Anna Kettermann

Prostate-Specific Antigen Kinetics During Follow-Up Are an Unreliable Trigger for Intervention in a Prostate Cancer Surveillance Program

PURPOSE To assess the predictive ability of prostate-specific antigen (PSA) velocity (PSAV) and doubling time (PSADT) for biopsy progression and adverse pathology at prostatectomy among men with low-risk prostate cancer enrolled on an active-surveillance program. METHODS We evaluated 290 men who met criteria for active surveillance (ie, PSA density < 0.15 ng/mL/cm(3) and Gleason score < or = 6 with no pattern > or = 4, involving < or = 2 cores with cancer, and < or = 50% involvement of any core by cancer) with two or more serial PSA measurements after diagnosis from 1994 to 2008. Follow-up included twice-yearly digital rectal exam and PSA measurements and yearly surveillance biopsy. Treatment was recommended for biopsy progression (ie, Gleason score > or = 7, or > 2 positive cores, or > 50% core involvement). Sensitivity and specificity of postdiagnostic PSAV and PSADT were explored by using receiver operating characteristic (ROC) analysis. RESULTS Overall, 188 (65%) men remained on active surveillance, and 102 (35%) developed biopsy progression at a median follow-up of 2.9 years. PSADT was not significantly associated with subsequent adverse biopsy findings (P = .83), and PSAV was marginally significant (P = .06). No PSAV or PSADT cut point had both high sensitivity and specificity (area under the curve, 0.61 and 0.59, respectively) for biopsy progression. In those who eventually underwent radical prostatectomy, PSAV (P = .79) and PSADT (P = .87) were not associated with the presence of unfavorable surgical pathology. CONCLUSION Postdiagnostic PSA kinetics do not reliably predict adverse pathology and should not be used to replace annual surveillance biopsy for monitoring men on active surveillance.

Accuracy of PCA3 Measurement in Predicting Short-Term Biopsy Progression in an Active Surveillance Program

PURPOSE PCA3 is a prostate specific noncoding mRNA that is significantly over expressed in prostate cancer tissue. Urinary PCA3 levels have been associated with prostate cancer grade and extent, suggesting a possible role in monitoring patients on active surveillance. We assessed the relationship between PCA3 and prostate biopsy results in men in a surveillance program. MATERIALS AND METHODS Urine specimens were obtained from 294 men with prostate cancer enrolled in the Johns Hopkins surveillance program. The followup protocol included semiannual free and total prostate specific antigen measurements, digital rectal examination and annual surveillance prostate biopsy. Cox proportional hazards regression was used to evaluate the association between PCA3 results and progression on surveillance biopsy (defined as Gleason pattern 4 or 5, more than 2 positive biopsy cores or more than 50% involvement of any core with cancer). RESULTS Patients with progression on biopsy (12.9%) had a mean PCA3 score similar to that of those without progression (60.0 vs 50.8, p = 0.131). ROC analysis suggested that PCA3 alone could not be used to identify men with progression on biopsy (AUC 0.589, 95% CI 0.496-0.683, p = 0.076). After adjustment for age and date of diagnosis PCA3 was not significantly associated with progression on biopsy (p = 0.15). CONCLUSIONS In men with low risk prostate cancer who were carefully selected for surveillance the PCA3 score was not significantly associated with short-term biopsy progression. Further analysis is necessary to assess the usefulness of PCA3 in combination with other biomarkers or in selected subsets of patients undergoing surveillance.

Prostate Specific Antigen Testing Among the Elderly—When To Stop?

PURPOSE Prostate specific antigen testing is common in the elderly despite evidence that older men without aggressive prostate cancer are unlikely to benefit from diagnosis and treatment. We evaluated the relationship between prostate specific antigen and the risk of aggressive prostate cancer developing in men of various ages. MATERIALS AND METHODS This longitudinal cohort study consisted of 849 men (122 with and 727 without prostate cancer) with serial prostate specific antigen measurements participating in the Baltimore Longitudinal Study of Aging. The primary outcome measure was the proportion of men by prostate specific antigen and age who died of prostate cancer or in whom aggressive prostate cancer developed (death from prostate cancer, a prostate specific antigen 20 ng/ml or greater, or Gleason score 8 or greater). RESULTS No participants between 75 and 80 years old with a prostate specific antigen less than 3.0 ng/ml died of prostate cancer. In contrast, men of all ages with a prostate specific antigen of 3.0 ng/ml or greater had a continually increasing probability of death from prostate cancer (Fishers exact test p <0.001). The time to death or diagnosis of aggressive prostate cancer after age 75 years was not significantly different between the prostate specific antigen categories of 3 to 3.9 and 4 to 9.9 ng/ml (p = 0.634), whereas the time to death or diagnosis of high risk prostate cancer was significantly longer for the prostate specific antigen category of less than 3 vs 3 ng/ml or greater (p = 0.019). CONCLUSIONS Men 75 to 80 years old with a prostate specific antigen less than 3 ng/ml are unlikely to die of or experience aggressive prostate cancer during their remaining life, suggesting that prostate specific antigen testing might be safely discontinued for these men.

Serum testosterone is associated with aggressive prostate cancer in older men: results from the Baltimore Longitudinal Study of Aging

Study Type – Prognosis (inception cohort)
Level of Evidence 1b

Prostate Volume Changes Over Time: Results From the Baltimore Longitudinal Study of Aging

PURPOSE According to a 1944 publication by Swyer benign prostatic hyperplasia develops in some men after age 45 with further prostatic growth whereas in other men prostate size remains stable or decreases with advancing age. Although there is an abundance of literature describing prostatic enlargement in association with benign prostatic hyperplasia, less is known about the phenomenon of prostate atrophy. MATERIALS AND METHODS In the Baltimore Longitudinal Study of Aging serial pelvic magnetic resonance imaging was performed in men without prostate cancer beginning in 1993. From this population we retrospectively identified 278 men with 2 or more magnetic resonance imaging determined prostate volume measurements to examine differential growth rates in a cohort of community men over time. RESULTS Median age was 58 years and median prostate size was 28 cc at study entry. At a median followup of 4.3 years prostate size increased in 61.9% and remained stable or decreased in 38.1% of men. The median rate of volume change was 0.6 cc per year (range -9.9 to 62.1), corresponding to a median growth rate of 2.5% per year (range -29.2 to 176.4%). During followup 64.6% of men with an initial prostate size less than 40 cc had prostate growth compared to only 50.9% of men with an initial prostate size of 40 cc or greater. CONCLUSIONS These results suggest that changes in prostate size are highly variable among aging men. Although benign prostatic hyperplasia is common, a considerable proportion of aging men have a stable or decreasing prostate size. Further research is needed to identify the underlying mechanism for such differences in prostate growth.

PSA Doubling Time Versus PSA Velocity to Predict High-Risk Prostate Cancer: Data from the Baltimore Longitudinal Study of Aging

BACKGROUND Our group has previously shown that prostate-specific antigen (PSA) velocity (PSAV) is associated with the presence of life-threatening prostate cancer. Less is known about the relative utility of pretreatment PSA doubling time (PSA DT) to predict tumor aggressiveness. OBJECTIVE To compare the utility of PSAV and PSA DT for the prediction of life-threatening prostate cancer. DESIGN, SETTING, AND PARTICIPANTS From the Baltimore Longitudinal Study of Aging, we identified 681 men with serial PSA measurements. MEASUREMENTS Receiver operating characteristic analysis was used to evaluate the relationship between PSAV, PSA DT, and the presence of high-risk disease. RESULTS AND LIMITATIONS Within the period of 5 yr prior to diagnosis, PSAV was significantly higher among men with high-risk or fatal prostate cancer than men without it. By contrast, PSA DT was not significantly associated with high-risk or fatal disease. On multivariate analysis, including age, date of diagnosis, and PSA, the addition of PSAV significantly improved the concordance index from 0.85 to 0.88 (p<0.001), whereas PSA DT did not. CONCLUSIONS These data suggest that PSAV is more useful than PSA DT in the pretreatment setting to help identify those men with life-threatening disease.

Single nucleotide polymorphisms and the likelihood of prostate cancer at a given prostate specific antigen level.

PURPOSE Prostate specific antigen is used for prostate cancer screening but its specificity is limited. Specificity might be increased by considering genotype associated prostate specific antigen levels. MATERIALS AND METHODS We examined associations between single nucleotide polymorphisms on chromosomes 10 and 19 (previously shown to be associated with prostate specific antigen) with prostate specific antigen and prostate cancer in 505 men from the Baltimore Longitudinal Study of Aging. RESULTS In a model with age and date the risk ratio for prostate cancer was 1.18 (95% CI 1.13-1.23) per unit increase in prostate specific antigen. Including the interaction between alleles and prostate specific antigen significantly altered the risk ratio for prostate cancer (Cox proportional hazards p <0.001). Specifically prostate cancer risk per unit increase in prostate specific antigen was significantly different in carriers than in noncarriers of a minor allele (1.28 vs 1.10, respectively, Cox proportional hazards p <0.001), whereas men with a minor allele had a significantly higher risk of prostate cancer at prostate specific antigen levels greater than 6 ng/ml. CONCLUSIONS Our data suggest that genotype influences the risk of prostate cancer per unit increase in prostate specific antigen. Prostate cancer risk stratification using prostate specific antigen and genotype could improve prostate specific antigen test performance.

Should Prostate Specific Antigen be Adjusted for Body Mass Index? Data From the Baltimore Longitudinal Study of Aging

PURPOSE Obesity may be associated with lower prostate specific antigen through hemodilution. We examined the relationship between body mass index and prostate specific antigen by age in men without prostate cancer in a longitudinal aging study to determine whether prostate specific antigen must be adjusted for body mass index. MATERIALS AND METHODS The study population included 994 men (4,937 observations) without prostate cancer in the Baltimore Longitudinal Study of Aging. Mixed effects models were used to examine the relationship between prostate specific antigen and body mass index in kg/m(2) by age. Separate models were explored in men with prostate cancer censored at diagnosis, for percent body fat measurements, for weight changes with time and adjusting for initial prostate size in 483 men (2,523 observations) with pelvic magnetic resonance imaging measurements. RESULTS In men without prostate cancer body mass index was not significantly associated with prostate specific antigen after adjusting for age (p = 0.06). A 10-point body mass index increase was associated with a prostate specific antigen difference of -0.03 ng/ml (95% CI -0.40-0.49). Results were similar when men with prostate cancer were included, when percent body fat was substituted for body mass index, and after adjusting for prostate volume. Longitudinal weight changes also had no significant association with prostate specific antigen. CONCLUSIONS Consistent with prior studies, we found an inverse relationship between obesity and serum prostate specific antigen. However, the magnitude of the difference was small. Thus, adjusting prostate specific antigen for body mass index does not appear warranted.

Distribution of PSA Velocity by Total PSA Levels: Data From the Baltimore Longitudinal Study of Aging

OBJECTIVES To describe the distribution and implications of prostate-specific antigen velocity (PSAV) by prostate-specific antigen (PSA) in an unselected population. A PSAV >0.35 and >2.0 ng/mL/y have been associated with an increased risk of prostate cancer (CaP) death more than 10 years and 1 year before diagnosis, respectively. It is unknown how frequently PSAVs of this magnitude occur in community men. METHODS From the Baltimore Longitudinal Study of Aging, we examined the PSAV distribution in 786 men with serial PSA measurements (3474 PSAV observations) at total PSA levels <10 ng/mL. We also determined whether PSAV altered the probability of overall and life-threatening CaP at PSA levels <3 and 3-10 ng/mL. RESULTS Overall, the mean PSA and PSAV were 1.3 ng/mL and 0.05 ng/mL/y, respectively. PSAV rose continuously with increasing PSA (P <.0001), and was significantly higher in cancers than controls for observations at PSA levels <3 ng/mL (P = .02) and 3-10 ng/mL (P = .0008). The probability of life-threatening CaP was 3% at a PSA <3 ng/mL, but increased to 13.6% with PSAV >0.4 ng/mL/y. At PSA levels of 3-10 ng/mL, the probability of life-threatening CaP was 9.8% based on PSA alone vs 12% with PSAV >0.4 ng/mL/y. CONCLUSIONS PSAV was significantly higher in CaP observations than controls in all PSA ranges studied and altered the risk of overall and life-threatening CaP at a given PSA level. Because the value of PSAV is PSA-dependent, the PSA level should be taken into account when interpreting PSAV.

Does Prostate Growth Confound Prostate Specific Antigen Velocity? Data From the Baltimore Longitudinal Study of Aging

PURPOSE Although prostate specific antigen velocity was proposed to increase the specificity of prostate specific antigen-based screening, there are little published data on the effect of differential prostate growth on prostate specific antigen velocity. If a patient presents with rising prostate specific antigen over a year or more, it would be useful to know whether such a change in prostate specific antigen could be explained by prostate growth. Thus, we investigated the relationship between changes in prostate size and prostate specific antigen changes in a large cohort of men without prostate cancer. MATERIALS AND METHODS We identified 242 men without prostate cancer from the Baltimore Longitudinal Study of Aging who had 2 or greater serial pelvic magnetic resonance imaging studies and contemporaneous prostate specific antigen measurements. In this population we used the t test, correlation coefficients, and regression analysis to examine the relationship between prostate specific antigen changes and prostate volume changes, as assessed by magnetic resonance imaging. RESULTS The mean age was 55 years. During 4.2 years of median followup, the median rate of volume change was 0.6 cc per year (range -9.9 to 11.8), and the median prostate specific antigen change was 0.03 ng/ml per year. There was no correlation between prostate specific antigen changes and prostate growth, as measured in cc per year (r = -0.01, p = 0.9) or the percent change per year (r = 0.07, p = 0.3). On multivariate analysis, there was no significant relationship between changes in prostate volume and prostate specific antigen changes. CONCLUSIONS Our data suggest that volume increases alone do not cause a high prostate specific antigen velocity. Despite growth rates as high as 10 cc per year, prostate specific antigen velocity was less than 0.1 ng/ml per year in most men without prostate cancer. Thus, differential rates of prostatic growth should not confound the use of prostate specific antigen velocity for prostate cancer detection and prognostication.