Patricia Landis

Active surveillance program for prostate cancer: An update of the Johns Hopkins experience

PURPOSE We assessed outcomes of men with prostate cancer enrolled in active surveillance. PATIENTS AND METHODS Since 1995, a total of 769 men diagnosed with prostate cancer have been followed prospectively (median follow-up, 2.7 years; range, 0.01 to 15.0 years) on active surveillance. Enrollment criteria were for very-low-risk cancers, defined by clinical stage (T1c), prostate-specific antigen density < 0.15 ng/mL, and prostate biopsy findings (Gleason score ≤ 6, two or fewer cores with cancer, and ≤ 50% cancer involvement of any core). Curative intervention was recommended on disease reclassification on the basis of biopsy criteria. The primary outcome was survival free of intervention, and secondary outcomes were rates of disease reclassification and exit from the program. Outcomes were compared between men who did and did not meet very-low-risk criteria. RESULTS The median survival free of intervention was 6.5 years (range, 0.0 to 15.0 years) after diagnosis, and the proportions of men remaining free of intervention after 2, 5, and 10 years of follow-up were 81%, 59%, and 41%, respectively. Overall, 255 men (33.2%) underwent intervention at a median of 2.2 years (range, 0.6 to 10.2 years) after diagnosis; 188 men (73.7%) underwent intervention on the basis of disease reclassification on biopsy. The proportions of men who underwent curative intervention (P = .026) or had biopsy reclassification (P < .001) were significantly lower in men who met enrollment criteria than in those who did not. There were no prostate cancer deaths. CONCLUSION For carefully selected men, active surveillance with curative intent appears to be a safe alternative to immediate intervention. Limiting surveillance to very-low-risk patients may reduce the frequency of adverse outcomes.

Evaluation of serum prostate-specific antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastases☆

OBJECTIVE Serum prostate-specific antigen (PSA) values are most useful for prediction of disease recurrence after surgery. It is unknown whether a detectable PSA level after surgery indicates a local recurrence potentially benefiting from pelvic irradiation or distant metastases requiring hormonal treatment. METHODS We analyzed postoperative rate of change of serum PSA levels as a predictor of local versus distant disease recurrence after radical prostatectomy. Between 1982 and 1991, 1,058 men underwent radical prostatectomy for localized prostate cancer and follow-up consisted of determining serum PSA levels and digital rectal examinations. Clinical follow-up of 542 men for four or more years and 78 men for eight or more years yielded ten-year actuarial disease recurrence rates of 4 percent for local recurrence, 8 percent for distant metastases, and 23 percent for an isolated elevation of serum PSA level only. Fifty-one patients with isolated elevations of PSA levels only were followed expectantly until they were diagnosed with either local or distant metastases. RESULTS A linear mixed effects regression analysis was used to model these data. Using these models, the time to a serum PSA level of 0.5 ng/mL, the PSA level one year following surgery, pathologic stage, Gleason sum, and the rate of change of PSA (PSA velocity [PSAV]) were tested as predictors of local versus distant metastases. A combination of PSAV, pathologic stage, and Gleason grade best distinguished local from distant metastases. CONCLUSIONS These data suggest that PSAV in men with an isolated elevation of PSA levels following radical prostatectomy might aid in clinical decision making.

Plasma selenium level before diagnosis and the risk of prostate cancer development.

PURPOSE Epidemiological studies and a randomized intervention trial suggest that the risk of prostate cancer may be reduced by selenium intake. We investigated whether plasma selenium level before diagnosis correlated with the risk of later developing prostate cancer. MATERIALS AND METHODS A case control study was performed on men from the Baltimore Longitudinal Study of Aging registry, including 52 with known prostate cancer and 96 age matched controls with no detectable prostatic disease. Plasma selenium was measured at an average time plus or minus standard deviation of 3.83 +/- 1.85 years before the diagnosis of prostate cancer by graphite furnace atomic absorption spectrophotometry. Adjusted odds ratio and 95% confidence interval were computed with logistic regression. RESULTS After correcting for years before diagnosis, body mass index, and smoking and alcohol use history, higher selenium was associated with a lower risk of prostate cancer. Compared with the lowest quartile of selenium (range 8.2 to 10.7 microg./dl.), the odds ratios of the second (10.8 to 11.8), third (11.9 to 13.2) and fourth (13.3 to 18.2) quartiles were 0.15 (95% confidence interval 0.05 to 0.50), 0.21 (0.07 to 0.68) and 0.24 (0.08 to 0.77, respectively, p =0.01). Furthermore, plasma selenium decreased significantly with patient age (p <0.001). CONCLUSIONS Low plasma selenium is associated with a 4 to 5-fold increased risk of prostate cancer. These results support the hypothesis that supplemental selenium may reduce the risk of prostate cancer. Because plasma selenium decreases with patient age, supplementation may be particularly beneficial to older men.

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.

Expectant management of nonpalpable prostate cancer with curative intent: Preliminary results

PURPOSE We evaluate a strategy of expectant management for men with stage T1c prostate cancer. MATERIALS AND METHODS A total of 81 men (median age 65 years, range 52 to 72) with stage T1c prostate cancer who were thought to have small volume prostate cancer based on needle biopsy findings and prostate specific antigen (PSA) density were followed for more than 1 year with semiannual PSA and digital rectal examination, and annual prostate biopsies (median followup 23 months, range 12 to 58). A recommendation for treatment was made if disease progression was indicated by unfavorable followup needle biopsy findings (Gleason pattern 4 or 5, greater than 2 biopsy cores with cancer, greater than 50% involvement of any core with cancer). Curable disease was defined on pathological examination of radical prostatectomy specimens as 1) organ confined cancer of Gleason score 7 or less, 2) cancer with extraprostatic extension of Gleason score 7 (3+4) or less with negative margins, seminal vesicles and lymph nodes, or 3) cancer of Gleason score 6 or less regardless of margin status or extraprostatic extension if negative seminal vesicles and lymph nodes. RESULTS Of the 81 men 25 (31%) had progression of disease at followup. PSA density was statistically significantly higher (p = 0.01) and the percentage of free PSA was statistically significantly lower (p = 0.04) in men with compared to those without disease progression. Disease progression occurred in 22 of 39 men (56%) with every followup biopsy showing cancer compared to 3 of 42 (2%) men with 1 or more negative followup biopsies (p <0.001). Of the 25 men with progression 13 underwent radical prostatectomy and 12 of 13 (92%) had curable cancers. CONCLUSIONS Expectant management with curative intent may be a reasonable alternative for carefully selected older men who are thought to have small volume cancers.

Intermediate and Longer-Term Outcomes From a Prospective Active-Surveillance Program for Favorable-Risk Prostate Cancer

PURPOSE To assess long-term outcomes of men with favorable-risk prostate cancer in a prospective, active-surveillance program. METHODS Curative intervention was recommended for disease reclassification to higher cancer grade or volume on prostate biopsy. Primary outcomes were overall, cancer-specific, and metastasis-free survival. Secondary outcomes were the cumulative incidence of reclassification and curative intervention. Factors associated with grade reclassification and curative intervention were evaluated in a Cox proportional hazards model. RESULTS A total of 1,298 men (median age, 66 years) with a median follow-up of 5 years (range, 0.01 to 18.00 years) contributed 6,766 person-years of follow-up since 1995. Overall, cancer-specific, and metastasis-free survival rates were 93%, 99.9%, and 99.4%, respectively, at 10 years and 69%, 99.9%, and 99.4%, respectively, at 15 years. The cumulative incidence of grade reclassification was 26% at 10 years and was 31% at 15 years; cumulative incidence of curative intervention was 50% at 10 years and was 57% at 15 years. The median treatment-free survival was 8.5 years (range, 0.01 to 18 years). Factors associated with grade reclassification were older age (hazard ratio [HR], 1.03 for each additional year; 95% CI, 1.01 to 1.06), prostate-specific antigen density (HR, 1.21 per 0.1 unit increase; 95% CI, 1.12 to 1.46), and greater number of positive biopsy cores (HR, 1.47 for each additional positive core; 95% CI, 1.26 to 1.69). Factors associated with intervention were prostate-specific antigen density (HR, 1.38 per 0.1 unit increase; 95% CI, 1.22 to 1.56) and a greater number of positive biopsy cores (HR, 1.35 for one additional positive core; 95% CI, 1.19 to 1.53). CONCLUSION Men with favorable-risk prostate cancer should be informed of the low likelihood of harm from their diagnosis and should be encouraged to consider surveillance rather than curative intervention.

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.

Serial Prostate Biopsies are Associated With an Increased Risk of Erectile Dysfunction in Men With Prostate Cancer on Active Surveillance

PURPOSE We determined whether serial prostate needle biopsies predispose men to erectile dysfunction and/or lower urinary tract symptoms over time. MATERIALS AND METHODS Men with prostate cancer on an active surveillance protocol were administered the 5-item Sexual Health Inventory for Men and International Prostate Symptom Score questionnaires on protocol entry, and at a cross-sectional point in 2008. All men had at least 1, 10 to 12-core prostate biopsy at protocol entry and yearly surveillance biopsies thereafter were recommended. RESULTS Of 333 men 231 returned the followup questionnaires. Correlations were found between biopsy number and erectile dysfunction, with increasing biopsy number associated with a decrease in Sexual Health Inventory for Men score (p = 0.04) and a history of 3 or more biopsies associated with a greater decrease in Sexual Health Inventory for Men score than after 2 or fewer biopsies (p = 0.02). Multivariable analysis for biopsy number, age, prostate volume and prostate specific antigen showed that only biopsy number was associated with decreasing Sexual Health Inventory for Men score (p = 0.02). When men were stratified by baseline Sexual Health Inventory for Men, those without preexisting erectile dysfunction (Sexual Health Inventory for Men score 22 to 25) trended toward steeper decreases in Sexual Health Inventory for Men score after 3 or more biopsies (p = 0.06) than did men with baseline mild to moderate erectile dysfunction (Sexual Health Inventory for Men score 8 to 21). No correlation was found between biopsy number and International Prostate Symptom Score. CONCLUSIONS Serial prostate biopsies appear to have an adverse effect on erectile function in men with prostate cancer on active surveillance but do not affect lower urinary tract symptoms.

Percentage of free prostate-specific antigen in sera predicts aggressiveness of prostate cancer a decade before diagnosis

OBJECTIVES To evaluate serial measurements of free and total prostate-specific antigen (PSA) as a predictor of prostate cancer aggressiveness. METHODS Twenty men diagnosed with adenocarcinoma of the prostate in the pre-PSA era had serum PSA measurements made on multiple stored frozen sera samples available for up to 18 years prior to diagnosis. Subjects were categorized as having aggressive cancer (n = 12) based on the presence of clinical Stage T3, or nodal or bone metastases (N+, M+), or pathologic positive-margin disease, or a Gleason score of 7 or greater; nonaggressive cancer (n = 8) was identified by the absence of these criteria. RESULTS There was no statistically significant difference in free PSA levels among men with aggressive and nonaggressive prostate cancers from 0 to 15 years before diagnosis. Total PSA levels were significantly different between the groups by 5 years before diagnosis (P = 0.04). At a time when total PSA levels were not different between groups (10 years before diagnosis), there was a statistically significant difference in the percentage of free PSA between aggressive and nonaggressive cancers (P = 0.008). Among 14 men who had sera available for analysis at 10 years before diagnosis, all 8 men with aggressive cancers had a percent free PSA of 0.14 or less; this compares with only 2 of 6 men (33%) with nonaggressive cancer. CONCLUSIONS These data suggest that the percentage of free PSA in sera is predictive of tumor behavior at a time when total PSA levels provide no information on tumor aggressiveness. Evaluation of the percentage of free serum PSA may be helpful in making the decision between expectant management and treatment for those men who are diagnosed with early prostate cancers by PSA testing.

Association of [−2]proPSA with Biopsy Reclassification During Active Surveillance for Prostate Cancer

PURPOSE Previous studies have suggested an association between [-2]proPSA expression and prostate cancer detection. Less is known about the usefulness of this marker in following patients with prostate cancer on active surveillance. Thus, we examined the relationship between [-2]proPSA and biopsy results in men enrolled in an active surveillance program. MATERIALS AND METHODS In 167 men from our institutional active surveillance program we used Cox proportional hazards models to examine the relationship between [-2]proPSA and annual surveillance biopsy results. The outcome of interest was biopsy reclassification (Gleason score 7 or greater, more than 2 positive biopsy cores or more than 50% involvement of any core with cancer). We also examined the association of biopsy results with total prostate specific antigen, %fPSA, [-2]proPSA/%fPSA and the Beckman Coulter Prostate Health Index phi ([-2]proPSA/free prostate specific antigen) × (total prostate specific antigen)(½)). RESULTS While on active surveillance (median time from diagnosis 4.3 years), 63 (37.7%) men demonstrated biopsy reclassification based on the previously mentioned criteria, including 28 (16.7%) of whom had reclassification based on Gleason score upgrading (Gleason score 7 or greater). Baseline and longitudinal %fPSA, %[-2]proPSA, [-2]proPSA/%fPSA and phi measurements were significantly associated with biopsy reclassification, and %[-2]proPSA and phi provided the greatest predictive accuracy for high grade cancer. CONCLUSIONS In men on active surveillance, measures based on [-2]proPSA such as phi appear to provide improved prediction of biopsy reclassification during followup. Additional validation is warranted to determine whether clinically useful thresholds can be defined, and to better characterize the role of %[-2]proPSA and phi in conjunction with other markers in monitoring patients enrolled in active surveillance.