Andreas Reissigl

Prostate cancer mortality after introduction of prostate-specific antigen mass screening in the federal state of tyrol, Austria

Objectives. To monitor the impact of screening in a natural experiment by comparing prostate cancer mortality in Tyrol, where prostate-specific antigen (PSA) testing was introduced at no charge, with the rest of Austria, where it was not introduced. Methods. In 1993, PSA testing was made freely available to men aged 45 to 75 years in the Federal State of Tyrol, Austria. At least two thirds of all men in this age range have been tested at least once during the first 5 years of the study. Initially, only total PSA was measured, but free PSA measurement was added in 1995. The IMX assay was used. Digital rectal examination was not part of the screening examination. Results. Significant migration to lower stages has been observed since the introduction of this screening program. A reduction in mortality rates in the rest of Austria from 1993 onward has occurred, with the reduction in Tyrol much greater; the mortality remained fairly constant between 1993 and 1995 and subsequently fell. The trends in prostate cancer mortality rates since 1993 differ significantly between Tyrol (P = 0.006) and the rest of Austria. On the basis of the age-specific death rates averaged from 1986 to 1990, the difference between the number of expected and observed deaths from prostate cancer in Tyrol was 22 in the group aged 40 to 79 years in 1998 and 18 the following year. Conclusions. These findings are consistent with the hypothesis that the policy of making PSA testing freely available, and the wide acceptance by men in the population, is associated with a reduction in prostate cancer mortality in an area in which urology services and radiotherapy are available freely to all patients. It is our opinion that most of this decline is likely to be due to aggressive downstaging and successful treatment and that any contribution from detecting and treating early cancers will only become apparent in the years to come.

Complexed prostate-specific antigen, complexed prostate-specific antigen density of total and transition zone, complexed/total prostate-specific antigen ratio, free-to-total prostate-specific antigen ratio, density of total and transition zone prostate-specific antigen: results of the prospective multicenter European trial

This prospective, multicenter European Prostate Cancer Detection study evaluated the value and performance of the molecular forms of prostate-specific antigen (PSA) and their derivatives in combination with prostate gland and transition zone volumes in early detection of prostate cancer in patients with PSA levels between 4 and 10 ng/mL. Of 750 men enrolled at 7 different European urology centers into the study between November 2001 and March 2002, 340 (45.3%) had a total PSA (tPSA) between 4 and 10 ng/mL (age range, 46 to 87 years). In all patients, the ratio of complexed PSA (cPSA) to tPSA (c/tPSA), cPSA density (cPSAD), cPSAD of the transition zone, PSA, free PSA (fPSA), ratio of fPSA to tPSA (f/tPSA), tPSA density (PSAD), and PSAD of the transition zone were measured and collected 5 to 10 minutes before the sextant biopsy with 2 additional transition zone cores. Measurements of tPSA and fPSA were done with the AxSYM test, whereas cPSA was measured with the ACS 180 cPSA assay. All patients had a transrectal ultrasound-guided sextant prostate biopsy, and 2 additional transition zone biopsies and total and transition zone volumes were measured at the time of biopsy. Histopathologic findings revealed benign histology in 237 patients and prostate cancer in 103 patients (69.7% and 30.3%, respectively). Statistically significant differences included larger total volumes, larger transition zone volumes, and f/tPSA in patients with benign disease (P = 0.0009, P <0.0001, P <0.0001, respectively). At 90% and 95% sensitivity, specificity of cPSA was significantly greater than that for PSA (P <0.0001). At sensitivity levels of 90% and 95%, the specificity of the cPSA assay using cutoff values of 3.06 and 2.52 ng/mL was 20.3% and 9.1%, respectively. A cPSA cutoff value of 6.95 ng/mL and 7.57 ng/mL afforded 90% and 95% specificity for detecting prostate cancer. The area under the curve (AUC) in the receiver operating characteristics curve of cPSA was statistically significantly higher compared with tPSA (60.8 vs 56.9, P = 0.032). AUC for volume-related parameters PSAD, cPSAD, PSAD of the transition zone, and cPSAD of the transition zone were 62.8%, 63.1%, 63.0%, and 63.6%, respectively. cPSA performs better than tPSA in the differentiation between benign disease and prostate cancer and provides similar information to the f/tPSA ratio. In addition, cPSA and cPSA volume-related parameters (cPSAD, cPSAD of the transition zone) further improved the specificity of PSA in early detection of prostate cancer.

Prostate Cancer Screening in Tyrol, Austria: Experience and Results

Background: This article summarizes the experience and results of different prostate carcinoma screening projects using total prostate-specific antigen (PSA) and percent free PSA as the initial test. Methods: The twelve projects studied included: (1) a mass screening study using PSA as the initial test in 21,079 volunteers; (2) an investigation of the usefulness of normal and age-referenced PSA cut-offs in 1,618 men; (3) a PSA-based screening study of 2,272 asymptomatic blood donors; (4) an investigation of the evidence and significance of transition zone carcinoma in 340 men with negative digital rectal examination findings; (5) determination of percent free PSA in one retrospective and two prospective studies to determine the appropriate cutpoints for percent free PSA; (6) evaluation of the diagnostic benefit of PSA transition zone density in 308 screening volunteers; (7) a study of the impact of PSA-based screening on the percentage of incidental prostate carcinoma in 1,543 men undergoing transurethral resection of the prostate; (8) an evaluation of the changes in total PSA and pathologic stages in radical prostatectomy over 5 years in a PSA-based mass screening program; (9) a study evaluating the probability of having prostate cancer given the patient’s age, total PSA and digital rectal examination findings; (10) an evaluation of the correlation between preoperative predictors and pathologic features in radical prostatectomy specimens; (11) an investigation of the correlation of total PSA with pathologic stage and tumor volume in patients undergoing radical prostatectomy with low PSA cut-off level, and (12) a study whether age has an impact on the extension of prostate cancer. Results: (1) of the 21,079 volunteers, 1,618 (8%) had elevated PSA levels. Of these men, 778 (48%) underwent biopsies; 197 biopsies were positive for prostate carcinoma and 135 underwent radical prostatectomy. Ninety-five were found to be organ-confined. (2) A PSA cut-off of 2.5 ng/ml in men aged 45–49 years and of 3.5 ng/ml in men aged 50–59 years resulted in an 8% increase in the detection rate of organ-confined disease. (3) Of the 2,272 men, 284 had elevated PSA levels and prostate carcinoma was detected in 62 men. All patients underwent radical prostatectomy and histologic examination revealed organ-confined tumor in all but 8 men. (4) Ninety-eight of 340 men had biopsies positive for carcinoma; 28 of these patients (28.5%) had carcinoma that originated in the transition zone only. (5) In the retrospective study, receiver-operating characteristic curve analysis showed that by using a percent free PSA of 18% as a biopsy criterion, 37% of the negative biopsies could be eliminated although 94% of all carcinomas would still be detected. In the first prospective study, 106 of 158 men with elevated PSA levels <10.0 ng/ml were further evaluated and 37 prostate carcinomas were detected. By using a % free PSA of <22% as a biopsy criterion, 30% of the negative biopsies could be eliminated although 98% of the carcinomas would still be detected. In the second prospective study, 120 of 465 men with total PSA levels between 1.25 and 6.49 ng/ml and a % free PSA <18% were further evaluated and 27 (22.5%) were found to have prostate carcinomas. (6) Receiver-operating characteristic curve analysis for PSA transition zone density showed that by using a PSA transition zone density of >22 ng/ml/cm3 as a biopsy criterion, 24.4% of negative biopsies could be avoided without missing a single carcinoma. (7) In the prescreening era the incidence of T1a grade 1 and 2 carcinomas was 3.1% and the incidence of T1a grade 3 and T1b carcinoma was 2.3% whereas in the years after the establishment of PSA-based screening the incidence was 4.6 and 1.03% respectively. (8) The rate of organ-confined tumors increased from 28.7% in 1993 to 65.7% in 1997. (9) In this evaluation a new approach to proceed with a prostate biopsy based upon the individual risk of having prostate cancer rather than a single PSA cutpoint was developed. (10) High total PSA levels, PSA density and PSA transition zone density correlated significantly with high Gleason scores, capsular penetration, a high percentage of cancer in the prostatectomy specimen and a high cancer volume. (11) In this evaluation all of the 95 patients with PSA levels <3.99 ng/ml who underwent radical prostatectomy showed clinically significant, organ-confined prostate cancer with negative surgical margins. (12) The results of this evaluation suggest that older men have larger tumor volumes compared to younger men with the same PSA levels. Conclusions: These data suggest that PSA-based screening with low PSA cut-off values increase the detection rate of clinically significant, organ-confined and potentially curable prostate cancer. Percent free PSA and PSA transition zone density provide an additional diagnostic benefit over total PSA.

Basic fibroblast growth factor levels in cancer cells and in sera of patients suffering from proliferative disorders of the prostate.

Both benign and malignant growth of the prostate depend on the induction of a microvasculature. Basic fibroblast growth factor (bFGF), a potent angiogenic factor, is thought to play an important role in this process.

Evaluation and comparison of two new prostate carcinoma markers: Free-prostate specific antigen and prostate specific membrane antigen

Two new prostate cancer markers, free‐prostate specific antigen (f‐PSA) and prostate specific membrane antigen (PSMA) were recently introduced. This report summarizes a prospective two‐year multicenter test of their diagnostic or prognostic capabilities. Total PSA was also measured.

Comparison of different prostate-specific antigen cutpoints for early detection of prostate cancer: Results of a large screening study

OBJECTIVES This study was designed to compare the usefulness of the normal prostate-specific antigen (PSA) level and the age-referenced PSA level in a large screening study for early detection of prostate cancer. METHODS A total of 21,078 subjects (aged 45 to 75 years) were participants in a 1-year prostate cancer screening project with PSA as the initial test. Of the volunteers, 1618 (8%) showed an elevated PSA level according to age-specific reference ranges, and using the normal PSA cutoff point (4.0 ng/mL), 1872 (9%) had elevated PSA levels between 4.0 and 6.5 ng/mL. RESULTS Biopsies in both groups were performed if the PSA level was elevated. We evaluated the effect on biopsy rate and cancer detection. A PSA cutoff point of 2.5 ng/mL in men 45 to 49 years old and a PSA cutoff point of 3.5 ng/mL in men 50 to 59 years old with normal digital rectal examination findings resulted in an 8% increase in the number of biopsies (66 of 778) and an 8% increase in organ-confined cancer detection. An increasing cutoff of 4.5 ng/mL in men 60 to 69 years old and 6.5 ng/mL in men 70 to 75 years old resulted in 21% fewer biopsies (205 of 983) and would have missed 4% of organ-confined tumors (8 of 220). CONCLUSIONS We conclude that the use of PSA age-specific reference ranges increases the detection of clinically important and organ-confined cancers in young men and decreases the number of biopsies in older men.

TRANSURETHRAL ULTRASOUND: EVALUATION OF ANATOMY AND FUNCTION OF THE RHABDOSPHINCTER OF THE MALE URETHRA

PURPOSE A combined anatomic-sonographic study was undertaken to investigate whether the anatomical arrangement and the contractions of the rhabdosphincter of the male urethra could be visualized by transurethral ultrasound. Furthermore, this new technique was compared with standard urodynamic tests. MATERIALS AND METHODS In 7 cadavers transurethral ultrasound was performed to define sono-morphological criteria of the rhabdosphincter, and the sonographic pictures were then compared to histological sections. In 48 patients the rhabdosphincter of the male urethra was investigated by transurethral ultrasound and urodynamic techniques. Of these patients 40 were completely continent after radical prostatectomy and 8 presented with urinary stress incontinence after transurethral resection of the prostate or radical prostatectomy. The decrease of the distance between the rhabdosphincter and the transducer during contraction served as quantitative parameter for the contractility of the muscle. RESULTS The anatomical arrangement and contractions of the rhabdosphincter loop could be clearly visualized on transurethral ultrasound (during contraction the rhabdosphincter retracts the urethra, pulling it towards the rectum). Ultrasound showed scars in 3 patients with postoperative urinary stress incontinence, thinning of the muscle in 3 complete atrophy of the rhabdosphincter in 2 and minimal contractions of the rhabdosphincter in 1. Urethral closure pressures were decreased and decrease in rhabdosphincter-transducer distance was statistically significantly decreased in the incontinent patients. CONCLUSIONS Our sono-morphological data and anatomical histological results strongly suggest that the rhabdosphincter constitutes the main component of the continence mechanism in post-prostatectomy patients. Unlike urethral pressure profiles, which can only reveal zones of higher intraluminal pressure between the bladder and the penile urethra, transurethral ultrasound is highly specific for measurement of the function of the rhabdosphincter.

Frequency and clinical significance of transition zone cancer in prostate cancer screening

Approximately 20% of prostate cancers originate in the transition zone (TZ). Although transrectal ultrasound (TRUS) and systematic biopsies have improved peripheral zone (PZ) cancer diagnosis, additional biopsies directed into the TZ may further improve cancer detection.

Improvement of specificity in PSA-based screening by using PSA-transition zone density and percent free PSA in addition to total PSA levels

The clinical value of prostate‐specific antigen (PSA) density in differentiating between prostate cancer and benign prostatic hyperplasia has been the subject of several studies. In this context the question has been raised about the diagnostic benefit of PSA transition‐zone density (PSA‐TZ density = total PSA/transition‐zone volume) in the detection of prostate cancer. In the following study the value of PSA‐TZ density alone and in combination with free PSA was investigated.

Measurement of serum prostate-specific membrane antigen, a new prognostic marker for prostate cancer

OBJECTIVES To describe current results with Western blot assay for prostate specific membrane antigen (PSMA) using 7E11.C5 antibody and the development of an additional antibody measurement for PSMA by a new sandwich immunoassay. METHODS A population of patients from a screening group, from a difficult diagnostic group, from a pre- and postoperative radical prostatectomy group, and from a group with metastatic disease followed for a serial period, provided the serum values for a prospective assessment of PSMA by Western blot assay. A new monoclonal antibody was sought, reacting to the C-terminal region of PSMA in order to develop a sandwich radioimmunoassay. RESULTS PSMA values in screened patients correlate with the more advanced stage of the cancers determined. In postprostatectomy patients, the PSMA value corresponds more with preoperative values and with the values of those with a poor clinical course. In difficult diagnostic cases, the PSMA value is increased, specifically in hormone-refractory cases and particularly in those cases judged by other criteria, such as the National Prostatic Cancer Project, to be in clinical progression compared with those judged to be in clinical remission. The level of PSMA value appears to be independent of homogeneous tumor volume and to be more related to that of prior hormone treatment, or to where prostate cancer cells can be documented to be outside the prostate. A new monoclonal antibody, 3F5.4G6, reacts with the extracellular domain of PSMA near the C-terminal region. This is in contrast to the previously measured antibody 7E11.C5, which reacts with an N-terminal epitope. 3F5.4G6 recognizes the same PSMA protein as does 7E11.C5. The epitopes are essentially at opposite ends of the molecule. The 3F5.4G6 antibody reacts with the LNCaP line but not with DU145, or PC3. These two antibodies to PSMA are well suited for use in a new sandwich immunoassay. CONCLUSIONS PSMA provides a prostatic cancer serum test by using Western blot, which suggests a clinical prognostic value not seen with other markers. New antibodies, such as 3F5.4G6, reacting with the extracellular domain of PSMA combined with 7E11.C5, appear to offer an opportunity for a new sandwich immunoassay.