Clinical value of prostate specific antigen based parameters for the detection of prostate cancer on repeat biopsy: the usefulness of complexed prostate specific antigen adjusted for transition zone volume

PURPOSE: To our knowledge the indications for repeat prostate needle biopsy in men whose previous transrectal ultrasound guided biopsy results revealed no evidence of cancer have not yet been defined. We identified the most effective method for detecting prostate cancer on repeat biopsy. MATERIALS AND METHODS: One or more systematic repeat prostate biopsies were performed in 144 consecutive patients, including 86 with prostate specific antigen (PSA) levels between 4 and 10 ng./ml. at repeat biopsy. Men in whom cancer was detected on repeat biopsies were compared with their counterparts in terms of digital rectal examination findings, PSA based parameters and an atypical prostate on initial prostate biopsy. RESULTS: Prostate cancer was detected on repeat biopsy in 39 of the 144 patients and in 19 on subset analysis of 86. Serum PSA levels at repeat biopsy did not differ significantly in patients with and without prostate cancer. According to receiver operating characteristics analysis the alpha1-antichymotrypsin-PSA complex adjusted for transition zone volume had the greatest area under the curve values, that is 0.756 for all 144 patients and 0.768 for the subset analysis of 86. Multiple logistic regression analysis of the subset of 86 patients showed that alpha1-antichymotrypsin-PSA complex adjusted for transition zone volume was the only significant independent predictor of cancer. CONCLUSIONS: alpha1-Antichymotrypsin-PSA complex adjusted for transition zone volume was the most powerful predictor of cancer in men who had undergone previous negative prostate biopsies. This parameter may be used to avoid more unnecessary repeat biopsies with an acceptable decrease in sensitivity.     

Effects of systematic 12-core biopsy on the performance of percent free prostate specific antigen for prostate cancer detection

PURPOSE: The performance characteristics of percent free (f) prostate specific antigen (PSA) for differentiating between benign prostatic hyperplasia and prostate cancer were originally established using primarily sextant biopsy. We determined whether the addition of 6 laterally directed cores to the traditional sextant prostate biopsy affects the performance of percent fPSA. MATERIALS AND METHODS: We retrospectively evaluated a cohort of 350 consecutive biopsies in men with negative digital rectal examinations and PSA between 4 and 10 ng/ml who underwent systematic 12 core biopsy (S12C) biopsy at Scott Department of Urology between March 1999 and January 2003. The effects of 6 additional, laterally directed biopsies on the sensitivity, specificity and area under the ROC curve for percent fPSA was evaluated in the 277 men in whom percent fPSA was measured. RESULTS: Cancers detected exclusively in the 6 laterally directed cores were associated with percent fPSA values similar to those in patients with a benign S12C biopsy. This resulted in a modest and yet predictable decrease in the sensitivity of percent fPSA at each biopsy threshold value without affecting specificity. There was a nonstatistically significant decrease in the area under the ROC curve with the addition of 6 laterally directed cores to sextant biopsy (medial sextant cores 0.66 vs S12C 0.60). CONCLUSIONS: The 12 core biopsy strategies have a higher cancer detection rate than sextant biopsies and they are gaining widespread acceptance. The addition of 6 laterally directed cores to traditional sextant biopsy may result in a modest decrease in the sensitivity of percent fPSA at each selected biopsy threshold without affecting specificity.     

Relationship among initial serum prostate specific antigen, prostate specific antigen progression and prostate cancer detection at repeat screening visits

PURPOSE: We evaluated the probability of positive serum PSA (3 ng/ml or greater) and CaP detection at annual followup visits in men with negative initial PSA (less than 3 ng/ml) to optimize the re-screening schedule. MATERIALS AND METHODS: Data on 5,387 men 45 to 80 years old with negative PSA and no CaP diagnosis at the first screening visit were obtained from the Laval University Prostate Cancer Screening Program database. Accelerated failure time regressions were fitted to time from baseline to positive PSA and to time from positive PSA to CaP detection. The models were combined to estimate the cumulative probability of positive PSA followed by CaP detection at re-screening. RESULTS: The 5-year cumulative probability of detecting CaP at annual visits in men with baseline PSA up to 1.5 ng/ml remained below 0.8%, while it was 1.3%, 4.8% and 8.3% in men with PSA 1.5 to less than 2, 2 to less than 2.5 and 2.5 to less than 3 ng/ml, respectively. Time to positive PSA significantly decreased with increasing baseline PSA and age, while the time between positive PSA and CaP detection depended only on age. Men with PSA below 1.0 ng/ml could wait for 4 to 5 years before being re-tested, while men with PSA between 1.0 and 1.5 ng/ml should be screened every second year and men with PSA 1.5 ng/ml or greater should be screened every year. CONCLUSIONS: The proposed retesting schedule using current PSA and age decreases the number of visits by 38.1%, while delaying the detection of only 2.4% of CaPs that would have been detected using annual PSA testing.     

Prostate cancer detection at low prostate specific antigen

PURPOSE: At low prostate specific antigen (PSA) the indication for prostate biopsy is usually an abnormal digital rectal examination. We evaluate the diagnostic value of PSA, digital rectal examination, transrectal ultrasonography and tumor characteristics at low PSA (0 to 4.0 ng./ml.). We confirm and add to recent evidence that digital rectal examination has a low predictive value and that many significant cancers at this PSA range may be missed. MATERIALS AND METHODS: From 1994 to 1997 a total of 10,523 participants 54 to 74 years old were randomized to screening in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer. Of the participants 9,211 (87.5%) had PSA less than 4.0 ng./ml., and underwent digital rectal examination and transrectal ultrasonography. Expected rates of prostate cancer detection were calculated using logistic regression analysis. Radical prostatectomy was performed in about half of the 478 men diagnosed with prostate cancer. Tumors were characterized by pT category, Gleason score and cancer volume in 166 processed radical prostatectomy specimens. In 50 of these cases PSA was 0 to 4.0 ng./ml. RESULTS: The positive predictive value of digital rectal examination and transrectal ultrasonography at PSA 0 to 4.0 ng./ml. was only 9.7%. Positive predictive value strongly depended on PSA. Sensitivity was calculated by using estimates of the prevalence of sextant biopsy detectable prostate cancers. Of 760 detectable cancers 478 (67%) were diagnosed irrespective of PSA in men screened with digital rectal examination, transrectal ultrasonography and PSA. Only 127 of 348 detectable prostate cancers (36.5%) were actually diagnosed in men with PSA 2 to 4 mg./ml. The importance of these missed cancers was evaluated with parameters of tumor aggressiveness within PSA ranges. CONCLUSIONS: Approximately half of the tumors missed with PSA 0 to 4 ng./ml. had aggressive characteristics (Gleason score 7 or greater, Gleason 4-5 components) and were organ confined. These tumors should be diagnosed and treated according to the present understanding of their natural history. More sensitive and selective screening strategies are needed. Presently a wrong "window of opportunity" is used for early detection of prostate cancer.     

Influence of prostate volume and percent free prostate specific antigen on prostate cancer detection in men with a total prostate specific antigen of 2.6 to 10.0 ng/ml

PURPOSE: Percent free prostate specific antigen and prostate specific antigen density have been independently shown to increase the specificity of prostate cancer screening in men with prostate specific antigen levels between 4.1 and 10.0 ng/ml. Recent data suggest the total prostate specific antigen cutoff for performing a biopsy should be 2.6 ng/ml. We assessed the influence of percent free prostate specific antigen and prostate volume on cancer detection in men with a prostate specific antigen between 2.6 and 10.0 ng/ml. MATERIALS AND METHODS: From 1991 to 2005 all transrectal ultrasound guided prostate biopsies (5,587) for abnormal digital rectal examination and/or increased age specific prostate specific antigen were evaluated. A total of 1,072 patients with a prostate specific antigen between 2.6 and 10.0 ng/ml and any percent free prostate specific antigen were included in study. The cancer detection rate was calculated for each percent free prostate specific antigen/volume stratum. RESULTS: Prostate cancer was detected in 296 patients (27.6%). The mean age and prostate specific antigen of the patients with benign pathology and prostate cancer were similar. Mean percent free prostate specific antigen was 17.5% and 14.1% (p>0.05), and the mean volume was 62.0 and 46.0 cc (p=0.001), respectively. The strongest risk factors for a positive biopsy were percent free prostate specific antigen (odds ratio 0.004, p<0.001), volume (OR 0.977, p<0.001) and digital rectal examination (OR 1.765, p=0.007), but not total prostate specific antigen (p=0.303). When stratified by volume and percent free prostate specific antigen, distinct risk groups were identified. The probability of detecting cancer inversely correlated with prostate volume and percent free prostate specific antigen. CONCLUSIONS: In men with prostate specific antigen levels between 2.6 and 10.0 ng/ml, the probability of detecting cancer was inversely proportional to prostate volume and percent free prostate specific antigen. This table may assist in predicting patient risk for harboring prostate cancer.     

Prostate-specific antigen adjusted for the transition zone volume versus free-to-total prostate-specific antigen ratio in predicting prostate cancer

BACKGROUND: We performed this study to assess the efficacy of prostate-specific antigen adjusted for the transition zone volume (PSATZ) and free-to-total prostate-specific antigen (PSA) ratio (F/T ratio) in predicting prostate cancer in men with intermediate PSA levels of 4.1-10.0 ng/mL. METHODS: Between March 1997 and September 1998, PSATZ was obtained from 67 patients who underwent ultrasonography guided systemic sextant biopsies and had a PSA of 4.1-10.0 ng/mL. PSATZ was compared with F/T ratio via receiver operating characteristic (ROC) curves. RESULTS: Of 67 patients, 22 (32.8%) had prostate cancer and 45 (67.2%) had benign prostatic hyperplasia (BPH) on pathologic examination. Mean PSA, PSA density, F/T ratio and PSATZ were 7.96+/-2.01ng/mL, 0.28+/-0.14 ng/mL/cc, 0.10+/-0.06 and 0.70+/-0.28 ng/mL/cc in patients with prostate cancer and 6.39+/-1.68 ng/mL, 0.16+/-0.06 ng/mL/cc, 0.15+/-0.05 and 0.29+/-0.10 ng/mL/cc in patients with BPH, respectively. The ROC curve analysis demonstrated that PSATZ predicted the biopsy outcome significantly better than F/T ratio in all 67 patients (P<0.01) and in a subset of 53 men with normal digital rectal examination (P<0.01). With a cut-off value of 0.35 ng/mL/cc, PSATZ had a sensitivity of 86% and a specificity of 89% for predicting prostate cancer. CONCLUSIONS: These results suggest that PSATZ and F/T ratio may be useful in diagnosing prostate cancer with intermediate levels of PSA. Prostate-specific antigen adjusted for the transition zone volume is more accurate than F/T ratio in distinguishing benign prostatic disease from prostate cancer. But large prospective studies are required to assess the precise role of PSATZ and F/T ratio in early prostate cancer detection.     

Prospective evaluation of prostate cancer detection by prostate specific antigen related parameters: comparison in serum and plasma samples.

PURPOSE: We compared the usefulness of serum and plasma samples for enhancing the specificity of prostate cancer detection. MATERIALS AND METHODS: We analyzed receiver operating characteristics curves to evaluate prospectively the cancer detection performance of prostate specific antigen (PSA) related parameters derived from serum and plasma samples in 248 and 249 consecutive patients, respectively. RESULTS: Receiver operating characteristics curve analysis showed that PSA density and transition zone PSA density were more powerful predictors of prostate cancer than total or free PSA in the group overall at intermediate serum PSA 2.1 to 10 ng./ml. and in the subgroup with total PSA 4.1 to 10 ng./ml. regardless of digital rectal examination findings. Percent free PSA performed significantly better than total PSA in patients with serum total PSA 4.1 to 10 ng./ml. PSA density, transition zone PSA density and percent free PSA did not differ substantially in patients with serum total PSA 4.1 to 10 ng./ml. However, none of these parameters distinguished patients with prostate cancer from those with benign histology when PSA was in the lower range of 2.1 to 4 ng./ml. The performance of these parameters was worse when plasma sample data were used for calculation. CONCLUSIONS: The performance of percent free PSA appears at least comparable to that of PSA density and transition zone PSA density in patients in this cohort with serum total PSA 4.1 to 10 ng./ml. without regard to digital rectal examination. The poor performance of these parameters in the lower PSA range underscores the need for other parameters to improve the specificity of cancer detection in elderly Japanese males. Continued use of serum samples is justified for measuring PSA related parameters by current assay techniques.     

Prostate specific antigen and human glandular kallikrein 2 in early detection of prostate cancer

PURPOSE: Several tumor markers have recently been applied for prostate cancer screening. We analyze the effectiveness of prostate specific antigen (PSA), age specific PSA, PSA velocity, volume adjusted PSA densities, change in PSA level following antibacterial therapy, free-to-total PSA ratio, alpha1-antichymotrypsin bound PSA, alpha2-macroglobulin bound PSA, alpha1-protease inhibitor bound PSA and human glandular kallikrein 2 in detecting prostate cancer. MATERIALS AND METHODS: We conducted a review of the literature between September 2000 and February 2001. A total of 7,250 abstracts and articles published during the previous 12 years were retrieved from MEDLINE using the key words PSA and human glandular kallikrein 2. Of these reports 135 are included in this review. RESULTS: We analyzed and systematized data from studies regarding the effectiveness of PSA and human glandular kallikrein 2 and their derivatives in the detection of prostate cancer. CONCLUSIONS: Improvement in the specificity and sensitivity of PSA is imperative. Free-to-total PSA ratio, transition zone PSA density and change in PSA level increase the specificity of PSA to some extent. Protocols investigating the effectiveness of different combinations of these 3 measurements seem necessary for improving the effectiveness of prostate cancer screening among men within the diagnostic "gray zone." PSA velocity, age adjusted PSA levels and PSA density might be used in limited cases. alpha1-Antichymotrypsin, alpha2-macroglobulin and alpha1-protease inhibitor bound PSA, and human glandular kallikrein 2 are promising experimental methods.     

Prostate specific antigen velocity threshold for predicting prostate cancer in young men

PURPOSE: Longitudinal changes in prostate specific antigen are increasingly used to guide the recommendation for biopsy. Prostate specific antigen velocity 0.75 ng/ml yearly has been proposed to distinguish prostate cancer from benign prostate conditions. However, this threshold might be too high in young men with lower total prostate specific antigen. MATERIALS AND METHODS: In a large prostate cancer screening study 6,844 men were 60 years or younger at study entry and prostate specific antigen velocity calculation was possible. Of these men 346 (5%) were subsequently diagnosed with prostate cancer and various prostate specific antigen velocity thresholds were examined for prediction of prostate cancer risk. Multivariate analysis was performed to determine whether prostate specific antigen velocity is an independent predictor of prostate cancer in men younger than 60 years. RESULTS: Median prostate specific antigen velocity was significantly higher in men who were later diagnosed with prostate cancer than in those who were not (0.840 vs 0.094 ng/ml yearly, p<0.0001). On multivariate analysis prostate specific antigen velocity greater than 0.4 ng/ml yearly was more predictive of prostate cancer than age, total prostate specific antigen, family history or race. Multivariate analysis in the subgroup of men with total prostate specific antigen less than 2.5 ng/ml had similar results. Overall a cutoff of 0.4 ng/ml yearly was associated with 67.3% sensitivity, 81.2% specificity, 16% positive predictive value and 98% negative predictive value for prostate cancer detection in young men. CONCLUSIONS: The traditional prostate specific antigen velocity threshold of 0.75 ng/ml yearly is too high for men younger than 60 years and it misses 48% of prostate cancers. Young men with prostate specific antigen velocity greater than 0.4 ng/ml yearly are at significantly greater risk for prostate cancer and close followup is warranted.     

Comparative analysis of complexed prostate specific antigen, free prostate specific antigen and their ratio in detecting prostate cancer

PURPOSE: We evaluate the diagnostic use of total, free and complexed serum prostate specific antigen (PSA), and their ratios for enhancing the specificity in detecting prostate cancer. MATERIALS AND METHODS: A total of 354 nonconsecutive men undergoing prostate biopsy were eligible for this retrospective and prospective study. Cancer was found in 122 of these 354 men (34%). Receiver operating characteristics curve analyses were used to calculate and compare the performance of total PSA (Hybritech, San Diego California and Bayer, Tarrytown, New York), complexed PSA (Bayer), percent complexed PSA and percent free PSA. In addition, sensitivity and specificity were calculated and compared. RESULTS: The area under the receiver operating characteristics curve was highest for percent free PSA, followed by percent complexed PSA, complexed PSA and the 2 total PSA assays (Hybritech and Bayer). The cutoff value of 3.45 ng./ml. for complexed PSA detected the same number of cancers and resulted in 1 additional false-positive case compared with a Hybritech total PSA threshold of 4.0 ng./ml. At sensitivities of 80% to 95%, there were no significant differences for detection comparing the corresponding specificities between Hybritech total PSA and complexed PSA for all 354 men. Complexed PSA alone did not enhance the overall diagnostic accuracy compared with percent free PSA in the Hybritech total PSA range between 4.01 and 6.00 ng./ml., between 6.01 and 10.00 ng./ml., and between 2.50 and 6.00 ng./ml. At sensitivities of 80% to 95% specificity of percent complexed PSA was almost identical to that of percent free PSA except for the Hybritech total PSA range less than or equal to 4.00 ng./ml. CONCLUSIONS: This study suggests complexed PSA is equivalent to total PSA for the early detection of prostate cancer. Percent free PSA outperforms complexed PSA and percent complexed PSA performed equivalently to percent free PSA in all total PSA ranges analyzed between 2.5 and 10 ng./ml.     

The incidence of prostate cancer in men with prostate specific antigen greater than 4.0 ng/ml: a randomized study of 6 versus 12 core transperineal prostate biopsy

PURPOSE: The prostate cancer detection rate in patients with elevated prostate specific antigen (PSA) increases with extended needle biopsy protocols. Transperineal biopsy under transrectal ultrasound guidance is rarely reported, although notable cancer diagnoses are obtained with this technique. We describe the results of 6 and 12 core transperineal biopsy. MATERIALS AND METHODS: A total of 214 patients with PSA greater than 4.0 ng/ml were prospectively randomized to undergo 6 or 12 core transperineal biopsy. Each group of 107 patients was comparable in terms of clinical characteristics. The procedure was performed on an outpatient basis using local anesthesia. Specimens were obtained with a fan technique with 2 puncture sites slightly above the rectum (1 per lobe) under transrectal ultrasound guidance. Cores were taken from all peripheral areas, including the far lateral aspect of the prostate. RESULTS: The overall cancer detection rate was 38% and 51% for 6 and 12 core biopsy, respectively. In patients with PSA between 4.1 and 10 ng/ml the cancer detection rate was 30% and 49% for 6 and 12 core biopsy, respectively. CONCLUSIONS: The 12 core transperineal prostate biopsy is superior to 6 core biopsy. The technique provides optimal prostate cancer diagnosis. About half of the patients with PSA greater than 4.0 ng/ml and a slightly lower percent with PSA between 4.1 and 10 ng/ml have prostate cancer.