Prostate specific antigen kinetics at tumor recurrence after radical prostatectomy do not suggest a worse disease prognosis in black men

PURPOSE: It has been shown that black men with clinically localized prostate adenocarcinoma treated with radical prostatectomy have poorer disease-free and disease specific survival than white men with similar tumors. These findings suggest that a potentially more aggressive variant of prostate cancer exists in black men. Because prostate specific antigen (PSA) velocity at tumor recurrence is a good indicator of disease aggressiveness, we determine whether there was evidence that PSA velocity at biochemical recurrence after radical prostatectomy is faster in black men. MATERIALS AND METHODS: Our retrospective data search at 2 university centers resulted in 127 white and 37 black men with clinical stage cT1 to 2 prostate adenocarcinoma who underwent radical prostatectomy between 1990 and 1994 and had evidence of biochemical recurrence (PSA greater than 0.2 ng./ml.) on followup available for analysis. No neoadjuvant or adjuvant treatments were given before or after radical prostatectomy, and all PSA relapses and subsequent treatments were recorded. PSA velocity modeling was performed in patients before any form of treatment for PSA failure. Preoperative PSA, Gleason score and pathological stage were also included in the model to assess the impact on PSA velocity after recurrence. RESULTS: Our data suggested that PSA velocity at tumor recurrence was related to preoperative PSA on a continuous scale (p = 0.063). However, in our analysis there was little evidence that race had any effect on PSA velocity at tumor recurrence in our patient cohort (p = 0.58). Likewise, little difference in PSA velocity was seen in regard to Gleason score (p = 0.89) or pathological stage (p = 0.23) in these patients. With data on 37 black men available for analysis it was likely that only large or extreme trends could be detected. Results could be used to estimate required sample sizes for assessment of less extreme trends. CONCLUSIONS: Our data on tumor growth rate at recurrence, as reflected by PSA velocity kinetics, do not support the hypothesis that prostate tumors in black men are necessarily more aggressive due to enhanced growth. Further studies comparing the molecular and biological differences between prostate cancers in black and white males are needed to clarify reasons for the apparent differences in initial presentation, as compared to that at tumor recurrence in these 2 groups.     

The relationship between serum prostate specific antigen level and tumor volume persists in the current era

PURPOSE: We compared the relationships of serum prostate specific antigen to tumor volume and to noncancerous prostate tissue volume using multivariate analysis in men undergoing prostatectomy during 2 periods. MATERIALS AND METHODS: From our prostatectomy database we randomly selected 200 men from 1991 to 1994 (early group) and 200 from 2000 to 2003 (recent group) who underwent radical prostatectomy without neoadjuvant therapy. The variables analyzed were patient age, log prostate specific antigen, pathological stage, Gleason score, log total tumor volume and log noncancerous prostate tissue volume. Univariate correlation and multiple regression analyses were performed to assess the linearity of the relationships among the variables. RESULTS: There was a significant difference between the early and recent groups in age (median 64 years, IQR 58-67 vs 59, IQR 53-65; p<0.001), prostate specific antigen (8.3 ng/ml, IQR 5.7-12.5 vs 5.8, IQR 4.4-7.8; p<0.001), total tumor volume (2.0 cc, IQR 1.0-3.6 vs 1.4, IQR 0.6-2.9; p<0.001), Gleason score (7, IQR 7-8 vs 7, IQR 7-7; p<0.001) and the incidence of extraprostatic disease (39% vs 18.5%, p<0.001) but not in noncancerous prostate tissue volume (35.7 cc, IQR 28.6-46.5 vs 37.1, IQR 28.9-50.1). There was a relationship between log prostate specific antigen and log total tumor volume (r=0.486, p<0.001 and r=0.237, p<0.01), and between log prostate specific antigen and log noncancerous prostate tissue volume (r=0.179, p<0.05 and r=0.138, p=0.051) in the early and the recent groups, respectively. Multiple regression analyses revealed that log total tumor volume, log noncancerous prostate tissue volume and Gleason score were significant independent variables for predicting log prostate specific antigen in the 2 groups. In the recent group log noncancerous prostate tissue volume had the most significant association with log prostate specific antigen (p<0.001), whereas in the early group log total tumor volume had the most significant association (p<0.001). CONCLUSIONS: Although the relationship between serum prostate specific antigen and tumor volume decreased from early treatment years to recent years, the association remained at a significant level. In recent years noncancerous prostate tissue volume had the most significant association with prostate specific antigen.     

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.     

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.     

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 transition zone epithelial volume: the powerful predictor for the detection of prostate cancer on repeat biopsy

PURPOSE: The indications for repeat prostate biopsy for persistently increased prostate specific antigen (PSA) in men with prostate cancer never detected on previous biopsy are not clear. In this study we determined that PSA adjusted for transition zone (TZ) epithelial volume is the most powerful predictor for detecting prostate cancer on repeat biopsy. MATERIALS AND METHODS: Repeat prostate biopsies including additional TZ cores were performed in 75 men with PSA between 4.0 and 10.0 ng/ml. TZ epithelial volume was calculated by multiplying TZ volume by the percent of epithelium, which was measured by morphometric analysis using image analysis computer software. RESULTS: Prostate cancer was detected on repeat biopsy in 19 of the 75 patients. Patients with prostate cancer had a significant smaller percent area of epithelium or glandular lumen than those without cancer. In patients without prostate cancer TZ epithelial volume significantly correlated with total PSA. According to ROC analysis PSA adjusted for TZ epithelial volume had the greatest AUC for cancer detection (0.879). This parameter was able to avoid more than 90% of unnecessary repeat biopsies with 90% sensitivity. Multiple logistic regression analysis showed that PSA complex adjusted for TZ epithelial volume was the significant independent predictor of cancer. CONCLUSIONS: PSA adjusted for TZ epithelial volume is the most powerful predictor of cancer in men who have undergone previous negative prostate biopsies and in whom PSA remains between 4.0 and 10.0 ng/ml.     

Time to achieve a prostate specific antigen nadir of 0.2 ng./ml. after simultaneous irradiation for prostate cancer

PURPOSE: A prostate specific antigen (PSA) cutoff point of 0.2 ng./ml. has been suggested as the standard definition of disease freedom for curative treatment of localized prostate cancer. The time to achieve this goal after irradiation was determined in this study. MATERIALS AND METHODS: From August 1992 to December 1996, 539 consecutive men with clinical stage T1T2NX prostate cancer who had a minimum 5-year PSA followup and achieved a PSA nadir of 0.2 ng./ml. without hormones were evaluated. All patients were treated with simultaneous irradiation with a transperineal prostate iodine implant, followed by external beam irradiation. Time to achieve a PSA of 0.2 ng./ml. was retrospectively calculated from the date of implantation in all men and according to various factors. Recurrence was defined as a subsequent increase above a PSA of 0.2 ng./ml. Minimum followup was 5 years (median 6.5, range 5 to 9). RESULTS: In all 539 men the median time to a PSA nadir of 0.2 ng./ml. was 27 months, while 534 (99%) achieved this level by 60 months of followup. Median time to achieve this PSA goal was 20 and 39 months in patients without and with a PSA bounce, respectively. Pretreatment PSA, disease status and ultimately PSA bounce, Gleason score and stage had little or no effect on time to a PSA of 0.2 ng./ml. CONCLUSIONS: With rare exceptions to be potentially cured of prostate cancer by simultaneous irradiation men must achieve a PSA nadir of 0.2 ng./ml. within 5 years of implantation. Failure to reach this goal by 60 months of followup almost always indicates persistent disease.     

Pretreatment predictors of time to cancer specific death after prostate specific antigen failure

PURPOSE: Whether pretreatment factors that predict for time to prostate specific antigen (PSA) failure also predict for time to prostate cancer specific death after PSA failure for patients with competing causes of mortality treated during the PSA era was the subject of this study. MATERIALS AND METHODS: Of 415 men with a median age of 73 years who underwent external beam radiation therapy between 1988 and 2001 for clinically localized prostate cancer 160 (39%) experienced PSA failure and 96 (23%) died. In 46 men (48%) the cause of death was prostate cancer. Cox regression multivariable analyses (multivariable analysis) were performed to evaluate the ability of the pretreatment PSA and centrally reviewed biopsy Gleason score to predict time to prostate cancer specific death after PSA failure. RESULTS: When analyzed as categorical variables using multivariable analysis, biopsy Gleason score 4 + 3 (p = 0.02), 8 to 10 (p = 0.02) disease and a pretreatment PSA greater than 20 ng./ml. (p = 0.03) were significant predictors of time to prostate cancer specific death after PSA failure. Estimates of prostate cancer specific death 5 years after PSA failure were 24%, 40% and 59% (p = 0.01) for patients with a biopsy Gleason score < or = 6, 3 + 4, 4 + 3 or higher and 22%, 40% and 60% (p = 0.04) for patients with a pretreatment PSA of 10 or less, greater than 10 and 20 or less, or greater than 20 ng./ml., respectively. CONCLUSIONS: Patients at high risk for PSA failure after radiation therapy based on pretreatment PSA greater than 20 ng./ml. or biopsy Gleason score 4 + 3 or greater are also at high risk for death from prostate cancer after PSA failure despite competing causes of mortality.     

A validated strategy for side specific prediction of organ confined prostate cancer: a tool to select for nerve sparing radical prostatectomy

PURPOSE: Nerve sparing radical prostatectomy for prostate cancer should be restricted to patients who harbor tumors without capsular penetration. To our knowledge the selection criteria for nerve sparing radical prostatectomy are not clearly defined. We investigated a panel of preoperative tumor characteristics with respect to their ability to predict organ confined tumor growth for each lobe of the prostate to indicate unilateral or bilateral nerve sparing radical prostatectomy. MATERIALS AND METHODS: Nine preoperative tumor characteristics in 278 patients with clinically localized prostate cancer were included in retrospective univariate and multivariate tree structured regression analysis. The association of clinical stage, serum prostate specific antigen (PSA), PSA density, and results of transrectal ultrasound and systematic sextant biopsy, including a quantitative assessment of cancer in the biopsies with organ confined tumor growth, was statistically evaluated. Except for serum PSA and PSA density preoperative characteristics were considered separately for each prostate lobe. Multivariate analysis results were validated prospectively in 353 patients. RESULTS: On univariate analysis the number of positive biopsies was the most useful single parameter with a positive predictive value of 83% in 274 lobes and a negative predictive value of 55%, followed by mm. of tumor in the biopsy. Of all characteristics included in multivariate analysis only the number of biopsies with high grade cancer, the number of positive biopsies and serum PSA were independent for predicting organ confined cancer. When PSA was less than 10 ng./ml. and not more than 1 biopsy with high grade cancer was identified in a lobe, organ confined tumor growth was present in 86.1% of cases. On prospective validation the same criteria led to an 88.5% incidence of organ confined prostate cancer. Pooling the 2 most favorable groups led to 391 prostate lobes (70.8% of those investigated) with a positive predictive value of 82.1% (95% confidence interval 77.9% to 85.8%). Using the multivariate approach more prostate lobes were assigned to a favorable risk group than on univariate analysis. Clinical stage and simple Gleason grade did not contribute independent information for predicting organ confined disease. CONCLUSIONS: Quantifying cancer and high grade cancer by systematic biopsy and serum PSA concentration are useful preoperative characteristics for predicting organ confined prostate cancer. Side specific analysis of these parameters is a flexible and reliable tool for selecting patients for nerve sparing radical prostatectomy.     

Ratio of free-to-total prostate specific antigen correlates with tumor volume in patients with increased prostate specific antigen

PURPOSE: We evaluated the relationship between the ratio of free-to-total prostate specific antigen (PSA) and prostate pathology, including grade, stage and tumor volume, among patients with prostate cancer who underwent radical prostatectomy. MATERIALS AND METHODS: We prospectively analyzed 54 consecutive patients with prostate cancer who underwent radical prostatectomy and in whom frozen serum was available for assessment of free-to-total PSA ratio. Pathological review was done with whole mount sections, and total tumor volume was determined by planimetry. Comparison between free-to-total PSA ratio and pathological parameters was performed using the Pearson correlation coefficient. RESULTS: Among the 54 patients mean total and free-to-total PSA ratio were 5.81 and 14.2 ng./ml., respectively, and free-to-total PSA ratio directly correlated with prostate volume (p = 0.037), and inversely correlated with Gleason score (p = 0.012) and extracapsular disease (p = 0.0074). Furthermore, there was a significant relationship between free-to-total PSA ratio and pathological stage pT2a/b in 39 cases versus pT3a/b in 15 (p = 0.005). Overall, there was no correlation between free-to-total PSA ratio and tumor volume. However, among 37 patients with an increased PSA, defined as greater than 4.0 ng./ml., a significant inverse relationship between free-to-total PSA ratio and tumor volume was identified (p = 0.01). Among this subset there was only a weak correlation with prostate volume (p = 0.049). CONCLUSIONS: Our findings suggest that free-to-total PSA ratio may be predictive of tumor biology among those patients with a total PSA of greater than 4 ng./ml. as evidenced by good correlation with tumor grade and volume. This finding appears to be independent of prostate volume. These preliminary results suggest the need for additional studies among patients with an increased PSA designed to evaluate the potential role of free-to-total PSA ratio in combination with traditional clinical variables in the prediction of prostate cancer pathology.     

Making sense of prostate specific antigen: improving its predictive value in patients undergoing prostate biopsy

PURPOSE: The clinical usefulness of PSA for prostate cancer screening is unclear, although the test remains in common use. New methods to interpret PSA are needed. MATERIALS AND METHODS: We examined a cohort of 2,637 men who underwent prostate biopsies for abnormal DRE or PSA between 1999 and 2004. Using risk factors for prostate cancer, including patient age, ethnicity, family history of prostate cancer, previous negative biopsy, voiding symptoms and prostate volume, we developed risk groups for prostate cancer using recursive partitioning modeling independent of PSA or DRE. We then compared prostate cancer probabilities by PSA ranges by risk group. RESULTS: Of the 2,637 men 1,282 (48.6%) had prostate cancer. Age, ethnicity, family history, previous negative biopsy and prostate volume were predictive for cancer. We constructed 6 risk groups by combining these factors and created tables to assign patients to these groups. Independent of PSA and DRE the probability of cancer ranged from 15% in patients in group 1 to 78% in patients in group 6 (p <0.0001). By adding PSA and DRE to each risk group prostate cancer probabilities were refined from 0% to 100%. Patients in the higher risk groups also had higher grade cancer (p <0.0001). CONCLUSIONS: We generated 6 risk groups based on simple risk factors for prostate cancer. When used in the right context and patient, PSA is highly accurate for predicting prostate cancer and permitting rational decision making in patients with abnormal PSA.     

Prostate specific antigen testing and digital rectal examination before and during a randomized trial of screening for prostate cancer: European randomized study of screening for prostate cancer, Rotterdam

PURPOSE: Worldwide 2 large-scale randomized screening trials for prostate cancer have been initiated. Determining prostate specific antigen (PSA) involves a simple test that may influence the outcome of these trials if frequently done in the control arm or before study enrollment. We quantified PSA and digital rectal examination before and during the screening trial in Rotterdam, The Netherlands and in the general population. MATERIALS AND METHODS: Trial participants were administered study intake questionnaires on tests done before study participation. Data on PSA from the regional general practice laboratory were correlated with participant data. Various sources were used to quantify PSA tests and digital rectal examinations in the general population. RESULTS: Of men 55 to 74 years old 45% underwent digital rectal examination at 1 time and 13% reported that PSA was tested before trial participation. Each rate increased with age. No statistically significant effect of former PSA testing or digital rectal examination on the cancer detection rate was identified. The rate of PSA determination after initial screening and/or randomization in the control arm was 2-fold that in the screening arm (76 versus 33/1,000 person-years). PSA determination initially decreased in the screening arm but increased rapidly after some time. The number of PSA determinations in the general population was estimated to be 45/1,000 person-years at ages 55 to 69 years. CONCLUSIONS: PSA testing was moderate in the control arm but if different men undergo this test each year, the contamination rate may become rather high. In the final analysis of mortality PSA testing should be considered.     

4-year prostate specific antigen progression and diagnosis of prostate cancer in the European Randomized Study of Screening for Prostate Cancer, section Rotterdam

PURPOSE: The European Randomized Study of Screening for Prostate Cancer investigates the impact of screening on prostate cancer mortality and contributes to a better understanding of available screening tests. The present study evaluates the predictive value of a prostate specific antigen (PSA) increase to PSA 3.0 ng/ml or greater in a 4-year period in men who present with low PSA values (less than 3.0 ng/ml) at first screen. MATERIALS AND METHODS: A total of 42,376 men were randomized to screening vs control in Rotterdam. Of 6,467 men 5,771 had PSA values of less than 3.0 ng/ml, did not undergo biopsy at baseline and were rescreened after 4 years with PSA 3.0 ng/ml or greater as biopsy indication. PSA progression in a 4-year interscreening interval is evaluated by determining the positive predictive values, detection rates and parameters of aggressiveness of round 2 cancers. RESULTS: PSA progression to more than 3.0 ng/ml occurred in 0.9%, 9.3% and 48.6% of men who presented with PSA values less than 1.0, 1 to 1.9 and 2 to 2.9 ng/ml, respectively, in round 1. Their respective positive predictive values amounted to 19.0%, 23.8% and 27.9%. Cancer detection rates increased with increasing PSA values in round 1. The distribution of low, moderate and high risk cancers depends on round 2 but not on round 1 PSA ranges. CONCLUSIONS: PSA progression to the (arbitrary) cutoff value of 3.0 ng/ml and the diagnosis of prostate cancer in round 2 screening with a 4-year interval depends strongly on PSA values at the time of the 1st screen. These observations will be helpful to design future screening procedures. With levels less than 2.0 ng/ml PSA progression to levels of 3.0 ng/ml or greater is rare as it was seen only in 4.8% of all men.     

Strategies combining total and percent free prostate specific antigen for detecting prostate cancer: a prospective evaluation

PURPOSE: Determining total prostate specific antigen (PSA) in plasma can often identify men who are subsequently diagnosed with prostate cancer. However, excess false-positives create large financial and psychological burdens in prostate cancer screening. The percent free PSA is lower when prostate cancer is present, although to our knowledge no large prospective analyses to date have evaluated whether adding testing for free PSA may decrease false-positives, while maintaining or perhaps improving the detection of potentially curable tumors. MATERIALS AND METHODS: We measured total and percent free PSA in banked plasma samples from the Physicians' Health Study in 430 men who were later diagnosed with prostate cancer and 1,642 age matched controls who were not diagnosed with prostate cancer during a 12-year observation period. We calculated the number of cancers detected and the number of false-positives for various strategies of combined free and total PSA levels, and compared them to the use of total PSA alone. RESULTS: Total PSA with a cutoff of 4 ng./ml. detected 149 cases but also yielded 144 false-positives. A strategy that applied percent free PSA to men with total PSA 4 to 10 ng./ml. detected 133 to 140 cancers and decreased false-positives to 83 of 117 depending on the percent free PSA cutoff used. As the percent free PSA cutoff was lowered from 25% to 20%, additional undetected cancers did not occur until year 9 of followup and the 20% cutoff decreased false-positives and, thus, potential negative biopsies, by 42%. Percent free PSA was superior to total PSA for discriminating cases from controls within the total PSA range of 4 to 10 or 3 to 10 ng./ml. (p <0.0001). A percent free PSA cutoff of 20% in men with total PSA 3 to 10 ng./ml. detected 10% more cancers with 12.5% fewer false-positives than the conventional strategy of total PSA greater than 4 ng./ml. Cancers missed by combined total and free PSA testing had longer intervals between blood sampling and diagnosis, and a greater likelihood of later diagnosis at an organ confined stage. CONCLUSIONS: These results demonstrate that in a prospective setting with long-term followup free PSA strategies can be identified that decrease unnecessary biopsies, while preserving or even improving cancer detection. Thus, total and free PSA can be combined without the need to weigh subjectively the trade-offs and relative costs of false-negative and false-positive results.     

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.     

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.     

Conservative management of prostate cancer in the prostate specific antigen era: the incidence and time course of subsequent therapy

PURPOSE: The long natural history of early stage prostate cancer is well recognized and a conservative approach to the treatment of elderly men is often encouraged. We assessed the ability of patients and physicians to adhere to a policy of watchful waiting in the prostate specific antigen (PSA) era. MATERIALS AND METHODS: We retrospectively reviewed the records of all 199 men with stages T1-2 prostate cancer and PSA less than 20 ng./ml. who in our practice elected watchful waiting. Median followup in the population overall was 3.4 years. We performed Kaplan-Meier actuarial analysis of overall and disease specific survival, and most pertinent survival free from therapy. A questionnaire was administered to record the attitude of patients who ultimately proceeded to treatment to determine how therapy was triggered. RESULTS: Median patient age was 71 years and median PSA was 6.6 ng./ml. The tumor was impalpable in 52% of patients, Gleason sum was 6 or less in 80% and 11% used some form of herbal remedy or nutritional supplementation. Of the 37 men who died during observation, including 35 of co-morbid illness, only 6 underwent treatment. Overall survival at 5 and 7 years was 77% and 63% but disease specific survival was 98% and 98%, respectively. A total of 64 patients underwent treatment and actuarial freedom from treatment was 56% at 5 years, including 51% and 73% in those younger and older than 75 years at diagnosis. The likelihood of being alive and free from treatment was 43% at 5 years and 26% at 7. Of the 63 men treated 48 (76%) underwent radical therapy (brachytherapy in 17, external beam radiotherapy in 29 and prostatectomy in 2), while only 24% received androgen deprivation. The median PSA increase from diagnosis to treatment in treated patients was 2.9 ng./ml., and it was 0.9 ng./ml. from diagnosis to the last followup in those not treated. Of the treated patients 81% believed that the physician had initiated therapy due to a PSA increase or a nodule. However, physicians recorded having advocated treatment in only 24% of cases. CONCLUSIONS: When patients do not die of co-morbid illness, they are likely to proceed to therapy well within the first decade after diagnosis (57% by 5 years and 74% by 7). Therapy was usually definitive (radical) and triggered by slight, inevitable PSA increases. The patient perception was that the physicians initiated therapy in response to increasing PSA. However, the physicians more often perceived that treatment was initiated by patients. Therefore, watchful waiting in the PSA era often represents radical therapy delayed by a few years.