Cell Cycle Progression Score, but Not Phosphatase and Tensin Homolog Loss, Is an Independent Prognostic Factor for Metastasis in Intermediate- and High-risk Prostate Cancer in Men Treated With and Without Salvage Radiotherapy.

PURPOSE: The prognostic value for metastasis of the cell-cycle progression score and phosphatase and tensin homolog haven't been evaluated jointly in contemporary men with exclusively intermediate- or high-risk prostate cancer. We evaluated associations of cell-cycle progression and phosphatase and tensin homolog with metastasis-free survival in contemporary intermediate/high-risk prostate cancer patients overall, and intermediate/high-risk men receiving salvage radiotherapy. MATERIALS AND METHODS: In a case-cohort of 209 prostatectomy patients with intermediate/high-risk prostate cancer, and a cohort of 172 such men who received salvage radiotherapy, cell-cycle progression score was calculated from RNA expression, and phosphatase and tensin homolog was analyzed by immunohistochemistry. Proportional hazards regression, weighted for case-cohort design or unweighted for the salvage radiotherapy cohort, was used to evaluate associations of cell-cycle progression, phosphatase and tensin homolog with metastasis-free survival. Improvement in model discrimination was evaluated with the concordance index. RESULTS: In the case-cohort 41 men had metastasis, and 17 developed metastasis in the salvage radiotherapy cohort, at median follow-up of 3 and 4 years, respectively. For both case-cohort and salvage radiotherapy cohort, cell-cycle progression was independently associated with metastasis-free survival after adjustment for Cancer of the Prostate Risk Assessment Post-Surgical: hazard ratio (95% confidence interval) = 3.11 (1.70-5.69) and 1.85 (1.19-2.85), respectively. Adding cell-cycle progression to Cancer of the Prostate Risk Assessment Post-Surgical increased the concordance index from 0.861 to 0.899 (case-cohort), and 0.745 to 0.819 (salvage radiotherapy cohort). Although statistically significant in univariate analyses, phosphatase and tensin homolog was no longer significant after adjustment for Cancer of the Prostate Risk Assessment Post-Surgical. Analysis of interaction with National Comprehensive Cancer Network risk group showed that cell-cycle progression had the strongest effect among unfavorable intermediate-risk men. CONCLUSIONS: In the first study to evaluate metastasis risk associated with cell-cycle progression and phosphatase and tensin homolog in exclusively intermediate/high-risk prostate cancer, and in such men with salvage radiotherapy, cell-cycle progression but not phosphatase and tensin homolog was associated with significantly increased 2- to 3-fold risk of metastasis after Cancer of the Prostate Risk Assessment Post-Surgical adjustment.

Utility of Risk Models in Decision Making After Radical Prostatectomy: Lessons from a Natural History Cohort of Intermediate- and High-Risk Men.

BACKGROUND: Current guidelines suggest adjuvant radiation therapy for men with adverse pathologic features (APFs) at radical prostatectomy (RP). We examine at-risk men treated only with RP until the time of metastasis. OBJECTIVE: To evaluate whether clinicopathologic risk models can help guide postoperative therapeutic decision making. DESIGN, SETTING, AND PARTICIPANTS: Men with National Comprehensive Cancer Network intermediate- or high-risk localized prostate cancer undergoing RP in the prostate-specific antigen (PSA) era were identified (n=3089). Only men with initial undetectable PSA after surgery and who received no therapy prior to metastasis were included. APFs were defined as pT3 disease or positive surgical margins. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Area under the receiver operating characteristic curve (AUC) for time to event data was used to measure the discrimination performance of the risk factors. Cumulative incidence curves were constructed using Fine and Gray competing risks analysis to estimate the risk of biochemical recurrence (BCR) or metastasis, taking censoring and death due to other causes into consideration. RESULTS AND LIMITATIONS: Overall, 43% of the cohort (n=1327) had APFs at RP. Median follow-up for censored patients was 5 yr. Cumulative incidence of metastasis was 6% at 10 yr after RP for all patients. Cumulative incidence of metastasis among men with APFs was 7.5% at 10 yr after RP. Among men with BCR, the incidence of metastasis was 38% 5 yr after BCR. At 10 yr after RP, time-dependent AUC for predicting metastasis by Cancer of the Prostate Risk Assessment Postsurgical or Eggener risk models was 0.81 (95% confidence interval [CI], 0.72-0.97) and 0.78 (95% CI, 0.67-0.97) in the APF population, respectively. At 5 yr after BCR, these values were lower (0.58 [95% CI, 0.50-0.66] and 0.70 [95% CI, 0.63-0.76]) among those who developed BCR. Use of risk model cut points could substantially reduce overtreatment while minimally increasing undertreatment (ie, use of an Eggener cut point of 2.5% for treatment of men with APFs would spare 46% from treatment while only allowing for metastatic events in 1% at 10 yr after RP). CONCLUSIONS: Use of risk models reduces overtreatment and should be a routine part of patient counseling when considering adjuvant therapy. Risk model performance is significantly reduced among men with BCR. PATIENT SUMMARY: Use of current risk models can help guide decision making regarding therapy after surgery and reduce overtreatment.

A Phase II Randomized Trial of Lycopene-Rich Tomato Extract Among Men with High-Grade Prostatic Intraepithelial Neoplasia.

A diverse body of evidence suggests that lycopene might inhibit prostate cancer development. We conducted a 6-mo repeat biopsy randomized trial among men with high-grade prostatic intraepithelial neoplasia (HGPIN). Here we report results for serum lycopene, prostate specific antigen (PSA) and insulin-like growth factor (IGF) proteins, histopathological review, and tissue markers for proliferation [minichromosome maintenance protein 2 (MCM-2)] and cell cycle inhibition (p27). Participants consumed placebo or tomato extract capsules containing 30 mg/day lycopene. Pre- and posttreatment biopsies were immunostained and digitally scored. Serum lycopene was determined by LC-MS-MS. In secondary analyses, pathologists blindly reviewed each biopsy to score histological features. Fifty-eight men completed the trial. Serum lycopene increased 0.55 µmol/L with treatment and declined 0.29 µmol/L with placebo. We observed no meaningful differences in PSA, IGF-1, or IGF binding protein 3 concentrations between groups, nor any differences in expression of MCM-2 or p27 in epithelial nuclei. Prevalences of cancer, HGPIN, atrophy, or inflammation posttreatment were similar; however, more extensive atrophy and less extensive HGPIN was more common in the lycopene group. Despite large differences in serum lycopene following intervention, no treatment effects were apparent on either the serum or benign tissue endpoints. Larger studies are warranted to determine whether changes observed in extent of HGPIN and focal atrophy can be replicated.

Is clinical stage T2c prostate cancer an intermediate- or high-risk disease?

BACKGROUND: Clinical stage T2c (cT2c) is an indeterminate factor in prostate cancer (PC) risk stratification. According to the D'Amico grouping and American Urological Association guidelines, cT2c is a high risk, whereas the National Comprehensive Cancer Network and the European Urological Association classify cT2c as an intermediate risk. This study assessed whether cT2c tumors without other high-risk factors (clinical stage T2c, not otherwise specified [cT2c-NOS]) behaved as an intermediate or high risk through an analysis of biochemical recurrence (BCR) after radical prostatectomy. METHODS: Two thousand seven hundred fifty-nine men from the Shared Equal Access Regional Cancer Hospital (SEARCH) Database and 12,900 men from Johns Hopkins Hospital (JHH) from 1988-2011 and 1982-2012, respectively, were analyzed. Patients were grouped into low-risk (prostate-specific antigen [PSA] < 10 ng/mL, Gleason sum ≤ 6, and cT1-T2a), intermediate-risk (PSA = 10-20 ng/mL, Gleason sum = 7, or cT2b), and high-risk PC categories (PSA > 20 ng/mL, Gleason sum = 8-10, or cT3). Men with cT2c tumors who were not otherwise at high risk (ie, PSA< 20 ng/mL and Gleason sum < 8) were placed into a separate category termed cT2c-NOS. Associations between cT2c-NOS and intermediate- and high-risk patients and BCR were tested with the log-rank test and Cox proportional analysis models. RESULTS: Ninety-nine men (4%) from SEARCH and 202 men (2%) from JHH had tumors classified as cT2c-NOS. The cT2c-NOS patients had a BCR risk similar to that of the intermediate-risk patients (SEARCH, P = .27; JHH, P = .23) but a significantly lower BCR risk in comparison with the high-risk patients (SEARCH, P < .001; JHH, P < .001). When they were specifically compared with intermediate- and high-risk patients, after adjustments for year and center, cT2c-NOS patients had outcomes comparable to those of intermediate-risk patients (SEARCH, P = .53; JHH, P = .54) but significantly better than those of high-risk patients (SEARCH, P = .003; JHH, P < .001). CONCLUSIONS: Patients with cT2c disease without other high-risk features had outcomes similar to the outcomes of patients with intermediate-risk PC and significantly better than the outcomes of patients with high-risk PC. These findings suggest that men with cT2c disease should be considered to be at intermediate risk.

Racial disparities in oncologic outcomes after radical prostatectomy: long-term follow-up.

OBJECTIVE: To report race-based outcomes after radical prostatectomy (RP) in a cohort stratified by National Comprehensive Cancer Network (NCCN) risk category with updated follow-up. MATERIALS AND METHODS: Studies describing racial disparities in outcomes after RP are conflicting. We studied 15,993 white and 1634 African American (AA) pretreatment-naïve men who underwent RP at our institution (1992-2013) with complete preoperative and pathologic data. Pathologic outcomes were compared between races using appropriate statistical tests; biochemical recurrence (BCR) for men with complete follow-up was compared using multivariate models that controlled separately for preoperative and postoperative covariates. RESULTS: Very low- and low-risk AA men were more likely to have positive surgical margins (P <.01), adverse pathologic features (P <.01), and be upgraded at RP (P <.01). With a median follow-up of 4.0 years after RP, AA race was an independent predictor of BCR among NCCN low-risk (HR, 2.16; P <.001) and intermediate-risk (hazard ratio [HR], 1.34; P = .024) classes and pathologic Gleason score ≤ 6 (HR, 2.42; P <.001) and Gleason score 7 (HR, 1.71; P <.001). BCR-free survival for very low-risk AA men was similar to low-risk white men (P = .890); BCR-free survival for low-risk AA men was similar to intermediate-risk white men (P = .060). CONCLUSION: When stratified by NCCN risk, AA men with very low-, low-, or intermediate-risk prostate cancer who undergo RP are more likely to have adverse pathologic findings and BCR compared with white men. AA men with "low risk" prostate cancer, especially those considering active surveillance, should be counseled that their recurrence risks can resemble those of whites in higher risk categories.

Allogeneic versus autologous blood transfusion and survival after radical prostatectomy.

BACKGROUND: Potential adverse effects of blood transfusion (BT) remain controversial, especially for clinical outcomes after curative cancer surgery. Some postulate that immune modulation after allogeneic BT predisposes to recurrence and death, but autologous superiority is not established. This study assessed whether BT is associated with long-term prostate cancer recurrence and survival with a large single-institutional radical prostatectomy (RP) database. STUDY DESIGN AND METHODS: Between 1994 and 2012, a total of 11,680 patients had RP with available outcome and transfusion data. A total of 7443 (64%) had complete covariate data. Clinical variables associated with biochemical recurrence-free survival (BRFS), cancer-specific survival (CSS), and overall survival (OS) were identified with Cox proportional hazards models for three groups: no BT (reference, 27.7%, n = 2061), autologous BT only (68.8%, n = 5124), and any allogeneic BT (with or without autologous, 3.5%, n = 258). RESULTS: Median (range) follow-up was 6 (1-18) years. Kaplan-Meier analysis showed significantly decreased OS (but not BRFS or PCSS) in the allogeneic group versus autologous and no BT groups (p = 0.006). With univariate analysis, any allogeneic BT had a hazard ratio (HR) of 2.29 (range, 1.52-3.46; p < 0.0001) for OS, whereas autologous BT was not significant (HR, 1.04 [range, 0.82-1.32], p = 0.752). In multivariable models, neither autologous nor allogeneic BT was independently associated with BRFS, CSS, or OS, and a dose response was not observed for allogeneic units and BRFS. CONCLUSION: Although allogeneic but not autologous BT was associated with decreased long-term OS, after adjustment for confounding clinical variables, BT was not independently associated with OS, BRFS, or CSS regardless of transfusion type. Notably, no association was observed between allogeneic BT and cancer recurrence. Observed differences in OS may reflect confounding.

Identification of men with the highest risk of early disease recurrence after radical prostatectomy.

BACKGROUND: Men destined to have early biochemical recurrence (BCR) following radical prostatectomy (RP) may be optimal candidates for multimodal treatment. Here we identified pre-operative predictors of early BCR within a surgical cohort who recurred. METHODS: An institutional prostate cancer (PCa) database containing over 20,000 patients was queried to identify 1,471 men who had BCR after RP, and pre-operative predictors of early versus late BCR were assessed. Early BCR was defined as recurrence within 1 year after RP. Within the recurrence cohort, those with National Comprehensive Cancer Network (NCCN) high-risk features were more likely to experience early BCR. Therefore, in all NCCN high-risk men in the database, we abstracted detailed pathologic biopsy data. Among 753 high-risk men, 41 alternate multivariable criteria were assessed for their ability to predict early BCR in crude and adjusted logistic regression models. RESULTS: The criteria that best identified those likely to experience early BCR are primary Gleason pattern 5 on biopsy or ≥4 cores containing pattern 4 (odds ratio 3.17, P < 0.001). These criteria included 26.7% of NCCN high-risk men. Additionally, these criteria selected for men within the high-risk classification who were at significantly higher risk of subsequent metastasis (adjusted hazard ratio 3.04, P < 0.001) and cancer-specific death (adjusted hazard ratio 3.27, P < 0.001). CONCLUSIONS: In men with PCa who present with high-risk features, pre-operative criteria have the ability to discriminate the subgroup most likely to experience early BCR after RP. Men at risk for early disease recurrence may be the most suitable candidates for multimodal therapy.

African American men with very low-risk prostate cancer exhibit adverse oncologic outcomes after radical prostatectomy: should active surveillance still be an option for them?

PURPOSE: Active surveillance (AS) is a treatment option for men with very low-risk prostate cancer (PCa); however, favorable outcomes achieved for men in AS are based on cohorts that under-represent African American (AA) men. To explore whether race-based health disparities exist among men with very low-risk PCa, we evaluated oncologic outcomes of AA men with very low-risk PCa who were candidates for AS but elected to undergo radical prostatectomy (RP). PATIENTS AND METHODS: We studied 1,801 men (256 AA, 1,473 white men, and 72 others) who met National Comprehensive Cancer Network criteria for very low-risk PCa and underwent RP. Presenting characteristics, pathologic data, and cancer recurrence were compared among the groups. Multivariable modeling was performed to assess the association of race with upgrading and adverse pathologic features. RESULTS: AA men with very low-risk PCa had more adverse pathologic features at RP and poorer oncologic outcomes. AA men were more likely to experience disease upgrading at prostatectomy (27.3% v 14.4%; P < .001), positive surgical margins (9.8% v 5.9%; P = .02), and higher Cancer of the Prostate Risk Assessment Post-Surgical scoring system (CAPRA-S) scores. On multivariable analysis, AA race was an independent predictor of adverse pathologic features (odds ratio, [OR], 3.23; P = .03) and pathologic upgrading (OR, 2.26; P = .03). CONCLUSION: AA men with very low-risk PCa who meet criteria for AS but undergo immediate surgery experience significantly higher rates of upgrading and adverse pathology than do white men and men of other races. AA men with very low-risk PCa should be counseled about increased oncologic risk when deciding among their disease management options.

Increased incidence of pathologically nonorgan confined prostate cancer in African-American men eligible for active surveillance.

OBJECTIVE: To compare the clinicopathologic findings of African-American (AA) and White-American (WA) men with prostate cancer (PCa) who were candidates for active surveillance (AS) and underwent radical prostatectomy (RP). METHODS: Prospectively maintained database of men who underwent RP from 2 academic centers were analyzed retrospectively. Postoperative pathologic characteristics of patients who met the AS inclusion criteria of the University of California, San Francisco (UCSF) and National Comprehensive Cancer Network (NCCN) were evaluated. After RP, the rate of pathological upstaging and Gleason upgrading were compared between AA and WA men. RESULTS: In the AA cohort, 196 and 124 men met the UCSF and NCCN criteria for AS, respectively. With respect to WA patients, 191 and 148 fulfilled the AS criteria for UCSF and NCCN, respectively. AA men had a higher percentage of maximum biopsy core than WA men (15.3%-20.4% vs 11.5%-15.0%, P <.05, respectively) in both cohorts. In addition, a greater proportion of AA men had multiple positive biopsy cores compared to WA men (45.2% vs 33.1%, P = .046) under the NCCN criteria. A higher proportion of AA men were upstaged (≥pT3) compared to WA men (19.4% vs 10.1%, P = .037). A multivariate regression test revealed that age, preoperative PSA, and number of positive cores were independent predictors of more advanced disease (upstaging and/or upgrading) in AA men. CONCLUSION: AA men who were candidates for AS criteria had worse clinicopathological features on final surgical pathology than WA men. These results suggest that a more stringent AS criteria should be considered in AA men with prostate cancer.

Contemporary evaluation of the National Comprehensive Cancer Network prostate cancer risk classification system.

OBJECTIVE: To analyze the National Comprehensive Cancer Network prostate cancer guidelines pretreatment risk groups in a contemporary series of patients treated with radical prostatectomy. METHODS: We analyzed our institutional radical prostatectomy database, including all patients with clinically localized disease treated from 2000 to 2010. Using the National Comprehensive Cancer Network guidelines, the patients were classified into low-, intermediate-, or high-risk groups. The pathologic outcomes were assessed, and the biochemical recurrence (BCR)-free survival rates were calculated and compared using the log-rank test and Cox proportional hazards analysis. RESULTS: A total of 12 821 men met the inclusion criteria. The pathologic and 10-year BCR-free survival rates differed significantly by risk group (low risk, 92.1%; intermediate risk, 71.0%; and high risk, 38.8%; P < .01). Among the intermediate-risk men, the 10-year BCR-free survival was significantly greater for men assigned to the intermediate-risk group by clinical stage (88.8%) than for those deemed intermediate risk by the Gleason score (73.6%) or prostate-specific antigen (PSA) level (79.5%; P = .01). Likewise, in the high-risk men, a trend was seen toward improved 5-year BCR-free survival for patients with clinical stage T3a tumors (77.8%) compared with those considered high risk because of the Gleason score (53.7%) or PSA level (41.0%; P = .13). On multivariate analysis, clinical stage, Gleason score, and PSA level were all significantly associated with BCR. CONCLUSION: We observed heterogeneous outcomes among patients within the National Comprehensive Cancer Network intermediate- and high-risk groups. The BCR-free survival rates were superior for men with an advanced clinical stage compared with those with an advanced Gleason score or elevated PSA level. This within-group heterogeneity must be considered when choosing the treatment modality and predicting an individual patient's prognosis.