Clinical Chemistry
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Clinical Chemistry 54: 1999-2006, 2008. First published October 16, 2008; 10.1373/clinchem.2007.102699
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Supplemental Data
Right arrow All Versions of this Article:
clinchem.2007.102699v1
54/12/1999    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Web of Science (3)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jansen, F. H.
Right arrow Articles by van Schaik, R. H. N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jansen, F. H.
Right arrow Articles by van Schaik, R. H. N.
(Clinical Chemistry. 2008;54:1999-2006.)
© 2008 American Association for Clinical Chemistry, Inc.

Cancer Diagnostics

Clinical Impact of New Prostate-Specific Antigen WHO Standardization on Biopsy Rates and Cancer Detection

F. H. Jansen1, M. Roobol1, C. H. Bangma1 and R. H. N. van Schaik2,a

Departments of1 Urology and 2 Clinical Chemistry, Erasmus MC, Rotterdam, The Netherlands.

aAddress correspondence to this author at: Department of Clinical Chemistry (AKC), Erasmus MC—Rm. L134, ’s Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. Fax +31(0)10-43 67894; e-mail r.vanschaik{at}erasmusmc.nl.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Clinicians may be unaware that replacement of the historical total prostate-specific antigen (tPSA) standard with the WHO 96/670 international standard leads to difficulties in interpreting tPSA results. Our aim was to investigate the relationship between the Hybritech and WHO calibrations of the Beckman Coulter tPSA assay, and to assess the impact on prostate cancer (PCa) detection.

Methods: tPSA concentrations were measured in 106 serum samples with both Hybritech and WHO calibrations. The established relationships were used for an in silico experiment with a cohort of 5865 men. Differences in prostate biopsy rates, PCa detection, and characteristics of missed cancers were calculated at biopsy thresholds of 3.0 and 4.0 µg/L.

Results: A linear relationship was observed between the 2 calibrations, with a 20.3% decrease in tPSA values with the WHO standard compared with the Hybritech calibration. Applying the WHO calibration to the cohort of 5865 men yielded a 20% or 19% decrease in prostate biopsies and a 19% or 20% decrease in detected cancers compared with the Hybritech calibration, at a cutoff for biopsy of 3.0 or 4.0 µg/L, respectively. The decrease in detected cancers declined to 9% or 11% if an abnormal result in a digital rectal examination or a transrectal ultrasound evaluation was used as trigger for prostate biopsy (cutoff of 3.0 or 4.0 µg/L, respectively).

Conclusions: Application of the WHO standard for tPSA assays with commonly used tPSA thresholds leads to a significant decrease in PCa detection. Careful assessment of the relationship between the WHO standard and the thresholds used for prostate biopsy is hence necessary.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Numerous prostate-specific antigen (PSA)1 reagent sets are available for the measurement of total PSA (tPSA) concentrations. Several publications have shown that this wide variety of assays leads to very different values for tPSA. These findings cannot always be satisfactorily explained, but possible underlying reasons include differences in assay design, such as differential epitope recognition, cross-reactivity with PSA-homologous antigens, and the lack of equimolarity (1)(2)(3)(4)(5). The last issue, which causes tPSA assays to overreport tPSA concentrations in patients with benign prostate hyperplasia compared with those with prostate cancer (PCa), has largely been resolved through major modifications in many of the tPSA assays. Several studies have reported a small improvement in diagnostic performance, which has been attributed to changes in the equimolar response (6)(7).

If the assay method applied and the specific reference range for the assay are unknown to the clinician, tPSA values may be misinterpreted, possibly influencing the decision to recommend that patients undergo a prostate biopsy for PCa detection (3). There may be clinical implications if serial tPSA measurements are used to calculate tPSA velocity or doubling time for the purpose of indicating PCa aggressiveness or treatment failure (8)(9)(10)(11)(12)(13). In addition, the lack of interchangeability of the various assays may prevent objective judgment and unbiased comparison of the results of previous studies.

The First Stanford Conference was convened in 1992 to improve the interchangeability of tPSA assays. The Second Stanford Conference resulted in a reference standard consisting of 90% purified PSA–antichymotrypsin and 10% free PSA on a molar basis (14). The WHO adoption of this standard resulted in the First International Standard for tPSA under the National Institute of Biological Standards and Control, also known as WHO 96/670 (15)(16). Later, the WHO also introduced a standard for free PSA (15)(16). Differences among tPSA assays seem to have decreased since the introduction of the WHO 96/670 calibration, but they have not been completely resolved and eliminated (14)(17)(18). Therefore, the term "harmonization" has become favored instead of "standardization," because not all assays perform equally, even after standardization (19)(20). To minimize the likelihood of clinical errors, several countries now require their laboratories to report tPSA concentrations in accordance with the WHO 96/670 preparation (21).

Although most clinicians are familiar with the fact that different tPSA assays produce different results, they may not be aware that restandardization from a historical standard to the WHO calibration causes a shift in mass units, which yields a potential for underestimating tPSA values. If this shift is not fully appreciated, especially with respect to the tPSA threshold value for biopsy, a resulting decrease in PCa detection may produce life-altering consequences for individual patients. Thus, different cutoff values are required for the historical standard and the WHO calibration to achieve the same clinical performance.

With the introduction of the WHO 96/670 calibration for tPSA, however, the question has arisen as to how this calibration would influence the clinical outcomes for the current tPSA thresholds. It is clear that the thresholds and methods used to measure tPSA are coupled; therefore, maintaining the established clinical validity requires that significant changes in the assay be evaluated for changes in reference values and cutoff thresholds. We describe our study focusing on the effects of implementing the WHO standard on the Beckman Coulter tPSA assay. This assay, the first tPSA assay to be approved by the US Food and Drug Administration, established the conventional 4.0-µg/L cutoff value for prostate biopsy on the basis of a large multicenter prospective study by applying the gold standard Hybritech tPSA assay (22). Although age-specific reference intervals are now available for tPSA, the 4.0-µg/L tPSA threshold for prostate biopsy is well known, not only by health care professionals but also by the general public. We also applied a cutoff value of 3.0 µg/L because this concentration is currently used as indication for prostate biopsy by the European Randomized Study of Screening for Prostate Cancer (ERSPC) (23).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
An overview of the analyses and an outline of the present study are depicted in Fig. 1 . First, we used the Access Hybritech Total PSA assay with both the Hybritech calibrator and the WHO calibrator to measure tPSA concentrations in 106 fresh serum samples to compare the Beckman Coulter Hybritech calibration with the WHO 96/670 standard. The 106 serum samples were obtained from men included in the screening program of the Rotterdam center of the ERSPC. The study was approved by the Medical Ethics Committee of the Erasmus MC (24). Hybritech tPSA concentrations varied from 0.1 µg/L to 9.1 µg/L. PCa was detected after prostate biopsy in 4 of the 106 patients. The relationship between the WHO 96/670 and Hybritech tPSA calibrations was calculated with the Cusum test for linearity (25).


Figure 1
View larger version (29K):
[in this window]
[in a new window]

  		Figure 1. Overview of the present study.

After establishing the relationship between the WHO 96/670 and Hybritech calibrations, we performed an in silico experiment to assess the clinical implications of the WHO 96/670 reference preparation.

The resulting formula was then used to perform an in silico calculation of the tPSA concentrations based on the WHO 96/670 standard for a cohort of men selected from the database of the Rotterdam center of the ERSPC. Patients were eligible for inclusion if they had undergone sextant biopsy of the prostate. Men were biopsied in the study either because of a Hybritech tPSA concentration ≥3.0 µg/L or because of a Hybritech tPSA concentration of <3.0 µg/L at a repeat screening during a side study to test the value of free PSA for PCa detection (26)(27). Digital rectal examination (DRE) and transrectal ultrasound (TRUS) results were known for all men. All of the 5865 men included in the study were unbiopsied at the start of the study and were 55 to 75 years of age. The median tPSA concentration was 4.0 µg/L (range, 0.1–315.7 µg/L; see Fig. 1Up in the Data Supplement that accompanies the online version of this article at http://www.clinchem.org/content/vol54/issue12). On the basis of the sextant biopsy results, PCa was diagnosed in 1539 patients (26%) in this cohort, 539 of whom eventually underwent a radical prostatectomy (RP). The characteristics of the PCa patients within the cohort are summarized in Table 1 . This cohort of 5865 men was used in an in silico experiment that evaluated cutoff values for prostate biopsy of ≥3.0 µg/L and ≥4.0 µg/L for both the Hybritech and WHO 96/670 calibrations. We subsequently calculated differences in prostate biopsy rates, PCa detection, and characteristics of the missed cancers. The SPSS 12.0 software package was used for statistical analyses.


View this table:
[in this window]
[in a new window]

  		Table 1. Characteristics of PCa patients in a cohort of previously unbiopsied men from the Rotterdam center of the ERSPC (n = 1539).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
We observed a linear relationship between the Hybritech and WHO 96/670 tPSA calibrations. This relationship is described by the formula: WHO calibration = (0.7964 x Hybritech calibration) + 0.007 µg/L. The 95% confidence intervals for the slope and the y intercept were 0.78–0.81 and –0.004–0.024 µg/L, respectively (Fig. 2 ).


Figure 2
View larger version (21K):
[in this window]
[in a new window]

  		Figure 2. tPSA concentrations measured with the Beckman Coulter Hybritech calibration plotted against those obtained with the WHO 96/670 calibration (n = 106).

Use of this formula to calculate the WHO 96/670 tPSA concentrations for the cohort of previously unbiopsied men (characteristics summarized in Table 1Up ) yielded a 20.3% decrease in tPSA concentrations compared with the known Hybritech tPSA concentrations. A tPSA biopsy threshold of ≥3.0 µg/L for the Hybritech calibration yielded 4419 biopsied patients from the 5865 cases (75%), leading to a total of 1430 detected PCa cases (92%) (Table 2 ). A tPSA biopsy threshold of ≥4.0 µg/L for the Hybritech calibration yielded 3004 biopsied patients (51%), leading to a total of 1073 detected PCa cases (70%).


View this table:
[in this window]
[in a new window]

  		Table 2. In silico analysis of the clinical implications of the new PSA WHO calibration.

Without adjusting the cutoffs for the WHO 96/670 tPSA calibration (i.e., ≥3.0 or ≥4.0 µg/L, which is equal to a Hybritech tPSA cutoff of ≥3.6 or ≥4.8 µg/L, respectively), one obtains 3218 men (55%) as candidates for prostate biopsy, leading to 1130 detected cases of PCa (73%) with a cutoff of ≥3.0 µg/L (Table 2Up ). Nonadjustment yields a 20% decrease in the number of prostate biopsies (from 75% to 55%) and a 19% decrease in detected cancers (from 92% to 73%). Thus, a tPSA biopsy threshold of ≥3.0 µg/L for the WHO 96/670 calibration would miss 300 PCa cases that would have been detected with the Hybritech tPSA calibrator at the same threshold for prostate biopsy. At a cutoff of ≥4.0 µg/L for the WHO 96/670 tPSA calibration, 1873 men (32%) were candidates for prostate biopsy, leading to 767 detected cases of PCa (50%) and yielding a 19% decline in the biopsy rate and a subsequent 20% decrease in PCa detection.

In the group of patients who underwent an RP, 507 (94%) of 539 cancers were detected by applying the Hybritech tPSA calibration at a biopsy threshold of ≥3.0 µg/L, in contrast with the WHO calibration detecting 406 (75%) of 539 PCa cases, a decrease of 19%. Thus, use of the WHO calibration with a tPSA biopsy threshold of ≥3.0 µg/L specifically missed 101 RP cases that would have been detected with the Hybritech tPSA calibrator at the same threshold for prostate biopsy. At a cutoff of ≥4.0 µg/L, application of the Hybritech tPSA calibration detected 386 (72%) of 539 cancers, in contrast with 272 (50%) of 539 PCa cases detected with the WHO calibration.

The clinical and pathologic stages and the biopsy and RP sample Gleason scores of the missed cancers are depicted in Tables 3 and 4 . At biopsy thresholds of ≥3.0 µg/L and ≥4.0 µg/L, there are significant differences in cancer characteristics between the cancers that are missed by application of the WHO 96/670 standard and the cancers that are detected with the Hybritech calibration. Overall, the group of missed cancers consists of tumors with lower clinical and pathologic tumor stages and lower biopsy and RP Gleason scores.


View this table:
[in this window]
[in a new window]

  		Table 3. Characteristics of PCa cases detected by the Hybritech calibration (column 2) and of PCa cases specifically missed by applying the WHO 96/670 calibration that were detected by the Hybritech calibration (column 3), at tPSA biopsy thresholds of ≥3.0 µg/L and ≥4.0 µg/L.


View this table:
[in this window]
[in a new window]

  		Table 4. Characteristics of RP cases that were detected with the Hybritech calibration (column 2) and of RP cases specifically missed by applying the WHO 96/670 calibration that were detected with the Hybritech calibration (column 3), at biopsy thresholds of ≥3.0 µg/L and ≥4.0 µg/L.

At a 3.0-µg/L cutoff, an abnormal DRE result is found in 109 (36%) of the 300 missed cancer cases, and an abnormal TRUS result is present in 97 (32%) of the 300 missed cancer cases. When an abnormal DRE or TRUS result is used as a trigger for prostate biopsy, 146 (49%) of the 300 missed cancer cases will be detected despite the application of the WHO 96/670 reference standard. This approach yields a decrease in PCa detection of 9% compared with the Hybritech calibration. At a threshold of 4.0 µg/L, an abnormal DRE result and an abnormal TRUS result are found in 111 cases (36%) and 90 cases (29%), respectively, of the 306 missed PCa cases. Use of an abnormal DRE or TRUS result as a trigger for prostate biopsy results in the detection of 139 (45%) of the 306 missed cancer cases, leading to a decrease in PCa detection of 11% compared with the Hybritech calibration.

Biopsy frequencies and PCa-detection rates were similar after the linear relationship between the 2 calibrations was used to correct the biopsy threshold for the WHO 96/670 calibration to 2.4 or 3.2 µg/L.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our results show that application of the WHO 96/670 calibration for tPSA yields a 20.3% decrease in tPSA values compared with the historical Beckman Coulter Hybritech calibration. If the threshold for prostate biopsy is not adjusted accordingly, there will be a significant decline in prostate biopsy rates (20% or 19%) and a subsequent decrease in detected PCa cases (19% or 20%) for the Beckman Coulter tPSA assay at commonly used cutoffs for biopsy (3.0 and 4.0 µg/L, respectively). This decrease in detected PCa cases is limited to 9% or 11% if an abnormal DRE or TRUS result is used as a trigger for prostate biopsy (threshold of 3.0 or 4.0 µg/L, respectively). In addition, significant shifts in tumor stages and Gleason scores were observed with the application of the WHO 96/670 tPSA calibration. Missed PCa cases showed fewer high-stage tumors and fewer tumors with high Gleason scores than for PCa cases that were detected with the Hybritech calibration at a biopsy threshold of ≥3.0 µg/L or ≥4.0 µg/L. Biopsy and PCa-detection rates were similar after the linear relationship between the WHO and Hybritech calibrations was used to correct the biopsy threshold for the WHO 96/670 calibration to 2.4 µg/L or 3.2 µg/L, respectively.

One possible limitation of our study is that the second part is based on in silico calculations of WHO 96/670 tPSA concentrations, instead of on direct measurements of serum concentrations. This in silico calculation was based on the linear relationship established in a study of a smaller cohort (n = 106) that used both calibrations for actual serum measurements; however, the 20.3% negative shift in tPSA values that is introduced by application of the WHO calibration is virtually identical to the findings of earlier studies by Kort et al. and Roddam et al., who found a 22% and 19% difference, respectively, in tPSA concentrations (mean, 20.5%) between the WHO 96/670 and Hybritech calibrations (18)(21). Whereas we used an in silico experiment to evaluate the clinical effects of applying the WHO standard for tPSA, the actual relationship between the WHO calibration and the original Hybritech calibration was established with clinical serum samples. Because tPSA assays are known to be highly sensitive to the matrix of the sample, the use of clinical samples avoids biases that arise from the use of artificial samples (19).

A second limitation is that a cohort of screen-detected PCas in asymptomatic men was used instead of a cohort of clinically detected PCa cases to assess the clinical impact of the new WHO calibration. Implications for a cohort of clinically detected PCas will be similar, more or less, with probably fewer missed PCa cases because of initially higher tPSA concentrations.

We did not investigate the relationships between other tPSA assays and the new WHO standard in this study. This choice was partly because tPSA measurements made within the screening program of the ERSPC have always been based on the Hybritech system. The strategy has been to use the same method during the entire study to minimize errors in medical decision making. Such errors may occur if different assays are used during patient monitoring. Kort et al. recently concluded that the results of other assays also deviate from expected tPSA values if the WHO 96/670 reference preparation is applied (regression slopes between 0.99 and 1.08), showing that further efforts are needed to improve the interchangeability of tPSA assays (17)(18)(21). In addition, we emphasize that although use of a biopsy cutoff of 3.0 or 4.0 µg/L is common practice, tPSA is a continuous, not a dichotomous, biomarker; therefore, the risk of PCa increases as the PSA concentration increases (28).

As far as we know, this study is the first to evaluate the clinical effects of the WHO 96/670 calibration for tPSA in a large screening cohort. Therefore, we have not been able to compare the number of missed cancers and the shifts in PCa characteristics with those of previous studies. Significant changes in PCa detection and PCa characteristics have also been observed in studies that have assessed the interchangeability of various tPSA assays, although a study by Yurdakul et al. concluded that different tPSA assays detected PCa cases with identical histologic features (4)(13)(29)(30). This study and others, however, evaluated the effects of different tPSA assays, which have different performance characteristics. This approach contrasts with that of our study, in which the only difference was the reference standard. For the present study, the difference in cancer characteristics between the cancers missed by the WHO 96/670 calibration and the cancers detected by the Hybritech calibration can be explained by the distribution of tumor stages and Gleason scores in the entire population of the screening cohort. The group of missed cancers has Hybritech tPSA values of 3.0– 3.6 µg/L or 4.0–4.8 µg/L and contains fewer high-stage and high-grade tumors than the cohort of all PCa cases with Hybritech tPSA concentrations ≥3.0 µg/L or ≥4.0 µg/L, respectively.

The finding of a decrease in cancer detection caused by application of the WHO 96/670 calibration may also have positive implications in light of the current discussions on limiting PCa overdetection and subsequent overtreatment (31)(32)(33)(34). Because the group of missed cancers contains significantly fewer tumors with a high stage or a high Gleason score and more tumors with favorable characteristics (Tables 3Up and 4Up ), missing these cancers may not have clinical consequences and so may limit the overdetection and overtreatment of PCa.

Furthermore, we have shown that the decrease in detected PCa cases caused by application of the WHO 96/670 standard is less dramatic when abnormal DRE or TRUS results are applied as triggers for prostate biopsy. Given the limited predictive value of an abnormal DRE or TRUS result in a screening setting, however, especially in the low tPSA range of approximately 3.0 µg/L or 4.0 µg/L, the actual decrease in PCa detection most likely will be closer to 19% or 20%, respectively, than to 9% or 11% (35)(36)(37)(38)(39).

The recalibration is also expected to affect PCa detection through effects on other PSA threshold values for biopsy. Adaptation to the WHO 96/670 reference standard will also affect tPSA-derived variables, such as tPSA velocity, tPSA doubling time, and age-adjusted tPSA values, with potential consequences for the individual patient.

In conclusion, the present study has shown that a decision to adapt tPSA testing to the WHO 96/670 reference standard requires both careful assessment of the relationship between the historical standard and the WHO standard and subsequent establishment of a new threshold for prostate biopsy. In this study, we found that the threshold for prostate biopsy shifted from 3.0 µg/L or 4.0 µg/L with the historical Hybritech calibration to 2.4 µg/L or 3.2 µg/L, respectively, after application of the WHO 96/670 calibration. If not adjusted, this leads to a 19% or 20% decrease in PCa detection. Hence, if clinicians are unaware of the replacement of their historical tPSA standard with the WHO 96/670 reference preparation and do not adapt the threshold concentration for prostate biopsy, the number of prostate biopsies and subsequent PCa-detection rates will shift considerably in their clinic.


   Acknowledgments
 
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors’ Disclosures of Potential Conflicts of Interest: Upon manuscript submission, all authors completed the Disclosures of Potential Conflict of Interest form. Potential conflicts of interest:

Employment or Leadership: None declared.

Consultant or Advisory Role: C.H. Bangma, member of an advisory group to Beckman Coulter.

Stock Ownership: None declared.

Honoraria: None declared.

Research Funding: None declared.

Expert Testimony: None declared.

Other: An educational grant for this study was provided by Beckman Coulter International.

Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, or preparation or approval of manuscript.

Acknowledgments: The authors are indebted to Dr. Axel Semjonow for a critical review of this manuscript.


   Footnotes
 
1 Nonstandard abbreviations: PSA, prostate-specific antigen; tPSA, total PSA; PCa, prostate cancer; ERSPC, European Randomized Study of Screening for Prostate Cancer; DRE, digital rectal examination; TRUS, transrectal ultrasound; RP, radical prostatectomy.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Patel D, White PA, Milford WA. A comparison of six commercial assays for total and free prostate specific antigen (PSA): the predictive value of the ratio of free to total PSA. BJU Int 2000;85:686-689.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  2. Rittenhouse HG, Finlay JA, Mikolajczyk SD, Partin AW. Human kallikrein 2 (hK2) and prostate-specific antigen (PSA): two closely related, but distinct, kallikreins in the prostate. Crit Rev Clin Lab Sci 1998;35:275-368.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  3. Semjonow A, Brandt B, Oberpenning F, Roth S, Hertle L. Discordance of assay methods creates pitfalls for the interpretation of prostate-specific antigen values. Prostate Suppl 1996;7:3-16.[Medline] [Order article via Infotrieve]
  4. Yurdakul G, Bangma CH, Blijenberg BG, van Zelst BD, Wildhagen MF, van der Kwast TH, Schröder FH. Different PSA assays lead to detection of prostate cancers with identical histological features. Eur Urol 2002;42:154-158.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  5. Zhou AM, Tewari PC, Bluestein BI, Caldwell GW, Larsen FL. Multiple forms of prostate-specific antigen in serum: differences in immunorecognition by monoclonal and polyclonal assays. Clin Chem 1993;39:2483-2491.[Abstract]
  6. Oberpenning F, Weining C, Brandt B, De Angelis G, Heinecke A, Hamm M, et al. A new modification of the Chiron ACS assay for total prostate-specific antigen achieves equimolar response characteristics and improves the detection of prostate cancer. Clin Chem Lab Med 2003;41:90-94.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  7. Semjonow A, Oberpenning F, Weining C, Schon M, Brandt B, De Angelis G, et al. Do modifications of nonequimolar assays for total prostate-specific antigen improve detection of prostate cancer?. Clin Chem 2001;47:1472-1475.[Free Full Text]
  8. D'Amico AV, Chen MH, Roehl KA, Catalona WJ. Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med 2004;351:125-135.[Abstract/Free Full Text]
  9. D'Amico AV, Kantoff P, Loffredo M, Renshaw AA, Loffredo B, Chen MH. Predictors of mortality after prostate-specific antigen failure. Int J Radiat Oncol Biol Phys 2006;65:656-660.[Web of Science][Medline] [Order article via Infotrieve]
  10. D'Amico AV, Renshaw AA, Sussman B, Chen MH. Pretreatment PSA velocity and risk of death from prostate cancer following external beam radiation therapy. JAMA 2005;294:440-447.[Abstract/Free Full Text]
  11. Link RE, Shariat SF, Nguyen CV, Farr A, Weinberg AD, Morton RA, et al. Variation in prostate specific antigen results from 2 different assay platforms: clinical impact on 2304 patients undergoing prostate cancer screening. J Urol 2004;171:2234-2238.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  12. Sengupta S, Myers RP, Slezak JM, Bergstralh EJ, Zincke H, Blute ML. Preoperative prostate specific antigen doubling time and velocity are strong and independent predictors of outcomes following radical prostatectomy. J Urol 2005;174:2191-2196.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  13. Stephan C, Klaas M, Muller C, Schnorr D, Loening SA, Jung K. Interchangeability of measurements of total and free prostate-specific antigen in serum with 5 frequently used assay combinations: an update. Clin Chem 2006;52:59-64.[Abstract/Free Full Text]
  14. Stamey TA, Chen Z, Prestigiacomo AF. Reference material for PSA: the IFCC standardization study. International Federation of Clinical Chemistry. Clin Biochem 1998;31:475-481.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  15. Rafferty B, Rigsby P, Rose M, Stamey T, Gaines Das R. Reference reagents for prostate-specific antigen (PSA): establishment of the first international standards for free PSA and PSA (90:10). Clin Chem 2000;46:1310-1317.[Abstract/Free Full Text]
  16. . World Health Organization. WHO Expert Committee on Biological Standardization. Forty-eighth report. WHO technical report series, no. 889 1999:111pp World Health Organization Geneva, Switzerland. .
  17. Blijenberg BG, Yurdakul G, Van Zelst BD, Bangma CH, Wildhagen MF, Schröder FH. Discordant performance of assays for free and total prostate-specific antigen in relation to the early detection of prostate cancer. BJU Int 2001;88:545-550.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  18. Kort SA, Martens F, Vanpoucke H, van Duijnhoven HL, Blankenstein MA. Comparison of 6 automated assays for total and free prostate-specific antigen with special reference to their reactivity toward the WHO 96/670 reference preparation. Clin Chem 2006;52:1568-1574.[Abstract/Free Full Text]
  19. Stephan C, Semjonow A. Accuracy assessment of PSA methods must be based on clinical instead of artificial samples—a response to AW Roddam et al., Ann Clin Biochem 2006; 43: 35–48. Ann Clin Biochem 2006;43:421-422, author reply 422–3.[Free Full Text]
  20. Zelst B, Blijenberg B. PSA-comparability: standardization or harmonization?. Ned Tijdschr Klin Chem 2002;27:25-30.
  21. Roddam AW, Rimmer J, Nickerson C, Ward AM. Prostate-specific antigen: bias and molarity of commercial assays for PSA in use in England. Ann Clin Biochem 2006;43:35-48.[Abstract/Free Full Text]
  22. Catalona WJ, Richie JP, Ahmann FR, Hudson MA, Scardino PT, Flanigan RC, et al. Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men. J Urol 1994;151:1283-1290.[Web of Science][Medline] [Order article via Infotrieve]
  23. Roobol MJ, Kirkels WJ, Schröder FH. Features and preliminary results of the Dutch centre of the ERSPC (Rotterdam, the Netherlands). BJU Int 2003;92(Suppl 2):48-54.
  24. Roobol MJ, Schröder FH. European Randomized Study of Screening for Prostate Cancer: achievements and presentation. BJU Int 2003;92(Suppl 2):117-122.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  25. Rowlands RJ, Griffiths K, Kemp KW, Nix AB, Richards G, Wilson DW. Application of Cusum techniques to the routine monitoring of analytical performance in clinical laboratories. Stat Med 1983;2:141-145.[CrossRef][Medline] [Order article via Infotrieve]
  26. Raaijmakers R, Blijenberg BG, Finlay JA, Rittenhouse HG, Wildhagen MF, Roobol MJ, Schröder FH. 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. J Urol 2004;171:2245-2249.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  27. Roobol MJ, Kranse R, de Koning HJ, Schröder FH. Prostate-specific antigen velocity at low prostate-specific antigen levels as screening tool for prostate cancer: results of second screening round of ERSPC (ROTTERDAM). Urology 2004;63:309-313, discussion 313–5.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  28. Thompson IM, Ankerst DP, Chi C, Goodman PJ, Tangen CM, Lucia MS, et al. Assessing prostate cancer risk: results from the Prostate Cancer Prevention Trial. J Natl Cancer Inst 2006;98:529-534.[Abstract/Free Full Text]
  29. Roddam AW, Price CP, Allen NE, Ward AM. Assessing the clinical impact of prostate-specific antigen assay variability and nonequimolarity: a simulation study based on the population of the United Kingdom. Clin Chem 2004;50:1012-1016.[Abstract/Free Full Text]
  30. Sotelo RJ, Mora KE, Perez LH, Novoa J, Carmona O, De Andrade R, et al. Assay standardization bias: different prostate cancer detection rates and clinical outcomes resulting from different assays for free and total prostate-specific antigen. Urology 2007;69:1143-1146.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  31. Draisma G, Boer R, Otto SJ, van der Cruijsen IW, Damhuis RA, Schröder FH, de Koning HJ. Lead times and overdetection due to prostate-specific antigen screening: estimates from the European Randomized Study of Screening for Prostate Cancer. J Natl Cancer Inst 2003;95:868-878.[Abstract/Free Full Text]
  32. Schröder FH, Bangma CH, Roobol MJ. Is it necessary to detect all prostate cancers in men with serum PSA levels <3.0 ng/ml? A comparison of biopsy results of PCPT and outcome-related information from ERSPC. Eur Urol 2008;53:901-908.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  33. Schröder FH, Carter HB, Wolters T, van den Bergh RC, Gosselaar C, Bangma CH, Roobol MJ. Early detection of prostate cancer in 2007. Part 1: PSA and PSA kinetics. Eur Urol 2008;53:468-477.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  34. Steyerberg EW, Roobol MJ, Kattan MW, van der Kwast TH, de Koning HJ, Schröder FH. Prediction of indolent prostate cancer: validation and updating of a prognostic nomogram. J Urol 2007;177:107-112, discussion 112.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  35. Candas B, Cusan L, Gomez JL, Diamond P, Suburu RE, Levesque J, et al. Evaluation of prostatic specific antigen and digital rectal examination as screening tests for prostate cancer. Prostate 2000;45:19-35.[Web of Science][Medline] [Order article via Infotrieve]
  36. Gosselaar C, Roobol MJ, Roemeling S, de Vries SH, Cruijsen-Koeter I, van der Kwast TH, Schröder FH. Screening for prostate cancer without digital rectal examination and transrectal ultrasound: results after four years in the European Randomized Study of Screening for Prostate Cancer (ERSPC), Rotterdam. Prostate 2006;66:625-631.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  37. Gosselaar C, Roobol MJ, Roemeling S, van der Kwast TH, Schröder FH. Screening for prostate cancer at low PSA range: the impact of digital rectal examination on tumor incidence and tumor characteristics. Prostate 2007;67:154-161.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  38. Schröder FH, Roobol-Bouts M, Vis AN, van der Kwast T, Kranse R. Prostate-specific antigen-based early detection of prostate cancer—validation of screening without rectal examination. Urology 2001;57:83-90.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  39. Schröder FH, van der Maas P, Beemsterboer P, Kruger AB, Hoedemaeker R, Rietbergen J, Kranse R. Evaluation of the digital rectal examination as a screening test for prostate cancer. Rotterdam section of the European Randomized Study of Screening for Prostate Cancer. J Natl Cancer Inst 1998;90:1817-1823.[Abstract/Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Supplemental Data
Right arrow All Versions of this Article:
clinchem.2007.102699v1
54/12/1999    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Web of Science (3)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jansen, F. H.
Right arrow Articles by van Schaik, R. H. N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jansen, F. H.
Right arrow Articles by van Schaik, R. H. N.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS