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Japanese Journal of Clinical Oncology Advance Access originally published online on October 21, 2008
Japanese Journal of Clinical Oncology 2008 38(12):844-848; doi:10.1093/jjco/hyn107
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© The Author (2008). Published by Oxford University Press. All rights reserved

The Outcome of Prostate Cancer Screening in a Normal Japanese Population with PSA of 2–4 ng/ml and the Free/Total PSA Under 12%

Shigeto Ishidoya1, Akihiro Ito1, Kazuhiko Orikasa1, Sadafumi Kawamura2, Tatsuo Tochigi2, Masaaki Kuwahara2, Takuya Yamanobe3, Yoshihiko Tomita3, Naoya Masumori4, Taiji Tsukamoto4, Daisuke Shibuya5 and Yoichi Arai1

1 Department of Urology, Tohoku University Graduate School of Medicine, Sendai
2 Department of Urology, Miyagi Cancer Center, Natori, Miyagi
3 Department of Urology, Yamagata University School of Medicine, Yamagata
4 Department of Urology, Sapporo Medical University School of Medicine, Sapporo
5 Miyagi-Taigan Kyokai, Sendai, Japan

For reprints and all correspondence: Shigeto Ishidoya, Department of Urology, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi Aoba-ku, Sendai 980-8574, Japan. E-mail: ishidoya{at}uro.med.tohoku.ac.jp

Received July 16, 2008; accepted September 10, 2008


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 References
 
Objective: No previous study has reported the numbers of prostate cancer (PC) patients existing among a normal Japanese population with prostate-specific antigen (PSA) < 4 ng/ml. The aim of this study was to elucidate the performance of %free PSA as a screening tool for a normal Japanese population with PSA of 2–4 ng/ml and to examine the characteristics of cancer detected using this criterion.

Methods: We conducted a prospective, multi-center study to evaluate the performance of %free PSA among a normal Japanese population. We decided on a %free PSA cutoff value of 12% according to the preliminary results. A total of 5548 consecutive screening volunteers aged 50–79 years were enrolled in the project. Men with total PSA > 4 ng/ml, or men with total PSA of 2–4 ng/ml and %free PSA of ≤12% were indicated to undergo 12 core biopsies.

Results: There were 826 (14.9%) men with PSA of 2–4 ng/ml. Among them, those with %free PSA of ≤12% numbered 100 (12.1%). Forty-nine out of 100 men (49%) received biopsy, and 16 PC patients were detected. Among 10 patients undergoing radical prostatectomy, seven were associated with extra-prostatic extension (pT3) or high-grade cancer (Gleason score ≥ 8).

Conclusions: We confirmed the ability of %free PSA and demonstrated that there are considerable numbers of PC patients among the normal Japanese population with PSA of 2–4 ng/ml. We ascertained that cancers detected in this study had a variety of tumor characteristics, including those of an aggressive nature.

Key Words: prostate cancer • screening • PSA • %free PSA


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 References
 
Prostate-specific antigen (PSA) is useful in the early detection, clinical staging and post-treatment monitoring of prostate cancer (PC). PSA is widely utilized in PC screening, and a cutoff value of 4 ng/ml has long been applied (1). The efficacy of PSA as a screening tool has been established; however, PSA screening is associated with unnecessary biopsies. Several investigators in the USA and Europe reported the results that examined the ability of the free-to-total PSA ratio (%free PSA) as a screening tool against the normal population with PSA between 4 and 10 ng/ml (2) or <4 ng/ml (3,4).

Catalona et al. (5) reported that when a %free PSA cutoff value of 15% was used as a criterion for biopsy, 54% of cancers would have been detected, compared with 33% of non-PCs undergoing biopsy in normal American men with PSA of 2.51–4 ng/ml. Eventually, a higher %free PSA cutoff could not be applicable in terms of selecting true cancer patients, and leads to low specificity.

The data from Thompson et al. (6) show that PC was detected in 23.9% of normal American controls with PSA of 2.1–3 ng/ml and in 26.9% of those with a PSA of 3.1–4 ng/ml in the PC Prevention Trial (PCPT). Although Asian people have a low incidence of PC compared with the people of the USA or Europe, little is known about the incidence of PC in the normal Japanese population, especially those with PSA of 2–4 ng/ml.

In Japan, the cutoff value of 4 ng/ml has dominantly been accepted and utilized in PC screening. Based on these reports regarding the ability of %free PSA and the results of the PCPT, we expected to detect significant number of PC patients with PSA of 2–4 ng/ml by taking %free PSA selection in Japan.

Therefore, we conducted a prospective, multi-center study for PC screening. The aim of this study was to investigate the performance of %free PSA as a screening tool for a normal Japanese population with PSA ranging from 2 to 4 ng/ml. Moreover, we examined the characteristics of the cancer detected using this criterion.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Funding
 References
 
Study Design
We have carried out a preliminary PSA screening program in Miyagi prefecture, Japan in 2001 and 2002 and performed prostate biopsy in men with PSA over 4 ng/ml. We also evaluated both the free and total PSA values in all men. We analyzed 39 men with PSA 4–10 ng/ml who received prostate biopsy. Figure 1A shows the distribution of the value of %free PSA with 12 PC and 27 non-PC men in this preliminary study. (It is significant that the mean value of %free PSA with PC men is lower compared with that with non-PC men.) When a %free PSA cutoff value was set at 12%, the sensitivity and the specificity were 58.3 and 77.8%, respectively, which appeared eligible (Fig. 1B, AUC date not shown).


Figure 1
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  		Figure 1. (A) A dot plot shows an individual %free cutoff value. * versus **P < 0.01. (B) Percent-free PSA cutoff value, sensitivity and specificity obtained from men with PSA 4–10 ng/ml. When a cutoff value is 12%, sensitivity and specificity show an eligible performance. PC, prostate cancer; Sens., sensitivity; Spes, specificity; PSA, prostate-specific antigen.

 
From 2003, we started the Northern Japan %free PSA Screening Project.

The indication for biopsy was expanded, which is PSA over 4 ng/ml or PSA ranging from 2 to 4 ng/ml with selection using %free PSA. Based on the preliminary results obtained from men with PSA 4–10 ng/ml, we experimentally decided on a %free PSA cutoff value of 12%. Four facilities participated in this co-operative prospective project, and a total of 11 communities located in Hokkaido and the Tohoku district (northern part of Japan) were enrolled. Male volunteers, 50- to 79-year old, participated in the project and received PSA testing along with ordinary health checks held by the community. Digital rectal examinations (DREs) were not performed in the community screening and thus were not used as an indication for biopsy.

PSA Analysis
Serum samples were collected in each community and total and free PSA values (Architect®, Abbott, USA) were measured 3–5 h after the collection. The value of %free PSA was then calculated. Men with a total PSA of >4 ng/ml, or men with total PSA ranging from 2 to 4 ng/ml and %free PSA of ≤12% were indicated to undergo subsequent biopsy.

Prostate Biopsy
Our project unified the biopsy method. Each staff urologist of four facilities performed DRE and transrectal ultrasound (TRUS)-guided systematic biopsy and collected 12 cores of the prostate. The central pathologist of the project made a diagnosis based on the biopsy specimens, and the Gleason scores of the detected cancers were also evaluated.

Statistics
Statistical analyses were performed using an unpaired t-test on the Stat View program and values of P < 0.05 were considered statistically significant.


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Funding
 References
 
A total of 5548 consecutive screening volunteers aged 50–79 years were enrolled and analyzed in the Northern Japan %free PSA Screening Project in 2003 and 2004 (Table 1). Men with PSA ranging from 2 to 4 ng/ml numbered 826 (14.9%). Among them, those with a %free PSA of ≤12% comprised 100 (12.1%). Forty-nine out of 100 men (49%) received TRUS-guided systematic biopsy, and 16 PC patients were detected. The positive predictive value (PPV) was 32.7%. Fifty-one men did not undergo biopsy mostly because of individual refusal. All men with PSA over 4 ng/ml were also indicated to undergo systematic biopsy. A total of 218 men received biopsy and 79 cancer patients were detected in this category. The PPV of men with PSA ranging from 4.01 to 10 ng/ml was 36.2%. Statistically significant difference of PPV was not observed between the group of men with PSA ranging from 2 to 4 ng/ml and 4.01 to 10 ng/ml. Overall cancer detection rate was 2.5% in this project.


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  		Table 1. The Northern Japan %free PSA Project (2003–04)

 
The characteristics of patients with PSA of 2–4 ng/ml, detected by %free PSA, are demonstrated in Table 2. Retropubic radical prostatectomy (RRP) was performed in 10, watchful waiting in 3, external beam radiation therapy and androgen ablation therapy in 1 patient, respectively (one patient's data are not available). Among 10 patients undergoing RRP, seven were associated with extra-prostatic extension (pT3) or high-grade cancer (Gleason score ≥8), and two showed PSA failure within 24 months after surgery. These pathological diagnoses of extirpated specimens were made by local pathologists of each facility.


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  		Table 2. Patients characteristics detected by %free PSA

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Funding
 References
 
In this study, we initiated a prospective multi-center PSA screening program and especially investigated how many PC patients exist in a normal Japanese population with a PSA range of 2–4 ng/ml by utilizing %free PSA and also examined the characteristics of these cancers. Our project is the first study to target PC patients among a normal Japanese population with PSA between 2 and 4 ng/ml.

With regard to deciding on a cutoff %free PSA value for this category, we experimentally chose 12% according to the preliminary PSA screening results. Our choice was associated with eligible sensitivity and specificity obtained from biopsied men with PSA of 4.01–10 ng/ml. We assumed that the data of the men with a PSA between 4.01 and 10 ng/ml would, to some extent, serve as an eligible source to determine the appropriate %free PSA cutoff for biopsy in Japanese men with a PSA between 2 and 4 ng/ml. In fact, we had little data on the percentage of PCs in a normal Japanese population with low PSA levels. As the 12% cutoff was not verified yet, a future comprehensive survey is expected to be conducted for normal Japanese men with PSA of 2–4 ng/ml.

There are several PSA screenings for normal populations with PSA < 4 ng/ml in the USA and Europe. The results of these studies are summarized in Table 3. Pelzer et al. (7) reported that 559 screening volunteers with PSA of 2.6–4 ng/ml received prostate biopsy in Austria, and the cancer detection rate was 20.2%. They also evaluated the efficacy of %free PSA in the group and showed a significantly higher cancer detection rate when the %free PSA cutoff value was <15%. It has been established that nearly 20–25% of PC patients exist in this category in the USA or Europe (3–9). In Japan, Kobayashi et al. (10) examined the utility of the PSA–{alpha}1-antichymotripsin (ACT) complex and %free PSA for Japanese patients presenting lower urinary tract symptoms and PSA levels of 2–4 ng/ml. They reported that PSA–ACT was more specific than %free PSA and achieved a cancer detection rate of 23.3% on 6–10 core biopsies; however, the group consisted of symptomatic patients and not normal volunteers.


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  		Table 3. Results of the PC screenings for normal population with PSA <4 ng/ml

 
In the present study, 16 cancers were detected from 49 biopsies (32.7%) using a cutoff value of 12 as the %free PSA in this normal group with PSA of 2–4 ng/ml. The cancer detection rate of 32.7% is almost identical to that of PSA with 4.01–10 ng/ml in this study. We think that our cutoff value of 12% is feasible in this regard; moreover, we are confident that there are a considerable number of PC patients among healthy Japanese men with PSA between 2 and 4 ng/ml.

It has been argued whether PCs detected by means of %free PSA in the low PSA range have an aggressive nature (5,11,12). Catalona et al. (5) reported that all men with cancer spreading beyond the prostate showed a %free PSA value of <15%. Meanwhile, Pepe et al. (12) reported that a %free PSA cutoff is not useful for the preoperative staging of patients with PC. Our study revealed that the patients detected have a variety of tumor characteristics. Although the sample size of this study was small and the significance difficult to ascertain, we confirmed that seven patients out of 16 detected men had high-grade cancers (pT3 and/or Gleason score ≥8). Our results are likely to support the idea that lower PSA levels do not always lead to mild tumor characterization, especially in cases with a lower %free PSA value. We could not explain the mechanisms by which the number of significant cancers was high with poor characteristics. It is possible that the low PSA level itself and/or low %free PSA may influence the pathophysiology of an aggressive nature in these patients. Ongoing studies are investigating comparisons of pathological features of cancers detected in the subjects with PSA of 2–4 ng/ml and >4 ng/ml.

There seems to be an overt racial or environmental difference in PC prevalence between Japanese and Americans or Europeans. Previous reports examined all men with PSA of 2 (2.5)–4 ng/ml (3–9); meanwhile, our study investigated only 12.1% (100 of 826) within this category. The cancer detection rate was 20–25% and 32.7%, respectively. Furthermore, the co-investigators (M.K., T.T. and S.K.) previously carried out PC screening both in Japan and China and reported that the cancer incidence and prevalence were higher in Japan (13). It is plausible that not only genetic but also epigenetic or environmental factors may affect the prevalence of PC because the lifestyle in Japan is more similar to that in the USA or Europe compared with that in China. Cross-cultural comparative studies of the cancer detection rate, using common screening indications, will certainly contribute to elucidating the problem.

There are some limitations in this study. First, the sample size is too small to achieve significance. The percentage of men in this category (PSA 2–4 ng/ml) was 14.9%, which is almost identical to that reported in the USA (8); however, men undergoing biopsy comprised less than half in this project, resulting in the relatively small number. The main reason was the patients’ refusal of biopsy, so we must pay attention in this regard to continue the project. Second, the cutoff value of 12% has not been verified yet. It is naturally estimated that several PC patients potentially exist in the group with PSA of 2–4 ng/ml and %free PSA over 12%. A comprehensive survey is needed to be performed in this category. Third, we cannot definitely determine the efficacy of our screening system and the characterization of the cancer detected because the follow-up period is not sufficient thus far. Ongoing studies (the Northern Japan %free PSA Screening Project) are investigating the effects of screening and may overcome these problems.


   Funding
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
References
 
This project was supported in part by a Grant-in Aid from Kurokawa Cancer Research Foundation and Abbott Japan Co.

Conflict of interest statement

None declared.


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 References
 
1 Brawer MK, Chetner MP, Beatie J, Buchner DM, Vessella RL, Lange PH. Screening for prostatic carcinoma with prostate specific antigen. J Urol (1992) 147:841–5.[Web of Science][Medline]

2 Vessella RL, Lange PH, Partin AW, Chan DW, Sokoll LJ, Sasse EA, et al. Probability of prostate cancer detection based on a multicenter study using the AxSYM free PSA and total PSA assays. Urology (2000) 55:909–14.[CrossRef][Web of Science][Medline]

3 Djavan B, Zlotta A, Kratzik C, Remzi M, Seitz C, Schulman CC, et al. PSA, PSA density, PSA density of transition zone, free/total PSA ratio, and PSA velocity for early detection of prostate cancer in men with serum PSA 2.5 to 4.0 ng/mL. Urology (1999) 54:517–22.[CrossRef][Web of Science][Medline]

4 Catalona WJ, Partin AW, Slawin KM, Brawer MK, Flanigan RC, Patel A, 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. J Am Med Assoc (1998) 279:1542–7.[Abstract/Free Full Text]

5 Catalona WJ, Partin AW, Finlay JA, Chan DW, Rittenhouse HG, Wolfert RL, et al. Use of free prostate-specific antigen to identify men at high risk of prostate cancer when PSA levels are 2.51 to 4.0 ng/mL and digital rectal examination is not suspicious for prostate cancer: an alternative model. Urology (1999) 54:220–4.[CrossRef][Web of Science][Medline]

6 Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, Parnes HL, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level <4.0 ng per milliliter. N Engl J Med (2004) 350:2239–46.[Abstract/Free Full Text]

7 Pelzer AE, Volgger H, Bektic J, Berger AP, Rehder P, Bartsch G, et al. The effect of percentage free prostate-specific antigen (PSA) level on prostate cancer detection rate in a screening population with low PSA levels. BJU Int (2005) 96:995–8.[CrossRef][Web of Science][Medline]

8 Schroder FH. Diagnosis, characterization and potential clinical relevance of prostate cancer detected at low PSA ranges. Eur Urol (2001) 39:49–53.[CrossRef][Web of Science][Medline]

9 Babaian RJ, Johnston DA, Naccarato W, Ayala A, Bhadkamkar VA, Fritsche HA Jr. The incidence of prostate cancer in a screening population with a serum prostate specific antigen between 2.5 and 4.0 ng/mL: relation to biopsy strategy. J Urol (2001) 165:757–60.[CrossRef][Web of Science][Medline]

10 Kobayashi T, Kamoto T, Nishizawa K, Mitsumori K, Ogura K, Ide Y. Prostate-specific antigen (PSA) complexed to {alpha}1-antichymotrypsin improves prostate cancer detection using total PSA in Japanese patients with total PSA levels of 2.0–4.0 ng/mL. BJU Int (2005) 95:761–5.[CrossRef][Web of Science][Medline]

11 Bangma CH, Kranse R, Blijenberg BG, Schroder FH. The free-to-total serum prostate specific antigen ratio for staging prostate cancer. J Urol (1997) 157:544–7.[CrossRef][Web of Science][Medline]

12 Pepe P, Panella P, Pietropaolo F, Pennisi M, Allegro R, Aragona F. Is free/total PSA predictive of pathological stage and Gleason score in patients with prostate cancer and serum PSA ≤10 ng/ml? Urol Int (2006) 76:232–5.[CrossRef][Web of Science][Medline]

13 Kuwahara M, Tochigi T, Kawamura S, Ogata Y, Xu N, Wang H, et al. Mass screening for prostate cancer: a comparative study in Natori, Japan and Changchun, China. Urology (2003) 314:137–41.


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This Article
Right arrow Abstract Freely available
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hyn107v1
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