Effect of Combination of Total PSA and Free/Total PSA Ratio on Diagnosis of Prostate Cancer during PSA Screening Test in Chinese Men*
Ling Zhang 1, Guoyi Ji 1, Xingyi Zhang 2, Xiaomeng Li 1, Weihua Wang 1,Hongwen Gao 1, Yuzhuo Pan 1, Kuwahara Masaaki 3, Xuejian Zhao 1**
Abstract: We have investigated the effect of combination of total PSA (TPSA) and free/total PSA (F/T PSA) ratio on diagnosis of prostate cancer (PCa) during PSA screening test in Chinese men. F/T PSA ratio in serum was analyzed prospectively in 187 men when TPSA was in the ranges of 4.0~20.0ng/ml. All of them underwent ultrasound-guided sextant prostate biopsies. Sensitivity, specificity, positive and negative predictive values were calculated by SPSS 10.0 software. Prostate cancer detection rates were 18.1% and 22.5% when TPSA was in the rages of 4.0~10.0ng/ml and >10.0~20.0ng/ml, respectively. F/T PSA ratio was more significant than TPSA in all of the men. When a cut-off value of F/T PSA ratio was set at 0.25, 90.5% and 87.5% of cancers could be detected, while 26.7% and 11.3% unnecessary biopsies could be reduced in the range of 4.0~10.0ng/ml and >10.0~20.0ng/ml respectively. This study reveals that in the cohort of Chinese men in the area of Changchun TPSA is in the range of 4.0~10.0ng/ml, PSA screening candidates with F/T PSA ratio less than 25% should be advised for prostate biopsy. However, for candidates with TPSA in the range of 10.0~20.0ng/ml an optimal cut-off value of F/T PSA ratio need to be established and warrants further investigation.
Key words: prostate cancer; prostate-specific antigen; F/T PSA ratio
Measurement of serum prostate-specific antigen (PSA) is widely used in the early detection of prostate cancer (PCa) . However, PSA can't be regarded as a reliable tumor marker because it lacks sufficient specificity. It only has a cancer detection rate of 25% when total PSA (TPSA) values is in the range of 4.0~10.0ng/ml in a screening population, and a detection rate of >30% when the TPSA is >10.0ng/ml . A recent strategy that enhance the specificity of serum PSA by measuring of free/total PSA (F/T PSA) ratio can well differentiate benign prostate hyperplasia from PCa and improve the specificity of PCa detection in patients with elevated total serum PSA [2-9].
Up to now, reports on mass screening of PCa of China have not been available in the literature. It is important to pursue investigation of PCa in China that is entering an aged country. Since 1998, we have been the first in China conducting the mass screening of PCa by means of TPSA. In the present study, the use of measuring F/T PSA ratio to avoid unnecessary biopsies was evaluated in the cohort of Chinese men with TPSA of 4.0~20.0ng/ml and suitable cut-off value of TPSA for Chinese men was explored.
MATERIALS AND METHODS
Between April 1998 and April 2003, a project of mass-screening test of PCa was conducted using serum TPSA in the urban area of Changchun, China. A total of 13,714 men over 50 years old were screened. Of the 13,714 men, 187 men had elevated TPSA 4.0~20.0ng/ml and underwent ultrasound-guided sextant prostatic biopsies. In this study, these 187 men were divided into the PCa [n=37, 19.8% (37/187)] and non-cancer group [n=150, 80.2% (150/187)]. In the PCa group, the 37 men with the mean age of 54~82 (69.19¡À6.89) were microscopically diagnosed as PCa. In the non-cancer group that was served as control to the PCa group, the 150 men (80.2%) at the age of 50~83 (68.50¡À7.78) who underwent the biopsy of the prostate were microscopically excluded the diagnosis of PCa.
2. Serum TPSA and FPSA assays
The blood samples were taken before any prostate manipulation. After centrifugation, the serum was obtained and kept at -20¡ãC until use. The concentration of serum TPSA and FPSA was measured using an automated, polyclonal-monoclonal immunochemiluminometric assay kit (CanAg, Gothenburg, Sweden).
3. Statistic analysis
Data of PSA concentration were expressed as ¡ÀS. The Mann-Whitney T test was used. Receiver operating characteristics (ROC) curves for PCa detection were generated by plotting the sensitivity versus (1-specificity) for TPSA, and F/T PSA ratio, in the subsets of patients with TPSA between 4.0 and 10ng/ml and between 10.0 and 20.0ng/ml. Areas under the ROC curves (AUC) were calculated for F/T PSA ratio in each subset, and a McNemar test was used to measure differences. The statistic analysis was accomplished with SPSS 10.0 software. p<0.05 was considered significant.
Serum TPSA (9.79¡À4.66ng/ml) in the PCa group was higher than that (8.65¡À3.33ng/ml) in non-cancer group but no significance was achieved (p>0.05). F/T PSA ratio in the PCa group was significantly higher than that of non-cancer group (0.13¡À0.07 vs 0.19¡À0.11; p<0.01). The detection rate of prostate cancer was 18.1% for TPSA value within range of 4.0~10.0ng/ml, and cancer detection rate of 22.5% for TPSA in the range of 10.0~20.0ng/ml. Distribution of biopsy results of the PCa and non-cancer group in F/T PSA ratio and TPSA in the range of 4.0~20.0ng/ml is shown in Fig. 1.
As Fig. 2 shown, the ROC curves according to the range of TPSA are analyzed. In men with TPSA between 4.0~10.0ng/ml, the AUC for F/T PSA was significantly higher than that for TPSA (0.691 vs 0.505, p<0.01). In men whose values of TPSA were in the range of 10.0~20.0ng/ml, the AUC for F/T PSA was significantly higher than that for TPSA (0.669 vs 0.595, p<0.05).
Fig. 2 Receiver operating characteristic (ROC) curves that analyze the efficacy of TPSA
and F/T PSA ratio according to the intervals of TPSA
The sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV), and unnecessary biopsy rate according to different cutoff values of F/T PSA ratio are shown in table 1. When TPSA was at the range of 4.0~10.0ng/ml, a 0.15 F/T PSA ratio cutoff resulted in 57.1% of cancer detection rate leading to reduction of unnecessary biopsy rate to 51.7%, while TPSA was at the range of 10.0~20.0ng/ml, a 0.15 F/T PSA ratio cutoff resulted in 62.5% of cancer detection rate and 35.2% of unnecessary biopsy rate.
Table 1. Sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV)
and using F/T PSA ratio (%)
TPSA>4.0~10.0 ng/mlTPSA>10.0~20.0 ng/mlF/TSensitivitySpecificityPPVNPVunnecessary biopsy rate (%)SensitivitySpecificityPPVNPVunnecessary
biopsy rate (%)¡Ü0.1557.163.826.185.751.762.545.525.080.635.2¡Ü0.1766.757.424.585.746.681.338.227.793.932.4¡Ü0.1971.455.329.592.744.087.532.727.59025.4¡Ü0.2181.042.626.191.537.187.525.525.587.519.7¡Ü0.2385.740.426.395.032.887.520.024.184.615.5¡Ü0.2590.531.924.193.926.787.514.523.080.011.3¡Ü0.2895.224.522.592.621.61007.332.91005.6DISCUSSION
On the basis of a clinical epidemiological study in the 1990s in Shanghai, Deng et al  reported that the incidence rate of PCa in China was 2.4 per 100,000. However, their study was neither population-based nor community-based data. Through the mass-screening test by measuring serum PSA for 3 years in Changchun, China, the estimated cancer detection rate was 1.3% [11, 12]. Our study suggested that in the region of Changchun, China, the annual average incidence of PCa during 1999 and 2001 has increased 4.72 times compared with that during the period between 1986 and 1989 . This has changed the view of a definitely lower incidence of PCa in China.
It has been shown that the measurement of PSA can lead to an improved early diagnosis rate of PCa . However, approximately 70% of the men with elevated PSA in PCa screening test do not have PCa . In this study, PCa detection rates were only 18.1% and 22.5% when TPSA was in the ranges of 4.0~10.0ng/ml and 10.0~20.0ng/ml, respectively. Therefore, it is necessary to explore the diagnosis efficacy of PCa using of F/T PSA ratio with TPSA levels in the range of 4.0~20.0ng/ml.
Recent researches have suggested that the measurement of F/T PSA ratio can increase the specificity of PSA testing and may be useful in the differentiation of PCa from benign diseases, especially when TPSA is <10ng/ml [2-9]. In the present study, we found that in addition to TPSA within the range of 4.0~10.0ng/ml, F/T PSA ratio could increase PCa detection rate when TPSA was in the range of 10.0~20.0ng/ml. This is consistent with the results reported by Morote et al .
Despite the importance of F/T PSA ratio cutoff value in the diagnosis of PCa, an optimal cutoff value of it has not yet been established. In a screening study in the cohort of American men, a F/T PSA ratio estimated at ¡Ü0.23 with TPSA within the range of 4.0~10.0ng/ml resulted in 31.3% reduction of unnecessary prostatic biopsies and maintained a detection rate of 90% . In this range in Spanish men, Morote et al  reported that an F/T PSA ratio estimated at ¡Ü0.25 reduced unnecessary biopsies by 26.9% and achieved a detection rate of 95% in PCa. Other studies have shown that F/T PSA ratio cutoff values set from 0.15 to 0.20 resulted in 75% to 29% reduction of unnecessary biopsies and gave rise to a detection rate of 71~95% in prostate cancers [7-9]. Our study showed that F/T PSA ratio cutoff value set at ¡Ü0.25 resulted in a detection rate of 90.5% in prostate cancers and a 26.7% reduction of unnecessary biopsies.
However, when TPSA was in the range of 10.0~20.0ng/ml, Morote et al  found that given F/T PSA ratio cutoff value less than 0.25, a 16.7% reduction of unnecessary biopsies and 95.4% of detection rate for prostate cancers were achieved. In this study, a 0.25 F/T PSA ratio cutoff value could give rise to a cancer detection rate of 87.5% and achieved reduction of unnecessary biopsies by 11.3%. Therefore, on the basis of the present study data, we believe that it is unlikely to establish the optimal cutoff value of F/T PSA ratio for men with TPSA in the range of 10.0~20.0ng/ml.
In conclusion, the results from this study suggest that in the cohort of Chinese men in the area of Changchun with TPSA in the range of 4.0~10.0ng/ml, PSA screening candidates having F/T PSA ratio between 0~0.25 should be advised for prostate biopsy. This study represents the first report to the F/T PSA ratio cutoff value with TPSA in the range of 4.0~10.0ng/ml in Chinese men. However, for candidates with TPSA in the range of 10.0~20.0ng/ml an optimal cutoff value of F/T PSA ratio need to be established and warrants further investigation.
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* Supported by Japan International Cooperation Agency (JICA) and the Ministry of Science & Technology of China.
** Corresponding to Xuejian Zhao, professor of Department of Pathophysiology, College of Basic Medicine, Jilin University; Address: No.2 Xinmin Street, Changchun, Postcode: 130021; Tel: 0431-5632348, 13944827950; Fax: 0431-5632348. E-mail: firstname.lastname@example.org
1 Prevention and Treatment Research Center for Prostate Diseases, Jilin University, Changchun, China, Postcode: 130021
2 Department of Thoracic and Cardiovascular Surgery, the Second Hospital of Jilin University, Changchun China, Postcode: 130041
3 Division of Urology, Miyagi Cancer Center, No. 981 Natori, Japan