Circulating tumour-associated plasma DNA represents an independent and informative predictor of prostate cancer

OBJECTIVE: To investigate whether preoperative plasma levels of free DNA can discriminate between men with localized prostate cancer and benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: In all, 161 referred patients suspicious for prostate cancer either by an elevated prostate-specific antigen (PSA) level and/or abnormal digital rectal examination (DRE) were included in this prospective study. Peripheral plasma was taken before prostate biopsy and genomic DNA was extracted from the plasma using the a commercial kit and a vacuum chamber. After controlling for age, PSA level, the percentage free/total (f/t) PSA and prostate volume, the median prostate cancer plasma DNA concentration served as diagnostic threshold in uni- and multivariate logistic regression models. Multivariate models were subjected to 200 bootstraps for internal validation and to reduce over-fit bias. RESULTS: Subgroups consisted of 142 men with clinically localized prostate cancer and 19 with BPH. The median plasma concentration of cell-free DNA was 267 ng/mL in men with BPH vs 709 ng/mL in men with prostate cancer. In univariate analyses, plasma DNA concentration was a statistically significant and informative predictor (P = 0.032 and predictive accuracy 0.643). In multivariate analyses, it remained statistically significant after controlling for age, tPSA, f/tPSA and prostate volume, increasing the predictive accuracy by 5.6%. CONCLUSIONS: Our data suggest that plasma DNA level is a highly accurate and informative predictor in uni- and multivariate models for the presence of prostate cancer on needle biopsy. The predictive accuracy was substantially increased by adding plasma DNA level. However, larger-scale studies are needed to further confirm its clinical impact on prostate cancer detection.     

Distribution of prostate specific antigen (PSA) and percentage free PSA in a contemporary screening cohort with no evidence of prostate cancer

OBJECTIVE: To explore the distribution of total prostate specific antigen (PSA) and percentage free/total PSA (%f/tPSA) in healthy volunteers with no clinical evidence of prostate cancer, who participated in prostate cancer screening. SUBJECTS AND METHODS: PSA and %f/tPSA values from 2323 men, who participated in one of three annual prostate cancer screening events between 2004 and 2006, were tabulated according to age strata of 40-49, 50-59, 60-69 and 70-79 years. Local regression smoothing plots provided a graphical display of the relation between age and PSA or %f/tPSA, respectively. All PSA and %f/tPSA analyses were repeated for each age category after excluding, respectively, the top and the bottom 10% of PSA and %f/tPSA values. RESULTS: Within the entire cohort, the median PSA level was 1.0 ng/mL and the median %f/tPSA was 25%. According to the age categories the PSA level and %f/tPSA medians within the entire cohort were, respectively, 0.7, 0.9, 1.3, 1.8 ng/mL and 28.0, 26.0, 24.0 and 25.0%. Of the 2323 men, 438 (18.9%) had a PSA level of >2.5 ng/mL and 1172 (50.5%) had a %f/tPSA of < or = 25%. When either a PSA level of >2.5 ng/mL or a %f/tPSA of < or = 25% were considered, 1235 (53.2%) had one or two abnormal values. Finally, if either a PSA level of >2.5 ng/mL or %f/tPSA of < or = 15% was used, 617 (26.6%) were considered abnormal. CONCLUSION: Half of men with no clinical evidence of prostate cancer should have PSA levels of <1.0 ng/mL and a %f/tPSA of >25%. A PSA level threshold of 2.5 ng/mL would require a biopsy in 20% of men and a %f/tPSA threshold of < or = 25% in half of the men. Alternatively, a %f/tPSA threshold of < or = 15% would decrease the probability to 15%.     

The influence of prostate volume on the prostate-specific antigen (PSA) level adjusted for the transition zone volume and free-to-total PSA ratio: a prospective study

OBJECTIVES: To evaluate the influence of prostate volume on the prostate-specific antigen (PSA) level adjusted for the transition zone volume (PSAT) and free-to-total PSA ratio (f/tPSA) in detecting prostate cancer in men with intermediate PSA levels of 4.1-10.0 ng/mL. PATIENTS AND METHODS: From March 1997 to June 1999, the f/tPSA and PSAT were measured in 105 patients who underwent ultrasound-guided systemic biopsies and had a PSA level of 4.1-10.0 ng/mL, with an apparently normal prostate on a digital rectal examination. The PSAT and f/tPSA were evaluated in all patients and in subgroups of patients with small (< 40 mL) or large (> or = 40 mL) prostates, using receiver operating characteristic (ROC) curves. RESULTS: Total prostate volume was highly correlated with transition zone volume in all patients and in both subgroups (P < 0.001). In all 105 patients, PSAT had a sensitivity of 82% and its use would have avoided the largest number of unnecessary biopsies (87% specificity) at a threshold value of 0.35 ng. In men with small prostates f/tPSA and PSAT had a high sensitivity and specificity, at threshold values of 0.12 and 0.35 ng, respectively. In large prostates the PSAT was superior to f/tPSA in detecting prostate cancer. CONCLUSIONS: These results suggest that both f/tPSA and PSAT are useful in detecting prostate cancer in men with small prostates, while PSAT is superior to f/tPSA in detecting prostate cancer in men with large prostates.     

Prostate cancer detection in men with a 'normal' total prostate-specific antigen (PSA) level using percentage free PSA: a prospective screening study

OBJECTIVE: To assess the utility of percentage free/total prostate-specific antigen (f/tPSA) levels for detecting prostate cancer in a prospectively screened population of men with a 'normal' total PSA level. PATIENTS AND METHODS: Men aged 50-65 years were contacted via their general practitioner and invited for prostate cancer screening. All had their total and f/tPSA levels measured; those meeting the biopsy criteria (PSA 1.1-3.99 ng/mL and f/tPSA < or = 20%) were offered a biopsy. The cancer detection rate was then evaluated and compared with other methods of detection. In all, 773 men were screened, of whom 115 met the criteria and agreed to undergo a prostate biopsy. RESULTS: Cancer was detected in 13 of the 115 men (11.3%) of whom most would have been missed by lowering the age-adjusted threshold for total PSA to 2.5 ng/mL. There was no significant difference in total and f/tPSA values in men with and without prostate cancer. Those cancers that could be evaluated were found to be clinically significant. CONCLUSION: In this study prostate cancer was detected solely on the basis of a low f/tPSA value. Most men with cancer would have been missed by simply lowering the age-adjusted threshold for total PSA. Using the f/tPSA level may allow the detection of clinically significant cancer in men at a time when they are most likely to benefit from treatment.     

Variation in percentage-free prostate-specific antigen (PSA) with prostate volume, age and total PSA level

OBJECTIVE: To examine the correlation between prostate volume, patient age and total prostate-specific antigen (tPSA) with the percentage-free PSA (f/tPSA) in a population-based cohort of men with no prostate cancer and with a tPSA of < 10.0 ng/mL. SUBJECTS AND METHODS: Men who in 1988-1989, after randomized selection in the general population, participated in a population-based screening study for prostate cancer, were investigated. In all, 1622 of the men (aged 55-70 years) were considered free from prostate cancer and had a tPSA level of < 10.0 ng/mL. The f/tPSA and tPSA were determined in frozen sera from each individual, and related to prostate volume and age measured at the time of the study. The entire population was investigated, as were four subpopulations based on tPSA levels (< 2.0, 2.0-3.9, 4.0-6.9 and 7.0-9.9 ng/mL). Statistical calculations included multiple regression and correlation analysis. RESULTS: The f/tPSA level varied with prostate volume and age, but the decisive factor for this variation was the tPSA level. The closest correlation was in the tPSA interval 7.0-9.9 ng/mL, where volume and age together explained 47% of the variation in f/tPSA. Also, for men with tPSA levels in each of the intervals 2.0-3.9, 4.0-6.9 and 7.0-9.9 ng/mL, the f/tPSA increased with higher prostate volumes and age. In men with tPSA levels of < 2.0 ng/mL the f/tPSA was not affected by variations in prostate volume or age. CONCLUSION: The variation in f/tPSA with prostate volume, age and tPSA is highly dependent on the tPSA level. Volume and age in the tPSA interval 7.0-9.9 ng/mL can explain almost half the variation in f/tPSA, whereas this influence is insignificant in men with a tPSA of < 2.0 ng/mL.     

The effect of percentage free prostate-specific antigen (PSA) level on the prostate cancer detection rate in a screening population with low PSA levels

OBJECTIVE: To evaluate the prostate cancer detection rate at low total prostate-specific antigen (tPSA) ranges of 2.6-4 and 4.1-10 ng/mL, according to different percentage free (f/t) PSA levels in a screening population. SUBJECTS AND METHODS: In all, 1809 consecutive screening volunteers with a tPSA level of 2.6-10.0 ng/mL were assessed. Ten systematic ultrasonography-guided prostate biopsies and, since 2000, an additional five Doppler-enhanced targeted biopsies were taken on the basis of age-specific tPSA reference ranges. We analysed the detection rate of prostate cancer according to f/tPSA ranges of 0-9%, 10-14%, 15-18% and >18%. RESULTS: The detection rates for the subgroups with tPSA levels of 2.6-4.0 and 4.1-10.0 ng/mL were 20.2% and 27.0%, respectively. The cancer detection rate in the first group (2.6-4.0 ng/mL) at 0-10% fPSA was 22.9%, and that in the second group (4.1-10.0 ng/mL) at 0-10% was 36.9%. There were significant differences between these groups. If the f/tPSA was 10-15%, the cancer detection rate for the two groups were 22.6% and 32.5%, respectively (P < 0.05). There was no statistically significant difference in the cancer detecting rates at an f/tPSA of 15-18% or >18%. CONCLUSION: There is a statistically significantly higher cancer detection rate when the f/tPSA is <15% than in groups of men with a f/tPSA of >15% in screening population assessed primarily using tPSA level.     

Elevated serum prostate specific antigen levels in conjunction with an initial prostatic biopsy negative for carcinoma: who should undergo a repeat biopsy?

OBJECTIVE: To determine the outcome of repeated prostatic biopsies in men attending with suspected prostate cancer but an initial negative biopsy. PATIENTS AND METHODS: Patients who had undergone two or more transrectal ultrasonography (TRUS)-guided prostate biopsies were identified from the Hospital Information Support System database. Indications for TRUS were a raised prostate-specific antigen (PSA) level (>4.0 ng/mL), with or without an abnormal digital rectal examination (DRE). Sextant prostate biopsies plus biopsies of any suspicious hypoechoic area or area of DRE abnormality were obtained for histology. Forty-eight patients underwent repeat TRUS-guided prostatic biopsies (mean age 67.5, sd 7. 25, range 53-82 years). RESULTS: The mean (sd, median, range) PSA level was 16.9 (13.5, 11.6, 5.2-61.8) ng/mL. Fifteen patients (31%) had carcinoma on repeat biopsy, 11 after the second and four after a third biopsy. The positive repeat biopsy rate was 24% where the PSA level was 4.0-9.9 ng/mL, 33% if the level was 10.0-19.9 ng/mL and 39% if it was >/=20.0 ng/mL. There was no significant difference in age or initial PSA concentration between those men with positive and those with negative repeat biopsies. However, patients with cancer had significantly higher PSA levels before repeat biopsy than at first biopsy (P=0.0043) and had greater PSA velocities than had patients with no diagnosis of cancer (P=0.0067). CONCLUSION: Where sufficient clinical suspicion exists, despite an initial negative biopsy, repeat TRUS-guided prostate biopsies should be carried out to exclude carcinoma of the prostate.     

Complexed prostate specific antigen (PSA) reduces unnecessary prostate biopsies in the 2.6-4.0 ng/mL range of total PSA

OBJECTIVE: To compare the performance of complexed prostate-specific antigen (cPSA) to total PSA (tPSA) and percentage free PSA (f/tPSA) in the diagnosis of prostate cancer for the tPSA range 2.6-4.0 ng/mL. PATIENTS AND METHODS: Consecutive men scheduled for prostate biopsy were enrolled prospectively at 14 different sites in two multicentre studies in Europe and the USA. Serum obtained before biopsy was tested with the ACS:180 and Immuno 1 tPSA and cPSA assays (Bayer Diagnostics, Tarrytown, NY, USA) and the Access fPSA and tPSA assays (Beckman, Inc., San Diego, CA, USA). Receiver operating characteristics (ROC) curves were generated to compare the diagnostic performance of tPSA, cPSA and f/tPSA. RESULTS: Of 316 men with a tPSA of 2.6-4.0 ng/mL, 82 (26%) were diagnosed with prostate cancer on biopsy. ROC analysis of all 316 men showed an area under the curve (AUC) for cPSA of 0.63, significantly greater than the AUC for tPSA of 0.56 (P = 0.008). At a sensitivity of 95%, threshold values of 2.3 ng/mL for cPSA and 2.73 ng/mL for tPSA provided specificities of 20.1% and 9.8%, respectively. f/tPSA was only available for 205 of the 316 (65%) men and the AUC for cPSA was 0.63, and did not significantly differ from the f/tPSA AUC of 0.64 (P = 0.58). CONCLUSIONS: As a single test, cPSA provides improved specificity over tPSA and comparable specificity to f/tPSA for detecting prostate cancer, and may reduce the number of unnecessary prostate biopsies in the 2.6-4.0 ng/mL tPSA range.     

Problems with prostate specific antigen screening for prostate cancer in the primary healthcare setting in South Africa

OBJECTIVES: To assess the feasibility of detecting early-stage prostate cancer in the primary healthcare setting, and to investigate whether there is a higher incidence of prostate cancer in Black African men. PATIENTS AND METHODS: The study was a collaboration with registrars in the authors' institutions and primary healthcare centres serving mainly a Black African or mixed ancestry (Coloured) population in the semi-urban Cape Town metropolitan area of South Africa. Men aged 50-70 years attending the clinics were counselled about prostate cancer and invited to have a digital rectal examination (DRE), serum prostate-specific antigen (PSA) assay and transrectal ultrasonography-guided sextant prostate biopsy if the DRE was clinically suspicious of malignancy or the serum PSA was > or = 4.0 ng/mL. An American Urological Association Symptom Index (AUA-SI) was obtained, and urine analysed using dipsticks. RESULTS: From May 2000 to November 2001, 660 men were assessed (mean age 59.4 years, range 30-82); 60.6% were Black African, 37.3% mixed (Coloured), 1.8% White (Caucasian) and 0.2% Asian (Indian). The mean (range) AUA-SI was 5.98 (0-35) in the whole group; the DRE was recorded as clinically suspicious of malignancy in 3.2%. The mean PSA was 20.39 (0.04-10 000) ng/mL in the whole group, but when two outliers (1865 and 10 000 ng/mL) were disregarded, it was 2.4 ng/mL. In Black patients the mean PSA was 31.8 (0.04-10 000) ng/mL, and without the outliers, 2.1 ng/mL; in Coloured patients it was 2.94 (0.05-50) ng/mL. The PSA was > or = 4.0 ng/mL in 9.6% of the whole group, in 7.8% of Black and in 13% of Coloured patients. Prostate biopsies were taken in 21 patients (3.2% of the whole group and a third of those with a PSA of > or = 4.0 ng/mL); in Black patients, biopsies were taken in 1.5% and 19.4%, respectively, and in Coloured patients in 6.1% and 46.9%, respectively. The prostate biopsy showed cancer in 43% of the whole group, in a third of Black and in 47% of Coloured patients; prostate cancer was detected in 1.4%, 0.5% and 2.8%, respectively. CONCLUSIONS: That prostate biopsies were obtained in only 19% of Black and in only 47% of Coloured men with a serum PSA of > or = 4.0 ng/mL is of concern. This indicates that there is a significant problem in getting men with an elevated serum PSA level to undergo a prostate biopsy in the primary healthcare setting in South Africa.     

Prostate-specific antigen changes in hypogonadal men treated with testosterone replacement

Testosterone supplementation is commonly used as a treatment for hypogonadal men with or without erectile dysfunction. The effect of parenteral testosterone replacement therapy on the development or growth of prostate cancer is unclear. We assessed the effect of this treatment on serum prostate-specific antigen (PSA) levels and risk of prostate cancer in hypogonadal men with erectile dysfunction. Criteria for inclusion were a normal pre-treatment PSA (<4.0 ng/mL) in conjunction with a normal digital rectal examination (DRE) or a negative pretreatment prostate biopsy for men with either an abnormal DRE or an elevated PSA. Patients received intramuscular injections every 2 to 4 weeks, allowing for dose titration. In this retrospective analysis, 54 hypogonadal men with erectile dysfunction were included, with a mean age of 60.4 years (range 42.0-76.0) and a mean follow-up of 30.2 months (range 2.0-82.0) on testosterone therapy. Mean pretreatment total testosterone level was 1.89 ng/mL (range 0.2-2.92), which increased during treatment to a mean of 9.74 ng/mL (range 1.50-26.30, P <.001). Mean pretreatment PSA was 1.86 ng/mL (median 1.01 ng/mL, range 0.0-15.80), which increased to a mean PSA level of 2.82 ng/mL (median 1.56 ng/mL, range 0.0-32.36, P <.01) with testosterone treatment. Of the 54 men included in this study, 6 (11.1%) required prostate biopsy while on testosterone therapy because of a rise in serum PSA above 4.0 ng/mL. One patient (1.9%) was diagnosed with prostate cancer. In conclusion, testosterone replacement therapy in men with erectile dysfunction and hypogonadism is associated with a minor PSA elevation, but there does not appear to be a short-term increase in risk for the development of prostate cancer.     

Age, prostate-specific antigen, and digital rectal examination as determinants of the probability of having prostate cancer

Objectives. The decision to perform prostate biopsy has traditionally been based on an abnormal prostate-specific antigen (PSA) level or abnormal digital rectal examination (DRE) findings. For example, a 60-year-old man with a benign DRE and PSA level of 4.1 ng/mL would be counseled for biopsy, and the same man with a PSA level of 3.9 ng/mL might be counseled against biopsy. However, the difference in these PSA levels and in the likelihood of these two men having prostate cancer is not significant. We constructed a probability nomogram for the likelihood of detecting prostate cancer, thus aiding in the decision of whether to perform a prostate biopsy.Methods. Using multivariate logistic regression analysis and data from 2054 men (mean age 64 years) participating in the Tyrol Screening Project between January 9, 1993 and January 9, 1997, patient age, PSA level, and DRE findings were analyzed for their ability to determine the likelihood of finding prostate cancer on transrectal ultrasound-guided biopsy.Results. DRE was suspicious in 278 men (13.5%). Overall, 498 (24.5%) of 2054 men biopsied had prostate cancer. The probability of discovering cancer on biopsy was calculated using patient age, DRE findings, and PSA level.Conclusions. DRE status had a large influence on the likelihood of positive biopsy across all PSA and age ranges. A combination of PSA, DRE result, and age better defined the probability of a positive biopsy than any factor alone. Using this nomogram, the decision to proceed with or defer prostate biopsy can be based on an actual probability of discovering prostate cancer rather than a single PSA-based cutpoint. These data may aid physicians and patients in decision-making.     

PSAD在PSA 4～10ng患者前列腺癌诊断中的价值

目的探讨前列腺特异性抗原密度（PSAD）在前列腺特异性抗原（PSA）值介于4～10ng之间患者前列腺腺癌诊断中的应用价值。方法回顾性分析183例血清PSA值介于4～10ng之间疑似前列腺癌患者的临床资料,所有患者均经直肠B超测得前列腺体积后再行经直肠超声引导下前列腺穿刺术,通过接受者工作特征曲线分析法评价PSAD在预测诊断前列腺癌中的应用价值。结果 183例患者中36例经直肠超声下前列腺活检的患者被诊断为前列腺癌,占19.7%。良性前列腺增生组与前列腺癌患者之间,PSA（0.681 5）与PSAD（0.721 4）的曲线下方面积比较相似,而游离前列腺特异性抗原与总前列腺特异性抗原比值（f/tPSA）的曲线下面积只有0.318 2,相比PSA,PSAD值将是一个更好的预测前列腺癌的指标。结论 PSAD对于PSA值介于4～10ng/mL的中国患者是一项更好的预测前列腺癌的指标。     

Clinical utility of human glandular kallikrein 2 within a neural network for prostate cancer detection

OBJECTIVE

To assess, using artificial neural networks (ANNs), human glandular kallikrein 2 (hK2), prostate‐specific antigen (PSA), and percentage free/total PSA (f/tPSA), for discriminating between prostate cancer and benign prostatic hyperplasia (BPH).

MATERIAL AND METHODS

Serum samples from 475 patients with prostate cancer (n = 347) or BPH (n = 128) within the PSA range of 1–20 ng/mL were analysed for tPSA, fPSA and hK2 (research assay, Toronto, Canada). Data were analysed in the ranges of 1–4, 2–4, 4–10, and 2–20 ng/mL tPSA. Back‐propagation ANN models with the variables PSA, f/tPSA, and hK2, hK2/fPSA and hK2/(f/tPSA) were constructed. The diagnostic validity was evaluated by receiver‐operating characteristic (ROC) curve analysis.

RESULTS

Whereas the median concentration of hK2 was not significantly different between patients with BPH or prostate cancer in any of the tPSA ranges, the f/tPSA, hK2/fPSA and hK2/(f/tPSA), and the hK2‐based ANN outputs were always significantly different between patients with prostate cancer or BPH. Using ROC curve comparison, all variables were significantly better than hK2 in all ranges. The hK2‐based ANN performed better than f/tPSA except in the 4–10 ng/mL tPSA range. At 90% and 95% sensitivity, the hK2‐based ANN was also significantly better than f/tPSA in the 1–4 ng/mL tPSA range. hK2/(f/tPSA) achieved equal results to the hK2‐based ANN except in the range 2–20 ng/mL tPSA.

CONCLUSIONS

The hK2‐based ANN improves the outcome of f/tPSA but not hK2/(f/tPSA) in almost all analysed subgroups. When comparing the results at 90% and 95% sensitivity the hK2‐based ANN only performed significantly better than f/tPSA in the lowest tPSA range. Only in lower tPSA ranges do hK2‐based ANNs show an advantage for further improving prostate cancer detection.

     

The significance of the free-to-complexed prostate-specific antigen (PSA) ratio in prostate cancer detection in patients with a PSA level of 4.1-10.0 ng/mL

OBJECTIVE: To compare the ratio of free prostate specific antigen (fPSA), total PSA (tPSA) and complexed PSA (cPSA, measured using a novel immunoassay) with other variables used to detect prostate cancer in patients with intermediate serum PSA levels of 4.1-10.0 ng/mL. PATIENTS AND METHODS: From July 1997 to August 1998, 140 consecutive patients were assessed; all had intermediate serum PSA levels and/or abnormal findings on a digital rectal examination. All patients underwent transrectal ultrasonography (TRUS)-guided biopsy, and the prostate and transition zone volumes were determined by TRUS. Free and tPSA were measured using the Tandem-R assay (Hybritech Corp., San Diego, CA). PSA complexed with alpha1-antichymotrypsin (cPSA) was measured using an appropriate assay. The ability of cPSA, free-to-total PSA ratio (f/tPSA), free-to-complexed PSA ratio (f/cPSA), tPSA density of the whole prostate (PSAD), of the transition zone (tPSATZ), and cPSA density of the whole prostate (cPSAD) and of the transition zone (cPSATZ) to improve the power of PSA in detecting prostate cancer was evaluated using receiver operating characteristic (ROC) curves. Results Of the 140 patients, 126 had histologically confirmed benign disease and 14 had prostate cancer. The cPSA alone had better specificity for detecting prostate cancer than had tPSA alone but the difference was not significant. The area under the ROC curve for f/cPSA was larger than those for all other variables. With a 93% sensitivity for detecting prostate cancer, a f/cPSA threshold of 25% would result in fewer unnecessary biopsies (40% f/cPSA specificity) than with all other PSA variables. The difference in the resolution was significant between f/cPSA and tPSA, cPSA, tPSAD and tPSATZ, but not with f/tPSA, cPSAD or cPSATZ. In patients with a prostate volume of < 30 mL, the cPSATZ showed better specificity for prostate cancer than tPSA alone. CONCLUSION: Measuring the level of cPSA and its derivatives may provide better differentiation of prostate cancer and benign disease than tPSA alone in patients with a tPSA level of 4.1-10.0 ng/mL.     

The role of the digital rectal examination in subsequent screening visits in the European randomized study of screening for prostate cancer (ERSPC), Rotterdam

BACKGROUND: The value of digital rectal examination (DRE) as a screening test for prostate cancer (PC) is controversial in the current prostate-specific antigen (PSA) era. OBJECTIVES: To determine (1) the additional value of a suspicious DRE for the detection of PC in men with an elevated PSA level in subsequent screenings and (2) the tumour characteristics of PCs detected in men with a suspicious DRE. DESIGN, SETTING, PARTICIPANTS: Within the screening study, from 1997-2006 men aged 55-75 years were invited for an every 4-yr PSA determination. A PSA level >/=3.0ng/ml prompted a DRE and a transrectal ultrasound (TRUS)-guided, lateralized sextant biopsy. Throughout the three screenings of the ERSPC, Rotterdam, 5040 biopsy sessions were evaluated. MEASUREMENTS: We determined the positive predictive values (PPVs) of a suspicious DRE and normal DRE, which entailed, respectively, the proportion of PCs detected in men with a suspicious DRE or normal DRE divided by, respectively, all biopsied men with a suspicious DRE or normal DRE. RESULTS AND LIMITATIONS: At initial screening, the PPV of a suspicious DRE, in conjunction with an elevated PSA level, to detect PC was 48.6% compared to 22.4% for men with a normal DRE. Both PPVs decreased in consecutive screens: respectively, 29.9% versus 17.1% (screen 2) and 21.2% versus 18.2% (screen 3). Respectively, 71.0% (p<0.001), 68.8% (p<0.001), and 85.7% (p=0.002) of all PCs with a Gleason score >7 were detected in men with a suspicious DRE at screens 1, 2, and 3. A limitation is that only biopsied men were evaluated. CONCLUSIONS: At initial and subsequent screenings, the chance of having cancer at biopsy was higher in men with a suspicious DRE compared to men with a normal DRE (to a lesser extent in subsequent screenings), and the combination of a PSA level >/=3.0ng/ml with a suspicious DRE resulted in detecting significantly more PCs with Gleason score >7. DRE may be useful in more selective screening procedures to decrease unnecessary biopsies and overdiagnosis.     

Use of prostate-specific antigen (PSA) isoforms for the detection of prostate cancer in men with a PSA level of 2-10 ng/ml: systematic review and meta-analysis

OBJECTIVE: Measurement of serum prostate-specific antigen (PSA) for the detection of prostate cancer has poor specificity in men with PSA levels between 2 and 10 ng/ml. It has been suggested that measurement of the ratio of free to total PSA (f/tPSA) or complexed PSA (cPSA) might offer an improvement. We performed a systematic review and meta-analysis to evaluate the diagnostic performance of these tests among men with PSA levels between 2 and 10 ng/ml. METHODS: Data on sensitivity and specificity were extracted from 66 eligible studies. Likelihood ratios and summary receiver operating characteristic curves were estimated and possible sources of heterogeneity between studies examined. RESULTS: Use of the f/tPSA or the cPSA test improved diagnostic performance among men with a total PSA (tPSA) of 2-4 or 4-10 ng/ml compared to tPSA alone. The diagnostic performance of the f/tPSA test was significantly higher in the tPSA range of 4-10 ng/ml compared to a tPSA range of 2-4 ng/ml (p < 0.01); at a sensitivity of 95%, the specificity was 18% in the 4-10 ng/ml tPSA range and 6% in the 2-4 ng/ml tPSA range. Among studies that measured both isoforms, the diagnostic performance of the f/tPSA test and the cPSA was equivalent in both PSA ranges. CONCLUSIONS: The use of the f/tPSA or cPSA test among men with PSA levels between 2 and 10 ng/ml can reduce the number of unnecessary biopsies whilst maintaining a high cancer detection rate.     

Comparison of two investigative assays for the complexed prostate-specific antigen in total prostate-specific antigen between 4.1 and 10.0 ng/mL

OBJECTIVES: To determine the ability of complexed prostate-specific antigen (cPSA) levels to diagnose prostate cancer. METHODS: Between September 1998 and March 1999, cPSA levels in 182 consecutive patients with an abnormal digital rectal examination (DRE) or a total PSA (tPSA; Tandem-R assay) level greater than 4.1 ng/mL were examined. Levels of cPSA were measured by the Markit-M PSA-ACT (alpha(1)-antichymotrypsin) assay (cPSA-MM) and Bayer Immuno 1 complexed PSA assay (cPSA-BI). Free PSA (fPSA) was measured by the Tandem-R free PSA assay. RESULTS: Of the 140 patients with tPSA between 4.1 and 10.0 ng/mL, 116 were histologically confirmed as having benign tissue; the remaining 24 were diagnosed with prostate cancer. To ensure a 92% sensitivity of cancer detection, a cutoff value for the tPSA, cPSA-MM, and cPSA-BI assays of 4.8 ng/mL, 2.7 ng/mL, and 4.6 ng/mL, respectively, was determined. The percentage of negative biopsies prevented at these cutoff (ie, specificity) values was 14%, 23%, and 24%. No significant differences among these three assays were found. At 92% sensitivity, the cutoff value for the fPSA/tPSA, fPSA/cPSA-MM, and fPSA/cPSA-BI ratios was 18%, 27%, and 18%, respectively. The specificity was 35%, 49%, and 51%. No significant differences were found among these three fPSA ratios. Significant differences were noted between tPSA and the fPSA/cPSA-MM ratio and between tPSA and the fPSA/cPSA-BI ratio. No differences were seen among the other PSA parameters. CONCLUSIONS: No difference in the ability of cPSA levels to distinguish prostate cancer and noncancer was observed between cPSA-MM and cPSA-BI or between their fPSA ratios. Only the fPSA/cPSA-MM and fPSA/cPSA-BI ratios provided significantly enhanced diagnostic performance compared with tPSA.     

Are prostatic biopsies necessary in men aged > or =80 years?

OBJECTIVE: To examine whether prostatic biopsies are necessary in all men aged > or =80 years, as men found to have prostate cancer are frequently treated with a 'watch and wait' policy or with hormonal withdrawal alone, and biopsies are associated with a small but significant complication rate. PATIENTS AND METHODS: The findings on a digital rectal examination (DRE), the prostate-specific antigen (PSA) level, the biopsy and staging bone scan results for all men aged > or = 80 years who had prostatic biopsies over a 3-year period were reviewed, together with those in a group of men aged <80 years for comparison. All biopsy samples had been examined in one of three histopathology units, and 33 consultant urological surgeons contributed. RESULTS: In all, 210 biopsies from 205 men aged > or = 80 years were identified, of whom 163 (79%) had biopsy-confirmed prostate cancer. All 29 men with a PSA level of > or = 100 ng/mL, 98% of 47 with > or = 50 ng/mL, 97% of 76 with > or = 30 ng/mL and 92% of 101 with > or = 20 ng/mL had biopsy cores containing cancer; 63% of men with a PSA level of <20 ng/mL had cancer on biopsy. In men with cancer and a PSA level of > or = 30 ng/mL, 92% had Gleason grade > or = 7 and 93% were treated with hormonal withdrawal alone. In all men with cancer the DRE was abnormal in 91%, the mean number of positive cores was 59% and the bone scan was positive in 18%. The DRE was abnormal in 77% of men with benign biopsies. CONCLUSIONS: In men aged > or = 80 years with a PSA level of > or = 30 ng/mL, at least 97% had prostate cancer, >90% of whom had high-grade disease, and nearly all with cancer received active pharmacological treatment. In the vast majority of these men prostate biopsies did not alter their cancer management. The value of prostatic biopsy in this age group, with a PSA level of > or = 30 ng/mL, is questionable.     

Population-based screening for prostate cancer by measuring total serum prostate-specific antigen in Iran

OBJECTIVE: To report the results from an Iranian large population-based randomized study of screening using prostate-specific antigen (PSA) to detect prostate cancer. MATERIALS AND METHODS: A total of 3758 Iranian men older than 40 years were mass checked by PSA-based screening. Men with an abnormal digital rectal examination (DRE) and serum total PSA level of greater than 4 ng/mL, underwent transrectal ultrasonography (TRUS)-guided extended prostate biopsy. RESULTS: The PSA value (mean +/- standard deviation, SD) in all men without prostate cancer was 1.6 +/- 1.1 ng/mL and in those with cancer 18 +/- 44.8 ng/mL (P = 0.001). PSA values increased with age. In those aged 40-49, 50-59, 60-69 and > or = 70 years, the mean +/- SD PSA values were 1.3 +/- 0.7, 1.4 +/- 0.8, 1.8 +/- 1 and 2.2 +/- 1.6 ng/mL, respectively. Among the screened men, 323 (8.6%) had a serum PSA concentration greater than 4 ng/mL. Of patients who underwent prostate biopsy (230, 71.2%), 129 (positive predictive value, 56.1%) had prostate cancer. Additionally, nine cancers were detected among 16 patients with PSA of less than 4 ng/mL who had a doubtful DRE finding. The overall cancer detection rate was 3.6%; 1.4% at 40-49, 1.6% at 50-59, 4.2% at 60-69 and 12.9% at >/=70 years. Conventional systematic sextant biopsies, which accounted for six of the 10 cores in our biopsy scheme, detected 98 (71%) of the cancers. CONCLUSIONS: The Iranian male population develops prostate cancer quite commonly if their serum PSA levels are greater than 4.0 ng/mL. In this study, 65.9% of the detected cancers were clinically significant. The conventional systematic sextant technique may be inappropriate for detection of all prostate cancers. The results need to be confirmed in other randomized trials.     

Serendipity in detecting disease in low prostate-specific antigen ranges

OBJECTIVE: To assess the magnitude of prostate cancer detection by serendipity (the coincidental detection of prostate cancer during the evaluation of an abnormal screening test result) when a digital rectal examination (DRE) and transrectal ultrasonography (TRUS) are used as initial screening tests for prostate cancer in men with low levels of prostate-specific antigen (PSA; 0.0-3.9 ng/mL). PATIENTS AND METHODS: In all, 117 participants of a population-based screening study were diagnosed with prostate cancer after a standard evaluation of an abnormal screening test result; 49 underwent radical prostatectomy. Serendipity was defined as either: (i) the presence of prostate cancer opposite to the side that raised suspicion for cancer on DRE and/or TRUS; (ii) a negative lesion-directed biopsy while cancer was present in one or more of the cores of the sextant biopsy; (iii) a tumour volume of < 0.5 mL on radical prostatectomy. RESULTS: Depending on the definition, 27-63% of prostate cancers detected at low PSA values were detected coincidentally and not as a result of a true-positive test result. The proportion of cancers detected by serendipity was inversely correlated with serum PSA level. CONCLUSION: A relatively high proportion of prostate cancers diagnosed in men with low PSA levels, and in which a biopsy was prompted by a suspicious DRE and/or TRUS, are considered to be detected by chance only. As these cancers are mostly small (< 0.5 mL), with potentially low biological aggressiveness, relying on serendipity seems disadvantageous in prostate-cancer screening. The level of serendipity in prostate cancer detection, the poor performance of the screening test, and high inter-observer variability, casts further doubt on the utility of DRE (and TRUS) as initial screening tests for prostate cancer in population-based screening.