Bert G. Blijenberg

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.).

The value of screening tests in the detection of prostate cancer. Part I: Results of a retrospective evaluation of 1726 men

OBJECTIVES The ratio between free and total prostate-specific antigen (PSA) in serum (F/T ratio) was shown to improve the differentiation between prostate carcinoma and benign conditions in selected series of patients. In this study the F/T ratio was analyzed for its ability to improve the specificity of total serum PSA, digital rectal examination (DRE), and transrectal ultrasonography (TRUS) for the detection of prostate cancer in an unselected screening population of men identified in the Rotterdam population. METHODS In 1726 men between 55 and 76 years old, 67 prostate carcinomas were detected by DRE, TRUS, and total serum PSA (Abbott IMx, Hybritech Tandem E). The DELFIA ProStatus PSA EQM and ProStatus PSA Free/Total assays (Wallac) were applied in retrospect to determine total and free serum PSA. Age, total prostate and inner zone volumes were taken into consideration. RESULTS Sixty-seven carcinomas were detected, two by TRUS and three by DRE alone. Total serum PSA was the most important single predictor of prostate cancer, followed by DRE. The F/T ratio increased the specificity of total serum PSA in the PSA range between 4.0 and 10.0 ng/mL. However, this improved specificity was not significant, nor for gland volumes restricted to 50 mL or less. CONCLUSIONS The combination of total serum PSA and DRE remains the standard for detection of prostate carcinoma in a screening population. Their specificity may be improved minimally by the F/T ratio, but not significantly in a sample of 1726 screened men. The threshold of the F/T ratio, and the optimal PSA range for its application, remains to be assessed prospectively.

THE VALUE OF SCREENING TESTS IN THE DETECTION OF PROSTATE CANCER. PART II: RETROSPECTIVE ANALYSIS OF FREE/TOTAL PROSTATE-SPECIFIC ANALYSIS RATIO, AGE- SPECIFIC REFERENCE RANGES, AND PSA DENSITY"

OBJECTIVES The ratio between free and total prostate-specific antigen (PSA) in serum (F/T ratio) was shown to improve the specificity of total serum PSA for the detection of prostate carcinoma in selected populations. In this study, the value of the F/T ratio for screening of prostate cancer was compared with that of age-specific reference ranges for PSA and PSA density (PSAD) by a simulation experiment. METHODS In 1726 men between 55 and 76 years old, 67 prostate carcinomas were detected by application of digital rectal examination (DRE), transrectal ultrasonography (TRUS), and total serum PSA. A serum PSA of 4.0 ng/mL or more, an abnormal DRE, or an abnormal TRUS were the indications to perform 308 biopsies. A simulation was performed in which an F/T ratio of 0.20 (ProStatus PSA Free/Total), age-specific PSA reference ranges, and a PSAD of 0.12 ng/mL/cc were used to study their capability to increase the specificity of total serum PSA in predicting prostate biopsy results. RESULTS Using age-specific PSA reference ranges and DRE as indicators for biopsy, a reduction of 37% (113) of biopsies would have been obtained with a loss of detected cancers of 12% (11). For the use of PSAD and DRE, these numbers were 28% (96) and 11% (7), respectively. Application of a serum PSA of 4.0 ng/mL or more and an F/T ratio of 0.20 or less and an abnormal DRE as indicators for biopsy would reduce the number of biopsies by 37% (112) and the number of detected cancers by 11% (7). The biopsy to prostate cancer ratio of these simulations varied between 3.3 and 3.6. Minimal loss of cancer detection of 3% (2) with a reduction in the number of biopsies of 17% (53) is obtained when TRUS is omitted from the screening protocol. Selecting men by a total serum PSA value of 2.0 ng/mL for further diagnostic workup by TRUS and DRE would have reduced the number of biopsies by 30% (102), and the number of cancers detected by 6% (4). CONCLUSIONS The most cost-effective protocol for screening prostate carcinoma appears to be prescreening by total serum PSA. The F/T ratio might be used to detect carcinomas in the PSA range below 4.0 ng/mL, but the best threshold remains to be assessed.

European randomized study of screening for prostate cancer—The Rotterdam pilot studies

Five randomized pilot studies of screening for prostate cancer (PC) have been conducted in the area of Rotterdam from 1991 to 1994. The purpose of these studies was to establish the feasibility of a randomized screening protocol with PC mortality as the major end point in The Netherlands and at a European level. All procedures related to recruitment of participants, to application of the screening tests and to data collection were evaluated. Men (7,200) aged 55–74 years were invited through the Rotterdam Population Registry. The recruitment rate over the 5 pilot studies averaged 38.2% (2,747 men). Recruitment procedures proved to be relevant for establishing higher participation rates (invitation and consent by mail). The screening tests were well accepted and tolerated. The general population‐based character of the sample was confirmed by studying symptoms of prostatic disease in participants and in men who refused participation. Data based on one PSA serum determination, rectal examination and transrectal ultrasonography are presented; 204/1,403 men (14.5%) had a positive screening result by either test combination and underwent biopsy. Forty‐nine cancers were found in 1,403 men (3.5%); 65% of prostate cancers (17/26) identified in men who eventually underwent radical prostatectomy proved to be locally confined. From the pilot studies, we conclude that a large contribution to a European Randomized Study of Screening for Prostate Cancer (ERSPC) can be made by recruiting about 40,000 men in the area of Rotterdam. The preliminary data suggest that after confirmation of the present data during the first years in the European study, DRE and TRUS can be withheld depending on the PSA result in a large proportion of the screening population.

The Free-to-Total Serum Prostate Specific Antigen Ratio for Staging Prostate Carcinoma

PURPOSE We analyzed the relationship between the free-to-total PSA ratio and prostate cancer tumor stage and grade compared to total serum PSA. MATERIALS AND METHODS In 123 patients clinical and pathological grade and stage were related to total serum PSA and free-to-total PSA ratio. RESULTS Total serum PSA paralleled clinical staging of prostate cancer. The distributions of total serum PSA and the free-to-total PSA ratio were significantly different between benign and malignant diseases (any stage), and between any T category and nodal disease. For serum PSA significant differences were noted between the distributions of men with locally confined (stages T1 and T2) and locally extended (stage T3) disease, and between all T categories and systemic metastatic disease. This finding was not noted for the free-to-total PSA ratio. CONCLUSIONS The free-to-total PSA ratio has no additional value in clinical staging of prostate carcinoma compared to serum PSA. The free-to-total PSA ratio may be considered the result of cell differentiation and not an indicator of tumor load.

The value of (-7, -5)pro-prostate-specific antigen and human kallikrein-2 as serum markers for grading prostate cancer.

To assess the value of the precursor form (−7,5pro) of prostate‐specific antigen (PSA) and human kallikrein‐2 (hK2) for detecting and grading prostate cancer, as better serum markers with improved specificity are needed in men with lower ranges of total (t)PSA.

Discordant performance of assays for free and total prostate-specific antigen in relation to the early detection of prostate cancer

Objective To assess the value of applying rigid threshold values in interpreting prostate specific antigen (PSA) results, by selecting and comparing five current methods for measuring free and total PSA.

Different PSA Assays Lead to Detection of Prostate Cancers with Identical Histological Features

OBJECTIVE Because different PSA assays still show a wide inter-assay variation, we wondered what influence these discrepancies could have on the individual tumour characteristics of the cancers that each of these assays detect in a critical low PSA range. We analysed five different PSA assays in a biopsy simulation with PSA cut-offs of 3.0 and 4.0 ng/ml. MATERIALS AND METHODS Randomly taken samples of 360 men with prostate cancer and 96 with benign prostatic disease from a screened population with PSA range of 1.0-6.0 ng/ml (Tandem-E) were investigated. In all cases the diagnosis was confirmed by sextant biopsies. One hundred and thirty-seven men (38%) underwent radical prostatectomy. Variability amongst assays was illustrated in terms of missed cancers and unnecessary biopsies, and in terms of pathologic features of detected cancers at both PSA cut-offs. RESULTS Compared to Tandem-E, all assays, except Access, showed significant differences in PSA measurements. Furthermore, none of the assays discriminated significantly between benign and malignant prostatic disease (p>0.05). Tandem-E and Elecsys lead significantly more frequently to the detection of cancers at the cost of more unnecessary biopsies compared to the other assays. Yet, at both PSA cut-offs the proportion of cancers with a certain pathologic grade or stage that were detected by each assay were approximately the same. CONCLUSIONS Our study shows that the use of different PSA assays only have consequences for the number, and not for the tumour characteristics of the prostate cancers that are detected. Thus, different PSA assays detect prostate cancers with the same tumour features.

On the use of prostate-specific antigen for screening of prostate cancer in European Randomised Study for Screening of Prostate Cancer.

Prostate-specific antigen (PSA) has been the main drive for early detection of prostate cancer (PCa), including in population-based screening as in the European Randomised Study for Screening of Prostate Cancer (ERSPC). The specificity of PSA to indicate men with biopsy detectable prostate cancer can be improved by adding information obtained by new biomarkers, such as PSA isoforms. This improvement is needed to increase the efficacy of the screening procedure for the population-based as well as the individual screening. Various PSA isoforms, kallikreins and molecular markers have been validated in various cohorts from ERSPC of men with and without PCa in order to design the optimal diagnostic procedure for screening asymptomatic men. So far, most promising results have been obtained from the analysis of free PSA, proPSA, nicked PSA and hK2. The use of free PSA in addition to total PSA reduces the number of negative sextant biopsies at a PSA cut-off level of 3 ng/ml at initial screening with 30%, at the cost of losing 10% of detectable cancers that are predominantly well differentiated on histology. Further addition of PSA isoforms and hK2 only improve ROC curves in selected samples by a maximum of 5%. Molecular markers like PCA3 and TMPRSS2 in urine do not appear to be useful but they have been assessed insufficiently so far. The level of PSA at initial screening is highly predictive for the chance of being diagnosed with PCa later on in life. The changes in PSA over time after initial screening (like PSA-velocity and PSA-doubling time) are statistically different between men with detectable cancers versus those without (PSA-doubling time 5.1 versus 6.1 years), but this does not contribute significantly to population-based screening overall. Changes in specificity need to be related to a cost efficacy evaluation in the final analysis of ERSPC.