Determination of Reference Values for Total PSA, Frr and PSAD According to Prostatic Volume in Japanese Prostate Cancer Patients

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1 Jpn J Clin OncoI1999;29(l2) Determination of Reference Values for Total PSA, Frr and PSAD According to Prostatic Volume in Japanese Prostate Cancer Patients with Slightly Elevated Serum PSA Levels Manabu Kuriyama1, Hiromi uno', Hiroki Watanabe 2, Hidetoshi Yamanaka 3, Yutaka Saito 4 and Keizo Shida 5 1Department of Urology, Gifu University School of Medicine, Gifu, 2Third Department of Basic Medicine, Meiji University of Oriental Medicine, Kyoto, 3Department of Urology, Gunma University School of Medicine, Maebashi, Gunma, 4Sasebo General Hospital, Sasebo, Nagasaki and 5Japanese Foundation of Prostate Research, Tokyo Japan Background: For screening prostate cancer (CAP) using prostate-specific antigen (PSA), the indications of biopsies for patients showing slightly elevated PSA values are still controversial. Furthermore, the dependence of total PSA, free-to-total PSA ratio (FIT) and PSA density (PSAD) on prostatic volume in gray zone cases is unclear. Methods: By analyzing 1913 patients with a serum total PSA ranging from 2.0 to 20 ng/ml, we evaluated the correlation between total PSA and age or prostatic volume and positive predictive value (PPV) in each range for total PSA, c;lge and prostatic volume. Then suitable reference values for total PSA, FIT and PSAD were decided according to prostatic volume. Results: There was no close correlation between PSA and age or volume. The PPV was high in the group with a prostatic volume of ml. Prostatic volume was categorized into three groups, <20, and ~40 ml, and reference values for obtaining a sensitivity of 90% were proposed. The reference values of total PSA and PSAD were lowered and that of FIT was raised with increase in prostatic volume. The specificity was very low for the ~40 ml group. The highest specificity of 36% in PSAD was obtained for the <20 ml group. Conclusion: The reference values for total PSA, FIT and PSAD must be changed according to prostatic volume in order to maintain a sufficient diagnostic sensitivity of CAP. Of these parameters, PSAD showed a high specificity in the group with a prostatic volume of <40 ml. Key words: prostate cancer - PSA gray zone - FIT- PSAD - prostatic volume INTRODUCTION The determination of serum prostate-specific antigen (PSA) has become an essential tumor marker for the diagnosis, evaluation of treatment and follow-up of patients with prostate cancer (CAP) (1-3). Owing to the biological nature ofpsa, its serum values may be elevated even in benign prostatic diseases such as acute prostatitis and benign prostatic hyperplasia (BPH). Therefore, the screening and diagnosis of CAP is not accurate for cases showing slightly elevated serum PSA values. Received August 3, 1999; accepted September 27, 1999 For reprints and all correspondence: Manabu Kuriyama, Department of Urology, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu , Japan. rnkuriyam-gif@umin.ac.jp Abbreviations: PSA, prostate-specific antigen; CAP, prostate cancer; NEM, no evidence of malignancy of the prostate; BPH, benign prostatic hyperplasia; Frr, free-to-total PSA ratio; PSAD, PSA density; PPV, positive predictive value In attempts to improve diagnostic specificity while maintaining sensitivity, age-specific PSA reference values (4), PSA velocity (5), detection of PSA molecular forms and calculation of the ratio in total PSA (6-12) and PSA density (PSAD) (13,14) have been studied. Of these, the free-to-total PSA ratio (F/T) and PSAD are considered to be promising tools. However, a suitable reference value of Fff has not yet been decided even in theusa or Europe owing to the lack of evaluation of identity among free PSA assays. In Japan, it has recently been reported that the detection rate of CAP differs according to the size of the prostate (9,15,16). Therefore, we evaluated positive predictive values according to the total PSA, patient's age and prostatic volume in the group having serum PSA values of ng/ml. We then proposed suitable reference values for total PSA, Fff and PSAD according to the volume. MATERIALS AND METHODS Patients with a total PSA value of ng/ml were enrolled in this study from the Institutes participating in the National 1999Foundation for Promotion of CancerResearch

2 618 Volume-specific PSA, FIT and PSAD Table 1. Statistical comparison ofeach parameter in patients with a total PSA of2-;!0~g/ml Parameter CAP NEM p-value n Range Mean±SD Median n Range Mean±SD Median Age (years) ± ± x 10-6 Volume (rnl) ± ± x Total PSA (ng/ml) ± ± x 10_ 35 Free PSA (ng/m!) ± ± FIT ± ± x 10_ 14 PSAD ± ± x CAP, prostate cancer; NEM, no evidence ofmalignancy ofthe prostate; n, numbers ofpatients examined. Research Project on the Efficacy of Mass Screening for Prostate Cancer, Japan, funded by the Cancer Research of the Japanese Ministry of Health and Welfare (Project Director Professor Hiroki Watanabe) (n = 577) and data for patients showing the same range of total PSA as mentioned above were collected from the 13th Tokyo Prostate Symposium held in December 1997 (n =1336). Serum total PSA values were mainly detected by Tandem-R PSA (n =479) and compatible methods such as Abbott, Eiken, Tosoh and CanAg (n = 892). Those measured by other methods such as MARKIT-M PA (n = 541) were converted to those of Tandem-R using the equation proposed by the Japanese Urological Association (17). Serum free PSA values were detected by Hybritech in 479 cases and those by other methods (n =479) were converted to those of Hybritech using an equation that we reported previously (18). The prostates were examined by transrectal ultrasonography (TRUS) and their volumes were calculated as a rotary ellipse. All patients were histologically confirmed by six-sectant systematic core needle biopsy or transurethral resection of the prostate. Serum detection oftotal PSA and free PSA was performed before treatment. Of the total of 1913 patients enrolled in this study, 491 were of CAP and the other 1422 had no evidence of malignancy of the prostate gland (NEM). BPH was mainly seen in the NEM cases. The clinical stage of CAP according to the criteria of the Japanese Urological Association (19) was stage A in 47, B in 267, C in 81, D in 73 and unclear in 23. Histopathological grade in CAP (19) was well differentiated adenocarcinoma in 176, moderately differentiated adenocarcinoma in 208, poorly differentiated adenocarcinoma in 62 and unclassified adenocarcinoma in 45. Of these cases, a total of 714 patients (CAP 184 and NEM 530) could be evaluated for total PSA, Frr and PSA as determined simultaneously. We evaluated the correlation between total PSA values and age or prostatic volume and positive predictive values (PPV) of CAP in terms of each serum PSA range, age and prostatic volume. We then proposed suitable reference values for total PSA, Frr and PSAD according to the prostatic volume. All statistical analyses were performed by SPSS (20) and a difference with a p value by Student's r-test of <0.05 was regarded as significant. No. of CAP 64 cases NEM 450 RESULTS > Total PSA (ng/ml) Figure 1. Positive predictive values indetection ofprostate cancer according tototal PSA values of2-20 nglml. Positive predictive values (PPV) tended to become high with increase intotal PSA values. CORRELATION BETWEEN TOTAL PSA AND AGE OR PROSTATIC VOLUME AND PPY Total PSA values and other parameters such as patient's age at diagnosis, prostatic volume, free PSA, Frr and PSAD were compared according to total PSA in the range 2-20 ng/ml (Table 1). In this range of total PSA, the mean total PSA values were 9.61 ng/ml in patients with CAP and 6.51 ng/ml in those with NEM, with a significant difference. Although there was overlap in the ranges, marked significant differences in the age, prostatic volume, Frr and PSAD values between patients with CAP and.t\tem were observed. Only free PSA values showed no significant difference with slightly lower values in CAP patients than in NEM. The PPY according to total PSA range is shown in Fig. 1. A total of 491 patients with CAP were detected among 1913 patients examined, PPY being 25.7% in total. The PPY increased from 12.5% in the group with a total PSA of

3 Jpn ] Clin Oncol 1999;29(12) ~. Ṃ 60 :t CAP( + }, y = R' = (,,:427) 160, , o. 0.lb NEM(O }, y = 1.162, R' = ("=1063) CAPC+ }, y = 0.28" R' = ("=327) 40 B NEMCO}. y = , R' = ("=1135) Total PSA (" &1m!) Tot.1PSA ("&1m!) Figure 2. Correlationbetween total PSA and age inpatients with a total PSA of2-20 ng/m\. There was nopositive correlation between PSA values and age for either CAP ornem cases. The linear regression lines were y = x (r'- =0.0005) incap (n =427) andy =0.2252x ( r'- =0.0108) in"'"'em (n = 1135). Figure 4. Correlation between total PSA and prostatic volume inpatients with a total PSA of2-20 ng/m!. There was aslight positive correlation between total PSA and prostatic volume innem cases. The linear regression lines were y = 0.281x (r" =0.0044) incap (11 =327) andy=l.j62x (r 2 = ) innem (11 = 1063). > a a- > c, o, Age (years) No. of --7.C~A;-;P-~7--~;;--~-~~---i:: cases NEM Figure 3. Positive predictive values in detection ofprostate cancer according topatient's age. Inthe age group years,there was nomarked age-related tendency inppy ng/ml to 46.5% in the group with a total PSA >10 ng/ ml, The correlation between total PSA values and patient's age or prostatic volume was compared. In the range ng/ml, total PSA was not correlated with age (Fig. 2). The linear regression lines in both CAP and NEM were almost parallel to the x-axis and the correlation coefficient in both groups was <0.02. The PPV showed an extremely low incidence in the age group of <55 years old; only three of the 427 CAP cases were distributed in this range and the detection rate was high in the age group 290 years. In the age group years PPV showed a mild increasing trend according to age (Fig. 3). On the other hand, a slightly positive correlation between total PSA value and prostatic volume was observed in NEM patients (Fig. 4). In NEM patients, an increase in volume of I mi means an elevation in total PSA value of 0.86 ng/ml, The Prostatic volume (mil No. of -f,c;;:a;-;p:-----;;:;;---;-;7--~;- ;=- 7=_-_,.!,! cases NEM Figure 5. Positive predictive values indetection ofprostate cancer according toprostatic volume. The group with aprostatic volume of mj had a high incidence ofprostate cancer. PPV according to the volume is presented in Fig. 5. The CAP cases showed a high frequency distribution in the group with a prostatic volume of ml. In patients with a prostatic volume 260 ml, the PPV was about one third of that in patients with a value of ml and accounted for only 17 of the 327 CAP patients. SUITABLE REFERENCE VALUES ACCORDING TO PROSTATIC VOLUME The specificity of total PSA, FfT and PSAD and also suitable cut-off values for obtaining a diagnostic sensitivity of 90% were compared in the 714 patients (184 in CAP and 530 in NEM) in which all parameters were simultaneously evaluable (Table 2). Total PSA showed a specificity of 20.4%. Therefore, biopsy could be avoided ini7.6% of the cases. Similarly,

4 620 Volume-specific PSA, FfJ and PSAD Table 2. Comparison of specificity of total PSA, FfT and PSAD in patients with serum PSA values of 2-20 ng/ml for maintaining a diagnostic sensitivity of 90% Parameter Total PSA FfT PSAD Reference values 3.8 ng/ml Sensitivity (%) Specificity (%) No. of patients with avoidable biopsy % The data were obatained from 184 CAP and 530 NEM patients. All parameters were examined simultaneously. FIT and PSAD showed specificities of 17.9 and 28.5%, respectively. The fixed cut-off values were calculated to be 3.8 ng/ml for total PSA, 0.31 for F/T and for PSAD. The PSAD test gave the best result; biopsy could be avoidable in 23.7% of the cases. After the prostatic volume had been categorized into three groups, <20, and 240 ml, suitable reference values for total PSA, FIT and PSAD were proposed for obtaining a sensitivity of 90% and the specificity in each category was also calculated ( Table 3). The reference values for total PSA fluctuated from 4.1 to 3.7 and then to 4.7 ng/ml with increase in volume. The reference values for FIT increased from to as the volume increased. The reference values for PSAD decreased from to with increase in the volume. As shown in Fig. 6, the specificity tended to be low in larger prostatic glands. PSAD showed the best specificity in patients with a prostatic volume of <40 ml and total PSA in those with a volume of 240 ml. DISCUSSION There is a limitation to the application of serum PSA determination for differential diagnosis between CAP and NEM in those patients showing slightly elevated serum PSA values. This is natural because PSA itself is not a cancer-specific tumor marker. PSA is a prostate-tissue specific proteinase (21). Several attempts have been made to improve the diagnostic Prostat ic ~ 40 Volume (mt) Figure 6. Comparison of specificity for obtaininga sensitivity of 90%. When the prostatic volume was >40 ml, the specificity was extremely low for total PSA, FfT and PSAD. accuracy in patients with slightly elevated PSA levels, especially the evaluation of specificity to obtain a sufficient diagnostic sensitivity. Of these, FIT (10,12) and PSAD (13,15) seem to show a relatively good specificity. In many reports from Western countries, the specificity using FIT in patients with a serum PSA of 4-10 ng/ml was about 30% (6,10-12). However, a uniform cut-off value for FIT has not been decided; according to Brawer et al. (22), one reason is that the difference in free PSA values among assays leads to different FIT values. In Japan, the specificity of FIT in patients with PSA of 4-10 ng/ml was reported by Kuriyama et al. (15) to be 19.6% with 90.7% sensitivity. In another study (8) we found FIT to be the most effective for the differential diagnosis of CAP from NEM in a group of higher PSA levels in the gray zone; the specificity increased to 60.7% in the 5-10 ng/ml group from 18.8% in the 4-10 ng/ml group with the same sensitivity of 90%. Furthermore, the specificity of PSAD showed better results than FIT (15). Akimoto et al. (16) also found a closer relation between PSA and prostatic volume than patient's age in Japanese mass screening subjects. They recommended a PSA reference range calculated with a stratified prostatic volume. Therefore, we re- Table 3. Comparison of reference values and specificities of total PSA, FIT and PSAD according to prostatic volume range in patients with serum PSA values of 2-20 ng/ml for maintaining a diagnostic sensitivity of 90% Prostati c volume (ml) Sensitivity (%) No. of patient s Total PSA FfT PSAD <20 91 CAP: 45 Reference value 4.1 ng/ml NEM: 86 Specificity (%) CAP: 98 Reference value 3.7 ng/ml NEM: 246 Specific ity (%) CAP: 41 Referen ce value 4.7 ng/ml NEM: 196 Specificity (%)

5 Jpn J Clin OncoI1999;29(12) 621 evaluated the relationship between total PSA and patient's age or prostatic volume in a large number of cases. To our knowledge, this is the largest study series in Japan to date. If the prostatic volume or patient's age can be shown to work as an independent indicator for the prediction of CAP in the group with a total PSA of ng/ml, we can propose a kind of volume-specific or age-specific reference value for total PSA, FIT and PSAD. In each condition, various specificities maintaining a sensitivity of 90% were also obtained because many clinicians expect at least this level of diagnostic sensitivity in this group. Catalona et al. also compared the specificity of FIT at the point showing a diagnostic sensitivity of 95 or 90% (10). Furthermore, in our studies, since the total PSA and free PSA values were either detected by the Tandem-R series or converted by using the equation obtained in our previous studies (17,18), the difference derived from assay methods for total and free PSA could be ignored. The correlation between total PSA and patient's age was extremely low in the group with a total PSA value of 2-20 ng/ml, as Akimoto et al. reported (16). There was no difference between patients with CAP and NEM. Total PSA and prostatic volume in NEM cases showed a mild positive correlation. The PPV was 12.5% in the group with a PSA value of ng/ml and gradually increased, as expected, with elevation of the total PSA value. When the total PSA was ;:::6.0 ng/ml, the PPV exceeded 20%; this level might be acceptable to patients for biopsy (23). The PPV showed a slight increase with age. The PPV was low in patients aged <55 and high in those of ~90 years. However, the incidence of CAP was low in both age groups: only three and five patients, respectively, out of 427 patients with CAP in this series. In those aged between 55 and 90 years, the PPV could be classified into two groups: about 25% in those <70 years and about 30% in those in their seventies or eighties. The PPV differed greatly with prostatic volume. The patients with a prostatic volume of ml showed a higher PPV than the average,which was 23.5%. Imai et al. (9) described the possibility of CAP being very low in patients with a total PSA of <10 ng/ml and a prostatic volume of <40 ml. In our series, the number of CAP patients with a prostate volume of >40 ml was 64 of the 327 (19.6%) whose prostate volume was examined. The overall specificities calculated in 714 patients who were simultaneously evaluated for total PSA, FIT and PSAD were 20.4,17.9 and 28.5%, respectively. The usefulness of FIT was less than that of total PSA for maintaining a diagnostic sensitivity of >90%. Then, suitable reference values were calculated according to the prostatic volume. The reference values for total PSA fluctuated. However, when calculated on 327 CAP patients and 1063 NEM patients who had been subjected to simultaneous determination of total PSA and prostatic volume, regardless of free PSA determination, the reference values decreased as the volume increased: 4.1 ng/ml in the <20 ml group, 3.9 in the ml group and 3.5 ng/ml in the ;:::40 ml group. The specificities were 32.5,34.2 and 15%, respectively. Similarly, the reference values and specificities for PSAD were and 27.6% in the <20 ml group, and 44.3% in the ml group and and 14.3% in the ;:::40 ml group. Hence the reference values must be changed according to prostatic volume, and with an increase in prostatic volume to keep the sensitivity sufficiently high, a lower total PSA and PSAD and a higher FIT. Moreover, it must be noted that the specificity in the ;:::40 ml group was still low regardless of the method. In a large prostate with especially small cancer foci, the diagnosis of CAP by SSB may be underestimated, which leads to a low specificity using these parameters. Although CAP cases with a large prostate are not common, a large prostate may cause worse symptoms of lower urinary obstruction than expected and should be checked by urologists with other diagnostic imaging methods. The prostatic volume is neither easy to measure, especially by TRUS, nor as objective as serum total or free PSA detection. Moreover, a suitable detection method has not yet been decided. Transabdominal ultrasonography (TAUS) of the prostate may be used alternatively to TRUS only for volume detection (14,16). This may be easy especially in mass screening. Although it will be complicated and less cost-effective to detect prostatic volume than PSA determination, PSAD showed a 5 10% higher specificity than total PSA in the group with a prostatic volume of <40 ml. This difference is large. For every million people with a PSA gray zone in mass screening, we may avoid 50, ,000 unnecessary and harmful biopsies. In conclusion, the reference values for total PSA, FIT and PSAD must be changed according to the prostatic volume to maintain a high diagnostic sensitivity. Of these parameters, PSAD showed the highest specificity in patients with a prostatic volume of <40 ml. The specificity of <19% of total PSA was low in the group with a larger prostatic volume (;:::40 ml). Acknowledgments The authors express their sincere appreciation to researchers participating in the National Research Project on the Efficacy of Mass Screening for Prostate Cancer, Japan, funded by the Cancer Research of the Japanese Ministry of Health and Welfare, and the 13th Tokyo Prostate Symposium for providing cases and medical records. References 1. Kuriyama M. Prostate-specific antigen as a tumor marker in prostate cancer. Int J UrolI994;1: Oesterling JE. 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