Int Urol Nephrol (2006) 38:565–569 DOI 10.1007/s11255-006-0086-2
R E S E A R C H A RT I C L E
Usefulness of an immunochromatographical assay, PSA Rapid Test as a primary screening test for prostate cancer Kazushi Shigeno Æ Naoko Arichi Æ Tatsuaki Yoneda Æ Hirofumi Kishi Æ Hiroaki Shiina Æ Mikio Igawa
Received: 5 February 2006 / Accepted: 28 March 2006 / Published online: 16 November 2006 Springer Science+Business Media B.V. 2006
Abstract Background The recent rapid increase of mass screening for prostate cancer by measuring PSA in Japan will increase the economic burden to the healthcare system. PSA Rapid Test (PRT) is a simple inexpensive test. The usefulness of PRT as a primary screening test for prostate cancer was evaluated. Methods When we conducted educational lectures for prostate cancer in our city, screening for prostate cancer using PRT was offered to the male participants. The results of the tests were handed to participants in writing at the end of the lectures. When the results were judged as positive, letters of referral to our institute were enclosed. Results One hundred and fourteen (18.6%) of 614 men were judged as positive by PRT. Of the 114 men with positive PRT, 73 (64%) visited our institution. Finally, 37 men underwent a transrectal prostate biopsy and a diagnosis of prostate cancer was made in 21 men (3.4% of all participants). The total costs for the PSA tests in this study were summed to be approximately $2,300, while they would be approximately $9,200 if all participants had undergone screening using the conventional
K. Shigeno (&) Æ N. Arichi Æ T. Yoneda Æ H. Kishi Æ H. Shiina Æ M. Igawa Shimane University School of Medicine, 89-1 Enya-cho, Izumo 6938501, Japan e-mail:
[email protected]
quantitative method from the outset. Conclusion PRT is a low-cost method to detect patients with prostate cancer. We believe the PRT is useful as an initial screening test for detecting prostate cancer and that the combination of the PRT and more precise quantitative testing would be a reasonable way to reduce the cost and achieve high detection rate. Keywords Prostate cancer Æ Screening Æ Prostate specific antigen Æ Rapid test
Introduction The incidence and mortality rate of patients with prostate cancer is increasing rapidly in Japan. The age-adjusted death rate of patients with prostate cancer rose from 3.3 per 10,000 in 1970 to 8.5 per 10,000 in 2003 with 8,418 men dying of prostate cancer in 2003 [1]. It is generally accepted that mass screening for prostate cancer using PSA testing does result in earlier detection and an increase in the number of patients whose tumors can be cured with local therapy [2, 3]. On the other hand, there are several problems with PSA testing, which may be related to scientific, ethical, legal and economic issues. The cost of the laboratory techniques such as radioimmunoassays or enzyme immunoassays usually required to determine PSA levels is a main issue. Another
123
566
issue is that only 56–83% of the men with PSA levels greater than the cut-off level in mass screening programs visit urologists for further examination [4–6]. PSA Rapid Test (PRT) is a simple test using an immunochromatographical technique without special instruments and has a much lower cost compared with the conventional quantitative PSA test. Moreover, the results of PRT could be obtained in a very short period of time. Therefore, participants to the screening programs can receive the result of the test on the spot and this would be expected to raise their concern about prostate cancer and lead them to visit urologists. We evaluated the usefulness of the PRT as an initial screening test for prostate cancer detection from the standpoint of cost and whether the immediate notification of a positive result could increase the number of men visiting a urologist for further examination and investigation.
Materials and methods PSA Rapid Test (PRT) PRT kits were purchased directly from Usdahiya International Inc. (CA, USA). The PRT is an immunochromatographical assay and the device consists of three discrete sections comprising a sample well and two reaction zones within the result window; a test zone and a control zone (Fig. 1). Following the addition of 100 ll of test serum to the sample well, the PSA in the sample reacts with a colloidal gold-anti-PSA antibody (monoclonal anti-total PSA antibody) conjugate embedded adjacent to the sample well and forms an antigen–antibody conjugate complex. As the Fig. 1 PSA Rapid Test kit. After 100 ll of serum specimen is dropped on the sample well, the test is judged as positive if both test (T) and control (c) lines appear, or negative if only control line appears
123
Int Urol Nephrol (2006) 38:565–569
mixture of sample-conjugate migrates into the test zone, the PSA-antibody conjugate complex is captured by an immobilized anti-PSA antibody to form an antibody–antigen–antibody conjugate ‘‘sandwich’’ and this is indicated by a magenta test line. As the fluid further migrates into the control zone, an immobilized conjugate capturing reagent reacts with the conjugate to form a magenta control line that indicates that the reagents are functional and the procedure has been performed correctly. The test is considered invalid if the control line does not appear within 10 min and the sample should be retested. The result of the test is judged as being positive or negative 10 min after sample application. The test is designed to have a detection limit of approximately 4 ng/ml of PSA. Validation of PRT For the validation of PRT, serum samples of 126 consecutive patients who were suspected of having or followed up for prostate cancer were tested for PRT and quantitative PSA test, E test TOSOHII PA (Tosoh corp., Tokyo, Japan). The sensitivity and specificity of the PRT assay were determined using the cut-off of 4.0 ng/ml. Screening for prostate cancer using PRT We offered screening for prostate cancer using PRT to males between the age of 50 and 80 years when we conducted educational lectures for prostate cancer in our city between October 2001 and July 2004. Blood samples were taken before the lectures commenced and the PRT procedure was started immediately. The results of the tests were handed to them in writing at the end of the
Int Urol Nephrol (2006) 38:565–569
lectures. We enclosed letters of referral to our institute in cases where the results were judged as positive. Each participant was provided with oral and written information regarding the prostate cancer screening. Written informed consent was obtained regarding the fact that the residual serum samples of cases with positive results would be stored at )70C in our institution. These samples would be used for a quantitative measurement of PSA level when they visited us for further examination including digital rectal examination, transrectal ultrasonography and a transrectal prostate biopsy. The indication for a prostate biopsy was based upon the findings of digital rectal examination or transrectal ultrasonography as well as elevated PSA levels > 4 ng/ml confirmed by the quantitative assay. The costs for PSA tests The cost of PRT and PSA test E test TOSOHII PA were $2 (US) and $15 (US), respectively.
Results Validation of PRT The PSA levels of the 126 serum samples varied from 0.1 to 205.2 ng/ml with a mean of 17.3 ng/ml (Fig. 2). The PRT was positive in 51 of the 57 samples with PSA values greater than 4.0 ng/ml. The PSA levels of the six false-negative samples for PRT were between 4.1 and 5.1 ng/ml. Four of 69 samples with a PSA level equal to or less than 4.0 ng/ml were judged as false-positive by PRT. These results indicated that the sensitivity of PRT was 89.5% (51/57) and the specificity was 94.2% (65/69). Screening for prostate cancer using PRT Six hundred and fourteen men aged 41–88 years old (median 68 years) were enrolled in this study. Of the 614 men, 114 (18.6%) had a positive PRT (Table 1). Seventy-three men (64% of men with a positive result) visited our institution and their PSA levels were measured quantitatively using
567
Fig. 2 Correlation between PSA Rapid Test (PRT) and EIA assay. One hundred and twenty-six samples varied from 0.1 to 205.2 ng/ml of PSA level were judged by PRT. The sensitivity of PRT was 89.5% (51/57) and the specificity was 94.2% (65/69)
the stored serum samples. Thirty-four of these samples had PSA levels greater than 4.0 ng/ml. Finally, 34 men with a PSA level greater than 4.0 ng/ml and three with a PSA level less than 4.0 underwent a transrectal prostate biopsy. A diagnosis of prostate cancer was made in 21 men (3.4% of all participants). The characteristics of the patients diagnosed with prostate cancer are shown in Table 2. Fifteen patients underwent radical prostatectomy and six are receiving endocrine therapy. Only one of the 15 prostatectomized cancers was a so-called insignificant cancer with a Gleason score of 5 and a tumor volume of 0.4 ml. The costs for PSA tests The total cost for the PSA tests in this study were summed to be approximately $2,323: $1,228 (2 · 614) for PRT plus $1,095 (15 · 73) for additional quantitative testing. If the PSA levels of all 114 patients with a positive PRT test had been confirmed using the quantitative method, then the total costs would be $2,948: $1,228 plus $1,710 (15 · 114) for quantitative testing. The cost of all of the 614 participants in this study undergoing the usual quantitative method at the outset would be approximately $9,210.
Discussion Screening for prostate cancer using PSA testing is now spreading rapidly throughout Japan. A
123
568
Int Urol Nephrol (2006) 38:565–569
Table 1 Results of screening for prostate cancer using the PSA Rapid Test No. (%) Men Men Men Men Men Men
who received PSA screening with positive PRT who visited for further examination with PSA > 4.0 ng/ml who underwent prostate biopsy with prostate cancer detected
614 114 73 34 37 21
(18.6) (11.9) (5.5) (6.0) (3.4)
Table 2 Patients and tumors characteristics No. of patients
21
Median age (range) PSA (ng/ml) Median (range) Gleason score 5–6 7 8–9 Clinical stage T1c T2a T2b T3a T2bN0M1b Treatment Radical prostatectomy Endocrine therapy
73 (69–84) 19.7 (3.4–160.7) 5 10 6 6 6 4 4 1
15 6
simple and cost effective method is preferable for mass screening. The cost of the PRT used in this study is apparently smaller than that of the usual quantitative method. The total expenses of this study for PSA tests were approximately $2,300, while they would be approximately $9,200 if all participants had undergone screening using the conventional quantitative method. The costs using PRT as a primary screening was roughly a quarter of those using conventional method. Even if the PSA levels of all the participants with a positive PRT were confirmed using quantitative methods, the costs would be one-third (approximately $2,900). It can be appreciated that this would result in significant cost savings in mass screening programs in which many thousands of men are examined annually. The detection rate of prostate cancer by mass screening using PSA testing has been reported to be 1.3–2.3% of participants in Japan [5–7]. In our study, 37 of 614 participants (3.4%) were diagnosed with prostate cancer and only one of the
123
patients who underwent prostatectomy had a socalled clinically insignificant cancer. These results from our study mainly using PRT as a primary screening are comparable to those of conventional screening using quantitative PSA testing at the outset. The number of participants who subsequently visited urologists for further examination was small contrary to our expectations. Reporting the results of the PRT on the spot might have little advantage on this matter. The main reason for this unexpected result may be that the lecture was not fully understandable for the participants. The contents should be reconsidered in order to improve the number of individuals with a positive PRT who return for further examination. We are now conducting questionnaire surveys in every lecture to provide a good understanding about the contents. A high false positive rate was a problem of this test. Almost half the men with positive PRT had a PSA level of 4.0 ng/ml or less. The cause of these results is unclear although it is possible that our tendency to read faint test lines as positive in order not to miss cancer may be a factor. Though immediate reports of the results may be desirable, it is feasible that the PSA levels of the samples that are positive by PRT will be confirmed using a quantitative method before informing the participants, with the final results being sent to them later. Approximately 20% of participants are positive by PRT and, even if all samples with a positive PRT result are formally quantified, the total cost is still approximately one-third of that when all participants are examined using the usual quantitative method. Recently, it has been reported that different molecular forms of PSA (free PSA and complexed PSA) has improved the poor positive predictive value of total PSA as a screening biomarker [8, 9]. However, this improvement will be accompanied by some increase in cost. Primary mass screening does not necessarily require precise values of PSA. The combination of the PRT as a preliminary test and more precise testing using these new PSA isoforms would be a reasonable way to limit the cost and achieve high accuracy rate of prostate cancer detection.
Int Urol Nephrol (2006) 38:565–569
Conclusion In Japan, the recent rapid increase of mass screening for prostate cancer by measuring PSA will increase the economic burden to the healthcare system because conventional quantitative PSA testing requires great expense. It is impossible to disregard this economic issue for the future. A potential solution is to use a low-cost method like PRT to roughly screen patients for prostate cancer. Although quantitative PSA testing is still necessary for men with a positive PRT, the total cost is still much lower than if all men are screened using a quantitative method from the outset. We believe the PRT is useful as an initial screening test for detecting prostate cancer in combination with more precise quantitative testing.
References 1. Statistics and Information Department, M.o.L., Health and Welfare: Vital population Statistics in Heisei 15 (2003) in Japan. Table 5-24. Mortality and mortality rate per 100,000 from the standpoint of the etiology, http:// www.dbtk.mhlw.go.jp/toukei/data/010/2003/toukeihyou/ 0004652/t0098908/mc240_001.html 2. Catalona WJ, Richie JP, Ahmann FR, et al (1994) Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men. J Urol 151(5):1283–1290
569 3. Rietbergen JB, Kranse R, Kirkels WJ, et al (1997) Evaluation of prostate-specific antigen, digital rectal examination and transrectal ultrasonography in population-based screening for prostate cancer: improving the efficiency of early detection. Br J Urol 79(Suppl 2):57–63 4. Kobayashi M, Takezawa Y, Nakata S, et al (2000) The result of mass screening of 1997 for prostatic cancer in Isesaki City. Nippon Hinyokika Gakkai Zasshi 91(1):1– 7 5. Kanayama HO, Kagawa S, Utsunomiya M, et al (2004) Mass screening for prostate cancer in Tokushima City: the results of 2001. Nippon Hinyokika Gakkai Zasshi 95(3):596–603 6. Uchida K, Takeshima H, Akaza H, et al (2000) Screening for prostate cancer using prostate-specific antigen alone as a first-line checkup parameter: results of the health checkup system. Jpn J Clin Oncol 30(2):95–100 7. Ito K, Kubota Y, Banzai R, Yuasa H, Shimizu N, Kurokawa K, et al (1999) The present status, problems, and future of mass screening for prostate cancer in Gunma prefecture. The report of mass screening for prostate cancer study meeting in 1998. Kitakanto Med J 49:81–88 8. Stephan C, Jung K, Brux B, et al (2000) ACT-PSA and complexed PSA elimination kinetics in serum after radical retropubic prostatectomy: proof of new complex forming of PSA after release into circulation. Urology 55(4):560–563 9. Brawer MK (2000) Prostate-specific antigen. Semin Surg Oncol 18(1):3–9
123
