Longitudinal assessment of urinary PCA3 for predicting prostate cancer grade reclassification in favorable-risk men during active surveillance.

BACKGROUND: To assess the utility of urinary prostate cancer antigen 3 (PCA3) as both a one-time and longitudinal measure in men on active surveillance (AS). METHODS: The Johns Hopkins AS program monitors men with favorable-risk prostate cancer with serial PSA, digital rectal examination (DRE), prostate magnetic resonance imaging and prostate biopsy. Since 2007, post-DRE urinary specimens have also been routinely obtained. Men with multiple PCA3 measures obtained over ⩾3 years of monitoring were included. Utility of first PCA3 score (fPCA3), subsequent PCA3 (sPCA3) and change in PCA3 were assessed for prediction of Gleason grade reclassification (GR, Gleason score >6) during follow-up. RESULTS: In total, 260 men met study criteria. Median time from enrollment to fPCA3 was 2 years (interquartile range (IQR) 1-3) and from fPCA3 to sPCA3 was 5 years (IQR 4-6). During median follow-up of 6 years (IQR 5-8), 28 men (11%) underwent GR. Men with GR had higher median fPCA3 (48.0 vs 24.5, P=0.007) and sPCA3 (63.5 vs 36.0, P=0.002) than those without GR, while longitudinal change in PCA3 did not differ by GR status (log-normalized rate 0.07 vs 0.06, P=0.53). In a multivariable model including age, risk classification and PSA density, fPCA3 remained significantly associated with GR (log(fPCA3) odds ratio=1.77, P=0.04). CONCLUSIONS: PCA3 scores obtained during AS were higher in men who underwent GR, but the rate of change in PCA3 over time did not differ by GR status. PCA3 was a significant predictor of GR in a multivariable model including conventional risk factors, suggesting that PCA3 provides incremental prognostic information in the AS setting.

Intermediate and longer-term outcomes from a prospective active-surveillance program for favorable-risk prostate cancer. Tosoian JJ, Mamawala M, Epstein JI, Landis P, Wolf S, Trock BJ, Carter HB.J Clin Oncol. 2015 Oct 20;33(30):3379-85. [Epub 2015 Aug 31]. doi: 10.1200/JCO.2015.62.5764.

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 = 66y) with a median follow-up of 5 years (range: 0.01-18.00y) 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: 0.01-18y). Factors associated with grade reclassification were older age (hazard ratio [HR] = 1.03 for each additional year; 95% CI: 1.01-1.06), prostate-specific antigen density (HR = 1.21 per 0.1 unit increase; 95% CI: 1.12-1.46), and greater number of positive biopsy cores (HR = 1.47 for each additional positive core; 95% CI: 1.26-1.69). Factors associated with intervention were prostate-specific antigen density (HR = 1.38 per 0.1 unit increase; 95% CI: 1.22-1.56) and a greater number of positive biopsy cores (HR = 1.35 for one additional positive core; 95% CI: 1.19-1.53). 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.

Use of the Prostate Health Index for detection of prostate cancer: results from a large academic practice.

BACKGROUND: The Prostate Health Index (phi) outperforms PSA and other PSA derivatives for the diagnosis of prostate cancer (PCa). The impact of phi testing in the real-world clinical setting has not been previously assessed. METHODS: In a single, large, academic center, phi was tested in 345 patients presenting for diagnostic evaluation for PCa. Findings on prostate biopsy (including Grade Group (GG), defined as GG1: Gleason score (GS) 6, GG2: GS 3+4=7, GG3: GS 4+3=7, GG4: GS 8 and GG5: GS 9-10), magnetic resonance imaging (MRI) and radical prostatectomy (RP) were prospectively recorded. Biopsy rates and outcomes were compared with a contemporary cohort that did not undergo phi testing (n=1318). RESULTS: Overall, 39% of men with phi testing underwent prostate biopsy. No men with phi<19.6 were diagnosed with PCa, and only three men with phi<27 had cancer of GG⩾2. Phi was superior to PSA for the prediction of any PCa (area under the receiver operating characteristic curve (AUC) 0.72 vs 0.47) and GG⩾2 PCa (AUC 0.77 vs 0.53) on prostate biopsy. Among men undergoing MRI and phi, no men with phi<27 and PI-RADS⩽3 had GG⩾2 cancer. For those men proceeding to RP, increasing phi was associated with higher pathologic GG (P=0.002) and stage (P=0.001). Compared with patients who did not undergo phi testing, the use of phi was associated with a 9% reduction in the rate of prostate biopsy (39% vs 48%; P<0.001). Importantly, the reduction in biopsy among the phi population was secondary to decreased incidence of negative (8%) and GG1 (1%) biopsies, whereas the proportion of biopsies detecting GG⩾2 cancers remained unchanged. CONCLUSIONS: In this large, real-time clinical experience, phi outperformed PSA alone, was associated with high-grade PCa, and provided complementary information to MRI. Incorporation of phi into clinical practice reduced the rate of unnecessary biopsies without changing the frequency of detection of higher-grade cancers.

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.

Dedifferentiation of prostate cancer grade with time in men followed expectantly for stage T1c disease.

PURPOSE: We assess whether the Gleason grade changes in men followed expectantly with clinical stage T1c prostate cancer. MATERIAL AND METHODS: We studied 70 men with stage T1c prostate cancer who underwent watchful waiting with repeat needle biopsy sampling to assess for progression. After the initial cancer diagnosis all men had at least 1 other biopsy demonstrating cancer. RESULTS: Of 70 cases 9 (12.9%) showed a significant change in grade from Gleason scores 6 or less to 7 or greater. The average followup of those patients without a change in grade was 22 months and greater than those with a change in grade. There was no difference between the groups with and without changes in grade in regard to initial prostate specific antigen (PSA), percent-free PSA, or PSA density or velocity. Of 9 cases there were 5 (56%) and 8 (89%) with grade change that occurred at 12 and 15 months or less after initial biopsy, respectively. In contrast, only 1 of 24 (4%) patients in whom last re-biopsy was performed 24 months or greater after the initial cancer diagnosis had a change in grade. Of the 21 men who underwent radical prostatectomy 5 (24%) had worsening of grade on the radical prostatectomy specimen compared to biopsy, with a mean interval of 18 months between the initial cancer diagnosis and prostatectomy. This prevalence of grade change is less than in our population that underwent prostatectomy within 1 to 3 months after biopsy. CONCLUSIONS: Because most grade changes occurred relatively soon after biopsy, it implies that tumor grade did not evolve but rather the higher grade component was not initially sampled. During a 1 1/2 to 2-year period after biopsy there is no evidence that prostate cancer grade worsens significantly. Men with prostate cancer need not feel concerned about waiting several months before undergoing surgery after biopsy. Furthermore, men undergoing watchful waiting can be reassured that there is little evidence that prostate cancer grade worsens during the short term.

Low levels of prostate-specific antigen predict long-term risk of prostate cancer: results from the Baltimore Longitudinal Study of Aging.

OBJECTIVES: To evaluate the relationship between low prostate-specific antigen (PSA) levels that are considered normal and the long-term risk of prostate cancer. METHODS: The relative risk of, and cumulative probability of freedom from, prostate cancer by PSA level and age decade was evaluated in male participants of a longitudinal aging study, the Baltimore Longitudinal Study of Aging (National Institute on Aging). The relative risk was estimated from a Cox proportional hazards regression model for men aged 40 to 49.9 (n = 351) and 50 to 59.9 (n = 445). The disease-free probability was determined by Kaplan-Meier survival analysis. RESULTS: The relative risk of prostate cancer for men aged 40 to 49.9 was 3.75 (range 1.6 to 8.6) when the PSA level was at or greater than the median (0.60 ng/mL) compared with men with PSA levels less than the median. This risk was similar for men aged 50 to 59.9 when comparing those with PSA levels greater than and less than the median (0.71 ng/mL). At 25 years, the cumulative probability of freedom from prostate cancer for men aged 40 to 49.9 was 89.6% (range 81% to 97%) and 71.6% (range 60% to 83%) when the PSA level was less than and greater than the median, respectively. The 25-year disease-free probability for men aged 50 to 59.9 was 83.6% (range 76% to 91%) and 58.9% (range 48% to 70%) when the PSA level was less than and greater than the median, respectively. CONCLUSIONS: The association between the baseline serum PSA level and the subsequent risk of prostate cancer suggests that the biologic events that predispose to prostate cancer begin early in middle age. Men who have baseline PSA levels that are "normal" but reflect a higher risk of prostate cancer may be the most appropriate candidates for future prevention trials. Those men with the lowest risk of prostate cancer on the basis of the baseline PSA measurements are unlikely to benefit from frequent PSA surveillance in an effort to detect prostate cancer early.

Effect of local anesthetics on patient recovery after transrectal biopsy.

OBJECTIVES: To determine the analgesic efficacy of local anesthetics injected lateral to the seminal vesicles before prostate biopsy, during and immediately after the procedure, because pain is a common side effect of transrectal ultrasound-guided prostate biopsy. METHODS: Patients were randomized to receive 5 mL of either 1% lidocaine or sterile normal saline injected (under ultrasound guidance) lateral to the seminal vesicles bilaterally before performance of the prostate biopsies, with the patient and physician unaware of the treatment group. Five minutes after the injection, a series of 12 prostate biopsies were performed. A visual analog scale (VAS) for pain at rest and with activity was obtained before the biopsy (preprocedure VAS) and immediately (intraprocedure VAS) and 30 minutes (postprocedure VAS) after the biopsy. Surveys examining the patients' expectations for biopsy pain were administered before and immediately after the biopsy. RESULTS: No significant differences were found between the groups with regard to demographic data, VAS pain scores at rest and with activity, and survey results. CONCLUSIONS: Injection of lidocaine lateral to the seminal vesicles before prostate biopsy did not diminish biopsy-associated pain.

Importance of posterolateral needle biopsies in the detection of prostate cancer.

OBJECTIVES: To determine whether needle biopsy of the posterolateral aspects of the prostate aids in prostate cancer detection. In the routine sextant biopsy strategy, the posterolateral aspects of the prostate are not sampled. METHODS: Using an 18-gauge biopsy gun, we performed sextant biopsies and an additional nine needle biopsies in the pathology laboratory on 150 radical prostatectomy specimens performed for Stage T1c prostate cancer. The additional nine biopsies consisted of three midline biopsies and six (three each from the left and right) posterolaterally aimed biopsies from the apex, mid, and base regions of the gland. Significant tumors were defined as those greater than 0.5 cm3, or with a Gleason score of 7 or greater, or non-organ confined. RESULTS: Of the 123 cases with cancer on repeated biopsy, in only 3 (2.4%) was the only cancer found in the midline biopsies. For the following analysis, we analyzed the data as if we had not done the midline biopsies. If one had performed only the routine sextant needle biopsies, in 31 (25.2%) of the 123 cases, tumor would have been missed; 20 of these tumors were significant, including 5 with extraprostatic extension. If one had performed only the more posterolateral six biopsies, in 15 cases (12.2%), tumor would have been missed; 5 of these tumors were significant, all of which were organ confined. CONCLUSIONS: Adding routine midline biopsies does not appreciably increase the detection of cancer. If one were to only perform six needle biopsies of the prostate, these biopsies should be aimed more toward the posterolateral aspect of the gland. Maximum cancer detection results from combining both routine sextant and posterolateral needle biopsies.

Today men with prostate cancer have larger prostates.

OBJECTIVES: To examine the relationship between prostate size and the method of cancer detection in men with organ-confined prostate cancer, and compare prostate size in men with and without cancer. METHODS: Prostate volume was evaluated in 720 men who had undergone radical prostatectomy for Stage T1c or Stage T2 cancer. Men with Stage T2 cancer were divided into those treated before 1989 (when widespread prostate-specific antigen [PSA] testing began), or not. Gland volume was also examined in 265 men participating in the Baltimore Longitudinal Study of Aging who had no clinical evidence of cancer. Volumes were compared using linear regression to allow for age. RESULTS: Prostate volume in men with Stage T1c cancer was statistically significantly larger than in men with Stage T2 cancer diagnosed in the pre-PSA era after adjusting for age (P = 0.0001), and statistically significantly larger than in men without cancer above age 47 years based on 95% confidence intervals. Prostate volumes in men with Stage T2 cancer diagnosed in the pre-PSA era and in men without cancer were not statistically significantly different. CONCLUSIONS: Prostate volume in men with PSA-detected, organ-confined cancer is larger than in men with palpable organ-confined cancer diagnosed in either the pre-PSA era or PSA era. These discrepancies may reflect a diagnostic bias due to the effect of benign prostatic hyperplasia on serum PSA that results in the selection of men with larger prostates for biopsy.

Serum levels of insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-3, and prostate-specific antigen as predictors of clinical prostate cancer.

Insulin-like growth factors (IGFs) may play a role in prostate growth, hyperplasia, and malignancy. High plasma IGF-I has been associated with increased prostate cancer risk. In a prospective, cohort, case-control study in the Baltimore Longitudinal Study on Aging population, we examined prostate volume by magnetic resonance imaging, and prostate-specific antigen (PSA), IGF-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) in sera obtained approximately 9 yr before diagnosis of prostate cancer in cases (n = 72) or age-matched controls (n = 127) and in 76 additional Baltimore Longitudinal Study on Aging men (normal subjects) with measured prostate volumes and no prostate cancer. We calculated adjusted odds ratios (OR) by logistic regression, relative risks for significant ORs, and receiver operator curves for prostate cancer, using serum measures alone and in combination. Adjusted ORs for the high vs. low tertile were: for IGF-I, 3.1 [confidence interval (CI), 1.1-8.7]; for IGF-II, 0.2 (CI, 0.07-0.6); for IGFBP-3, 0.71 (CI, 0.3-1.7); and for PSA, 12.5 (CI, 3.8-40.9). For significant ORs, relative risk estimates remained significant at 2.0 for IGF-I, 0.3 for IGF-II, and 5.5 for PSA. Receiver operator curves showed PSA to be the most powerful predictor of prostate cancer. Adding IGF-II to PSA improved prediction. IGF-II was significantly and inversely related (r = -0.219; P < 0.01) and PSA was directly and significantly related (r = 0.461; P < 0.0001) to prostate volume, whereas IGF-I and IBFBP-3 were not. High IGF-I and low IGF-II are independently associated with increased risk of prostate cancer, but PSA level is a much stronger predictor of prostate cancer in the ensuing 10 yr than either IGF-I or IGF-II. The absence of a relationship of IGF-I to prostate size is inconsistent with increased ascertainment in men with large prostates as the source of greater prostate cancer risk associated with IGF-I. Our data suggest that IGF-II may inhibit both prostate growth and development of prostate cancer.

Is preoperative donation of autologous blood rational for radical retropubic prostatectomy?

PURPOSE: We investigated differences in the rate of homologous blood transfusion and the degree of anemia to determine whether it is rational to have patients donate autologous blood before radical prostatectomy. MATERIALS AND METHODS: We retrospectively reviewed the charts of 221 consecutive men who underwent radical retropubic prostatectomy performed by 1 surgeon in a 14-month period. About half of the patients donated autologous blood preoperatively. We evaluated perioperative hemoglobin, and the rate of autologous and homologous transfusion. RESULTS: The groups did not significantly differ in terms of demographic data, co-morbid conditions, clinical variables or hospitalization. Preoperatively mean hemoglobin plus or minus standard deviation was 13.4 +/- 1 and 14.7 +/- 1 gm./dl. in patients who did and did not donate blood, while homologous transfusion was required in 1 (1%) and 4 (3.5%), respectively (p = 0. 18). At hospital discharge anemia was more prevalent in nondonors. Of the men who did versus did not donate blood hemoglobin was less than 10 and less than 9 gm./dl. in 8.4% versus 34% (p <0.0001), and 12.5% versus 0% (p <0.0004), respectively. CONCLUSIONS: Our retrospective review of a cohort of patients who underwent radical retropubic prostatectomy showed no difference in homologous blood transfusion based on preoperative autologous donation status. Autologous donors had lower hemoglobin preoperatively, a higher rate of transfused units and higher hemoglobin at hospital discharge. Preoperative donation of autologous blood may not decrease the need for homologous transfusion in healthy patients undergoing radical retropubic prostatectomy.

Comparative efficiency of prostate-specific antigen screening strategies for prostate cancer detection.

CONTEXT: Despite widespread use of serum prostate-specific antigen (PSA) testing to detect prostate cancer, the relative effectiveness of different PSA screening strategies is unknown. OBJECTIVE: To compare prostate cancer mortality, PSA testing rates, and biopsy rates using various PSA screening strategies, including the standard strategy of annually testing men aged 50 through 75 years. DESIGN AND SETTING: A Monte-Carlo simulation based on a Markov model was used to simulate the natural history of prostate cancer using different starting ages, testing intervals, and PSA thresholds for prostate biopsy. Age-specific PSA levels and prostate biopsy detection probabilities were determined from population data and surgical series. MAIN OUTCOME MEASURES: Numbers of prevented prostate cancer deaths, PSA tests, and prostate biopsies per 1000 men aged 40 through 80 years, compared among 7 different strategies vs no screening. RESULTS: Compared with annual PSA testing beginning at age 50 years, the strategy of PSA testing at ages 40 and 45 years followed by biennial testing beginning at age 50 years was estimated to simultaneously reduce prostate cancer mortality and number of PSA tests and biopsies performed per 1000 men. Specifically, compared with no screening, the standard strategy prevents 3.2 deaths, with an additional 10,500 PSA tests and 600 prostate biopsies, while the earlier but less frequent strategy prevents 3.3 deaths, with an additional 7500 PSA tests and 450 prostate biopsies. Strategies that lowered the PSA threshold for prostate biopsy to below 4.0 ng/mL or strategies that used age-specific PSA levels were not more efficient than use of a PSA threshold of 4.0 ng/mL. These 2 findings remained true under all sensitivity analyses performed to test assumptions of the model. CONCLUSION: Recognizing that the efficacy of PSA screening is unproved, the standard strategy of annual PSA screening beginning at age 50 years appears to be less effective and more resource intensive compared with a strategy that begins earlier but screens biennially instead of annually. JAMA. 2000;284:1399-1405.

Cancer cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transfer as vaccines for the treatment of genitourinary malignancies.

When irradiated and administered intradermally as vaccines, cancer cells engineered to secrete high levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) by gene transfer elicit potent anticancer immune responses in a variety of animal tumor models. Upon vaccination, antigens present in the cancer cells are phagocytosed and processed by skin dendritic cells. These dendritic cells then prime anticancer immune responses by presenting antigenic peptides to T cells. The immune responses generated are capable of eradicating small but lethal cancer cell inocula with minimal toxicity in preclinical animal tumor studies. To develop this vaccination strategy for the treatment of human genitourinary cancers, we have conducted phase I clinical trials using human genitourinary cancer cells as sources of cancer cell antigens. In the first human clinical trial of genetically engineered cancer cell vaccines, a phase I clinical trial of kidney cancer cell vaccines (n = 18), kidney cancer cells were removed at surgery, propagated briefly in vitro, and then genetically modified to secrete high levels of GM-CSF via ex vivo transduction with the retrovirus MFG-GM-CSF. After irradiation, the kidney cancer cells were administered as vaccines to 18 patients with advanced kidney cancers. Vaccine treatment, which caused few side effects, nonetheless appeared to trigger anticancer immune responses manifest as conversion of delayed-type hypersensitivity (DTH) skin responses against irradiated autologous cancer cells after vaccination. Biopsies of vaccine sites yielded findings reminiscent of biopsies from preclinical animal model studies, with evidence of vaccine cell recruitment of dendritic cells, T cells, and eosinophils. One patient with measurable kidney cancer metastases treated at the highest vaccine dose level experienced a partial treatment response. The bioactivity of GM-CSF-secreting autologous cancer cell vaccines was confirmed in a phase I clinical trial for prostate cancer (n = 8). Vaccine cells were prepared from surgically harvested prostate tumors by ex vivo transduction with MFG-GM-CSF in a manner similar to that used for the kidney cancer trial. Vaccine treatment was well tolerated and associated with induction of anticancer immunity as assessed using DTH skin testing. In addition, new antiprostate cancer cell antibodies were detected in serum samples from treated men as a consequence of vaccination. These first clinical trials of GM-CSF-secreting cancer cell vaccines for the treatment of genitourinary cancers have demonstrated both safety and bioactivity, in that very few side effects have been seen and anticancer immune responses have been detected. Future clinical studies will be required to assess vaccine treatment efficacy, refine vaccination dose and schedule, define the appropriate clinical context for the use of such vaccines, and ascertain optimal combinations involving vaccines and other local or systemic anticancer treatments.

The role of prostate-specific antigen velocity in prostate cancer early detection.

Prostate-specific antigen velocity (PSAV) is the rate of change in prostate-specific antigen (PSA) values with repeated measurement over time. Accurate use of PSAV for prostate cancer early detection requires the use of two or more PSA levels collected over approximately 1.5 to 2 years. When these specimen collection criteria are met, more than 95% of men without prostate cancer will have a PSAV less than 0.75 ng/mL/y, whereas approximately 70% of men with prostate cancer will have a PSAV above this threshold. PSAV is thus more specific than routine PSA testing for the presence of prostate cancer, because few men (< 5%) without prostate cancer have a PSAV sufficient to trigger prostate biopsy. The use of PSAV in the increasing number of men with lengthy PSA histories obtained in systematic efforts at prostate cancer early detection may aid in diagnosing prostate cancer and spare some men unnecessary prostate biopsy. This review briefly summarizes the theoretic basis and clinical utility of PSAV in prostate cancer early detection.