1 A Multicenter Study of [-2]Pro-Prostate Specific Antigen Combined With Prostate Specific Antigen and Free Prostate Specific Antigen for Prostate Cancer Detection in the 2.0 to 10.0 ng/ml Prostate Specific Antigen Range William J. Catalona,*, Alan W. Partin, Martin G. Sanda, John T. Wei, George G. Klee, Chris H. Bangma, Kevin M. Slawin, Leonard S. Marks, Stacy Loeb, Dennis L. Broyles, Sanghyuk S. Shin, Amabelle B. Cruz, Daniel W. Chan, Lori J. Sokoll, William L. Roberts, Ron H. N. van Schaik and Isaac A. Mizrahi From the Department of Urology, Northwestern University Feinberg School of Medicine (WJC), Chicago, Illinois, Departments of Urology (AWP, SL) and Pathology (DWC, LJS), The Johns Hopkins University School of Medicine, Baltimore, Maryland, Division of Urology, Beth Israel Deaconess Medical Center, Harvard Medical School (MGS), Boston, Massachusetts, Department of Urology, University of Michigan School of Medicine (JTW), Ann Arbor, Michigan, Department of Pathology, Mayo Clinic (GGK), Rochester, Minnesota, Departments of Urology (CHB) and Clinical Chemistry (RHNvS), Erasmus University Medical Center, Rotterdam, The Netherlands, Vanguard Urologic Institute and Texas Prostate Center (KMS), Houston, Texas, Department of Urology, University of California-Los Angeles (LSM), Los Angeles, California, Beckman Coulter, Inc. (DLB, SSS, ABC, IAM), Carlsbad, California, and ARUP Laboratories, Department of Pathology, University of Utah (WLR), Salt Lake City, Utah Abbreviations and Acronyms DRE digital rectal examination fpsa free PSA NIH/NCI National Institutes of Health/National Cancer Institute p2psa [-2]proPSA PCa prostate cancer PHI prostate health index PSA prostate specific antigen Purpose: Prostate specific antigen and free prostate specific antigen have limited specificity to detect clinically significant, curable prostate cancer, leading to unnecessary biopsy, and detection and treatment of some indolent tumors. Specificity to detect clinically significant prostate cancer may be improved by [-2]pro-prostate specific antigen. We evaluated [-2]pro-prostate specific antigen, free prostate specific antigen and prostate specific antigen using the formula, ([-2]pro-prostate specific antigen/free prostate specific antigen prostate specific antigen 1/2 ) to enhance specificity to detect overall and high grade prostate cancer. Materials and Methods: We enrolled 892 men with no history of prostate cancer, normal rectal examination, prostate specific antigen 2 to 10 ng/ml and 6-core or greater prostate biopsy in a prospective multi-institutional trial. We examined the relationship of serum prostate specific antigen, free-to-total prostate specific antigen and the prostate health index with biopsy results. Primary end points were specificity and AUC using the prostate health index to detect overall and Gleason 7 or greater prostate cancer on biopsy compared with those of free-to-total prostate specific antigen. Results: In the 2 to 10 ng/ml prostate specific antigen range at 80% to 95% sensitivity the specificity and AUC (0.703) of the prostate health index exceeded those of prostate specific antigen and free-to-total prostate specific antigen. An increasing prostate health index was associated with a 4.7-fold increased risk of prostate cancer and a 1.61-fold increased risk of Gleason score greater than or equal to disease on biopsy. The AUC of the index exceeded that of free-to-total prostate specific antigen (0.724 vs 0.670) to discriminate prostate cancer with Gleason 4 or greater 3 from lower grade disease or negative biopsy. Prostate health index results were not associated with age and prostate volume. Conclusions: The prostate health index may be useful in prostate cancer screening to decrease unnecessary biopsy in men 50 years old or older with prostate specific antigen 2 to 10 ng/ml and negative digital rectal examination with minimal loss in sensitivity. Key Words: prostate, prostatic neoplasms, prostate specific antigen, diagnosis, mass screening /11/ /0 Vol. 185, , May 2011 THE JOURNAL OF UROLOGY Printed in U.S.A by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. DOI: /j.juro
2 [-2]PRO-PROSTATE SPECIFIC ANTIGEN FOR PROSTATE CANCER DETECTION 1651 Submitted for publication August 30, Study received institutional review board approval at each participating institution. Supported by NIH/NCI Johns Hopkins Prostate SPORE Grant P50CA58236, Early Detection Research Network NIH/NCI Grant U01-CA86323, NIH/NCI U01 CA86323 (AWP), U24 CA (DWC) and U01CA (MGS), Urological Research Foundation, Northwestern-University of Chicago Prostate SPORE Grant NIH/NCI P50 CA S2, Robert H. Lurie Comprehensive Cancer Center Grant NIH/NCI P30 CA60553, Beckman Coulter, Inc. (WJC) and Mayo Clinic Prostate SPORE Grant NIH/NCI CA (GGK). Presented at annual meeting of American Urological Association, San Francisco, California, June 2, Supplementary material for this article can be obtained at * Correspondence: Northwestern University Feinberg School of Medicine, 675 North St Clair St., Chicago, Illinois ( Financial interest and/or other relationship with Beckman Coulter, decode Genetics, OHMX and Nanosphere. Financial interest and/or other relationship with Beckman Coulter. Financial interest and/or other relationship with Sanofi-Aventis, Beckman Coulter, Envisioneering and American Medical Systems. Financial interest and/or other relationship with Beckman Coulter, Bellicum, Sanofi-Aventis, Allergan and Molecular Insights. Financial interest and/or other relationship with ARUP Laboratories. For another article on a related topic see page PROSTATE specific antigen testing was Food and Drug Administration approved using a 4.0 ng/ml cutoff to recommend prostate biopsy. Lower cutoffs further enhance early PCa detection 1 since PSA correlates with the risk of overall and high grade PCa at PSA less than 4 ng/ml. 2 However, PSA testing may be confounded by benign conditions. The low specificity at PSA less than 10 ng/ml has created a diagnostic gray zone in which PCa is found on biopsy in about 25% of patients. This is important since most PCa is curable at PSA less than 10 ng/ml while PSA greater than 10 ng/ml often portends advanced disease. 3 Serum PSA is complexed with proteins or circulates in an unbound form called fpsa. 4 At PSA 4.0 to 10.0 ng/ml the free-to-total PSA ratio significantly improves discrimination between PCa and benign conditions. 5 Different prostate regions contain varying proportions of fpsa isoforms, including propsa, which is associated with PCa. The primary form in PCa tissue is p2psa. 6 8 At PSA 2.0 to 10.0 ng/ml p2psa further improves specificity for PCa detection relative to the free-to-total PSA ratio The usefulness of p2psa at PSA less than 4.0 ng/ml and its relationship to PCa aggressiveness are relevant to the PCa screening debate, including concerns about over diagnosis and overtreatment Preliminary evidence suggests that higher percent p2psa may be associated with more aggressive PCa. 10,12,13,18 Selecting thresholds for clinical use of p2psa has received limited study. We evaluated the relationship of p2psa (the assay for which is not available in the United States), combined with fpsa and PSA in a mathematical formula called PHI, with PCa detection and tumor features. METHODS Study Design. We performed a multicenter, double-blind, casecontrol clinical trial to validate PHI in the 2.0 to 10.0 ng/ml PSA range. The formula was developed from an independent data set, 19 that is p2psa is measured in pg/ml and fpsa and PSA are measured in ng/ml. The study protocol was approved by the institutional review board at each participating institution and all participants provided informed consent. Population. We evaluated 1,372 men from a total of 8 medical centers from October 2003 to June The study cohort included men 50 years old or older who met certain criteria, including 1) no PCa history, 2) nonsuspicious DRE, 3) pre-study PSA 1.5 to 11.0 ng/ml, 4) 6-core or greater biopsy and 5) a histological diagnosis from prostate biopsy. Study exclusion criteria were 1) medications or surgical interventions that alter PSA before blood draw, 2) urinary infection at blood draw, 3) a final Access Hybritech PSA value outside the 2.0 to 10.0 ng/ml range, 4) no blood draw or biopsy at the appropriate time or 5) prior androgen replacement therapy. A total of 326 participants did not meet study eligibility requirements, such as no appropriate informed consent in 107, no PSA within 2 to 10 ng/ml in 92 and other study specific exclusions in 120. Seven men were excluded from analysis due to unevaluable tests from hemolyzed or hyperlipidemic samples, or p2psa duplicate results with a high coefficient of variation that could not be retested. Finally, at 1 site only 154 men 62 to 74 years old were enrolled. They were not included in final analyses since the age distribution at this site may not have been representative of the target population. The final study population of 892 men included 121 (13.6%) who were prospectively enrolled and 743 (83.3%) who were prospectively enrolled under separate protocols as well as 28 retrospective samples (3.1%). The study population included 706 initial (79.2%) and 159 repeat (17.8%) biopsies, and 27 men (3%) with an unknown biopsy history. At each institution an approximately equal number of men with (430 or 48.2%) and without (462 or 51.8%) PCa was enrolled. Participants and investigators were blinded to p2psa results and personnel at testing sites were blinded to individual clinical information. Testing Access Hybritech p2psa, PSA and fpsa assays were measured on the Access 2 Immunoassay Analyzer. Thus, our results apply to Access Hybritech p2psa, PSA and fpsa assays on the Access Immunoassay System. Serum samples were collected, processed within 8 hours and stored frozen at 70C or less before testing, which allowed accurate PHI measurement. 20 The p2psa assay was run in duplicate. Evaluation of the first replicate compared to the mean of duplicates using Passing-Bablock regression
3 1652 [-2]PRO-PROSTATE SPECIFIC ANTIGEN FOR PROSTATE CANCER DETECTION analysis showed no difference (Spearman s r ). The p2psa assay is a 2-site immunoenzymatic sandwich assay that uses specific monoclonal antibodies and 6 calibrators from 0 to 5,000 pg/ml. Statistical Analysis Minimum sample size was estimated as 295 patients without PCa to detect a 10% difference in specificity between PHI and percent fpsa at 0.05 and Also, a minimum sample size of 350 patients with PCa was determined to accurately estimate sensitivity at 95% with 95% CI less than 3%. Target sample size was increased to 400 participants per group. The primary null hypothesis was that PHI has no greater specificity than the free-to-total PSA ratio at 95% sensitivity. This hypothesis was tested using bootstrap based ROC analysis. 21 Briefly, 1,000 data sets of patients with benign conditions and those with PCa were generated to repetitively sample the study population Differences in the specificity between PHI and free-to-total PSA at 95% sensitivity were calculated for the 1,000 pairs of replicate data sets. The SE of the difference in specificity was then estimated with adjustment for correlation between the 2 tests. Finally, the bootstrap estimated SE was used to evaluate whether the difference in specificity was greater than 0, assuming normal distribution of the differences. A 1-sided statistical test was used for this analysis. This method was also used to compare the specificity of PHI and free-to-total PSA at 90%, 85% and 80% sensitivity. The secondary null hypothesis, which was that the ROC AUC of PHI was equal to that of free-to-total PSA, was tested by evaluating whether the difference between their estimated AUCs equaled 0 using empirical methods. 25,26 The AUCs of PHI and free-to-total PSA were also estimated for each prostate volume tertile to determine whether the observed trend in AUCs differed by prostate volume. The validity of pooling data across sites was evaluated by fitting a logistic regression model with PCa status as the dependent variable using PHI and site as independent predictors, including interaction terms for site and PHI. Comparisons between participant subgroups were made using the Wilcoxon rank sum test for continuous variables and the chi-square test for categorical variables. Two-sided statistical tests were used in all analyses except as noted with statistical significance considered at p All analysis was done using SAS, version 9.2. Individual Risk Assessment A 25% PCa detection rate was previously reported in men with PSA 2.0 to 10.0 ng/ml. 3 Since the proportion of PCa was determined by design, direct calculation of PCa probability would have resulted in inflated estimates for detecting PCa. Therefore, to obtain more accurate risk estimates for PCa we adjusted the proportion of PCa to 25% by repetitively sampling the study population 1,000 times. Each replicate data set consisted of 462 benign (75%) and 154 cancer (25%) cases The mean probability of cancer in the bootstrapped data sets for each PHI range was used as the point estimate and bootstrap estimated SEs were used to calculate 95% CIs. Likewise, RR estimates were calculated for each replicate data set by dividing the probability of PCa in each PHI range by that of PHI 0 to The mean RR and bootstrap estimated SEs were used to calculate the risk estimate and 95% CIs. PHI and Gleason Score Of participants with PCa we calculated the proportion in each PHI range with Gleason score 7 or greater. Risk ratios were estimated by dividing the probability of Gleason 7 or greater in each PHI range by that of PHI 0 to The Cochrane-Armitage test for trend was used to determine whether increasing PHI ranges corresponded to increasing the probability of Gleason 7 or greater PCa. ROC analysis was used to evaluate the clinical usefulness of PHI to detect PCa with Gleason scores greater than or equal to RESULTS Participants PHI and p2psa were significantly higher in patients with PCa than in controls while fpsa and free-tototal PSA were lower. Total PSA and age were comparable between the groups. Of the participants 89.8% underwent 12-core or greater biopsy and 98% underwent 10-core or greater biopsy. Overall 30.6%, 49.9% and 19.6% of participants were 50 to 59, 60 to 69 and 70 to 84 years old, respectively. Also, no interaction terms in the statistical model to evaluate heterogeneity by site was significant, supporting data pooling across sites. There were no significant differences in age (p 0.123), PSA (p 0.106), p2psa (p 0.088), free-to-total PSA (p 0.125) or PHI (p 0.848) between white and black men. ROC Results The figure shows sensitivity and specificity for all observed PSA, fpsa, p2psa, free-to-total PSA and PHI cutoffs in the 2.0 to 10.0 ng/ml PSA range. At 95% sensitivity the specificity of PHI was 16.0% compared to 8.4% for free-to-total PSA (p 0.015), 7.6% for p2psa, 6.5% for PSA and 3.5% for fpsa, rejecting the primary null hypothesis. At lower 90%, 85% and 80% sensitivity for PCa detection PHI specificity was significantly greater than that of free-tototal PSA, including 26% vs 18% (p 0.036), 39% vs 28% (p 0.006) and 45% vs 37% (p 0.031), respectively. The AUC of PCa detection was significantly greater for PHI (AUC 0.703) than for free-to-total PSA (AUC 0.648, p 0.004), fpsa (AUC 0.615), p2psa (AUC 0.557) or PSA (AUC 0.525), rejecting the secondary null hypothesis. Individual Risk Assessment Higher PHI values were associated with an increased risk of PCa detection (see table). Of the study population 25%, 33%, 30% and 13% had a PHI of 0 to 24.9, 25.0 to 34.9, 35.0 to 54.9 and 55.0 or greater, respectively. Compared to PHI less than
4 [-2]PRO-PROSTATE SPECIFIC ANTIGEN FOR PROSTATE CANCER DETECTION 1653 PHI Association with Gleason score. PHI also had a significant relationship with biopsy Gleason score (r 0.138, p 0.004). Of participants with PCa biopsy Gleason score was less than 7 in 290 (67.6%) and 7 or greater in 139 (32.4%). The probability of Gleason score 7 or greater PCa increased with increasing PHI (p 0.013, see table). The AUC of PHI exceeded that of free-to-total PSA (0.724 vs 0.670) in discriminating Gleason score greater than or equal to vs lower grade PCa or negative biopsy. Relationship with TRUS volume. The AUCs of PHI exceeded those of free-to-total PSA in all 3 prostate volume tertiles, that is 38 or less, 39 to 53 and 54 cc or greater (first tertile AUC vs 0.614, second tertile AUC vs and third tertile AUC vs 0.559). Excluded Participant Evaluation The AUCs of PHI with and without the excluded site were and 0.703, respectively. The AUCs of free-to-total PSA were and 0.648, respectively. PSA, fpsa, [-2]proPSA, free-to-total PSA and PHI (phi) ROC curves in 2 to 10 ng/ml PSA range show sensitivity 1 specificity at sequential cutoffs the RR of PCa detection on biopsy was 1.6, 3.0 and 4.7-fold higher at PHI 25.0 to 34.9, 35.0 to 54.9 and 55.0 or greater, respectively. Overall PHI 55.0 or greater was associated with a 52.1% probability of PCa. Age and PCa Probability Higher PHI was also associated with higher PCa risk estimates in each age group. The probability range of PCa was 10.9% (PHI 0 to 24.9) to 53.4% (PHI greater than 55) (RR 4.9) at ages 50 to 59 years, 12.5% (PHI 0 to 24.9) to 54.5% (PHI greater than 55) (RR 4.4) at ages 60 to 69 years and 5.8% (PHI 0 to 24.9) to 44.8% (PHI greater than 55) (RR 7.7) at ages greater than 70 years. DISCUSSION Prostate biopsy is routinely recommended for suspicious DRE regardless of PSA. 3 Biopsy is also recommended using PSA thresholds of 2.5 to 4.0 ng/ ml. 1,2,14 However, this leads to unnecessary biopsies and possible over detection of some cancers To elucidate whether PHI PSA isoform measurement could improve PCa early detection we examined a large, prospective cohort to predict biopsy findings in patients with moderate PSA elevations and nonsuspicious DRE. Prostate biopsy may be associated with discomfort, anxiety and financial costs. Minor complications occur frequently and major complications are possible, underscoring the need for more specific markers to decrease unnecessary biopsy. We determined the usefulness of p2psa and PHI for this clinical goal. PCa probability risk assessment using PHI and PHI relationship with biopsy Gleason score PHI Range Risk: % PCa probability (95% CI) 11.0 ( ) 18.1 ( ) 32.7 ( ) 52.1 ( ) RR (95% CI) ( ) 3.0 ( ) 4.7 ( ) % Pts Biopsy Gleason score:* No. less than 7 (%) 34 (73.9) 74 (71.8) 116 (69.9) 66 (57.9) No. 7 or greater (%) 12 (26.1) 29 (28.2) 50 (30.1) 48 (42.1) RR (95% CI) (0.61, 1.92) 1.15 (0.67, 1.98) 1.61 (0.95, 2.75) * One participant excluded with missing Gleason score (Cochran-Armitage test for trend p 0.01).
5 1654 [-2]PRO-PROSTATE SPECIFIC ANTIGEN FOR PROSTATE CANCER DETECTION Precursor forms of PSA improve the accuracy of PSA for detecting PCa. 5,6,9 12,27,28 Preliminary reports suggest that p2psa may be useful at PSA 2.0 to 10.0 ng/ml. 6,9 12,27,28 Some but not all studies suggest an association between propsa and PCa aggressiveness. 10,12,19 Thus, p2psa and PHI are being investigated in active surveillance programs to help decrease overtreatment of insignificant PCa. 18,29 Catalona et al previously reported that the propsa-to-fpsa ratio yielded higher specificity than the free-to-total PSA ratio. 9 Results in a separate multisite study also supported the role of p2psa combined with PSA and fpsa to decrease unnecessary biopsies. 12,13 In the current study specificity for PHI was higher than for free-to-total PSA at all prespecified sensitivities and the PCa risk increased with increasing PHI values. This suggests a role for PHI as a patient monitoring tool since increasing PHI values reflect PCa risk. 18 For example, at 95% sensitivity the specificity of PHI was 16.0% compared to 8.4% for free-to-total PSA. At lower sensitivities (90%, 85% and 80%) for PCa detection PHI had a significantly greater specificity than free-to-total PSA. These results were consistent across age groups, PSA concentrations and ethnic groups. For individual risk assessment the probability of PCa varied considerably based on PHI. For example, a man with PHI greater than 55 had a greater than 52% probability of PCa and 4.7-fold increased RR of positive biopsy. In contrast, at approximately 90% sensitivity a patient with PHI less than 25 had an 11% probability of PCa. In the PCa group higher PHI was also significantly associated with a higher percent of biopsy Gleason grade 7 or greater. In the entire study population the AUC of PHI exceeded that of free-to-total PSA (0.724 vs 0.670) to discriminate Gleason score greater than or equal to PCa vs lower Gleason grade PCa or negative biopsy. At a PHI cutoff of 21.3 Gleason score was 7 or greater in 25% of missed cancers. Thus, careful surveillance is needed. The AUCs of PHI also exceeded those of free-to-total PSA in all 3 prostate volume tertiles, suggesting that PHI improves PCa detection compared to free-to-total PSA across the spectrum of prostate volumes. Since PHI did not differ by age and race, these results suggest that PHI may be broadly applicable as an adjunct to predict clinically significant PCa. The strengths of the current validation study are the large number of participants and sites, providing confidence in the PHI cutoffs determined. PHI is highly effective when used in patients with moderately increased PSA, who may be most likely to benefit from early diagnosis and curative PCa treatment, and avoid unnecessary biopsy. A study limitation is that we did not evaluate the addition of PHI to predictive nomograms, which are often used for prostate cancer risk assessment. Future studies are warranted to examine this issue. Also, PSA was the primary indication for biopsy in this study, which should be considered when evaluating the ROC results. In addition, since p2psa and PHI were not used as the indications for biopsy in this study, future randomized trials would be useful to evaluate their use in screening compared to current protocols. CONCLUSIONS The PHI measurement, [-2]proPSA/fPSA PSA 1/2, may be useful to decrease unnecessary biopsies with improved specificity at various sensitivities for PCa detection in men 50 years or older with PSA 2.0 to 10.0 ng/ml and negative DRE findings. Our results apply to the Access Hybritech p2psa, PSA and fpsa assays on the Access Immunoassay System. 30 ACKNOWLEDGMENTS Drs. Alain Artus, Claude Darte, Bianca Gago, Malu Macairan, Simpa Salami, Edward F. Vonesh and Mark Wildhagen, and Jessica Banks, Willeke Bolle, Gerardina Bueti, Janna Chamberlin, Phillip Cooper, Renu Dua, Willard Dunn, Debra Elliott, Marcia Goodmanson, Robin Gurganus, Donghui Kan, Joep Kurstjens, Maureen Lemens, Lisa Ledebuhr, Lori Lofaro, Kathleen Loveland, Jiuliu Lu, Leslie Mangold, Patricia Nunnelly, Daniel O Brien, Kellie Paich, Mindy Rawlins, Javed Siddiqui and Sara Wyness assisted with the study. REFERENCES 1. Krumholtz JS, Carvalhal GF, Ramos CG et al: Prostate-specific antigen cutoff of 2.6 ng/ml for prostate cancer screening is associated with favorable pathologic tumor features. Urology 2002; 60: Thompson IM, Pauler DK, Goodman PJ et al: Prevalence of prostate cancer among men with a prostate-specific antigen level or 4.0 ng per milliliter. 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6 [-2]PRO-PROSTATE SPECIFIC ANTIGEN FOR PROSTATE CANCER DETECTION Mikolajczyk SD, Catalona WJ, Evans CL et al: Proenzyme forms of prostate-specific antigen in serum improve the detection of prostate cancer. Clin Chem 2004; 50: Mikolajczyk SD, Grauer LS, Millar LS et al: A precursor form of PSA (ppsa) is a component of the free PSA in prostate cancer serum. Urology 1997; 50: Chan TY, Mikolajczyk SD, Lecksell K et al: Immunohistochemical staining of prostate cancer with monoclonal antibodies to the precursor of prostate-specific antigen. Urology 2003; 62: Catalona WJ, Bartsch G, Rittenhouse HG et al: Serum pro prostate specific antigen improves cancer detection compared to free and complexed prostate specific antigen in men with prostate specific antigen 2 to 4 ng/ml. J Urol 2003; 170: Catalona WJ, Bartsch G, Rittenhouse HG et al: Serum pro-prostate specific antigen preferentially detects aggressive prostate cancers in men with 2 to 4 ng/ml prostate specific antigen. J Urol 2004; 171: Sokoll LJ, Chan DW, Mikolajczyk SD et al: Proenzyme PSA for the early detection of prostate cancer in the ng/ml total PSA range: preliminary analysis. Urology 2003; 61: Sokoll LJ, Wang Y, Feng Z et al: [-2]proenzyme prostate specific antigen for prostate cancer detection: a national cancer institute early detection research network validation study. J Urol 2008; 180: Sokoll LJ, Sanda MG, Feng Z et al: A prospective, multicenter, National Cancer Institute Early Detection Research Network study of [-2]proPSA: improving prostate cancer detection and correlating with cancer aggressiveness. Cancer Epidemiol Biomarkers Prev 2010; 19: Schröder FH, Hugosson J, Roobol MJ et al: Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009; 360: Andriole GL, Grubb RL 3rd, Buys SS et al: Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 2009; 360: Welch HG and Albertsen PC: Prostate cancer diagnosis and treatment after the introduction of prostate-specific antigen screening: J Natl Cancer Inst 2009; 101: Hugosson J, Carlsson S, Aus G et al: Mortality results from the Goteborg randomised population-based prostate-cancer screening trial. Lancet Oncol 2010; 11: Makarov DV, Isharwal S, Sokoll LJ et al: Proprostate-specific antigen measurements in serum and tissue are associated with treatment necessity among men enrolled in expectant management for prostate cancer. Clin Cancer Res 2009; 15: Jansen FH, van Schaik RH, Kurstjens J et al: Prostate-specific antigen (PSA) isoform p2psa in combination with total PSA and free PSA improves diagnostic accuracy in prostate cancer detection. Eur Urol 2010; 57: Semjonow A, Kopke T, Eltze E et al: Pre-analytical in-vitro stability of [-2]proPSA in blood and serum. Clin Biochem 2010; 43: Qin G, Hsu YS and Zhou XH: New confidence intervals for the difference between two sensitivities at a fixed level of specificity. Stat Med 2006; 25: Hosmer DW and Lemeshow S: Applied Logistic Regression. New York: John Wiley & Sons Efron B: The Jackknife, the Bootstrap, and Other Resampling Plans. Philadelphia: Society for Industrial and Applied Mathematics Efron B: Better bootstrap confidence intervals. J Am Stat Assoc 1987; 82: Pepe MS: The Statistical Evaluation of Medical Tests for Classification and Prediction. New York: Oxford University Press DeLong ER, DeLong DM and Clarke-Pearson DL: Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988; 44: de Vries SH, Raaijmakers R, Blijenberg BG et al: Additional use of [-2] precursor prostate-specific antigen and benign PSA at diagnosis in screendetected prostate cancer. Urology 2005; 65: Naya Y, Fritsche HA, Bhadkamkar VA et al: Evaluation of precursor prostate-specific antigen isoform ratios in the detection of prostate cancer. Urol Oncol 2005; 23: Isharwal S, Makarov DV, Sokoll LJ et al: Prostate Health Index and diagnostic biopsy tissue DNA content combination improves accuracy to predict the need for prostate cancer treatment among men enrolled in a proactive surveillance program. Unpublished data. 30. Loeb S, Chan DW, Sokoll L et al: Prostate specific antigen assay standardization bias could affect clinical decision making. J Urol 2008; 180: 1959.
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