Faculty Bibliography

OBJECTIVES: Controversy exists about the preferred treatment of patients with high-risk or locally advanced prostate cancer. We examined the intermediate-term cancer control and quality-of-life outcomes after radical retropubic prostatectomy (RRP) in selected patients. METHODS: From 1984 to 2003, 288 men with Stage cT2b (Gleason score 8 to 10 or a prostate-specific antigen level greater than 15 ng/mL) or T3 disease underwent RRP by a single surgeon. The 7 and 10-year actuarial progression-free survival (PFS), cancer-specific survival (CSS), overall survival (OS), potency, and continence rates were recorded. RESULTS: The actuarial 7-year PFS, CSS, and OS rate after surgery was 39%, 92%, and 91%, respectively. The corresponding actuarial 10-year rates were 35%, 88%, and 74%. Only OS differed significantly by age group. On multivariate analysis, the pathologic stage was a significant independent predictor of progression. Ultimately, 31 men (11%) required hormonal therapy, 58 (20%) underwent postoperative radiotherapy, and 67 (23%) received both. Potency and continence were preserved in 64% and 92%, respectively. CONCLUSIONS: Overall, RRP offers excellent intermediate-term cancer control for selected men of all ages who present with high-risk or locally advanced disease. The PFS was significantly greater for men with high-risk Stage cT2b than for those with cT3 disease, but the CSS and OS were similar. Both continence and potency were preserved in most patients, although the potency rates were significantly greater for the younger men. RRP with appropriate postoperative radiotherapy and/or hormonal therapy is a reasonable treatment option for selected men with high-risk or locally advanced disease.

OBJECTIVES: Numerous commercial assays are available for measuring total and free prostate-specific antigen (PSA) levels in serum. These assays can be referenced to different laboratory standards, and interassay variability occurs. Patients and physicians might be affected by the variability between PSA assays that results from the use of different PSA standards. METHODS: We prospectively compared the free and total PSA measurements obtained using two commercially available PSA assays in 103 participants from a prostate cancer screening program in Caracas, Venezuela. We recommended biopsy to men with a total PSA level of 3 to 10 ng/mL and a free/total PSA ratio of 20% or less with either assay. We compared the sensitivity, specificity, and concordance index between the two assays to assess the effects of interassay variability on the cancer detection rate and clinical outcomes. RESULTS: Although the total PSA results were similar between the assays, the free PSA level was significantly greater with one assay. Therefore, the free/total PSA ratio was discordant between the two assays, resulting in different biopsy recommendations and cancer detection rates. CONCLUSIONS: Using a free/total PSA ratio of 20% or less as the threshold for biopsy, the differences in assay sensitivity and specificity for detecting prostate cancer are significant. Commercially available assays for PSA and its derivatives are not necessarily interchangeable, and these differences might lead to different clinical outcomes. When using free and total PSA measurements to make clinical decisions, patients and physicians should be aware of the potential standardization bias and which assay is being used.

High-intensity focused ultrasound (HIFU) has emerged in the past decade as a new addition to the armamentarium of treatment options for prostate cancer. Clinical studies have investigated its use as a treatment for clinically localized disease and as salvage therapy in the setting of failure after external beam radiotherapy. Additional studies with long-term follow-up are needed to further evaluate the cancer control and quality of life outcomes of this new therapeutic modality.

PURPOSE: We previously reported that the median prostate specific antigen for men 40 to 49 years old is 0.7 ng/ml and that a baseline prostate specific antigen between 0.7 and 2.5 ng/ml is associated with a 14.6-fold increased risk of prostate cancer. Although this suggests the need for close followup of men in their 40s with a prostate specific antigen level greater than 0.7 ng/ml, the appropriate screening strategy for men with a level less than the age specific median is unclear. MATERIALS AND METHODS: From a large prostate cancer screening study 581 participants 40 to 49 years old with a baseline prostate specific antigen level less than 0.7 ng/ml were identified. All men were classified as high risk due to a positive family history and/or black heritage. Changes in prostate specific antigen over time, the cancer detection rate and pathological tumor features were examined as a function of the baseline prostate specific antigen. RESULTS: At a median followup of 13 months 2 patients with an initial prostate specific antigen level less than 0.7 ng/ml reached the threshold for biopsy, and a single patient was diagnosed with prostate cancer. A significantly greater proportion of men with a baseline prostate specific antigen level greater than the age specific median had a prostate specific antigen velocity greater than 0.75 ng/ml per year (9% vs 3%, p=0.009) and were diagnosed with prostate cancer before age 50 (4.6% vs 0.16%, p<0.0001). CONCLUSIONS: Men 40 to 49 years old with a prostate specific antigen less than the age specific median have a low risk of prostate cancer in the short term. Performing a baseline prostate specific antigen measurement in the fifth decade led to few additional biopsies, and was extremely useful for risk stratification since men with levels greater or less than the age specific median had strikingly different risk profiles.

Currently, in the United States (US), most prostate cancers are diagnosed through screening with digital rectal examination (DRE) and measurement of serum prostate-specific antigen (PSA). The serum PSA level correlates directly with prostate cancer risk and aggressiveness, as well as the outcomes after treatment. PSA testing is also useful in monitoring patients for tumor recurrence after treatment. PSA testing has limited specificity for prostate cancer detection, and its appropriate clinical application has been the topic of debate. Accordingly, several variations on the PSA measurement have emerged as useful adjuncts for prostate cancer screening. These take into consideration additional factors, such as the proportion of different PSA isoforms (free PSA, complexed PSA, pro-PSA and B PSA), the prostate volume (PSA density), and the rate of change in PSA levels over time (PSA velocity or PSA doubling time). Widespread PSA screening is associated with a 75% reduction in the proportion of men who present with metastatic disease since 1985-89 in the US and a 32.5% reduction in the age-adjusted prostate cancer mortality rate through 2003. The history and evidence underlying each of these parameters are reviewed in the following article.

PURPOSE: It has been previously demonstrated that a prostate specific antigen velocity greater than 2 ng/ml per year is associated with reduced cancer specific survival following radical prostatectomy or external beam radiation. However, men with different initial prostate specific antigen levels may be more or less likely to reach this prostate specific antigen velocity threshold. Because prostate specific antigen and prostate specific antigen velocity contain much of the same predictive information, our objective was to further examine the relationship between them. MATERIALS AND METHODS: From a large prostate cancer screening study, serial prostate specific antigen measurements were available for 13,276 men, including 1,851 with a negative digital rectal examination who underwent biopsy and 894 who were diagnosed with prostate cancer. Prostate specific antigen velocity was calculated using simple linear regression of the prostate specific antigen values from the year before diagnosis. ANOVA and the Kruskal-Wallis test were used to compare the mean and median prostate specific antigen velocity of men in different total prostate specific antigen ranges. In addition, chi-square analysis was used to compare the number of men in each total prostate specific antigen range who presented with high risk prostate specific antigen velocity greater than 2 ng/ml per year. RESULTS: In the total prostate specific antigen ranges of 2.5 ng/ml or less, 2.6 to 4.0, 4.1 to 10.0 and more than 10.0 ng/ml, the proportion of screened men with a prostate specific antigen velocity of more than 2 ng/ml per year was 1%, 14%, 31% and 74%, respectively (p <0.0001). Mean and median prostate specific antigen velocity were also significantly higher as the total prostate specific antigen level increased. CONCLUSIONS: Prostate specific antigen velocity varies directly with total prostate specific antigen. Men with high initial prostate specific antigen levels are significantly more likely to present with a prostate specific antigen velocity of more than 2 ng/ml per year that is more frequently associated with prostate cancer specific mortality.

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.