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Background: In prostate cancer (PCa) screening men and their physicians aim to rule out the presence of potentially life threatening PCa. To date, prostate specific antigen (PSA) testing and systematic prostate biopsy (Bx)-in case of an elevated PSA-are still the main modes of PCa detection. Often uncertainty remains when a PSA-test is < 3.0 ng/mL or a Bx shows a benign result, leading to the continuous repeating of procedures. Here we assess the potential consequences of false negatives by studying follow-up data of a purely PSA-based approach with applying sextant Bx, an approach considered to have a high risk of missing PCa diagnosis. Methods: Our study population consisted of 19,970 men from the ERSPC project section Rotterdam, initially screened in 1993-1999. We assessed clinically significant Gleason ≥3+4 PCa (csPCa) diagnosis within the 4-year screening interval and subsequent screening round 4 years later in men having a PSA < 3.0 ng/mL at initial screening (no Bx) and men with Bx (PSA > 3.0 ng/mL), but no PCa detected at that time. In addition, we addressed PCa mortality and PCa diagnosis for men with a negative PSA test and negative Bx, who were retested every 4 years covering a 15-year follow-up. Results: A total of 14,935 men had PSA < 3.0 ng/mL in the initial screening round, of whom 75 (0.5%) were diagnosed with csPCa at a subsequent screening examination and 2 ( < 0.1%) in the 4-year screening interval. For 2,260 men with a previously negative Bx at first screening, the figures were 17 (0.8%) and 2 (0.1%) respectively. Indolent PCa (Gleason ≥3+3) was diagnosed in 312 (2%) men with PSA < 3.0 ng/mL initially and 115 (5%) men with initial negative Bx. After a 15-year follow-up, 45 (0.3%) PCa deaths occurred in men with initially low PSA, and 29 men (0.2%) had metastasis. For men with negative Bx, 11 (0.5%) PCa deaths occurred and 4 (0.2%) experienced metastasis. Conclusions: The false negative rates for men with PSA < 3.0 ng/mL and negative sextant Bx are extremely low but not negligible. Proper risk stratification before deciding to biopsy is expected to hardly miss any clinical significant PCa diagnosis. This is especially relevant with the increased use of the relatively expensive multi-parametric magnetic resonance imaging (mpMRI) guided targeted Bx procedures.

Introduction : Though recent research from the last decade has led to a harmonization of results for free and total PSA, we still have to accept variation between assays regarding recovery. Surveys held in 2002 and 2003 in The Netherlands show differences up till 20-25% for total PSA and even more for free PSA based on recovery values, differences that may influence clinical decision making. In this study we have tried to answer the question whether or not deviations from equimolarity play a role as contribution to the differences in PSA values. To that end we have compared three state-of-the-art assays for PSA with samples coming from an ongoing screening study for prostate cancer (ERSPC). Results : In total 199 serum samples were analyzed for free and total PSA by applying Beckman, PerkinElmer-Wallac and Roche. Excellent correlations were found between all assays for total PSA and minor correlations for free PSA. Access and E170 proved to differ by 6-7% for total PSA (Access being the highest) while Access and Prostatus were identical, statistically speaking. For free PSA the differences were 4% for the comparison Access and E170 and 11% for Access and Prostatus. A division of the whole collection into two groups wit a lower and a higher concentration free PSA didn't show any difference in regression line for total PSA with Access and E170 while Access and Prostatus differed by 3-4%. Furthermore, a considerable spread was found in all free PSA comparisons. Conclusions : 1. All assays proved to measure total PSA more or less equimolarly. We only found very small differences in the Access-Prostatus comparison with two sample groups based on a low and high free PSA concentration. These results show that limited differences in equimolarity cannot explain the differences in recovery of total PSA as seen in surveys. 2. We found differences in recovery for free PSA (though limited) and spread in the results. This means in our view that care must be taken in using free/total PSA values in clinical decision making. Measuring free and total PSA with assays from two different manufacturers should be avoided.

Objective: Investigation of the application of WHO calibrators for PSA (WHO 96/670 and WHO 96/668) in relationship with new developments regarding PSA measurements. Methods: The PSA assays used were those for Access, Elecsys and ACS: 180. We used 200 clinically described samples (BPH and PCa). Results: Comparing the manufacturer's calibration procedure with the WHO calibrators, revealed for total PSA slopes of 1.22, 0.92 and 1.04 for Access, Elecsys and ACS: 180 respectively. For free PSA we found 1.28, 0.83 and 1.62. Measurement of these calibrators in combination with the measurement of the clinical samples indicated that the methods for total PSA may be assumed equimolar. Conclusion: We found a good comparibility for free and total PSA. However, good interchangability of results is still not possible, due to the lack of reference methods.