A. Berenguer

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 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.

Reliability of the Routine Cytological Diagnosis in Bladder Cancer

Objectives: To establish the reliability of three cytopathologists for cytological diagnosis of primary bladder tumors. Methods: Preoperative voided urine specimens of 71 patients with bladder cancer and 55 noncancer controls were retrospectively and blindly reviewed by 3 independent cytologists, and their results compared. The estimation of the interobserver agreement was calculated using the weighted κ coefficient. A multivariate analysis was carried out to identify the factors associated with the disagreement between the three observers. The sensitivity and specificity for each of the participants was calculated in order to clearly identify the origin of the disagreement, in terms of the performance of the diagnostic test in the hands of each observer. A comparison of the overall diagnostic performance was made by plotting sensitivity versus 1-specificity. Results: The weighted κ coefficient among the 3 observers was 0.46. The multivariate analysis did not identify any variable that could have caused such disagreement. Vast differences in sensitivity and specificity were detected between observer 1 (sens. 0.90, spec. 0.45) and observers 2 (sens. 0.67, spec. 0.72) and 3 (sens. 0.71, spec. 0.80), but the overall diagnostic performance (sensitivity vs. 1-specificity) was superimposable in the 3 cases (p = NS). Conclusions: Simple, reproducible and agreed-on-diagnostic criteria should be established to yield reliable results in a group of cytologists. The consideration of individual diagnostic performances can give a false idea of homogeneity between observers. In this field, concordance analysis makes quality control reliable and should be a routine procedure of any pathology department.

PSA-Use in a Spanish Industrial Area

OBJECTIVES To document the extent of prostate-specific antigen (PSA)-testing in the general population at Getafe (Spain) outside our prostate cancer (PC) screening program, and to check its performance in terms of PC detection. METHODS A total of 5371 PSA-test records (1997-1999) were reviewed and testing rates estimated per 1000 person-years. The extent of patient referral (men referred to our facilities) was calculated adjusting for PSA levels. To approach the performance of testing in the general population, our PC screening program acted as a standard for comparison. The probability of missing one PC in the general population was estimated in terms of number of men necessary to screen (NNS). Calculations were made adjusting for PSA levels. RESULTS PSA-testing rate in the general population was 21.6/1000 person-years. In the age-group 55-69 years, this rate was 86.8/1000 (152.6 in men >70 years). Referral rates were 67.9 and 39.5% for men with PSA 4-10 and >10 ng/ml, respectively. Overall PC detection rate was 1.76%. Detection rates for PSA 4-10 and >10 ng/ml were 4.66 and 12.94%, respectively. When compared with the performance of the screening program, for every 17 men with a PSA in the range 4-10 ng/ml one cancer was missed (95% confidence interval (CI), 9-580). Similarly, one cancer was lost for every four men with a PSA >10 ng/ml (95% CI, 2-8). CONCLUSIONS The extent of opportunistic testing in our setting is very high, particularly in the older age groups. Opportunistic screening renders PC detection rates lower than expected for every PSA level and cannot be encouraged.

Prostate specific antigen variation in patients without clinically evident prostate cancer.

PURPOSE We address long-term within individual variation of serum prostate specific antigen (PSA) in men without clinical or biopsy evidence of prostate cancer. MATERIALS AND METHODS We studied 943 men from a prostate cancer screening program with 2 PSA (PSA1 and PSA2) measurements available. A third PSA (PSA3) was obtained from 571 men. Only participants with no clinical evidence of cancer were included in the study. Within individual PSA variability was calculated based on indexes of percent coefficient of variation, ratio difference and PSA velocity. The relationship among these indexes, interval between measurements and number of PSA samples was assessed. RESULTS Mean interval was 670.4 days between PSA1 and PSA2, and 801.8 days between PSA2 and PSA3 (p<0.001). Mean coefficient of variation was 18% after 2 and 15.7% after 3 PSA measurements. Mean ratio differences were -0.047 ng./ml. for 2 and 0.033 ng./ml. for 3 samples. Mean PSA velocity was -0.128 ng./ml. per year for 2 and -0.055 ng./ml. per year for 3 samples, with 95% confidence intervals of 0.634 and 0.315, respectively. Variability was higher if only 2 PSA measurements were done (p<0.001). No clear relationship was found between individual variability and interval between measurements. CONCLUSIONS PSA velocity is within normal limits in almost all men (more than 95%) without clinically relevant prostate cancer. PSA individual variability is not fully dependent on the time between measurements when intervals are long, and can be substantially decreased with a third PSA sample.

ROLE OF AUTONOMIC INNERVATION IN RAT PROSTATIC STRUCTURE MAINTENANCE: A MORPHOMETRIC ANALYSIS

PURPOSE To analyze the effects of major pelvic ganglion (MPG) excision on the structure of rat prostate. MATERIALS AND METHODS We studied 80 Sprague-Dawley rats (300-350 gm. weight). Forty-two were anesthetized and the right MPG excised. After 28-30 days, the same-side prostatic ventral lobe (VL) was obtained for macroscopic, light (LM), and transmission electron microscopy (TEM) evaluation. A computerized morphometric analysis was performed on epithelial and muscle cells. Results were compared with 38 right VL of non-operated, same-aged rats. RESULTS A 36.6% reduction (0.14 gm.) of VL fresh weight was found in the denervated group (p <0.001). Mean tissue proportions observed in the LM study were 27.9% (epithelial), 48.3% (stromal), and 51.8% (glandular) in the non-operated group, versus 14.8% (p <0.001), 55.7%, and 44.4% (not significant) respectively, after MPG excision. No difference was found regarding the vascular pattern. In the denervated rats, TEM analysis found a significant reduction in total and supranuclear cell height (change in cell polarity), as well as in cytoplasm, Golgi and endoplasmic reticulum areas. Secretory granule count, total area (p <0.001), and density of apical microvilli were also reduced. On the other hand, only an increase in the area of cytoplasm ribosomal aggregates was detected in the smooth muscle cell analysis. CONCLUSIONS Our study demonstrated a rat prostatic VL atrophy in the denervated side, due to a shrinkage in the epithelial component of the gland. Ultrastructural findings also suggest an overall decrease of epithelial cell secretory activity. Finally, the increase of ribosomal aggregates found in stromal smooth muscle could reflect an activation of these cells after denervation.

Final Results of a Screening Campaign for Prostate Cancer

Objective: To detect curable prostate cancer in a male Spanish population. The results of screening 2,576 men are reported. Patients and Methods: Patients underwent digital rectal examination (DRE) and serum prostate-specific antigen (PSA) determination. Any patient with suspicious DRE or PSA >4 ng/ml was further evaluated with transrectal ultrasonography (TRUS) and biopsy. The sensitivity, specificity and predictive value of the tests or combinations of tests were determined. Results: Mean age was 59.9 years (median 58 years). Ninety-four patients (3.6%) had abnormal DRE while PSA was >4 ng/ml in 169 patients (6.5% of the total). We needed 6.8 biopsies to prove one cancer. PSA had the highest sensitivity (93%), whereas DRE had the highest specificity (97%). The positive predictive value rose to 78.9% when both DRE and PSA were abnormal. Clinically advanced tumor stages (≥ T3) were commoner (39.4%) than in similar series. Conclusions: PSA should be the first diagnostic test in a screening program for prostate cancer. Neither DRE nor TRUS are necessary in patients with PSA <4 ng/ml. In the light of our findings, we cannot encourage screening programs for prostate cancer for the time being.

Application of self-expanding stents in prostate cancer with rectal involvement. Report of two cases and review of the literature

OBJECTIVES Rectal involvement due to local spread from prostate cancer is an uncommon finding. When this condition occurs, prognosis is ominous. Our objective is to report our experience in the use of self-expanding endorectal stents in the management of rectal invasion from prostate cancer. Two cases are presented and a review of the literature is carried out. METHODS AND RESULTS In both cases, self-expanding Wallstent devices were placed (under fluoroscopic control), in order to solve their episodes of bowel obstruction. It was successfully performed in both patients. Therefore, an open surgery procedure was avoided. CONCLUSIONS When facing the evidence of a tumor that invades the rectal wall, it is important to rule out the existence of prostate cancer (the surgical option in these patients carries an ominous prognosis). Therefore, we propose this new procedure whose results could be very satisfactory in certain settings.