Table 1. Descriptive characteristics, total prostate-specific antigen, and percentage of free/total prostate-specific antigen distribution Age Groups

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1 Oncology Population-based Analysis of Normal Total PSA and Percentage of Free/Total PSA Values: Results From Screening Cohort Umberto Capitanio, Paul Perrotte, Laurent Zini, Nazareno Suardi, Elie Antebi, Vincent Cloutier, Claudio Jeldres, Shahrokh F. Shariat, Alain Duclos, Philippe Arjane, Fred Saad, Francesco Montorsi, and Pierre I. Karakiewicz OBJECTIVES METHODS RESULTS CONCLUSIONS To examine the distribution of total prostate-specific antigen (tpsa) and percentage of free/total PSA (%f/tpsa) values in patients undergoing prostate cancer screening in Canada. The data from 4 consecutive annual prostate cancer screening events held in Montreal, Canada were examined with respect to age, tpsa, and %f/tpsa in 3222 men. Within the entire cohort, the median PSA level was 1.0 ng/ml and the median %f/tpsa was 26%. Using the interquartile range around the median, the upper bound for tpsa was situated at 1.9 ng/ml and the lower bound for %f/tpsa was at 19%. The 90th percentile for the median tpsa was 3.8, and the 10th percentile for the median %f/tpsa was 14. PSA and %f/tpsa showed a relation with age. The 75th percentile for the median tpsa level in the age category 40-49, 50-59, 60-69, and years was 1.1, 1.4, 2.6, and 3.6 ng/ml, respectively. The 25th percentile for the median %f/tpsa level in the age category 40-49, 50-59, 60-69, and years was 19, 21, 18 and 19 ng/ml, respectively. Our results can guide clinicians regarding the population-based distribution of serum tpsa and %f/tpsa values. Those values can be used for the purpose of counseling, as well as in the informed consent process before prostate biopsy. UROLOGY 73: , Elsevier Inc. Controversy persists regarding the definition of a normal total serum prostate-specific antigen (tpsa) level The Prostate Cancer Prevention Trial data have demonstrated that a large proportion of men with a tpsa level of 2.5 ng/ml harbor prostate cancer (PCa). 8 Several other investigators have also reported on normal serum tpsa values that were well below the previously accepted cutoff of 4 ng/ml. 3,5-9,13-16 For example, in the Prostate Cancer Prevention Trial, Thompson et al. 8 detected PCa in 15.2% of men whose tpsa level was 4.0 ng/ml. Even in the presence of very low tpsa values ( ng/ml), 16.7% had PCa on biopsy. 8 Fang et al. 5 relied on the Baltimore Longitudinal Study of Aging, which spanned 3 decades of follow-up, to demonstrate that a baseline tpsa level greater than the P. I. Karakiewicz is partially supported by the University of Montreal Heath Center Urology Associates, Fonds de la Recherche en Santé du Québec, the University of Montreal Department of Surgery and the University of Montreal Health Center (CHUM) Foundation. From the Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Quebec, Canada; Department of Urology, Vita-Salute University San Raffaele, Milan, Italy; and Department of Urology, University of Montreal, Montreal, Quebec, Canada Reprint requests: Pierre I. Karakiewicz, M.D., F.R.C.S.C., Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center (CHUM), 1058 Rue Street, Denis, Montreal H2X 3J4 QC, Canada. pierre.karakiewicz@ umontreal.ca Submitted: July 23, 2008, accepted (with revisions): October 6, 2008 median for the age group years (0.6 ng/ml) and years (l.71 ng/ml) increased the risk of PCa 3.6 and 3.5 times, respectively. Loeb et al. 13 showed that a baseline tpsa level between the age-adjusted (40-49 vs vs 60 years) median tpsa value (0.7, 0.9, and 1.4 ng/ml, respectively) and 2.5 ng/ml represents a significant risk factor (P.001) for developing PCa of any grade. 13 Men aged and years had, respectively, 14.6 and 7.6 times the risk of PCa than men with a baseline tpsa equal to or less than the median. 13 These data indicate that the normal values are well below the previously used cutoff of 4 ng/ml and that even a cutoff of 2.5 ng/ml might be too high. 8,13,14 Because of the lack of established normal definitions, we assessed the distribution of tpsa in a large screening cohort of healthy men with no diagnosis of PCa. Moreover, using the established value of the percentage of free/total PSA (%f/tpsa) in several multivariate models predicting the presence of PCa at needle biopsy, we also examined the distribution of %f/tpsa. MATERIAL AND METHODS Patient Population The study group consisted of 3222 men with no known PCa who had participated in 1 of 4 annual PCa screening events, the 2009 Elsevier Inc /09/$ All Rights Reserved doi: /j.urology

2 Table 1. Descriptive characteristics, total prostate-specific antigen, and percentage of free/total prostate-specific antigen distribution Age Groups (y) Variable All Patients (n) 3222 (100) 526 (16.3) 1241 (38.5) 947 (29.4) 508 (15.8) tpsa (ng/ml) (9.4) 3 (0.6) 58 (4.7) 126 (13.3) 115 (22.6) (18.1) 14 (2.7) 124 (10.0) 246 (26.0) 200 (39.4) %f/tpsa (%) (48.6) 208 (39.5) 560 (45.1) 530 (56.0) 269 (53.0) (13.5) 54 (10.3) 158 (12.7) 155 (16.4) 68 (13.4) tpsa 2.5 ng/ml or %f/tpsa (51.4) 210 (39.9) 570 (45.9) 561 (59.2) 315 (62.0) tpsa 2.5 ng/ml or %f/tpsa (25.1) 60 (11.4) 216 (17.4) 314 (33.2) 219 (43.1) tpsa (ng/ml) Mean Median Range th percentile th percentile Interquartile range th percentile %f/tpsa (%) Mean Median Range th percentile th percentile Interquartile range th percentile tpsa, total prostate-specific antigen; %f/tpsa, percentage free prostate specific antigen. Data presented as number of patients, with percentages in parentheses, unless noted otherwise. PCa Awareness Days in None of the men included in the present analysis participated in 1 annual screening event and none had suspicious digital rectal examination findings. Only men aged years were invited. The Hybritech (Beckmann-Coulter, Mississauga, ON, Canada) assay was used for both tpsa and %f/tpsa measurements. Statistical Analysis The tpsa level and %f/tpsa distributions were explored and tabulated for the entire cohort and stratified by age strata of 40-49, 50-59, 60-69, and years. We used regression plots with the intent of providing a graphic display of the relation between age and PSA and age and %f/tpsa. The Statistical Package for Social Sciences, version 15.0 (SPSS, Chicago, IL) was used for all analyses. All tests were 2-sided with the significance level set at P.05. RESULTS The median age of the 3222 study participants was 58 years (mean 59.0, range 40-79). Table 1 lists the descriptive characteristics of the total cohort of 3222 men. Of all 3222 men, 526 (16.3%), 1241 (38.5%), 947 (29.4%), and 508 (15.8%) were aged 40-49, 50-59, 60-69, and years. In the entire cohort, the median tpsa level was 1.0 ng/ml (range ) and the median %f/tpsa level was 26.0 ng/ml (range ). Figure 1 shows the scatterplots of the distribution between age and tpsa level (Fig. 1A) and between age and %f/tpsa (Fig. 1B). Figure 2 shows the interquartile range around the tpsa and %f/tpsa medians derived from the entire cohort. The 25th percentile for the median tpsa level in the age category of 40-49, 50-59, 60-69, and years was 0.5, 0.5, 0.8, and 1.0 ng/ml, respectively (Fig. 2A). The 75th percentile for the median tpsa level in the age category of 40-49, 50-59, 60-69, and years was 1.1, 1.4, 2.6, and 3.6 ng/ml, respectively (Fig. 2A). The 25th percentile for the median %f/tpsa level in the age category of 40-49, 50-59, 60-69, and years was 19, 21, 18, and 19 ng/ml, respectively (Fig. 2B). The 75th percentile for the median %f/tpsa level in the age category of 40-49, 50-59, and years was 34, 36, 33, and 31 ng/ml, respectively (Fig. 2B). COMMENT Contemporary cases of localized PCa are predominantly not palpable. 1-9,13-16,20-22 Therefore, PSA-based detection represents the best and only means of detecting these cancers. However, no definitive data are available regarding what constitutes a normal tpsa level. 1-9,13-16 Similarly, no definitive data are available indicating the optimal %f/tpsa that should be applied. Several efforts have been made to improve the sensitivity and specificity of serum tpsa. 1-9,13-16,23,24 Oesterling et al. 23 pioneered the use of age-specific tpsa ranges, using data from 471 men with no evidence of PCa. Morgan et al. 24 revised the age-specific ranges and reported substantially lower age UROLOGY 73 (6), 2009

3 Figure 2. Overall and age category-specific distribution of (A) median total prostate-specific antigen (tpsa) and (B) percentage of free/total prostate-specific antigen (%f/tpsa) level and interquartile range. Figure 1. Scatterplots illustrating (A) median total prostate-specific antigen (tpsa) values and (B) percentage of free/total prostate-specific antigen (%f/tpsa) stratified by age for 3222 asymptomatic men with no clinical evidence of prostate cancer. specific values for white (40-49, 50-59, 60-69, and years: 0.7, 1.0, 1.4, and 1.8 ng/ml, respectively) and black (40-49, 50-59, 60-69, and years: 0.7, 1.1, 1.6, and 2.2 ng/ml, respectively) men without evidence of PCa. Lilja et al. 25 assessed the PCa risk among men 50 years old who participated in a cardiovascular prevention project (MPM) in Malmö, Sweden. The investigators measured the tpsa levels at the beginning of the program. Overall, 462 participants were diagnosed with PCa within a median of 18 years from start of the study. The odds ratio for a PCa diagnosis at an initial tpsa value of ng/ml was 2.5 compared with a tpsa level of 0.50 ng/ml. The odds ratio increased to 7 for a tpsa of ng/ml, and to 19 for a tpsa level of ng/ml. 25 In another analysis of the same cohort, the value of the PSA assessments in these younger men were compared with the blood taken from 1167 men aged years. 26 In that study, the prognostic accuracy of tpsa decreased with age but was not affected by the interval between the measurement and the diagnosis. In contrast, %f/tpsa added more important predictive value in older men but especially when the PCa diagnosis was close to the start of the study. 26 European screening data have also indicated that a nonnegligible proportion of patients will be diagnosed with PCa despite low tpsa levels. 27,28 For example, on sextant biopsy, 7%-34% of men were found to have PCa, depending on prostate gland size. 27,28 However, the Prostate Cancer Prevention Trial questioned the validity of some of these values and indicated that PCa can be found even in patients with tpsa values below the lowest age-specific median values reported by Morgan et al. 24 and Lilja et al. 25 Therefore, few reference data exist to guide clinicians regarding a cutoff for biopsy in men with otherwise no evidence of a palpable abnormality. A similar paucity of referenced data exists regarding %f/tpsa. Catalona et al. 15 suggested a cutoff of 24% to detect 90% of cancers and to avoid 18% of benign biopsy findings in patients with a PSA value UROLOGY 73 (6),

4 ng/ml. In an update, Catalona et al. 14 examined a variety of cutoffs, some of which were as low as 10%. Other investigators have recommended cutoffs of 18%-27%. Taken together, these previously reported tpsa and %f/tpsa data indicate a lack of consensus regarding what tpsa and %f/tpsa values should be expected in patients with no clinical evidence of PCa. Thus, we decided to examine the tpsa and %f/tpsa values of our PCa screening cohort with the objective of adding to the existing knowledge. 23,24,29 Our data showed that one half the men had a PSA value of 1.0 ng/ml. The median of the entire cohort was 1.0 ng/ml and was 0.7, 0.9, 1.3, and 1.9 ng/ml for the age strata of 40-49, 50-59, 60-69, and years, respectively. Regarding %f/tpsa, older reports had suggested no relationship with age. 23,24,29 Moreover, a variety of cutoffs were proposed. 1,2,4,8,9,14,15,23,24,29,30 The present analysis demonstrated a relationship with age, with younger patients having substantially greater %f/tpsa median value (Figs. 1B and 2B) Moreover, our results have demonstrated that most men will have a %f/tpsa value 27%. This cutoff was recommended by Catalona et al. 15 in patients with a PSA value of and by Uzzo et al. 30 for patients with a PSA value of 2-20 ng/ml. Our results also indicated that a relative minority of patients will have a %f/tpsa value of 25%. Lower cutoffs of 10% or even 18% might lack sensitivity. 14 Taken together, our findings indicate the following points. First, patients without clinical evidence of PCa should have a PSA value 2.5 ng/ml. In men aged years, the tpsa value should be predominantly 1.5 ng/ml. The 2.5-ng/mL cutoff appears most appropriate for men aged years. Only men aged years should have a tpsa value of ng/ml. Second, the %f/tpsa is less strongly related to age. Nonetheless, an age relation is present such that younger patients will have greater values than older patients. With the lower %f/tpsa variability according to age, an overall cutoff of 27% can be proposed, which correlates perfectly with the cutoffs proposed by Catalona et al. 14,15 and Uzzo et al. 30 Third, our data originate from a patient population that is distinct from those included in previous analyses that focused on men from the United States and of various ethnic backgrounds. Our data originated from a French-Canadian population that virtually exclusively consisted of whites. In that respect, it is highly interesting that the data from African Americans or even white Americans have correlated that closely with our data. The present study had limitations. The most important was that biopsies were not taken as a part of the screening initiative. Therefore, men with a normal tpsa level might have had PCa. Moreover, we did not adjust for the effect of race, because virtually all the participants were white. Our findings might have been affected by a volunteer bias, because the men who volunteer to participate in a health initiative are usually more health conscious than those who do not. Thus, their PSA and %f/tpsa values might have been, respectively, lower and higher than those of the referral patients. Despite these limitations, our data represent a useful reference of what the tpsa level and %f/tpsa distribution might be in men with no clinical evidence of PCa. CONCLUSIONS Our results can guide clinicians regarding the populationbased distribution of serum tpsa and %f/tpsa values. Those values can be used for the purpose of counseling and in the informed consent process before prostate biopsy. References 1. Carter HB. Prostate cancers in men with low PSA levels must we find them? N Engl J Med. 2004;350: Ross KS, Carter HB, Pearson JD, et al. Comparative efficiency of prostate-specific antigen screening strategies for prostate cancer detection. JAMA. 2000;284: Catalona WJ, Smith DS, Ratliff TL, et al. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med. 1991;324: Labrie F, Candas B, Cusan L, et al. Screening decreases prostate cancer mortality: 11-year follow-up of the 1988 Quebec prospective randomized controlled trial. Prostate. 2004;59: Fang J, Metter EJ, Landis P, et al. Low levels of prostate-specific antigen predict long-term risk of prostate cancer: results from the Baltimore longitudinal study of aging. Urology. 2001;58: Schroder FH, van der Cruijsen-Koeter I, de Koning HJ, et al. Prostate cancer detection at low prostate specific antigen. J Urol. 2000;163: Lodding P, Aus G, Bergdahl S, et al. Characteristics of screening detected prostate cancer in men years old with 3-4 ng/ml prostate specific antigen. J Urol. 1998;159: 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. N Engl J Med. 2004;350: Bjartell A. PSA and prostate cancer screening: the challenge of the new millennium. Eur Urol. 2007;52: Roemeling S, Roobol MJ, de Vries SH, et al. Active surveillance for prostate cancers detected in three subsequent rounds of a screening trial: characteristics, PSA doubling times, and outcome. Eur Urol. 2007;51: Shariat SF, Karakiewicz PI. Screening for prostate cancer in 2007: the PSA era and its challenges are not over. Eur Urol. 2008;53: Avery KN, Blazeby JM, Lane JA, et al. Decision-making about PSA testing and prostate biopsies: a qualitative study embedded in a primary care randomised trial. Eur Urol. 2008;53: Loeb S, Roehl KA, Antenor JA, et al. Baseline prostate-specific antigen compared with median prostate-specific antigen for age group as predictor of prostate cancer risk in men younger than 60 years old. Urology. 2006;67: Catalona WJ, Partin AW, Slawin KM, et al. Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA. 1998;279: Catalona WJ, Smith DS, Ornstein DK. Prostate cancer detection in men with serum PSA concentrations of ng/ml and benign prostate examination: enhancement of specificity with free PSA measurements. JAMA. 1997;277: Horninger W, Cheli CD, Babaian RJ, et al. Complexed prostatespecific antigen for early detection of prostate cancer in men with 1326 UROLOGY 73 (6), 2009

5 serum prostate-specific antigen levels of 2-4 nanograms per milliliter. Urology. 2002;60: Tanguay S, Begin LR, Elhilali MM, et al. Comparative evaluation of total PSA, free/total PSA, and complexed PSA in prostate cancer detection. Urology. 2002;59: Chun FK, Graefen M, Briganti A, et al. Initial biopsy outcome prediction-head-to-head comparison of a logistic regression-based nomogram versus artificial neural network. Eur Urol. 2007;51: Karakiewicz PI, Benayoun S, Kattan MW, et al. Development and validation of a nomogram predicting the outcome of prostate biopsy based on patient age, digital rectal examination and serum prostate specific antigen. J Urol. 2005;173: Chun FK, Hutterer GC, Perrotte P, et al. Distribution of prostate specific antigen (PSA) and percentage free PSA in a contemporary screening cohort with no evidence of prostate cancer. BJU Int. 2007;100: Capitanio U, Scattoni V, Freschi M, et al. Radical prostatectomy for incidental (stage T1a-T1b) prostate cancer: analysis of predictors for residual disease and biochemical recurrence. Eur Urol. 2008;54: Chun FK, Suardi N, Capitanio U, et al. Assessment of pathological prostate cancer characteristics in men with favorable biopsy features on predominantly sextant biopsy. Eur Urol. Epub 2008 May Oesterling JE, Jacobsen SJ, Chute CG, et al. Serum prostatespecific antigen in a community-based population of healthy men: establishment of age-specific reference ranges. JAMA. 1993;270: Morgan TO, Jacobsen SJ, McCarthy WF, et al. Age-specific reference ranges for prostate-specific antigen in black men. N Engl J Med. 1996;335: Lilja H, Ulmert D, Bjork T, et al. Long-term prediction of prostate cancer up to 25 years before diagnosis of prostate cancer using prostate kallikreins measured at age years. J Clin Oncol. 2007;25: Vickers AJ, Ulmert D, Serio AM, et al. The predictive value of prostate cancer biomarkers depends on age and time to diagnosis: towards a biologically-based screening strategy. Int J Cancer. 2007; 121: Postma R, Schroder FH, van Leenders GJ, et al. Cancer detection and cancer characteristics in the European Randomized Study of Screening for Prostate Cancer (ERSPC) Section Rotterdam: a comparison of two rounds of screening. Eur Urol. 2007;52: van den Bergh RC, Roobol MJ, Wolters T, et al. The Prostate Cancer Prevention Trial and European Randomized Study of Screening for Prostate Cancer risk calculators indicating a positive prostate biopsy: a comparison. BJU Int. Epub 2008 Aug Oesterling JE, Jacobsen SJ, Klee GG, et al. Free, complexed and total serum prostate specific antigen: the establishment of appropriate reference ranges for their concentrations and ratios. J Urol. 1995;154: Uzzo RG, Pinover WH, Horwitz EM, et al. Free prostate-specific antigen improves prostate cancer detection in a high-risk population of men with a normal total PSA and digital rectal examination. Urology. 2003;61: UROLOGY 73 (6),