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.

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.

Prostate-specific antigen testing of older men.

BACKGROUND: Elevated serum prostate-specific antigen (PSA) levels are predictive of a future diagnosis of prostate cancer. To test the hypothesis that older men with low PSA levels may require less intensive PSA testing because of a reduced prostate cancer detection rate, we evaluated the association between age, baseline PSA level, and prostate cancer detection. METHODS: We conducted a prospective cohort study among participants in a study of aging who had serial PSA measurements taken from age 60 or 65 years until they either were diagnosed with prostate cancer (cancer case subjects) or reached the age of 75 years (subjects without prostate cancer). The time of cancer detection among cancer case subjects was defined as the measurement date on which a PSA level above 4.0 ng/mL was detected (i.e., PSA conversion). Cancer case subjects and subjects without prostate cancer were analyzed according to baseline PSA level and age. RESULTS: All cancer case subjects in the 60-year-old cohort had baseline PSA levels above 0.5 ng/mL, and 14 of 15 cancer cases that would have been detected by a PSA conversion among the 65-year-old cohort were associated with baseline PSA levels of 1.1 ng/mL or more. If PSA testing were discontinued in men aged 65 years with PSA levels of 0.5 ng/mL or less, 100% (95% confidence interval [CI] = 78%-100%) of the cancers would still be detected by age 75 years; if PSA testing were discontinued in men aged 65 years who had PSA levels of 1.0 ng/mL or less, 94% (95% CI = 70%-100%) of the cancers would still be detected by age 75 years. CONCLUSIONS: These data suggest that a decrease in the intensity of screening among older men with low PSA values may not lead to an increase in undetected prostate cancer.

Estimation of prostatic growth using serial prostate-specific antigen measurements in men with and without prostate disease.

Prostate growth curves were estimated from serial prostate-specific antigen (PSA) measurements on frozen sera in three groups of men: (a) 16 men with no prostatic disease by urological history and examination; (b) 20 men with a histological diagnosis of benign prostatic hyperplasia (BPH) who had undergone simple prostatectomy; and (c) 18 men with a histological diagnosis of prostate cancer. The median number of repeated PSA measurements over an 8- to 26-yr period prior to histological diagnosis or exclusion of prostate disease was eight and 11 for noncancer and cancer subjects, respectively. Predicted rates of change in PSA (PSA velocity) were linear and curvilinear for control and BPH subjects, respectively. Subjects with cancer demonstrated both a linear and an exponential phase of PSA velocity. Based on time to double PSA, we estimated the epithelial doubling time for men without prostate disease to range from 54 +/- 13 yr at age 40 to 84 +/- 13 yr at age 70. For men with BPH, doubling times ranged from 2 +/- 13 yr at age 40 to 17 +/- 5 yr at age 85. Subjects with local/regional and advanced/metastatic cancer had similar PSA doubling times of 2.4 +/- 0.6 yr and 1.8 +/- 0.2 yr, respectively. These data are consistent with what is known about prostatic growth with age in men without prostate disease and BPH, and the kinetics of prostate cancer growth. Estimates of prostatic growth rate from changes in PSA may be useful clinically in management of men with prostate disease.

Induction of immunity to prostate cancer antigens: results of a clinical trial of vaccination with irradiated autologous prostate tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transfer.

Vaccination with irradiated granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting gene-transduced cancer vaccines induces tumoricidal immune responses. In a Phase I human gene therapy trial, eight immunocompetent prostate cancer (PCA) patients were treated with autologous, GM-CSF-secreting, irradiated tumor vaccines prepared from ex vivo retroviral transduction of surgically harvested cells. Expansion of primary cultures of autologous vaccine cells was successful to meet trial specifications in 8 of 11 cases (73%); the yields of the primary culture cell limited the number of courses of vaccination. Side effects were pruritus, erythema, and swelling at vaccination sites. Vaccine site biopsies manifested infiltrates of dendritic cells and macrophages among prostate tumor vaccine cells. Vaccination activated new T-cell and B-cell immune responses against PCA antigens. T-cell responses, evaluated by assessing delayed-type hypersensitivity (DTH) reactions against untransduced autologous tumor cells, were evident in two of eight patients before vaccination and in seven of eight patients after treatment. Reactive DTH site biopsies manifested infiltrates of effector cells consisting of CD45RO+ T-cells, and degranulating eosinophils consistent with activation of both Th1 and Th2 T-cell responses. A distinctive eosinophilic vasculitis was evident near autologous tumor cells at vaccine sites, and at DTH sites. B-cell responses were also induced. Sera from three of eight vaccinated men contained new antibodies recognizing polypeptides of 26, 31, and 150 kDa in protein extracts from prostate cells. The 150-kDa polypeptide was expressed by LNCaP and PC-3 PCA cells, as well as by normal prostate epithelial cells, but not by prostate stromal cells. No antibodies against prostate-specific antigen were detected. These data suggest that both T-cell and B-cell immune responses to human PCA can be generated by treatment with irradiated, GM-CSF gene-transduced PCA vaccines.

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.

Isolated vasculitis of the seminal vesicle.

We present 2 cases of histologically identified necrotizing vasculitis found in the seminal vesicles of radical prostatectomy specimens containing prostatic adenocarcinoma. In neither case did the patient suffer from symptoms nor show signs of systemic vasculitis. In 1 case, the vasculitis correlated clinically with dense adhesions noted at surgery that simulated extraprostatic tumor extension. Isolated vasculitis of the seminal vesicle is similar to reports of isolated vasculitis limited to other organs, in that local clinical findings may or may not be present, but the patient is free of systemic disease. Careful clinical follow-up is warranted to exclude the subsequent development of systemic vasculitis in these patients.

Variables influencing radiation exposure during extracorporeal shock wave lithotripsy. Review of 298 treatments.

Retrospective review of 298 extracorporeal shock wave lithotripsy (ESWL) treatments was undertaken to determine the factors which influence radiation exposure during ESWL. Fluoroscopy time averaged 160 seconds (3-509), and the average number of spot films taken per patient was 26 (5-68). The average stone burden was 19.3 mm (3-64). Average calculated skin surface radiation exposure was 17.8 R per treatment. Radiation exposure increased with increasing stone burden and patient weight. Stones treated in the ureter resulted in a higher average patient radiation exposure than for renal stones (19 R vs 16 R), even though the average size of these ureteral stones (11.3 mm) was significantly less than the mean. However, type of anesthetic (general or regional) used was not a significant factor. Operator training, experience, and familiarity with radiation physics should significantly decrease the amount of imaging time and consequent patient radiation exposure during ESWL.

Influence of age and prostate-specific antigen on the chance of curable prostate cancer among men with nonpalpable disease.

OBJECTIVES: To evaluate the relation between age, prostate-specific antigen (PSA) level, and the probability of detecting curable prostate cancer. METHODS: A consecutive surgical series of radical prostatectomies was performed in 492 men with nonpalpable (Stage T1c) disease, who formed the study cohort (mean age 58 years). The cohort was systematically classified into three age groups ([1] 40 to 50 years [n = 69]; [2] 51 to 60 years [n = 227]; [3] 61 to 73 years [n = 196]) and five pretreatment PSA groups ([1] 2.5 to 4.0 ng/mL [n = 36]; [2] 4.1 to 6.0 ng/mL [n = 100]; [3] 6.1 to 8.0 ng/mL [n = 122]; [4] 8.1 to 10.0 ng/mL [n = 76]; [5] greater than 10.0 ng/mL [n = 135]). The percent probability of curable cancer was determined by logistic regression analysis. Curable cancer was defined as organ-confined tumor or a tumor with capsular penetration of low grade (Gleason score less than 7), with negative margins and no involvement of seminal vesicles or lymph nodes. RESULTS: A comparison within age groups and within PSA groups revealed that the probability of curable cancer was more closely associated with age than PSA level. Although the probability of curable cancer was closely related to PSA level across a wide range of PSA values (0.4 to 52 ng/mL), there was only minimal difference (2% to 4%) in the probability of curable cancer within the range of PSA values from 2.5 to 6.0 ng/mL for all ages. CONCLUSIONS: Age is a strong predictor of the probability of curable cancer. Thus, early detection efforts in younger men are more likely to lead to a decrease in prostate cancer mortality. These data suggest that the use of PSA thresholds below 4.0 ng/mL as an indicator of prostate cancer is unlikely to improve the probability of detecting curable cancer.

Relationship between changes in prostate-specific antigen and prognosis of prostate cancer.

Changes in prostate-specific antigen (PSA), used to estimate PSA doubling times, may reflect prostate cancer growth. To determine if PSA doubling time prior to diagnosis predicted outcome in men with prostate cancer, we evaluated 16 men with prostate cancer who had (1) serial PSA determinations (mean 9.9) on frozen sera from twelve to twenty-six years before diagnosis; (2) at least five years of follow-up in those subjects without metastatic disease (range 5.5-12.3 years); and (3) archival material from diagnosis available for pathologic evaluation. PSA doubling time prior to diagnosis was investigated with relation to patient outcome (regardless of treatment) and the known predictors of tumor behavior, Gleason score and nuclear morphometry. In 5 of 16 men who had evidence of metastatic disease at diagnosis, metastasis developed or they died of prostate cancer during follow-up (group 1). Eleven of 16 had no evidence of metastatic disease during follow-up (group 2). Both Gleason score and variance of nuclear roundness (VNR) were significantly greater for group 1 (p < 0.05). There was no significant difference between the two groups with respect to PSA doubling time, and the PSA level at diagnosis did not correlate with the development of metastatic disease. One of 5 men with no PSA level greater than 4.0 ng/mL prior to diagnosis died within two years of diagnosis. These data suggest that (1) a normal PSA at diagnosis does not exclude an aggressive cancer, and (2) changes in PSA that occur before the diagnosis of prostate cancer may not always predict outcome. Since PSA level is influenced by tumor grade, an inability to correct PSA for tumor grade could have influenced the results.

Role of prostate-specific antigen velocity in prediction of final pathologic stage in men with localized prostate cancer.

OBJECTIVES: Prostate-specific antigen (PSA) velocity prior to radical retropubic prostatectomy was evaluated to determine if men with a faster rate of rise in PSA have locally more extensive prostate cancer. METHODS: Of 368 men who underwent radical retropubic prostatectomy, 82 had two to seven PSA measurements between 1.3 and 6.7 years before prostate biopsy for evaluation of PSA velocity. PSA velocity and the pretreatment parameters of PSA, Gleason score, and T stage were evaluated as predictive parameters of pathologic stage. RESULTS: In men with pathologically organ-confined disease, PSA velocity was 1.12 ng/mL/yr; in non-organ-confined cases, it was 1.88 ng/mL/yr. There was a statistically significant relationship between a Gleason score of 7 and above and the pathologic extent of disease. There was no statistically significant relationship between T stage, the PSA at diagnosis, and PSA velocity with respect to final pathologic stage. CONCLUSIONS: PSA velocity is not a strong predictor of pathologic stage in men with localized prostate cancer.

Serum ferritin as a clinical marker for renal cell carcinoma: influence of tumor volume.

OBJECTIVES: At present, 35% to 50% of patients with clinically localized renal cell carcinoma (RCC) unpredictably have a recurrence after surgical therapy. Presently, no clinical serum marker exists to detect occult metastases and to allow measurement of response to therapy in RCC. Serum ferritin was previously reported to correlate with pathologic stage. We postulated that this increase in serum ferritin with increasing stage might reflect tumor volume, since higher stage tumors are often larger. METHODS: Serum ferritin levels were measured preoperatively in 30 patients with radiologic evidence of RCC. Tumor volume and the largest tumor dimension were calculated from either the pathologic specimen (n = 24) or from the computed tomography or magnetic resonance imaging (n = 30). Pathologic stage was determined for all patients undergoing surgery (T1 = 3, T2 = 12, and T3 = 9). RESULTS: Preoperative serum ferritin levels did not correlate with age, blood urea nitrogen levels, creatinine levels, hematocrit, race, or gender. Although mean serum ferritin levels increased with increasing stage (T1 = 113 +/- 75, T2 = 254 +/- 270, and T3 = 425 +/- 257 ng/mL), these differences did not reach statistical significance (P > 0.05). Serum ferritin did, however, correlate with tumor volume (R = 0.75; P < 0.0001) and the largest tumor dimension measured from radiographic studies (R = 0.8; P < 0.0001). Serum ferritin measured intraoperatively from the renal vein (666 ng/mL) and the inferior vena cava (564 ng/mL) from a patient with a 500 cc tumor (preoperative serum ferritin, 552 ng/mL) suggested that the tumor was the source of the elevated ferritin levels. Histologic sections from tumors taken from patients with high serum ferritin levels were more necrotic and stained intensely positively for iron and immunohistochemically for ferritin, whereas adjacent histologically normal tissue did not. CONCLUSIONS: These data suggest that ferritin may be a useful serum marker for monitoring patients with RCC, but the actual source of the ferritin remains unclear and dictates further investigation.

Prostate-specific antigen variability in men without prostate cancer: effect of sampling interval on prostate-specific antigen velocity.

OBJECTIVES: To evaluate short-term and long-term variability between prostate-specific antigen (PSA) measurements to determine the most appropriate PSA sampling interval and rate of PSA change (PSA velocity) to distinguish between men with and without prostate cancer. METHODS: Retrospective study of PSA variability and PSA velocity in three groups of men without a diagnosis of prostate cancer and PSA levels less than 10 ng/mL: 56 men with a histologic diagnosis of benign prostatic hyperplasia (BPH; histologic BPH group) and 527 men with no history of cancer (noncancer group) who were part of the Baltimore Longitudinal Study of Aging and had PSA sampled at 2-year intervals (long-term), and 223 men with a clinical diagnosis of BPH (clinical BPH group) who had PSA sampled at 3-month intervals (short-term). PSA variability (deviation between consecutive measurements) and PSA velocity based on both two consecutive measurements and three consecutive measurements (average velocity) were calculated for each study group. RESULTS: PSA velocity is the deviation in PSA measurements relative to the elapsed time between the measurements. Because the variability in PSA between measurements was similar for the groups, the major factors that influenced PSA velocity were the sampling interval between PSA measurements, and to a lesser extent, the number of repeat PSA measurements. The 99th percentile for PSA velocity was 0.7 (histologic BPH group) and 0.75 ng/mL per year for the noncancer group when three measurements with a 24-month PSA sampling interval were used. However, the 99th percentile for PSA velocity was 5.8 and 2.4 ng/mL per year when three measurements with 3-month and 6-month PSA sampling intervals were used. Using three measurements, the percentage of subjects with a PSA velocity more than 0.75 ng/mL per year was 1% for the groups with a 24-month PSA sampling interval and 28% and 17% for 3-month and 6-month PSA sampling intervals, respectively. The 99th percentile for PSA velocity and the percentage of subjects with a PSA velocity more than 0.75 ng/mL per year was higher using two measurements compared to three measurements regardless of PSA sampling interval. CONCLUSIONS: PSA velocity is inversely related to the interval between PSA measurements. A PSA velocity more than 0.75 ng/mL per year is useful in distinguishing between men with and without prostate cancer when: (1) velocity is based on three consecutive measurements; and (2) PSA is sampled long-term (2 years) but not short-term (3 to 6 months).

Relationship between changes in prostate-specific antigen and the percent of prostatic epithelium in men with benign prostatic hyperplasia.

OBJECTIVES: Pretreatment knowledge of prostate gland histology would allow a more scientifically based selection of medical therapy for men with benign prostatic hyperplasia (BPH) and may increase the effectiveness of the pharmacologic agents available. Changes in prostate-specific antigen (PSA), or PSA velocity, may reflect prostatic epithelial growth in BPH. Our objective was to determine if PSA velocity prior to diagnosis correlated with the relative amount of epithelium in BPH tissue. METHODS: We evaluated 39 men with BPH who had serial PSA determinations (mean, 5.4) on frozen sera from 2.3 to 25.1 years before diagnosis, and archival material from simple prostatectomy available for pathologic evaluation. We used an immunoenzymatic staining technique for PSA to bind prostatic epithelium selectively so that color differences in the stained tissue sections could be used to quantify stroma, epithelium, and glandular lumina. RESULTS: The average percentage of epithelium (%E) was 12.4 and the average stroma-epithelial ratio (SER) was 6.6. The correlation of PSA velocity for the three visits nearest to prostatectomy (n = 32) versus %E and SER was significant (P = 0.003 for both). The PSA value nearest to prostatectomy (n = 39) was directly correlated with %E and SER (P = 0.0001 and P = 0.001, respectively). CONCLUSIONS: These data suggest that PSA and PSA velocity are directly related to the histologic makeup of the prostate in men with BPH. Thus, pretreatment evaluation of PSA could be useful as part of an evaluation to direct BPH therapy.

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.

Prostate-specific antigen in men born with bladder exstrophy.

OBJECTIVES: To determine serum levels of prostate-specific antigen (PSA) in men born with bladder exstrophy and to investigate the clinical utility of this test in the bladder exstrophy population. METHODS: Ten men aged 19 to 45 years with a history of bladder exstrophy underwent digital rectal examination and free and total serum PSA determinations. Immunohistochemistry for PSA and prostate-specific acid phosphatase (PSAP) was performed on archival prostate tissue from 1 man with bladder exstrophy. RESULTS: Free and total serum PSA levels for all patients were measurable and below the upper limit for established age-specific reference ranges for normal men. Both PSA and PSAP were detectable by immunohistochemistry in prostate epithelial cells of a man with bladder exstrophy. CONCLUSIONS: Men born with bladder exstrophy have detectable serum PSA levels. However, because prostate cancer in men with bladder exstrophy has not been reported, whether PSA will have a clinical role as a serum tumor marker for prostate cancer in this population remains to be determined. If so, the PSA reference range for men with the exstrophy condition will need to be defined. Because prostate histology in men with exstrophy resembles that of normal men, careful clinical monitoring for benign and malignant tumors should not be overlooked in this particular population.

Longitudinal analysis of serial measurements of free and total PSA among men with and without prostatic cancer.

OBJECTIVES: Evaluation of free and total serum prostate specific antigen (PSA) levels before diagnosis of prostate cancer. METHODS: Free and total PSA levels were measured on frozen sera samples of 26 men with no history of prostate disease (controls), 29 men with a histologic diagnosis of benign prostatic hyperplasia (BPH) made at simple prostatectomy (BPH cases), and 23 men with a histologic diagnosis of prostatic cancer (cancer cases). Longitudinal regression analysis was used to evaluate PSA levels as a function of years before diagnosis of prostate disease. RESULTS: On average, mean total serum PSA was statistically significantly greater for subjects with cancer (5.0 ng/mL +/- 0.9) versus BPH (2.8 ng/mL +/- 0.3) and control subjects (0.8 ng/mL +/- 0.1) by 4 years before diagnosis, whereas free PSA levels were similar among groups at 4 years before diagnosis. The ratio of free to total serum PSA continuously decreased among cancer cases over the decade before cancer diagnosis. At a time when mean total and free PSA levels were similar among groups (8 years before diagnosis), the ratio of free to total PSA was statistically significantly lower for cancer cases (0.13 +/- 0.01) compared with BPH (0.17 +/- 0.01) and control cases (0.21 +/- 0.02). Use of a free to total PSA ratio of < or = 0.12 when total PSA was between 4.0 and 10.0 ng/mL resulted in the highest sensitivity (76%) and specificity (94%) for diagnosis among subjects with and without cancer. Lowering the reflex range to 2.5 ng/mL increased false positive tests more than it increased sensitivity. CONCLUSIONS: The ratio of free to total PSA is the earliest serum marker predicting a subsequent diagnosis of prostate cancer. Measurement of the free to total serum PSA ratio would appear to reduce false positive results among men without prostate cancer.

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.

The role of free/total prostate-specific antigen ratio in the prediction of final pathologic stage for men with clinically localized prostate cancer.

OBJECTIVES: The combined use of total prostate-specific antigen (PSA), clinical stage, and Gleason score accurately predicts final pathologic stage for men with clinically localized prostate cancer. Recently, the free/ total PSA ratio has been proposed as an adjunct for early detection of prostate cancer. We examined the association between free/total PSA and pathologic stage. METHODS: In a prospective study, 301 consecutive men with clinically localized prostate cancer (average age 58.8 years, range 45-72) underwent a staging pelvic lymphadenectomy and radical prostatectomy. Total PSA and free PSA were measured from preoperative sera. Pathologic stage was determined as organ-confined (OC, n = 169), capsular penetration (CP+, n = 108), seminal vesicle involvement (SV+, n = 13) and lymph node involvement (LN+, n = 11). RESULTS: Overall, 292/301 (97%) of the free/total PSA values were < 25%, and thus suspicious for prostate cancer. Combination of total PSA, Gleason score, and clinical stage predicted well OC (P = 0.00001) and LN+ (P = 0.023); whereas, replacing total PSA with free/total PSA ratio did not improve the prediction of OC (P = 0.0007) nor LN+ (P = 0.03). CONCLUSIONS: The free/total PSA ratio cutoff point of 25% had high sensitivity for prostate cancer among a group of men with clinically localized disease. The free/total PSA ratio did not significantly improve the prediction of pathologic stage provided by total PSA when used alone or in combination with Gleason score and clinical stage. These preliminary data demonstrate that free/total PSA levels provide no additional information for pathologic stage prediction when combined with Gleason score and clinical stage in men with clinically localized prostate cancer.