Screening for Prostate Cancer Using Prostate-specific Antigen Alone asafirst-linecheckupparameter:resultsofthehealthcheckup System

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1 Jpn J Clin Oncol 2000;30(2) Screening for Prostate Cancer Using Prostate-specific Antigen Alone asafirst-linecheckupparameter:resultsofthehealthcheckup System Katsunori Uchida 1, Hitoshi Takeshima 1, Hideyuki Akaza 1 and Yukio Ono 2 1 Department of Urology, Institute of Clinical Medicine, University of Tsukuba and 2 Tsukuba General Health Checkup Center, Tsukuba, Ibaraki, Japan Received June 9, 1999; accepted November 10, 1999 Background: The incidence of prostate cancer in Japan is not very high but it is the most increasing malignant tumor form. To decrease the mortality from cancer, detection of early cancer and early treatment are most effective. As a primary screening for prostate cancer, measurement of serum prostate-specific antigen(psa) added to the health checkup system has not been assessed. Methods: Among males who received a health checkup during a 30-month period, serum PSA levels were measured in males who desired prostate cancer screening. The cut-off value for PSA was 4.0 ng/ml. Males with serum PSA levels exceeding this value were referred for further screening by digital rectal examination (DRE) and transrectal ultrasonography (TRUS). In secondary screening, in all males with PSA levels of 10.0 ng/ml or more and in males in whom PSA levels were within the gray zone ( ng/ml) and either DRE or TRUS showed abnormal findings, systematic prostate sextant needle biopsy was performed. Results: Of males who received a health checkup, 1125 (4.6%) underwent prostate cancer screening. In 60 (5.3%) of these males, PSA levels exceeded the cut-off value. In 34 of 50 males who received further screening, prostate biopsy was performed. Seventeen males were diagnosed as having prostate cancer. Detection rates of prostate cancer were 1.53% (17/ 1125) in males overall and 2.1% (17/819) in males 50 years old. In 16 of 17 males, clinically localized cancer was suggested. In 12 of these patients, radical prostatectomy was performed. No lymph node metastasis was detected in any patient. Conclusions: These results suggest that prostate cancer screening using PSA as a primary screening parameter during general health checkups is very useful for efficiently detecting early-stage prostate cancer. Key words: prostate cancer screening prostate-specific antigen (PSA) health checkup system INTRODUCTION The incidence of prostate cancer is the highest for the male population of the USA, where it is the second most frequent cause of cancer-related death (1). Currently, the incidence of clinical prostate cancer in Japan is not very high, but it is the most increasing form of malignant male tumor (2). Incidences For reprints and all correspondence: Katsunori Uchida, Department of Urology, Institute of Clinical Medicine, University of Tsukuba, Tennodai, Tsukuba, Ibaraki , Japan. k-uchida@md.tsukuba.ac.jp Abbreviations: PSA, prostate-specific antigen; DRE, digital rectal examination; TRUS, transrectal ultrasonography; MRI, magnetic resonance imaging; PSAD, PSA density; CT, computed tomography; QOL, quality of life; PCa, prostate cancer; SD, standard deviation; PPV, positive predictive value of non-clinical prostate cancer such as latent cancer and incidental cancer do not differ markedly between Japan and Western countries (3). To decrease the mortality from cancer, detection of early cancer and early treatment are most effective. Therefore, screening may play an important role in decreasing the mortality of prostate cancer. In recent years, recognition of PSA as a useful tumor marker for prostate cancer and advances in diagnostic imaging methods such as TRUS and magnetic resonance imaging (MRI) have facilitated the detection of early-stage prostate cancer that can be radically treated. Watanabe et al. (4) initially performed mass screening for prostate cancer by TRUS to detect early cancer in Since then, this screening system has commonly been used in various areas to detect early prostate cancer in Japan. The health checkup system in Japan is commonly utilized by people ranging in age from 30 to 60 years to detect adult diseases earlier and has been supported by companies and local 2000 Foundation for Promotion of Cancer Research

2 96 Screening for prostate cancer using PSA alone government. This system used to require accommodation. However, in recent years, day-trip checkup in a short period is commonly performed using automatic instruments and computers. Since November 1995, in our institution, primary prostate cancer screening by measurement of serum PSA levels alone has been combined with the standard day-trip health checkup system only in males who desire prostate cancer screening. None of the previous studies reported results using this system consisting of day-trip health checkup and prostate cancer screening. We report here the usefulness of this system in the detection of prostate cancer and discuss some aspects that may facilitate more efficient prostate cancer screening. MATERIALS AND METHODS Of males undergoing a day-trip health checkup at Tsukuba General Health Checkup Center between November 1995 and April 1998 (30 months), primary screening for prostate cancer was conducted in males who desired prostate cancer screening that could be selected as an option. For prostate cancer screening, an age limit was not established. Day-trip health checkup included general blood test, biochemical blood test (including liver and renal functions, cholesterol level, neutral fat and uric acid level), blood sugar after fasting, measurement of hemoglobin (Hb)A1c, measurement of rheumatoid factors, measurement of hepatitis B (HB) virus antibody titer, electrocardiogram (ECG), measurement of the percentage of body fat, chest X-ray, respiratory function test, measurement of blood pressure, general urine analysis, radiography of the upper digestive tract, occult blood in stool, abdominal ultrasonography, visual acuity test, audiometry and funduscopy. Measurement of serum PSA levels was included in these examination parameters as a primary screening method for prostate cancer. The Hybritech Tandem-R method was used for this purpose. The cut-off value was 4.0 ng/ml. Males with PSA levels exceeding the cut-off value were referred to the Department of Urology of Tsukuba University Hospital for further screening. In further screening, PSA levels were examined again. In addition, total PSA and free PSA levels were measured by the Eiken AIA method using the same serum samples. The free-to-total PSA ratio (%) was calculated. In addition, DRE and TRUS were performed by urologists. In TRUS, the presence or absence of malignant prostatic findings was evaluated and prostate volume was measured. PSA density (PSAD) was calculated by dividing serum PSA levels by prostate volume. Prostate volume was calculated using the formula prostate length width height 0.52 (formula for calculating oval body volume). In all subjects with PSA levels of 10.0 ng/ ml on secondary screening regardless of DRE and TRUS findings and in those in whom PSA levels were within the gray zone ( ng/ml) and DRE or TRUS suggested cancer, TRUS-guided systematic prostate sextant needle biopsy was performed for pathological diagnosis, after informed consent had been obtained. In subjects with histopathologically diagnosed prostate cancer, MRI, computed tomography (CT) and Table 1. Age distribution of the subjects who took the medical checkup and the prostate cancer screening checkup Age (years) PCa: prostate cancer. bone scintigraphy were performed to evaluate the presence or absence and the extent of cancer invasion and metastasis. The clinical stage was evaluated according to the TNM classification (5) established by the Union International Contra la Cancrum (UICC) and the American Joint Committee on Cancer (AJCC). In addition, in patients who underwent radical prostatectomy, histopathological findings were examined and pathological stage was evaluated. In subjects in whom histopathological diagnoses were obtained through biopsies, PSA levels, the free-to-total PSA ratio and PSAD were compared between subjects with prostate cancer and those without and it was examined whether each parameter was useful for decreasing the frequency of biopsy. For comparisons of PSA levels, the free-to-total PSA ratio and PSAD between the two groups (subjects with prostate cancer and those without prostate cancer), significance was tested using Mann Whitney mean rank non-parametric analysis. RESULTS Medical checkup: No. (%) PCa screening checkup: No. (%) < (21.2) 19 (1.7) (39.6) 287 (25.5) (26.1) 432 (38.4) (11.1) 318 (28.3) (2.0) 69 (6.1) 13.9 Total (100) 1125 (100) 4.6 Overall, males received a health checkup between November 1995 and April 1998 (30 months). Of these males, 1125 (4.6%) received primary screening for prostate cancer by measurement of PSA alone. Among the males who received a health checkup, the proportion of age years was the highest, followed by those years old and those years old. Among the males who received prostate cancer screening, the proportion of those years old was highest, followed by those years old and those years old. The proportion of males receiving prostate cancer screening increased with age. However, the proportion was only 13.9% even in males years old (Table 1). After patients with prostate cancer had been excluded from all males who underwent prostate cancer screening, the subjects were stratified with respect to age and mean PSA levels were examined. Mean PSA levels were 0.9 ng/ml in males years old, 1.1 ng/ml in males years old, 1.8 ng/ml in males years old and 2.2 ng/ml in males years old. The mean PSA level increased markedly with age (Table 2). When the cut-off value for PSA was 4.0 ng/ml, the detection rate for abnormal PSA %

3 Jpn J Clin Oncol 2000;30(2) 97 Table 2. Serum prostate-specific antigen concentration as a function of age Age (years) No. of cases PSA (ng/ml) (mean ± SD) PSA, prostate-specific antigen; SD, standard deviation. No. of patients with PSA 4.0 ng/ml < ± ± (0.3%) ± (2.8%) ± (10.7%) ± (18.8%) Total (5.3%) values was examined with respect to age group. Detection rates were 0.3% (1/287) in males years old, 2.8% (12/432) in males years old, 10.7% (34/318) in males years old and 18.8% (13/69) in males 70 years old. The proportion of males with PSA levels exceeding the cut-off value increased with age. Overall, the proportion was 5.3% (60/1125) (Table 2). Sixty subjects with PSA levels exceeding the cut-off value were subsequently referred for further screening. However, only 50 subjects (83.3%) underwent secondary screening. Out of 10 subjects who did not undergo secondary screening in our hospital, six consulted urologists in other hospitals, received neither TRUS nor biopsy and none has been diagnosed as having prostate cancer. Another four subjects did not consult urologists following their own judgement. In these 50 subjects, serum PSA levels were examined again and DRE and TRUS were performed. Out of 50 subjects who underwent secondary screening, 10 showed normal PSA levels, 26 showed gray zone PSA levels and 14 showed PSA levels of 10.0 ng/ml in secondary screening. In these 50 subjects, four out of 10 with normal PSA levels, nine out of 26 with gray zone PSA levels and nine out of 14 with the PSA levels of 10.0 ng/ml showed abnormal findings in either DRE or TRUS or both. As a result, ultrasound-guided systematic prostate sextant needle biopsy was finally performed in 34 subjects. Seventeen subjects (50%) were histologically diagnosed as having prostate cancer. These patients corresponded to 1.53% (17/1125) of the males receiving prostate cancer screening overall, 34.0% (17/50) of those receiving further screening and 50.0% (17/34) of those undergoing prostate biopsy. In 10 of 17 patients with prostate cancer, DRE or TRUS showed abnormal findings. In the remaining seven patients, the stage was evaluated as T1c. Concerning metastases, a bone metastatic focus was detected in only one patient. In the remaining 16 patients, lesions were evaluated as clinically localized cancer (Table 3). In 12 of 16 patients, radical prostatectomy was performed. In one patient, neoadjuvant hormonal therapy was administered for 3 months before surgery. As a result, cancer could not be confirmed by histopathological investigation of resected specimens. Therefore, the remaining 11 patients without preoperative treatment were histologically examined. In four of the 11 Table 3. Diagnosed prostate cancers: screening findings, clinical stage and pathological findings No. Age (years) PSA (ng/ml) DRE TRUS PATHO ctnm Treatment ptnm POR T2N0M1 Horm Tx MOD T1cN0M0 Horm Tx +Total Px pt0n0m WEL T2N0M0 Total Px pt2bn0m WEL T2N0M0 No Tx MOD T1cN0M0 Total Px pt3n0m WEL T2N0M0 Total Px pt2an0m WEL T2N0M0 Total Px pt3n0m MOD T1cN0M0 Total Px pt3n0m WEL T1cN0M0 Total Px pt3n0m MOD/POR T2N0M0 Total Px pt3n0m WEL T2N0M0 Total Px pt3n0m WEL T1cN0M0 Horm Tx MOD T2N0M0 Horm Tx WEL/POR T2N0M0 Total Px pt3n0m MOD T1cN0M0 Total Px pt3n0m POR T3N0M0 Horm Tx POR T1cN0M0 Total Px pt2n0m0 PSA, prostate-specific antigen; TRUS, transrectal ultrasound; +, suspicious of PCa; WEL, well differentiated; MOD, moderately differentiated; POR, poorly differentiated; Horm Tx, hormonal therapy; Total Px, total prostatectomy; No Tx, no treatment.

4 98 Screening for prostate cancer using PSA alone Table 4. Serum PSA, free-to-total PSA ratio and PSAD for prostate and non-prostate cancer patients with total PSA levels of ng/ml No. of cases PSA (ng/ml) mean ± SD (range) F/T (%) mean ± SD(range) PSAD (ng/ml/cm 3 ) mean ± SD (range) PCa ± ± ± 0.20 ( ) ( ) ( ) Non-PCa ± ± ± 0.11 ( ) ( ) ( ) p* PSA, prostate-specific antigen; F/T, free-to-total PSA ratio; PSAD, prostate-specific antigen density; SD, standard deviation; PCa, prostate cancer. *Statistical analysis of the data was performed by Mann Whitney mean rank nonparametric analysis. Table 5. PSAD, free-to-total PSA ratio and both of them in relation to the diagnosis of prostate cancer in patients with serum PSA levels ranging from ng/ml No. of patients with PCa No. of patients without PCa Sensitivity (%) Specificity (%) F/T < 20% F/T 20% 0 15 PSAD 0.25 ng/ml/cm PSAD < 0.25ng/ml/cm F/T < 20% and/or PSAD 0.25 ng/ml/cm F/T 20% and PSAD < 0.25 ng/ml/cm PPV (%) PSA, prostate-specific antigen; F/T, free-to-total PSA ratio; PSAD, prostate-specific antigen density; PCa, prostate cancer; PPV, positive predictive value. patients, histologies indicated well-differentiated adenocarcinoma. In the remaining seven patients, lesions contained moderately or poorly differentiated adenocarcinoma, the tumor volume being 0.2, 4.2, 6.2 and 26.6 cm 3, respectively. Briefly, only one of these patients with well-differentiated adenocarcinoma had non-clinically important cancer corresponding to stage T1a. In five of 11 patients, cancer foci were localized in isolated prostatic tissues and there was no capsular invasion detected (pt2). However, in the remaining six patients, capsular invasion was observed and the stage was evaluated as pt3. Perineural invasion was observed in five of these patients, while seminal vesicle invasion was observed in one. None of the patients who underwent radical prostatectomy showed lymph node metastasis histologically. None of the subjects with normal PSA levels had been newly diagnosed as prostate cancer within 1 year after the screening. Among subjects in whom histological diagnosis was obtained through biopsies, only patients with PSA levels ranging from 4.0 to 10.0 ng/ml were divided into subjects with and without prostate cancer. PSA levels, free-to-total PSA ratio (%) and PSAD were compared between the two groups. In subjects without prostate cancer, the mean PSA level was 6.1 ± 2.2 ng/ml. In subjects with prostate cancer, the mean PSA level was 6.4 ± 1.28 ng/ml (p = 0.49). Free-to-total PSA ratios (%) were 14.0 ± 5.4 and 30.0 ± 14.4 (p = 0.007) in subjects with and without prostate cancer, respectively. PSAD was 0.34 ± 0.20 and 0.23 ± 0.11 ng/ml/cm 3 (p = 0.035) in subjects with and without prostate cancer, respectively (Table 4). When the cut-off values for free-to-total PSA ratio (%) and PSAD were 20 and 0.25 ng/ml/cm 3, respectively, sensitivity and specificity were calculated. The sensitivity and specificity for free-to-total PSA ratio were 100 and 88.2%, respectively, while the sensitivity and specificity for PSAD were 55.6 and 64.7%, respectively. In addition, biopsy was not required in 58.8% (10/17) of non-prostate cancer subjects without missing any patients with prostate cancer when subjects in whom neither free-to-total PSA ratio nor PSAD reached the cut-off values were excluded from biopsy (Table 5). DISCUSSION In this study, primary screening for prostate cancer was conducted by measuring serum PSA levels alone during health checkup to screen for adults diseases, which is commonly performed in Japan. This study included only males who desired prostate cancer screening during a recent 30-month

5 Jpn J Clin Oncol 2000;30(2) 99 period. The cut-off value for PSA was 4.0 ng/ml. In 17 of 1125 subjects, prostate cancer was detected. The detection rate was 1.51%. In this study, an age limit was not established. However, when the cut-off value for PSA was 4.0 ng/ml, an abnormal PSA value was noted in one patient (1/306) among males <50 years old. However, this patient had acute prostatitis and the PSA level in that patient was below the cut-off value on further screening. Therefore, none of the males <50 years old underwent prostate biopsy. If screening had included only males 50 years old based on this finding, the detection rate for prostate cancer would have been 2.1% (17/819). In Japan, Shimizu et al. (6) conducted mass screening for prostate cancer using PSA, prostate acid phosphatase (PAP) and DRE as indices without age limit and reported that the detection rate for prostate cancer was 1.0% (13/1249) when these three parameters were combined. However, they indicated that the detection rate was 0.56% (7/1249) when PSA alone was examined. Furthermore, Imai et al. (7) conducted mass screening using PSA, DRE and TRUS in males 50 years old and reported that the detection rate was 1.56% (51/3276). They indicated that 1.25% (41/3276) of the subjects showed abnormal PSA levels. In addition, Egawa et al. (8) conducted screening using PSA alone as an index in males 55 years old and reported that the detection rate for prostate cancer was 1.3% (16/1189). In Western countries, Brawer et al. (9) established the cut-off value for PSA as 4.0 ng/ml in males 50 years old and reported that the detection rate for prostate cancer was 2.6% (32/1249). Catalona et al. (10) conducted screening using PSA and DRE in males 50 years old and reported that the detection rate for prostate cancer was 5.8% when these two parameters were used. However, they indicated that the detection rate was 4.6% when PSA alone was employed. In this study, the detection rate for prostate cancer was 2.1% when screening using PSA alone included males 50 years old. This percentage was highest in Japan, although it was lower than the percentages reported in the Western countries. Our finding may reflect a recent increase in the incidence of prostate cancer in Japan. The mean PSA levels with respect to age obtained in this study were compared with the findings reported by Brawer et al. (9). In males years old mean PSA levels were 1.1 and 1.6 ng/ml, in males years old 1.8 and 2.7 ng/ml and in males years old 2.2 and 3.1 ng/ml, respectively. In the two studies, PSA levels increased with advancing age, showing a similar tendency. However, the latter showed relatively higher values for all ages (9). In Western countries, the proportion of PSA abnormalities has been reported to be approximately 10% of subjects when the cut-off value for PSA is 4.0 ng/ml (9 11). However, our results showed that the proportion was 5.6%, which was about half the percentage reported in Western countries, although the results should not be simply compared owing to differences in patient ages and backgrounds. Thus, PSA levels in Japanese males may be relatively lower than those in Western countries of the same age. This is an issue in establishing the cut-off value for PSA for prostate cancer screening. Since PSA levels depend markedly on age and may be markedly influenced by race or life-style, an appropriate cut-off value in Japanese should be established and age-related correction is needed. According to several studies in Western countries, about 40% or more of patients with early prostate cancer requiring treatment showed PSA levels of 4.0 ng/ml or less, indicating false-negative findings (12,13). When our patients who underwent radical prostatectomy were examined, no metastasis was detected in any patient. However, in six of 11 patients, capsular invasion was observed, suggesting locally invasive carcinoma. In these patients, strict follow-up is needed since local relapse or metastatic foci may appear in the future. To evaluate the usefulness of prostate cancer screening by this system, the presence or absence of relapse and prognosis in these patients should be carefully followed. In the future, to detect aggressively patients with stage pt2 or milder cancer, that is, early cancer that can be radically treated, the currently used cut-off value for PSA may be reduced or cut-off values with respect to age may be established depending on further investigations. Furthermore, one limitation of prostate cancer screening is the presence of latent cancer. It has been reported that the incidence of latent cancer increases with age. The incidence is about 40% in males 70 years old (14,15). It has been reported that well-differentiated latent cancer lesions measuring <1 cm in diameter are not clinically significant and that these lesions do not require treatment (16,17). Therefore, patients with prostate cancer corresponding to latent cancer, that is, non-clinically important cancer, should be excluded when evaluating the usefulness of prostate cancer screening. Only one of 11 patients who underwent radical prostatectomy in our department had non-clinically important cancer. This was consistent with the finding described by Ohori et al. (18); percentages of clinically important cancer ranged from 85 to 90% among prostate cancer lesions detected by screening. If a large number of non-clinically important cancer lesions are detected by aggressive screening and unnecessary treatment is indicated, complications such as urinary incontinence may develop, reducing the patient s quality of life (QOL). This is undesirable and should be avoided. The purpose of cancer screening is to decrease cancer mortality by early detection and treatment. Briefly, prostate cancer can be detected earlier by screening, as described above. However, it is difficult to demonstrate whether mortality can be decreased by screening. The most ideal method for demonstrating this issue would be to conduct a large-scale randomized comparative control study. However, this is difficult owing to ethical issues. None of the previous studies screened for prostate cancer using this method. For further screening, in recent years, the introduction of PSAD and free-to-total PSA ratio, which may improve specificity for non-prostate cancer patients, has been studied to avoid physically invasive treatment, prostate biopsy (19 21). In this study, these parameters were examined in 26 subjects with PSA levels ranging from 4.0 to 10.0 ng/ml in whom histological diagnoses were obtained through biopsies. The distributions of PSAD and free-to-total PSA ratio differed markedly between subjects with and without prostate cancer (Table 4).

6 100 Screening for prostate cancer using PSA alone Using a 20% free-to-total PSA ratio and 0.25 ng/ml/cm 3 PSAD as cut-off values, biopsy would have been unnecessary in 58.8% of the subjects without prostate cancer without missing any subjects with prostate cancer. Measurement of PSA levels and evaluation of PSAD and free-to-total PSA ratio may facilitate the more efficient detection of early prostate cancer, although this cannot be definitively concluded owing to the small number of patients in this study. In this study, almost all subjects have received prostate cancer screening for the first time in their life. Recently, Harris et al. (22) evaluated the 3-year longitudinal chances in serial serum PSA levels in men with normal PSA levels. They concluded that men with PSA of <2.0 ng/ml are at low risk of an abnormal PSA or cancer within 3 years and annual monitoring may not be necessary. However, they also concluded that annual monitoring is clinically useful in men with an initial PSA of ng/ml. We now recommend annual PSA evaluation for men with normal but near the PSA cut-off value. In conclusion, these results suggest that primary prostate cancer screening by measuring PSA alone in a health checkup system is very useful for more efficiently detecting early prostate cancer. However, in the future, a cut-off value for PSA that is more appropriate for Japanese should be established and a more efficient method of selecting patients undergoing biopsy from borderline patients using PSAD and free-to-total PSA ratio must be examined in a larger number of patients. References 1. Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, Cancer J Clin 1998;48: Kuriyama M. PSA as a screening method for prostate cancer in Japan. Presented at the First International Consultation on Prostate Cancer, Monaco, June Uchida K, Shimazui T, Ohtani M, Akaza H, Koiso K, Nemoto R, et al. 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