Clinical Significance of Prostate Specific Antigen for Early Stage Prostate Cancer Detection

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1 linical Significance of Prostate Specific Antigen for Early Stage Prostate ancer Detection Kyoichi Imai, Yoshio Ichinose, Yutaka Kubota, Hidetoshi Yamanaka, Jin Sato 2, Masahito Saitoh, Hiroki Watanabe and Hiroshi Ohe 4 Department of 'Urology, Gunma University School of Medicine, Maebashi, department of Urology, Gunma ancer enter Hospital, Oota, department of Urology, Kyoto Prefectural University of Medicine, Kyoto and department of Urology, Kyoto Second Red ross Hospital, Kyoto The characteristics of serum prostate specific antigen (PSA) in normal Japanese men were studied in 48 subjects examined by mass screening (MS) for prostate cancer (Pea) in Gunma Prefecture in 992. The serum PSA concentration was correlated with patient age. The average serum PSA level increased by.4 ng/ml/year. The upper normal limits (95 percentiles) of age specific PSA for normal men are. ng/ml for those aged 9-49 years,.65 ng/ml for those aged 5-59 years, 4.6 ng/ml for those aged 6-69 years, 5.9 ng/ml for those aged 7-79 years and 5.66 ng/ml for those aged 8-89 years. Among 227 normal men examined by our MS in 99 and 992, the PSA velocity (PSAV) was calculated to be.5 ng/ml/year. Among Pea patients with normal PSA levels ( <6 ng/ml) detected previously by our MS, three had an abnormal PSAV. We demonstrated the possibility that PSA density could distinguish between Pea and benign prostate hypertrophy. The significance of PSA as a Pea screening modality should be evaluated across multiple age ranges and in combination with previous PSA data and/or prostate volume estimated by sonography. (Jpn J lin Oncol 24: 6-65, 994) Key words: Prostate cancer Mass screening Prostate specific antigen Introduction It has been stated that digital rectal examination (DRE) is the most sensitive procedure for detecting prostate cancer (Pea) and that the diagnosis of Pea has relied upon a DRE and digitally guided biopsy. The subjectivity of DRE is a recognized factor in the low detection rate of Pca. 2) Transrectal ultrasonography (TRUS) is also subject to considerable subjectivity in interpretation, although its use as a screening modality has been reported to be twice as frequent as DRE alone. ' Prostate specific antigen (PSA) levels in the serum can be measured accurately, but interpretation of the significance of a specific measured level is not exact. The PSA diagnosis is especially crucial in patients with early stage Pea and in those with benign prostate hypertrophy (PH). It is apparently that DRE, Received: January, 994 Accepted: March 29, 994 For reprints and all correspondence: Kyoichi Imai, Department of Urology, Gunma University School of Medicine, 9-22, Showa-machi -chome, Maebashi, Gunma 7 TRUS and PSA are all imperfect modalities. In the present report, we demonstrate further the inaccuracy of these diagnostic procedures and try to establish the most reliable diagnostic system for Pea at the present time. Materials and Methods Since 98, we have been studying Pea by mass screening (MS) in the Gunma Prefecture of Japan. 4) From 98 to 99, 9828 subjects (7,5 examinations) were examined by DRE and prostatic acid phosphatase (PAP). In 992, 76 subjects were examined by DRE, TRUS and PSA. These subjects were diagnosed as "Pea suspected" whenever any small abnormality was found by DRE, hypoechoic image and/or deformity of prostate shape found by TRUS, and/or elevated PSA. These "Pea suspected" subjects were referred to a hospital to confirm the presence of Pea (Table I). To study age-specific PSA in normal men, 8 subjects who had a history of PH treatment were excluded from the analysis. We defined the meaning of a normal man as follows: 6 subjects who had Downloaded from at Pennsylvania State University on May 8, 26 6 Jpn J lin Oncol 24() 994

2 SREENING FOR PROSTATE ANER WITH PROSTATE SPEIFI ANTIGEN Table I. linical Findings of Subjects Examined by Mass Screening in 992 Digital rectal examination (DRE) Transrectal ultrasonography (TRUS) Prostate specific antigen (PSA) Subjects with no abnormal finding Subjects with abnormal finding Subjects biopsied Prostate cancer Normal men* , normal finding; +, abnormal finding. *, Subjects with no abnormal finding by DRE, TRUS and/or PSA, and subjects negative on biopsies for abnormal findings Table II. Serum PSA Levels of 48 Normal Men Range Age (yr) Average Median n Range *, 95 percentile; PSA, prostate specific antigen. normal DRE, TRUS and PSA and 7 (2-5) who had abnormal DRE, TRUS and/or PSA but in whom the presence of Pea was not confirmed by prostate biopsy. A total 48 subjects were treated as normal men and they were used for the investigation of age-specific PSA. All serum specimens were kept in our serum bank and serum PSA levels were measured with E-test Tosoh II kit (Tosoh o, Tokyo). PSA values obtained with the kit are almost the same as those obtained with the Tandem R kit (Hybritech Inc, A), which is the kit most widely used in the U.S.A. 5 ' The lowest reliable PSA value given by the kit is. ng/ml. In cases of <. ng/ml, the value obtained was used for the parameter calculation and statistical evaluation. The normal upper PSA limit was 6 ng/ml in our MS. 6) TRUS was performed with a Toshiba Sonolayer SSA25A equipped with an 8 MHz radial transrectal probe. ontinuous scanning was carried out from the base to the apex of the prostate. Two diameters of maximum prostate scanning size (W, width; H, height) were measured, and the prostate volume was estimated by the following formula:.52xwxwxh. TRUS findings for Pea were diagnosed by three doctors (M.S., H.W. and H.O.). Of the group of subjects, 227 had histories of prior examination by our MS in 99, and their PSA (ng/ml) Average Median %* sera had been kept in our serum bank for PSA measurement. The difference between the PSAs in 99 and 992 was designated PSA velocity (PSAV, ng/ml/year). The changing rate of PSA between the two years was calculated by the following formula: PSA in 992-PSA in 99 x PSA in 99 The significances of PSAV and changing rate were evaluated in Pea patients who had been examined by our MS in two consecutive years and who had had normal PSAs at the time of Pea diagnosis. All of these Pea patients had abnormal DREs. One Pea patient had a normal TRUS and nine Pea patients were not examined by TRUS because it was not performed during MS at the time of their cancer diagnosis. Results The detection rates of DRE, TRUS and PSA were compared in 68 subjects examined by MS in 992. Abnormal findings were observed in 7 subjects. iopsies were performed on 2 subjects, and 5 Peas were detected (Table I). The detection rate and positive predictive value (PPV) were.89% (5/68) and 4.7% (5/7), respectively. Downloaded from at Pennsylvania State University on May 8, 26 6

3 Table III. Postate ancer Patients Detected by Mass Screening in 992 IMAI ET AL. Patient Age PSA DR Pathological no. (yr) (ng/ml) differentiation Well Moderately + Poorly + Moderately Moderately Well + Moderately - Moderately + Moderately - Moderately Moderately PSA, prostate specific antigen; DRE, digital rectal examination; TRUS, transrectal ultrasonography; +, abnormal finding; -, normal finding. Eight of 5 Pea patients were detected by DRE, eight by TRUS and by PSA (Fig. ). The sensitivities were 5.% for DRE (8/5), 5.% for TRUS (8/5) and 7.% for PSA (/5). When PPVs were calculated by Pea per abnormal finding, they were 5.% for DRE, 5.4% for TRUS and 4.7% for PSA. When PPVs were calculated by Pea per biopsy, they were.% for DRE,.6% for TRUS and 27.5% for PSA. PSA had the highest sensitivity in our MS, followed by that of PPV. In 48 normal men (Table II), average serum PSA levels were calculated in -year increments. The average PSA concentrations were.8 ng/ml for men aged 4-49 years,.2 ng/ml for those aged 5-59 years,.6 ng/ml for those aged 6-69 years, 2. ng/ml for those aged 7-79 years and.8 ng/ml for those aged 8-89 years. It seemed that the serum PSA increased by approximately.4 ng/ml every years except for the eighty-year-old men. If the upper normal limit was determined by the 95% confidence range, the upper normal limits in these decades were. ng/ml,.7 ng/ml, 4. ng/ml, 5. ng/ml and 4.7 ng/ml, respectively. The effect of age-specific PSA on sensitivity was investigated in 5 Pea patients detected by MS in 992 (Table HI). In one patient (no. 4 in Table III), the PSA was lower than the normal limit (6. ng/ml) used in our MS; however, it was higher than the upper normal limit by age-specific PSA. Age-specific PSA therefore improved the sensitivity from 7.% (/5) to 8.% (2/5). Among the 48 normal men studied, there was D D Fig.. Screening modality and prostate cancer detected by mass screening in 992. PSA, prostate specific antigen; DRE, digital rectal examination; TRUS, transrectal ultrasonography. 7 2 PSA (ng/ml) 4 5 Fig. 2. Relation between serum prostate specific antigen concentration and prostate volume estimated by transrectal ultrasonography (r.5). no significant relation between PSA and prostate volume as estimated by TRUS (r.5, Fig. 2). There was, however, a significant relation between PSA and prostate volume (P<., by the chisquared test, Table IV) when the prostate volume was stratified into two categories (<25cm and > 5 cm ) and PSA was also stratified into three categories than (<2 ng/ml, 2-4 ng/ml, >4 ng/ml). The 48 subjects were next classified into 6 men with normal DRE and TRUS and 7 men with abnormal DRE and/or TRUS but in whom the presence of Pea was not confirmed by prostate biopsy. There was a statistically significant relation in the 6 men between PSA and prostate volume (P<.\). In the 7 men, it seemed that there was also a relation or trend between the two parameters; however, the subject number was too small to be evaluated statistically for significance. Downloaded from at Pennsylvania State University on May 8, Jpn J lin Oncol 24() 994

4 SREENING FOR PROSTATE ANER WITH PROSTATE SPEIFI ANTIGEN Table IV. Relation of PSA to Prostate Volume Volume (cm ) PSA (ng/ml) 2 >2 to s4 >4 Number (%) Number (%) Number (%) 6 men with normal DRE and TRUS 25 5(84.4) 62(.) (2.6) 248() >25 55(47.8) 7(2.2) 2(2.) 5() 8(8.) 99(4.6) 56(4.) 6() 7 men \ vith abnormal DRE and/or TRUS g25 >25 68 (68.) ( 5.9) 69(59.) (.) (7.6) (.) 22 (22.) (76.5) 5 (29.9) 48 normal men <25 2(8.2) >25 56 (42.4) 77(79.5) 72(2.8) 4(.) 22(4.) 55 ( 4.) 6(27.) 9 ( 6.) () 7() 7() 48() 2() 48() PSA, Prostate specific antigen; DRE, digital rectal examination; TRUS, transrectal ultrasonography. Table V. Prostate Specific Antigen Density (PSAD) and Prostate ancer Detection Non-prostate cancer Prostate cancer PPV PSA density >.5 to < PSAD was calculated by the follwing formula: PSA concentration (ng/ml)/prostate volume estimated by TRUS (cc). PSA, prostate specific antigen; PPV, positive predictive value; TRUS, transrectal ultrasonography. The significance of PSAD was evaluated in 2 biopsied subjects (Table V). The stratification of PSAD was carried out according to enson's method. 7 ' One Pea was detected in 7 subjects with <. PSAD, and the PPV was.4%. Fourteen Peas were detected in 62 subjects with ^. PSAD, and the PPV was 22.6%. The PSAVs of 227 normal men were calculated (Table VI). The average PSAV was.5 ng/ml/year and the 95 percentile range was from -.5 to +.6. In the present study, <+.6 ng/ml/year was determiend as the upper normal limit for PSAV. The average PSA changing rate was 9% and the 95 percentile range was from -9 to +68%. The cut off value for the changing rate was determined at 7%. The significances of PSAV and changing rate were evaluated in Pea patients Table VI. PSA Velocity and PSA hanging Rate for 227 Normal Men Number Average Range 95%* PSA velocity O.5~O.6 PSA changing rate 227 9% -6% -4% -9%- 68% *, 95 percentile; PSA, prostate specific antigen. The formula to obtain PSA velocity and PSA changing rate is described in Materials and Methods. Table VII. PSA* (ng/ml) PSA Velocity and PSA hanging Rate for Prostate ancer Patients with Normal PSA PSA velocity (ng/ml/year) PSA, prostate specific antigen. *, PSA value at the time of cancer diagnosis. PSA changing rate with normal PSA levels at the time of Pea diagnosis (see Materials and Methods and Table VII). PSAV was > +.6 ng/ml/year in three patients. It was expected that PSAV would be able to improve the % detection rate in the Pea patients with normal serum PSA levels. Only % were, however, improved by the changing rate. Discussion The significance of PSA in the detection of Pea, monitoring response to treatment and as a prognostic factor, has been reported by many authors. ' 6 ' 8 ' 9) The results of our MS in 992 showed that PSA had the highest sensitivity when compared to that of DRE or TRUS. To improve the Pea detection rate, a more appropriate application of PSA is indicated. We relied on a single reference range, for example 6. ng/ml in our MS. PSA concentration is, however, correlated with age. We demonstrated a.4 ng/ml increase in PSA in -year increments according to our age-specific PSA study, the average difference between two years being.5 ng/ ml/year according to our PSAV study. These Downloaded from at Pennsylvania State University on May 8, 26 6

5 IMAI ET AL. values are coincident with results reported in the U.S.A. ' In the present study, of 5 Pea patients were detected by abnormal PSA (>6ng/ml). Using age-specific PSA, sensitivity was slightly improved. In our MS in 992, however, subjects with <6ng/ml PSA, normal DRE and normal TRUS were treated as normal and were not biopsied. Whether or not these age-specific reference ranges can improve the detection rate and the PPV is not clear from the results presented. For imaging the volume difference between PH and the normal prostate, prostate volume was stratified into two groups, greater than and less than 25 cc, although it is difficult to define PH by prostate volume alone. Schroeder and lom " reported the weight of the normal prostate to amount to 2 ± 6 g, and a prostate considered to contain PH at autopsy to have a weight of ± 6 g. In analyzing the relation between prostate volume and PSA, we assumed the volume of PH to be >25 cc and that of the normal prostate to be ^25 cc. In the present study, we have demonstrated the possible effectiveness of PSAD, PSAV and PSA changing rate; however, it was difficult to come to any conclusion on their definitive values since the number of Pea patients detected by our MS was too small. From the facts of there being a significant relation between prostate volume and PSA level, and PSA in Pea patients being higher than in PH, the idea of PSAD was introduced by enson and ooner, 7 ' and it is expected that PSAD may be useful in distinguishing between PH and Pea. On the other hand, Weber et al. n) reported prostate size not to be a good predictor of PSA because of the tremendous variation in the relative amount of epithelium in a prostate. The ratio of prostatic size to epithelial weight varied threefold. The poor correlation of our direct analysis (volume vs PSA in Fig. 2) may have been caused by this tremendous variation. A significant relation between PSA and prostate volume was, however, observed after their stratification (Table IV). In enson's report, 7 ' 6 patients (2 PH and 4 Pea) were classified into three PSAD group: ^.5, >.5-. and ^., the detection rates being 2.5, 54.5 and 97.%, respectively. The present results gave detection rates of subjects with <. PSAD and those with so.l PSAD of.4 and 22.6%, respectively. After adequate stratification, it is expected that PSAD may be a useful indicator for distinguishing between Pea and non-pea. The cut-off value, however, should be investigated in samples comprising a greater number of Pea patients. At the Annual American Urological Association Meeting in 99, Keetch and atalona reported the possibility of PSAV distinguishing between Pea and non-pea, the cut-off value being O.8. ) arter et al. H) reported that five years before diagnosis when PSA levels did not differ between subjects with PH and Pea, the rate of change in PSA levels (.75 ng/ml/year) was significantly higher in subjects with Pea than in those with PH and those with no prostate disease. These values are slightly higher than the.6 ng/ml/year estimated by the present study. rawer et a/. 5 ' reported, however, that a 2% annual change in PSA may identify men at significant risk of developing Pea. It is expected that the changing rate may detect Pea patients with lower serum PSA values than the normal upper limit. Judging from these studies, PSAV or PSA changing rate may be a sensitive and specific early clinical marker in the development of Pea. Our MS was based on a questionnaire, DRE, PSA and TRUS in 992 and 99. In one MS, two doctors performed the examinations on approximately 5 subjects for two to three hours. If MS by PSA and questionnaire was performed, the examinations were completed by paramedical workers, thereby improving cost effectiveness. We concluded that PSA testing during Pea screening should be investigated across multiple reference ranges in order not to reduce the detection rate. References ) Imai K, Yamanaka H: Screening examination' for prostate cancer. Early detectionand mass screening. Nippon Hinyokika Gakkai Zasshi 84: 75-87, 99 2) ooner WH, Mosley R, Rutherford L Jr, eard JH, Pond HS, Terry WJ, Igel T, Kidd DD: Prostate cancer detection in a clinical urological practice by ultrasonography, digital rectal examination and prostate specific antigen. / Urol 4: 46-52, 99 ) Imai K, Zinbo S, Shimizu K, Yamanaka H, Kumasaka F, Sato Z: linical characteristics of prostatic cancer detected by mass screening. Prostate 2: 99-27, 988 4) Imai K, Suzuki T, Yamanaka H, Nakata S, Tomaru Y, Sato J, Kato N: Mass screening for prostate cancer and the bias relating to survival rate. Urol Int 5: -4, 99 5) Kuriyama M, Akimoto S, Akaza H, Arai Y, Usami M, Imai K, Tanaka Y, Yamazaki H, Kawada Y, Koiso K, Yoshida O, Kotake T, Yamanaka H, Machida T, Aso Y, Shimazaki J: omparison of various assay systems for prostate-specific antigen standardization. Jpn J Oin Oncol 22: 9-99, 992 6) Ito K, Ohtake N, Hatori M, Mashimo T, Jimbo S, Tomaru Y, Makino T, Yajima H, Imai K, Yamanaka H: Prostatic specific antigen (PA) in mass screening. for prostate cancer. Hinyokika Kiyo 8: , Downloaded from at Pennsylvania State University on May 8, Jpn J lin Oncol 24() 994

6 SREENING FOR PROSTATE ANER WITH PROSTATE SPEIFI ANTIGEN 992 (in Japanese) 7) enson M, Whang IS, Pantuck A, Ring K, Kaplan SA, Olsson A, ooner WH: Prostate specific antigen density: a means of distinguishing benign prostate hypertrophy and prostate cancer. J Urol 47: 85-86, 992 8) Leo ME, ilhartz DL, ergstralh EJ, Oesterling JE: Prostate specific antigen in hormonally treated stage D2 prostate cancer. Is it always an accurate indicator of disease status? J Urol 45: 82-86, 99 9) Ernst DS, Hanson J, Venner PM, Uro-Oncology Group of Northern Alberta: Analysis of prognostic factors in men with metastatic prostate cancer. J Urol 46: 72-76, 99 ) Oesterling JE, Jacobsen SJ, hute G, Guess HA, Girman J, Panser LA, Lieber MM: Serum prostatespecific antigen in a community-based population of healthy men. Establishment of age-specific reference ranges JAMA 27: , 99 ) Schroeder FH, lom JHM: Natural history of benign prostatic hyperplasia (PH). Prostate 4 (Suppl 2): 7-22, 989 2) Weber JP, Oesterling JE, Peters A, Partin AW, han DW, Walsh P: The influence of reversible androgen deprivation on serum prostate-specific antigen levels in men with benign prostatic hyperplasia. J Urol 4: , 989 ) Keetch DW, atalona WJ: Update on serial prostatic biopsies in patients with persistently elevated serum prostate specific antigen levels. J Urol 49: A, 99 4) arter H, Pearson JD, Metter EJ, rant LJ, han DW, Andres R, Fozard JL, Walsh P: Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA 267: , 992 5) rawer MK, eatie J, Wener MH, Vessella RL, Preston SD, Lange PH: Screening for prostatic carcinoma with prostate specific antigen: results of the second year. J Urol 5: 6-9, 99 Downloaded from at Pennsylvania State University on May 8, 26 65