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- .Original Article . -
Total and free prostate-specific antigen indexes in prostate cancer screening: value and limitation for Japanese populations
Noboru Hara1, 2, Yasuo Kitamura1, Toshihiro Saito1, Shuichi Komatsubara1
1Department of Urology, Niigata Cancer Center Hospital, Niigata 951-8133, Japan
2Division of Urology, Department of Regenerative and Transplant Medicine, Graduate School of Medical and Dental
Sciences, Niigata University, Niigata 951-8510, Japan
Abstract
Aim: To assess the efficacy and limitation of free/total prostate-specific antigen ratio (f/tPSA) at a single institution in
Japan, focusing on the avoidance of pointless prostate
biopsies. Methods: In total, 631 men between 44 and 93 years
old (mean 69.8 years) with elevated PSA underwent power-Doppler ultrasoundgraphy-guided transrectal 10-core
prostate biopsies at Niigata Cancer Center Hospital, and their histological features were investigated with total PSA
(tPSA) and f/tPSA. Results: PCa was detected in 126 of 134 patients (94.3%) with tPSA of 26 ng/mL or higher. The
detection rate was 59.4% for tPSA of 21_25 ng/mL, followed by 39.2% for 16_20 ng/mL, 30.0% for 11_15 ng/mL,
20.0% for 4.1_10 ng/mL and 7.6%
for¡Ü4.0 ng/mL. f/tPSA of the PCa group was significantly lower than that of
non-malignamt disorders in any tPSA ranges (mean 0.122
vs. 0.160, P < 0.001). Receiver-operating characteristics
analyses showed that f/tPSA (AUC : 0.664) performed more valuably than tPSA (AUC : 0.559) in patients with tPSA
between 3.0_10 ng/mL (P < 0.01). Although f/tPSA of 0.250 for the cut-off value might miss 1.8% PCa patients, it
potentially spares 9.2% of unnecessary
biopsies. Conclusion: f/tPSA is more valuable compared with tPSA alone for
the prediction of the occurrence of PCa. We recommend 0.250 as the cut-off value for f/tPSA in PCa screening for
Asian men having so-called grey-zone tPSA. (Asian J Androl 2006 Jul; 8:
429_434)
Keywords: prostate cancer screening; free/total prostate-specific antigen ratio; multi-site biopsy; single-institutional trial
Correspondence to: Dr Noburu Hara, Division of Urology,
Department of Regenerative and Transplant Medicine, Graduate School of
Medical and Dental Sciences, Niigata University, Kawagishicho 2, Niigata 951-8566, Japan.
Tel: +81-25-227-2287, Fax: +81-25-227-0784
E-mail: harasho@par.odn.ne.jp; harasho@med.niigata-u.ac.jp
Received 2005-08-29 Accepted 2006-02-20
DOI: 10.1111/j.1745-7262.2006.00155.x
1 Introduction
The prostate-specific antigen (PSA) test is a widespread tool used as an initial criterion for the early detection of
prostate cancer (PCa), and is also used to monitor the clinical course of PCa patients [1]. Yet, the elevation of PSA
does not necessarily indicate the presence of PCa, because PSA levels frequently rise in non-malignant disorders
(NMD), such as benign prostatic hyperplasia (BPH) or prostatitis [2]. In practice, the use of PSA in clinical staging
is restricted [3]. Various adjustments, such as PSA density (PSAD: PSA
divided by prostate volume) or blood-based
molecular diagnostics, have, therefore, been attempted to improve the diagnostic value of PSA-associated parameters
[4, 5], but the procedures are somewhat complicated.
Partin et al.[6] reported the ratio between free and total PSA
(f/tPSA) in serum to more accurately distinguish PCa from NMD, thereby enabling the avoidance of unnecessary
biopsies resulting in a negative finding for cancer [6]. In particular, for men with tPSA levels less than 10 ng/mL,
f/tPSA is shown to be more precise for the indication of prostate biopsies [7, 8]. f/tPSA is reported to enhance the
specificity in cancer detection as follows: fPSA, which is not complexed to the serum alpha-fraction protein, is mainly
released from the adenomatous tissue of the prostate [9]. Correspondingly, f/tPSA in PCa cases is lower compared
with those having NMD, such as BPH [5_8]. This relationship has been emphasized among patients with an elevated
PSA between 4.0_10.0 ng/mL, where the outcome of biopsies is most equivocal and unpredictable [6, 8]. However,
the use of f/tPSA is controversial [7, 10], because a largely overlapping fraction between PCa and NMD using varying
cut-off levels for f/tPSA provides conflicting data in the correlation between the f/tPSA value and pathological
outcome [6_8, 10]. Therefore, whether serological assays potentially improve the prediction of histological diagnosis
and contribute to avoiding redundant tissue sampling is of general interest.
To date, there has been no study that consistently enrolled participants and examined the practical use of
f/tPSA using well-designed prostate biopsies for Asian populations. In the current study, we assess the efficacy of tPSA and
f/tPSA with 10 or more core biopsies using power-Doppler ultrasoundgraphy for the early detection of PCa at a single
institution in Japan.
2 Materials and methods
2.1 Patients and their characteristics and measurement of serum prostate-specific antigen (PSA)
Peripheral blood samples were obtained prior to digital rectal examination and prostate biopsies, and biochemical
parameters including Tandem-R total and free PSA in the serum were measured [2, 11]. f/tPSA was acquired from
dividing fPSA by tPSA. Although the cut-off level of serum tPSA for PCa is generally
2.5_10 ng/mL, it is affected by age and is correlated with an increased prostate volume frequently found in elder males as BPH [2, 6]. In the present study,
all patients with total PSA 10 ng/mL or higher underwent prostate biopsies. We undertook prostate biopsies for 74.15% of patients with serum PSA levels less than 10 ng/mL, who provided informed consent. We did not apply any
exclusion criteria, and, in total, 631 patients between 44 and 93 years old (mean 69.8 years), who presented at the
Department of Urology, Niigata Cancer Center Hospital for PCa screening, were randomly enrolled in the present
study. Clinical stages of the PCa cases were determined according to International Union Against Cancer (1997)
guidelines using transrectal ultrasoundgraphy (TRUS) and computed tomography and/or magnetic resonance imaging
in addition to isotoped-bone-scanning [11].
2.2 Transrectal prostate biopsy with transrectal ultrasoundgraphy and histological evaluation
All patients underwent transrectal 10-core prostate
biopsies using transrectal power-Doppler
ultrasound-graphy (2102 Hawk, B-K medical, Glostrup, Denmark) with a 5.0_10.0 MHz biplanar probe, between August 1999 and
February 2003. The procedures followed the method of standard sextant biopsy in addition to those for bilateral
laterally directed biopsy and transition zone biopsy [11, 12]. Hypoechoic lesions seen by TRUS were additionally
sampled, when they were not included in 10-cores sampling. Each core was histologically examined for pathological
grading and mapping. Two experienced pathologists independently conducted histopathological examinations.
2.3 Statistical Analysis
Statistical comparisons were made using the Welch-corrected
t-test, ÷2 tests, regression analysis and
receiver-operating characteristics (ROC) analysis with StatView 5.0 software (Abacus Concepts, Berkeley, CA, USA) and
Prism Version 3.02 (GraphPad software, San Diego, CA) for Windows-based computers.
3 Results
3.1 total prostate-specific antigen (tPSA) level and the ratio between free and total prostate-specific antigen (f/tPSA)
value, stratified according to the histological outcome
First, we presented primary data for the relationship among tPSA, f/tPSA ratio and histological outcomes on a
scatter diagram for patients with tPSA of 25 ng/mL or less (Figure 1). In Table 1, the number of patients and average
f/tPSA were shown stratified according to the tPSA
range and histological diagnosis obtained from biopsies. PCa was
detected in 126 of 134 patients (94.3%) with tPSA of 26 ng/mL or higher.
The detection rate was 59.4% for tPSA of 21_25 ng/mL, followed by 39.2% for 16_20 ng/mL, 30.0% for 11_15 ng/mL, 20.0% for 4.1_10 ng/mL and 7.6% for 4.0
ng/mL or less. Overall, f/tPSA of the PCa group (0.122) was significantly lower than that of the prostatic intraepithelial
neoplasm (PIN)/atypical adenomatous hyperplasia (AAH) (0.166) and the NMD group (0.160)
(P < 0.005 and
P < 0.001, respectively). Yet, f/tPSA varied among PCa patients with tPSA of 10 ng/mL or higher, NMD with tPSA of
> 16 ng/mL or higher, and PIN/AAH cases (Figure 1).
3.2 Diagnostic accuracy using various cut-off values of the ratio between f/tPSA value obtained with
receiver-operating characteristics curve (ROC)
The appropriate cut-off value for f/tPSA was calculated on the ROC curve for respective tPSA ranges.
Comparisons were made between the PCa and the non-PCa group involving patients with NMD and PIN/AAH, and the area
under curve (AUC) for f/tPSA, sensitivity and specificity with most valuable f/tPSA cut-off are shown in Table 2.
AUC of the f/tPSA value varied among tPSA ranges, and it was smallest (0.573) for tPSA between 5.0 and 7.0,
whereas it was greatest (0.721) for tPSA between 7.0 and 10.0 (Table 2).
Between tPSA of 4.0_10 ng/mL (so-called grey-zone PSA), the AUC of
f/tPSA was 0.644, and between tPSA of
3.0_10 ng/mL, f/tPSA (AUC: 0.664) was more valuable than tPSA (AUC: 0.559) for the indication of prostate biopsies (Figure 2).
Simulated outcomes using various cut-off values for
f/tPSA are shown in Table 3. For further analyses of men with tPSA of 3.0_10 ng/mL,
we present data of 23 patients (2 PCa cases and 21 non-PCa cases) with tPSA levels of 3.0_4.0 ng/mL in addition to
272 patients with tPSA levels between 4.1 and 10 ng/mL (Table 3).
Table 3 includes results from 56 cancer-positive
biopsies and 239 negative biopsies in men with PSA between 3.0_10 ng/mL.
An f/tPSA cut-off value of 0.215_0.260 can spare 47_17 of 239 biopsies, maintaining 90_100%-sensitivity, respectively. When a f/tPSA cut-off value of
0.250 is applied, 9.2% biopsies can be withheld, resulting in missed PCa cases of 1.8%.
3.3 Influence of age on the ratio between free and total prostate-specific antigen value
We further investigated the age-affected f/tPSA shift both for PCa and non-PCa cases. Among PCa cases with
tPSA between 3.0 and 10, f/tPSA was not different between patients of < 70 and 70 years old or higher, whereas
among NMD cases with tPSA between 3.0 and 10.0, f/tPSA was higher in patients of 70 years or higher (data not
shown). Age-stratified analyses showed better performance of f/tPSA ratio in men of 70 years or older than in those
under 70 years, with AUC of 0.642
vs. 0.603 (P < 0.05) (Figure 3).
4 Discussion
In the present study, the incidence of PCa in men with PSA levels between 4.1 and 10 (20.0%) and less than
4.0 ng/mL (7.6%) is low compared with those in a recent large study in the USA (approximately 35% and 15%,
respectively) [13]. This discrepancy might be a result of racial difference and lifestyle [14]. However, in some
previous studies in Japan, detection rates in men with such PSA ranges were almost equal to those in the USA or
Western European countries [11]. We first discuss the significance of PCa screening for Asian men with PSA levels
less than 10 ng/mL. The accepted cut-off level of PSA for PCa screening was 4.0 ng/mL, until
Partin et al. [15] demonstrated that frequent extrapros-tatic extension even in cases with PSA levels ranged between 4.1 and 6.0 ng/mL. In
the present study, relatively high cancer detection rates in Asian men with PSA levels between 4.0 and 10 ng/mL or even
less than 4.0 ng/mL should also not be disregarded [16].
Moreover, recent evidence showed that 65% of cases with
PSA less than 4.0 ng/mL were accompanied by multi-focal cancers, and more than 35% of these were histologically
revealed to have highly malignant potential [17]. Correspondingly, many PCa patients with tPSA less than 4.0 ng/mL
in our present and previous studies were accompanied by clinically significant cancer (data not shown) [11].
In contrast, the fraction of men with PSA levels higher than 4.0 ng/mL represents approximately 21%, based on data
from PCa screening for more than 9 000 men at our institution and associates (unpublished personal data from Niigata
Cancer Certer), whereas the cause-specific mortality is approximately 1% in Japan [18]. This discrepancy might
provide a reason for why many prostate biopsies are supposed to be insignificant for Asian men with PSA levels
between 4.0_10 ng/mL. Therefore, the advent of more precise indexes/values is warranted to alleviate the
tioned dilemma.
In the current study, f/tPSA appeared useful for the prediction of the occurrence of PCa in comparison with tPSA
alone. Table 4 presents representative previous stu-dies that examined performances of f/tPSA with 90%-sensitivity
under grey-zone tPSA [19_22]. When given 90%-sensitivity, the cut-off value for f/tPSA ranged between 0.250 and
0.377 in these studies. Based on the present data, although the f/tPSA of 0.250 for the cut-off value might fail to
notice 1 of 56 (1.8%) PCa patients, it potentially spares approximately 10% of pointless biopsies. Therefore, we
propose a cut-off f/tPSA value of 0.250 for patients with grey-zone tPSA.
aforemenVarious adjustments such as PSAD have been shown to improve the diagnostic value of PSA-associated
parameters [4]. Also, the AUC of patients of 70 years or older is greater in the present study (Figure 3), sugges-ting
that many elderly men have developed prostatic hyperplasia. We believe that f/tPSA is not only more precise but also
concise for PCa screening, which does not require any special technique and equipment, but of course, patient¡¯s age,
prostate volume, digital rectal examination and tPSA levels should be concurrently considered.
Approximately 40% of patients clinically diagnosed as having organ-confined disease already have extracapsular
extension in the excised specimen [23]. Accor-dingly, 30_40% of patients with clinical T1c have locally advanced
disease [3, 15]. Yet, outcomes of f/tPSA as a predictor of pathologic stage varied among previous trials [4, 24].
Therefore, accuracy in the screening step is also critical for subsequent therapeutic options, and further enhancement
of the diagnostic modality is a challenging problem in the early check-up of prostate cancer for Asian populations. In
addition, follow-up for men with negative biopsy results would be a critical issue in the next step. We are currently
undertaking a study on the clinical course of such patient fractions in terms of increased velocity of PSA (PSA
velocity) and transit of f/tPSA, evaluated by second or more biopsy sessions.
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