Screening for prostate cancer: results of the Rotterdam section of the European randomized study of screening for prostate cancer.

BACKGROUND: Evidence from randomized trials on the effects of screening for prostate cancer (PCa) on disease-specific mortality accumulates slowly with increasing follow-up. OBJECTIVE: To assess data on PCa-specific mortality in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial. DESIGN, SETTING, AND PARTICIPANTS: A randomized controlled trial with randomization after signed, written informed consent (efficacy trial). In the period 1993-1999, a total of 42 376 men aged 54-74 yr were randomized to a screening arm (S-arm) (n = 21 210 with screening every 4 yr, applying a total prostate-specific antigen [PSA] level cut-off ≥ 3.0 ng/ml as biopsy indication) or a control arm (C-arm) (n = 21 166; no intervention). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Number of PCas detected per arm depicted by predefined time periods and prognostic groups. PCa-specific mortality analyses using Poisson regression in age group 55-74 yr at randomization and separately in the predefined age group of 55-69 yr. RESULTS AND LIMITATIONS: After a median follow-up of 12.8 yr, 19 765 men (94.2%) were screened at least once and 2674 PCas were detected (of which 561 [21.0%] were interval PCas). In the C-arm, 1430 PCas were detected, resulting in an excess incidence of 59 PCas per 1000 men randomized (61 PCas per 1000 in age group 55-69 yr). Thirty-two percent of all men randomized have died. PCa-specific mortality relative-risk (RR) reductions of 20.0% overall (age: 55-74 yr; p = 0.042) and 31.6% (age: 55-69 yr; p = 0.004) were found. A 14.1% increase was found in men aged 70-74 yr (not statistically significant). Absolute PCa mortality was 1.8 per 1000 men randomized (2.6 per 1000 men randomized in age group 55-69 yr). The number needed to invite and number needed to manage were 565 and 33, respectively, for age group 55-74 yr, and 392 and 24, respectively, for age group 65-69 yr. Given the slow natural history of the disease, follow-up might be too short. CONCLUSIONS: Systematic PSA-based screening reduced PCa-specific mortality by 32% in the age range of 55-69 yr. The roughly twofold higher incidence in the S-arm underlines the importance of tools to better identify those men who would benefit from screening.

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.).

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.

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.)

hK2 and free PSA, a prognostic combination in predicting minimal prostate cancer in screen-detected men within the PSA range 4-10 ng/ml.

OBJECTIVES: The purpose of screening for prostate cancer is to decrease the disease-specific mortality. However not every screen-detected prostate cancer is a threat to the patient's life. The risk of overdetection and subsequent overtreatment in prostate cancer has been recognised. The purpose of this investigation was to evaluate the role of tumour markers total PSA, free PSA, and hK2, and their combinations in predicting minimal prostate cancer. METHODS: Within the European Randomized Study of Screening for Prostate Cancer (ERSPC), section Rotterdam, The Netherlands, prebiopsy serum samples were analysed for 100 selected men who underwent a radical prostatectomy for their screen-detected prostate cancer. All had a PSA value between 4 and 10 ng/ml prior to diagnosis. Minimal prostate cancer is defined as organ confined, Gleason score

Assay-specific artificial neural networks for five different PSA assays and populations with PSA 2-10 ng/ml in 4,480 men.

Use of percent free PSA (%fPSA) and artificial neural networks (ANNs) can eliminate unnecessary prostate biopsies. In a total of 4,480 patients from five centers with PSA concentrations in the range of 2-10 ng/ml an IMMULITE PSA-based ANN (iANN) was compared with other PSA assay-adapted ANNs (nANNs) to investigate the impact of different PSA assays. ANN data were generated with PSA, fPSA (assays from Abbott, Beckman, DPC, Roche or Wallac), age, prostate volume, and DRE status. In 15 different ROC analyses, the area under the curve (AUC) in the PSA ranges 2-4, 2-10, and 4-10 ng/ml for the nANN was always significantly larger than the AUC for %fPSA or PSA. The nANN and logistic regression models mostly also performed better than the iANN. Therefore, for each patient population, PSA assay-specific ANNs should be used to optimize the ANN outcome in order to reduce the number of unnecessary biopsies.

Additional use of [-2] precursor prostate-specific antigen and "benign" PSA at diagnosis in screen-detected prostate cancer.

OBJECTIVES: To evaluate the adjuvant clinical use of [-2] precursor prostate-specific antigen ([-2]pPSA), which is associated with prostate cancer (PCa), and "benign" PSA, related to benign prostatic hyperplasia, in selecting a treatment strategy in patients with screen-detected PCa. METHODS: Research-use immunoassays (Beckman Coulter) were used to measure [-2]pPSA, sum [-7, -5, -4, and -2]pPSA, and benign PSA from the frozen serum of participants from the screen arm of the European Randomized Study of Screening for Prostate Cancer, section Rotterdam, diagnosed with PCa with a serum PSA level lower than 15 ng/mL. We compared men with relatively benign PCa (Epstein's criteria; group 1) and men with arbitrarily defined aggressive PCa characteristics (Gleason score greater than 4 + 4 and more than four cores with PCa invasion or pT3C disease; group 2). RESULTS: The data of 61 patients were evaluated. The median age in both groups was 68 years. Total PSA performed best in a univariate analysis, although in the multivariate analysis, the combination of pPSA and percent free PSA could correctly predict 95.5% of group 1 and 82.4% of group 2. The pPSA and percent free PSA forms remained statistically significant in the multivariate analysis of a subgroup of 30 participants normalized for PSA level and prostate volume; combined they correctly identified 89.5% and 54.5% of patients identified as having relatively favorable and aggressive PCa characteristics, respectively. CONCLUSIONS: Adjuvant clinical use of pPSA over traditional parameters in selecting treatment strategies for men with PCa cannot yet be definitely determined. However, the promising results in a subgroup analysis warrant further investigation.

Prostate cancer characteristics and prostate specific antigen changes in screening detected patients initially treated with a watchful waiting policy.

PURPOSE: We evaluated prostate cancer (PCa) characteristics at diagnosis and changes in prostatic specific antigen (PSA) with time in males with screening detected PCa that was initially managed with a watchful waiting policy. MATERIALS AND METHODS: Patients with histologically proven PCa and PSA less than 10 ng/ml were selected from the European Randomized Study of Screening for Prostate Cancer, section Rotterdam. The choice of initiating a watchful waiting policy was patient desire or physician advice. PSA slope and PSA doubling time (PSADT) were calculated in patients with 3 or more PSA tests results available. RESULTS: A total of 191 patients were included. Mean age at diagnosis was 69 years and mean PSA was 3.9 ng/ml. Of the patients 92.6% had a Gleason score of 3 + 3 or lower, 133 had a followup of greater than 12 months (mean 40) and 35 (29.2%) had a negative PSA slope. Mean PSADT was 9.7 years (range 0.3 to 155) in 85 males with a positive PSA slope. During followup 30 patients changed therapy. CONCLUSIONS: Watchful waiting remains a controversial prostate cancer treatment strategy. In select screening detected patients with PCa there appears to be a subgroup with stable or even decreasing PSA values with time. These males could profit from a watchful waiting policy with possible deferred treatment. Together with conventional tumor parameters at diagnosis PSADT and PSA slope during followup could be used to monitor tumor activity and possibly aid in determining the time of deferred treatment. Further followup is mandatory to validate these results.

Prostate cancer detection in the prostate specific antigen range of 2.0 to 3.9 ng/ml: value of percent free prostate specific antigen on tumor detection and tumor aggressiveness.

PURPOSE: We evaluated the positive predictive value and cancer detection rate in the prostate specific antigen (PSA) range of 2.0 to 3.9 ng/ml and assessed the value of percent free (F) PSA (FPSA) on tumor detection and tumor aggressiveness in this low PSA range. MATERIALS AND METHODS: Of 3623 men who were attending the second round of screening within the European Randomized Study of Screening for Prostate Cancer, section Rotterdam 883 had PSA values of 2.0 to 3.9 ng/ml. These men were offered laterally directed sextant biopsy. FPSA was prospectively determined from pretreatment serum. Cancers were classified as prognostically favorable and unfavorable using biopsy results and other pretreatment diagnostic features. RESULTS: Using the PSA range of 2.0 to 3.9 ng/ml as a biopsy indication 126 cancers were detected, resulting in a positive predictive value of 17.1% and a cancer detection rate of 14.3%. By using percent FPSA and setting relative sensitivity at 95% 9% of biopsies could have been avoided. Unfavorable tumor characteristics were found in 46.9% of the men with T1C tumors. Mean percent FPSA was significantly lower in such men compared to men with favorable tumor characteristics. Of the men with percent FPSA lower than 10% 90% had unfavorable tumor characteristics. CONCLUSIONS: The PSA range 2.0 to 3.9 ng/ml is accessible for prostate cancer screening. Percent FPSA is of moderate value in avoiding unnecessary biopsies in the PSA range of 2.0 to 3.9 ng/ml. However, when assessing tumor aggressiveness in biopsy results, percent FPSA is predictive and can be used to select treatment options, such as watchful waiting.

Technical performance and diagnostic utility of the new Elecsys neuron-specific enolase enzyme immunoassay.

This international multicenter study was designed to evaluate the technical performance of the new double-monoclonal, single-step Elecsys neuron-specific enolase (NSE) enzyme immunoassay (EIA) and to assess its utility as a sensitive and specific test for the diagnosis of small-cell lung cancer (SCLC). Intra- and interassay coefficients of variation, determined in five control or serum specimens in six laboratories, ranged from 0.7 to 5.3 (inter-laboratory median: 1.3%) and from 1.3 to 8.5 (inter-laboratory median: 3.4%), respectively. Laboratory-to-laboratory comparability was excellent with respect to recovery and inter-assay coefficients of variation. The test was linear between 0.0 and 320 ng/ml (highest measured concentration). There was a significant correlation between NSE concentrations measured using the Elecsys NSE and the established Cobas Core NSE EIA II in all subjects (n = 723) and in patients with lung cancer (n = 333). However, NSE concentrations were systematically lower (approximately 9%) with the Elecsys NSE than with the comparison test. Based on a specificity of 95% in comparison with the group suffering from benign lung diseases (n = 183), the cut-off value for the discrimination between malignant and benign conditions was set at 21.6 ng/ml. NSE was raised in 73.4% of SCLC patients (n = 188) and was significantly higher (p < 0.01) in extensive (87.8%) as opposed to limited disease (56.7%). NSE was also elevated in 16.0% of the cases with non-small cell lung cancer (NSCLC, n = 374). It is concluded that the Elecsys NSE EIA is a reliable and accurate diagnostic procedure for the measurement of NSE in serum samples. The special merits of this new assay are the wide measuring range (according to manufacturer's declaration up to 370 ng/ml) and a short incubation time of 18 min.

Persistent leukocyturia and loss of renal function in a prospectively monitored cohort of HIV-infected patients treated with indinavir.

Symptomatic nephrotoxicity is a well-known complication of indinavir treatment. However, little is known about the relevance of other abnormalities, such as leukocyturia during use of indinavir. We determined the prevalence, risk factors, and consequences of persistent leukocyturia in a prospectively monitored cohort of indinavir users in three adult outpatient clinics. Patients were monitored for nephrotoxicity at regular visits (every 3 months) between August 1998 and September 2000. Monitoring involved urine dipstick analysis and microscopy for pH, erythrocytes, leukocytes, and indinavir crystals. The urine albumin concentration/creatinine concentration ratio and serum creatinine and indinavir plasma concentrations were measured, and urinary tract infection was excluded. Urologic symptoms were retrieved from medical records. Of 184 patients with at least one assessment, 35% had leukocyturia (i.e., >75 cells/microL) at least once during the study period, which coincided with mild increase in the serum albumin level, erythrocyturia, and crystalluria. Thirty-two (24%) of 134 patients with two or more assessments had persistent leukocyturia (i.e., on two or more occasions). Risk factors were indinavir plasma concentration of >9 mg/L, urine pH of >5.7, and crystalluria. Persistent leukocyturia was associated with a gradual loss of renal function but not with urologic symptoms. The data show that leukocyturia is a frequent finding and emphasize the need for monitoring renal function during indinavir treatment, even in the absence of urologic symptoms.

Comparison of two assays for human kallikrein 2.

BACKGROUND: We compared two recently developed research assays for the measurement of human kallikrein 2 (hK2) in serum: one fully automated assay (Beckman Coulter Access immunoanalyzer) and one manual assay based on the DELFIA technology. METHODS: We used two subsets of clinical specimens consisting of 48 samples from prostate cancer patients and 210 samples from participants in an ongoing screening study (ERSPC). Both subsets were measured in the Rotterdam laboratory, and the prostate cancer samples were used for analytical comparison with the originating sites for the assays: Beckman Coulter Research Department (San Diego, CA) and Turku University (Turku, Finland). RESULTS: Both the Beckman Coulter and the Turku assays performed very similarly between the Rotterdam laboratory and the originating sites: the R(2) value for both comparisons was 0.99, and the slope difference between sites was <20%. Deming regression analysis of the DELFIA (y) and Access (x) assays yielded the following: for the prostate cancer group, y = 1.17x - 0.01 (R(2) = 0.88; n = 48); and for the ERSPC group, y = 0.62x - 0.01 (R(2) = 0.77). Breakdown of the latter group into subgroups (nondiseased, benign prostatic hyperplasia, and prostate cancer samples) gave only minor differences. The Access calibrators were underrecovered by 13% in the DELFIA assay, whereas the DELFIA calibrators were overrecovered by 45% in the Access assay. CONCLUSION: The DELFIA and Access assays for hK2, which have similar analytical features, show differences that cannot be explained by calibration.