA), and PSA bound to alpha(1)-antichymotrypsin (PSA-ACT) were also measured. Multivariate logistic regression analysis was used for evaluation of the best combinations of tumor markers. RESULTS Median hK2 and tPSA increased twofold from G1 to G2 tumors (hK2 0.07 versus 0.14 ng/mL, P <0.002; tPSA 6.1 versus 12.1 ng/mL, P <0.0002). Between G2 and G3 tumors, hK2 increased threefold (0.14 versus 0.43 ng/mL, P <0.02), and tPSA showed no significant increase (12.1 versus 26.5 ng/mL, P <0.18). The f/t PSA ratio decreased between G1 and G2 cancers (0.15 vs. 010, P <0.001); no difference was found between G2 and G3 tumors (0.10 versus 0.11, P = 0.93). However, the hK2/fPSA ratio distinguished between G1 and G3 tumors and G2 and G3 tumors (0.085 [G1] and 0.11 [G2] versus 0.22 [G3], P <0.0002 and P <0.002, respectively). Using multivariate regression analysis, the fPSA/(tPSA x hK2) ratio differentiated G2 and G3 tumors (P <0.01). In the tPSA range of 3 to 15 ng/mL, hK2, the hK2/fPSA ratio, and the fPSA/(tPSA x hK2) ratio differentiated between the G1/G2 and G3 tumors, and tPSA, the f/t PSA ratio, and PSA-ACT did not. In radical prostatectomy cases, hK2 (0.06 versus 0. 156, P <0.005) and the fPSA/(tPSA x hK2) ratio (2.104 versus 0.828, P <0.005) discriminated between pT2a-b and pT3a or greater PCa. CONCLUSIONS hK2 significantly improved the identification of poorly differentiated (G3) tumors compared with PSA. By multivariate logistic regression analysis, the hK2/fPSA and fPSA/(tPSA x hK2) ratios further improved the detection of PCa grade. This improvement was also seen with the intermediate range of tPSA. hK2 was also helpful in the prediction of organ-confined disease. Thus, hK2 may be a useful tool for more accurate prediction of tumor grade or stage and allow better clinical decision-making.

Quantitative Determination of Urinary Marker Proteins: A Model to Detect Intrarenal Bioeffects after Extracorporeal Lithotripsy

To detect the source of relevant acute intrarenal side effects after extracorporeal piezoelectric lithotripsy and its impact on repeat treatment, urinary excretion of highly specific marker proteins was determined before (day-1) and after (days 0, 1, 4, 7, 14 and 21) treatment. Marker proteins included high molecular weight alpha-2-macroglobulin, immunoglobulin G, albumin, alpha-1-microglobulin as well as the enzyme N-acetyl-beta-glucosaminidase. Of 50 patients who underwent 4,000 shock waves to caliceal stones (group 1) 15 were identically retreated after 5 (group 2) or 15 (group 3) days, respectively, to determine the shortest safe interval to repeat extracorporeal piezoelectric lithotripsy. The course of lithotripsy damage was also evaluated in 15 pre-damaged kidneys (group 4). The alpha-2-macroglobulin enhancement found in all groups on day 0 (p less than 0.005 to p less than 0.05) documented intrarenal bleeding from ruptured vessels. Ratios of alpha-2-macroglobulin/albumin greater than 2.00 on days 0 and 1 exclude a glomerular source of gross hematuria (groups 1 to 4). There was only slight acute tubular damage after extracorporeal piezoelectric lithotripsy (N-acetyl-beta-glucosaminidase increase, p less than 0.05 for groups 1 to 4). Retreatment after 5 days did not enhance the amount of proteinuria compared to the same patients from group 1 (statistically significant at p less than 0.45 to p less than 0.10). Group 3 also showed a similar elevation of proteinuria as the identical patients pretreated 15 days previously. Thus, the data seem to suggest that early repeat sessions of extracorporeal piezoelectric lithotripsy are as safe as delayed retreatments. The course of proteinuria in group 4 did not suggest enhancement of extracorporeal piezoelectric lithotripsy damage in pre-injured kidneys. The urinary marker alpha-2-macroglobulin detects intrarenal vessel ruptures, which are responsible for intrarenal hematomas, as evidenced by animal and human histology. A model is offered to understand and detect the most important parenchymal bioeffects to minimize the risk of injury.

Enhanced expression of prostate-specific antigen in the transition zone of the prostate. A characterization following prostatectomy for benign hyperplasia.

Objective: To determine whether the serum levels of total prostate-specific antigen (t-PSA), free PSA (f-PSA) and PSA complexed to α1-antichymotrypsin (PSA-ACT) result from different expressions in various prostatic zones. Methods: In a series of 127 consecutive men undergoing transurethral resection of the prostate (TURP) for BPH between May 1995 and February 1996, t-PSA, f-PSA (ProStatus™, Wallac) and PSA-ACT were measured before and 3–4 months after surgery. Pre- and postoperative prostate volumes were measured by TRUS. Resected tissue was assumed to be the transition zone (TZ) while postoperative volume was defined as peripheral zone (including the central one) (CPZ). Pre- and postoperative serum PSA was related to pre- and postoperative volume and resected tissue to the difference between pre- and postoperative serum PSA, respectively. The serum PSA per 1 g tissue was calculated. Group I consisted of 96 historically proven BPH with no signs of inflammation, group II of 19 BPH patients with transurethral catheters inserted sometime prior to surgery to relieve urinary retention, and group III of 12 patients with incidental carcinomas. Results: In patients undergoing TURP without prior catheterization (group I) t-PSA (group I) declined from median 3.43 to 0.96 ng/ml after TURP by 72%, even though the prostate volume did so only by 44%, whereas the ratio free-to-total (f/t) PSA remained stable (median 24.9% pre- vs. 26.6% postoperatively). The TZ expressed approximately 2.7-fold more t-PSA than the remaining CPZ: median 0.14 vs. 0.052 ng/ml/g, respectively, and as to f-PSA it did so likewise: median 0.032 vs. 0.012 ng/ml/g, respectively. With transurethral catheterization prior to surgery (group II) the t-PSA density within whole prostate increased 1.4-fold as compared to this density without such catheterization: from median 0.089 (group I) to 0.13 ng/ml/g tissue, respectively (p < 0.007), and within the TZ alone 1.6-fold elevation from median 0.14 to 0.23 ng/ml/g, respectively (p < 0.02) was observed. In incidental carcinoma (group III) a reduced ratio of f/t PSA of 11.7% in the TZ as compared to 22.1% in the CPZ (22.1%) was observed. Conclusions: In BPH both t-PSA and f-PSA are predominantly expressed within the TZ, which could help to improve the specificity of the PSA density in cancer detection by using the sum of the t-PSA densities of the TZ and CPZ: (0.14 ng/ml/g × TZ) + (0.052 ng/ml/g × CPZ). It is the first time that the supposed origin of the incidental carcinoma (from the TZ) is confirmed biochemically by a f/t PSA ratio exclusively reduced in the TZ but not in the CPZ. The post-TURP unchanged free-to-total ratio (26.6%) may be useful for the early detection of cancer in patients followed up after TURP.

Features and preliminary results of prostate cancer screening in Canton Aargau, Switzerland

To report the results from Switzerlands participation in the ERSPC from 1998; importantly, epidemiological data showed that Switzerland has one of the highest rates of morbidity and mortality from prostate cancer in the world. The local study protocol was accepted by the ethical committee and after the successful pilot study phase, the centre joined the ERSPC.

Pathological stage distribution in patients treated with radical prostatectomy reflecting the need for protocol‐based active surveillance: results from a contemporary European patient cohort

Study Type – Therapy (case series)

Bacillus Calmette-Guérin Failure in Patients with Non–Muscle-invasive Urothelial Carcinoma of the Bladder May Be Due to the Urologist's Failure to Detect Urothelial Carcinoma of the Upper Urinary Tract and Urethra

BACKGROUND Various reasons exist for so-called bacillus Calmette-Guérin (BCG) failure in patients with non-muscle-invasive urothelial bladder carcinoma (NMIBC). OBJECTIVE To explore whether urothelial carcinoma of the upper urinary tract (UUT) and/or prostatic urethra may be a cause for BCG failure. DESIGN, SETTING, AND PARTICIPANTS Retrospective analysis of 110 patients with high-risk NMIBC repeatedly treated with intravesical BCG, diagnosed with disease recurrence, and followed for a median time of 9.1 yr. INTERVENTION Two or more intravesical BCG induction courses without maintenance. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Primary outcome was pattern of disease recurrence (BCG failure) within the urinary tract categorised into UUT and/or urethral carcinoma (with or without intravesical recurrence), and intravesical recurrence alone. Secondary outcome was survival. Predictors of UUT and/or urethral carcinoma and the effect of pattern of disease recurrence on cancer-specific survival were assessed with multivariable Cox regression analysis adjusting for multiple clinical and tumour characteristics. RESULTS AND LIMITATIONS Of the 110 patients, 57 (52%) had UUT and/or urethral carcinoma (with or without intravesical recurrence), and 53 (48%) had intravesical recurrence alone. In patients with UUT and/or urethral carcinoma, bladder carcinoma in situ (Tis) before the first and second BCG course was present in 42 of 57 (74%) and 47 of 57 (82%) patients, respectively. On multivariable analysis, bladder Tis before the first and/or second BCG course was the only independent predictor of UUT and/or urethral carcinoma. Of the 110 patients, 69 (63%) were alive at last follow-up visit, 18 (16%) had died due to metastatic urothelial carcinoma, and 23 (21%) had died of other causes. Pattern of disease recurrence within the urinary tract was not an independent predictor of cancer-specific survival. Main study limitations were retrospective design and limited power for survival analysis. CONCLUSIONS In our patients with high-risk NMIBC failing after two or more courses of intravesical BCG, UUT and/or urethral carcinoma was detected in >50% of the cases during follow-up. The vast majority of these patients had bladder Tis before the first and/or second BCG course. In patients experiencing the so-called BCG failure, a diagnostic work-up of UUT and prostatic urethra should always be performed to exclude urothelial carcinoma before additional intravesical therapy or even a radical cystectomy is considered.