David G. McLeod

Bilateral orchiectomy with or without flutamide for metastatic prostate cancer

BACKGROUND Combined androgen blockade for the treatment of metastatic prostate cancer consists of an antiandrogen drug plus castration. In a previous trial, we found that adding the antiandrogen flutamide to leuprolide acetate (a synthetic gonadotropin-releasing hormone that results in medical ablation of testicular function) significantly improved survival as compared with that achieved with placebo plus leuprolide acetate. In the current trial, we compared flutamide plus bilateral orchiectomy with placebo plus orchiectomy. METHODS We randomly assigned patients who had never received antiandrogen therapy and who had distant metastases from adenocarcinoma of the prostate to treatment with bilateral orchiectomy and either flutamide or placebo. Patients were stratified according to the extent of disease and according to performance status. RESULTS Of the 1387 patients who were enrolled in the trial, 700 were randomly assigned to the flutamide group and 687 to the placebo group. Overall, the incidence of toxic effects was minimal; the only notable differences between the groups were the greater rates of diarrhea and anemia with flutamide. There was no significant difference between the two groups in overall survival (P=0.14). The estimated risk of death (hazard ratio) for flutamide as compared with placebo was 0.91 (90 percent confidence interval, 0.81 to 1.01). Flutamide was not associated with enhanced benefit in patients with minimal disease. CONCLUSIONS The addition of flutamide to bilateral orchiectomy does not result in a clinically meaningful improvement in survival among patients with metastatic prostate cancer.

Age-Specific Reference Ranges for Serum Prostate-Specific Antigen in Black Men

BACKGROUND The detection of prostate cancer by screening for prostate-specific antigen (PSA) in serum is improved when age-specific reference ranges are used, but these ranges have been derived from white populations. We determined the distribution of PSA and age-specific reference ranges in black men both with and without prostate cancer. METHODS From January 1991 through May 1995, we measured serum PSA in 3475 men with no clinical evidence of prostate cancer (1802 white and 1673 black) and 1783 men with prostate cancer (1372 white and 411 black). We studied the data as a function of age and race to determine the usefulness of measuring PSA in diagnosing prostate cancer. RESULTS Serum PSA concentrations in black men (geometric mean in controls, 1.48 ng per milliliter; in patients, 7.46) were significantly higher than those in white men (geometric mean in controls, 1.33 ng per milliliter; in patients, 6.28). The values in the controls correlated directly with age. The area under the receiver-operating-characteristic curve was 0.91 for blacks and 0.94 for whites. If traditional age-specific reference ranges were used in screening black men, with the test specificity kept at 95 percent, 41 percent of cases of prostate cancer would be missed. For the test to have 95 percent sensitivity among black men, the following normal reference ranges should be used: for men in their 40s, 0 to 2.0 ng of PSA per milliliter (test specificity, 93 percent); for men in their 50s, 0 to 4.0 ng per milliliter (specificity, 88 percent); for men in their 60s, 0 to 4.5 ng per milliliter (specificity, 81 percent); and for men in their 70s, 0 to 5.5 ng per milliliter (specificity, 78 percent). CONCLUSIONS Serum PSA concentrations can be used to discriminate between men with prostate cancer and those without it among both blacks and whites. Over 40 percent of cases of prostate cancer in black men would not be detected by tests using traditional age-specific reference ranges, which maintain specificity at 95 percent. In this high-risk population, the alternative approach--maintaining sensitivity at 95 percent--may be used with acceptable decrements in specificity.

Pathologic Variables and Recurrence Rates As Related to Obesity and Race in Men With Prostate Cancer Undergoing Radical Prostatectomy

PURPOSE To determine if obesity is associated with higher prostate specific antigen recurrence rates after radical prostatectomy (RP), and to explore racial differences in body mass index (BMI) as a potential explanation for the disparity in outcome between black and white men. PATIENTS AND METHODS A retrospective, multi-institutional pooled analysis of 3,162 men undergoing RP was conducted at nine US military medical centers between 1987 and 2002. Patients were initially categorized as obese (BMI > or = 30 kg/m(2)), overweight (BMI 25 to 30 kg/m(2)), or normal (BMI < or = 25 kg/m(2)). For analysis, normal and overweight groups were combined (BMI < 30 kg/m(2)) and compared with the obese group (BMI > or = 30 kg/m(2)) with regard to biochemical recurrence (prostate-specific antigen > or = 0.2 ng/mL) after RP. RESULTS Of 3,162 patients, 600 (19.0%) were obese and 2,562 (81%) were not obese. BMI was an independent predictor of higher Gleason grade cancer (P <.001) and was associated with a higher risk of biochemical recurrence (P =.027). Blacks had higher BMI (P <.001) and higher recurrence rates (P =.003) than whites. Both BMI (P =.028) and black race (P =.002) predicted higher prostate specific antigen recurrence rates. In multivariate analysis of race, BMI, and pathologic factors, black race (P =.021) remained a significant independent predictor of recurrence. CONCLUSION Obesity is associated with higher grade cancer and higher recurrence rates after RP. Black men have higher recurrence rates and greater BMI than white men. These findings support the hypothesis that obesity is associated with progression of latent to clinically significant prostate cancer (PC) and suggest that BMI may account, in part, for the racial variability in PC risk.

Frequent overexpression of ETS-related gene-1 (ERG1) in prostate cancer transcriptome.

Transcription factors encoded by the ETS family of genes are central in integrating signals that regulate cell growth and differentiation, stress responses, and tumorigenesis. This study, analysing laser microdissected paired benign and malignant prostate epithelial cells from prostate cancer (CaP) patients (n=114; 228 specimen) by GeneChip and quantitative real-time RT–PCR, identifies ETS-related gene (ERG), a member of the ETS transcription factor family, as the most frequently overexpressed proto-oncogene in the transcriptome of malignant prostate epithelial cells. Combined quantitative expression analysis of ERG with two other genes commonly overexpressed in CaP, AMACR and DD3, revealed overexpression of at least one of these three genes in virtually all CaP specimen (54 of 55). Comprehensive evaluation of quantitative ERG1 expression with clinicopathological features also suggested that ERG1 expression level in prostate tumor cells relative to benign epithelial cells is indicator of disease-free survival after radical prostatectomy.

Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer

To evaluate, in the ongoing Early Prostate Cancer (EPC) trial programme, the efficacy and tolerability of bicalutamide 150 mg once daily in addition to standard care for localized or locally advanced, nonmetastatic prostate cancer.

Bicalutamide as Immediate Therapy Either Alone or as Adjuvant to Standard Care of Patients with Localized or Locally Advanced Prostate Cancer: First Analysis of the Early Prostate Cancer Program

PURPOSE We determine the efficacy and tolerability of bicalutamide as immediate therapy, either alone or as adjuvant to treatment of curative intent, in patients with clinically localized or locally advanced prostate cancer. MATERIALS AND METHODS This international program consists of 3 ongoing, randomized, double-blind, placebo controlled clinical trials (trials 23, 24, and 25). Men with localized or locally advanced (T1-T4, Nx/N0, M0) prostate cancer were randomized to receive 150 mg. bicalutamide daily or placebo, in addition to standard care with radical prostatectomy, radiotherapy or watchful waiting. Primary end points are time to objective progression and overall survival. In this first analysis data from the trials were combined in a single overview analysis according to protocol. RESULTS Data are available for 8,113 patients (4,052 randomized to bicalutamide, 4,061 to standard care alone) at a median followup of 3.0 years. Treatment with bicalutamide provided a highly significant reduction of 42% in the risk of objective progression compared with standard care alone (9.0% versus 13.8%, hazards ratio 0.58; 95% confidence interval 0.51, 0.66; p <<0.0001). The overall result was reflected in 2 of the 3 trials (trials 24 and 25) with trial 3 (trial 23) showing a nonsignificant difference at this time. Reductions in the risk of disease progression were seen across the entire patient population, irrespective of primary treatment or disease stage. Overall survival data are currently immature and longer followup will determine if there is also a survival benefit with bicalutamide. The most frequently reported side effects of bicalutamide were gynecomastia and breast pain. CONCLUSIONS Immediate treatment with 150 mg. bicalutamide daily, either alone or as adjuvant to treatment of curative intent, significantly reduces the risk of disease progression in patients with localized or locally advanced prostate cancer. This benefit must be balanced with the morbidity associated with long-term hormonal therapy. Followup is ongoing to determine potential survival benefits of this treatment approach.

Early versus delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy

PURPOSE Hormonal therapy (HT) is the current mainstay of systemic treatment for prostate specific antigen (PSA) only recurrence (PSAR), however, there is virtually no published literature comparing HT to observation in the clinical setting. The goal of this study was to examine the Department of Defense Center for Prostate Disease Research observational database to compare clinical outcomes in men who experienced PSAR after radical prostatectomy by early versus delayed use of HT and by a risk stratified approach. MATERIALS AND METHODS Of 5,382 men in the database who underwent primary radical prostatectomy (RP), 4,967 patients were treated in the PSA-era between 1988 and December 2002. Of those patients 1,352 men who had PSAR (PSA after surgery greater than 0.2 ng/ml) and had postoperative followup greater than 6 months were used as the study cohort. These patients were further divided into an early HT group in which patients (355) received HT after PSA only recurrence but before clinical metastasis and a late HT group for patients (997) who received no HT before clinical metastasis or by current followup. The primary end point was the development of clinical metastases. Of the 1,352 patients with PSAR clinical metastases developed in 103 (7.6%). Patients were also stratified by surgical Gleason sum, PSA doubling time and timing of recurrence. Univariate and multivariate Cox proportional hazard models were used to evaluate the effect of early and late HT on clinical outcome. RESULTS Early HT was associated with delayed clinical metastasis in patients with a pathological Gleason sum greater than 7 or PSA doubling time of 12 months or less (Hazards ratio = 2.12, p = 0.01). However, in the overall cohort early HT did not impact clinical metastases. Race, age at RP and PSA at diagnosis had no effect on metastasis-free survival (p >0.05). CONCLUSIONS The retrospective observational multicenter database analysis demonstrated that early HT administered for PSAR after prior RP was an independent predictor of delayed clinical metastases only for high-risk cases at the current followup. Further study with longer followup and randomized trials are needed to address this important issue.

Elevated levels of apoptosis regulator proteins p53 and BCL-2 are independent prognostic biomarkers in surgically treated clinically localized prostate cancer

PURPOSE The tumor suppressor gene (TSG) p53 and the proto-oncogene bcl-2 have been shown to be involved in the regulation of cell growth and apoptosis and have been implicated in hormone refractory prostate cancer (PC) and poor prognosis. The goal of this study was to determine the clinical utility of the presence of p53 and bcl-2 immunohistochemical (IHC) protein in the primary tumor as predictors of disease progression following radical prostatectomy (RP). MATERIALS AND METHODS The expression of p53 and bcl-2 was evaluated in archival paraffin-embedded RP specimens from 175 patients followed from 1 to 9 years (mean = 4.6 years) and correlated with stage, grade, race and serologic (PSA) recurrence following surgery. RESULTS Overexpression of bcl-2 was noted in 47 of 175 (26.9%) patients; these patients had a significantly higher 5-year failure rate than those who did not overexpress bcl-2 (67.0% versus 30.7%). Expression of p53 was noted in 114 of 175 (65.1%) patients with a 5-year failure rate of 51.1% compared with a 5-year failure rate of only 22% in p53 negative patients. When expression rates for p53 and bcl-2 were combined, the 5-year failure rate was 75.3%. Conversely, when both p53 and bcl-2 IHC staining were negative, the 5-year failure rate was 20.4%. Univariate Kaplan-Meier analysis showed a statistically significant difference between p53 and bcl-2 positive and negative patients (p < 0.001). Multivariate Cox Regression Analysis with backward elimination controlling for age, race, stage and grade showed both p53 (p = .0185) and bcl-2 (p = .004) to be independent predictors of disease-free survival. CONCLUSION p53 and bcl-2 appear to be important biomarkers that predict recurrence in clinically localized PC after RP.

MULTICENTER PATIENT SELF-REPORTING QUESTIONNAIRE ON IMPOTENCE, INCONTINENCE AND STRICTURE AFTER RADICAL PROSTATECTOMY

PURPOSE We determined the incidence of patient self-reported post-prostatectomy incontinence, impotence, bladder neck contracture and/or urethral stricture, sexual function satisfaction, quality of life and willingness to undergo treatment again in a large multicenter group of men who underwent radical prostatectomy. We also determined whether the morbidities of sexual function satisfaction, quality of life and bladder neck contracture and/or urethral stricture are predictable from demographic and postoperative prostate cancer factors. MATERIALS AND METHODS A self-reporting questionnaire was completed and returned by 1,069 of 1,396 eligible patients (77%) who underwent radical prostatectomy between 1962 and 1997. Of the respondents 868 (85.7%) underwent surgery after 1990 and in all prostatectomy had been done a minimum of 6 months previously. Questionnaire results were independently analyzed by a third party for morbidity tabulation and the association of patient reported satisfaction. RESULTS The patient self-reported incidence of any degree of post-prostatectomy incontinence, impotence and bladder neck contracture or urethral stricture was 65.6%, 88.4% and 20.5%, respectively. The incidence of incontinence requiring protection was 33% and only 2.8% of respondents had persistent bladder neck contracture or urethral stricture. Although incontinence and impotence significantly affected self-reported sexual function satisfaction, quality of life and willingness to undergo treatment again (p = 0.001), 77.5% of patients would elect surgery again. This finding remained true even after adjusting for demographic variables, and the time between surgery and the survey by multiple logistic regression. CONCLUSIONS Although radical prostatectomy morbidity is common and affects self-reported overall quality of life, most patients would elect the same treatment again. Impotence and post-prostatectomy incontinence were significantly associated with sexual function satisfaction, quality of life and willingness to undergo treatment again. Bladder neck contracture and/or urethral stricture was associated with willingness to undergo treatment again after adjusting for demographic variables and time from surgery to the survey.

Black Race is an Adverse Prognostic Factor for Prostate Cancer Recurrence Following Radical Prostatectomy in an Equal Access Health Care Setting

PURPOSE We determined if black men with clinically localized adenocarcinoma of the prostate have the same recurrence-free outcome following radical prostatectomy, and whether they have similar preoperative, operative and pathological characteristics as white men in an equal access health care environment. MATERIALS AND METHODS We studied consecutive single hospital case series of 366 white and 107 black patients who underwent radical prostatectomy between 1975 and February 29, 1995. Evaluation included comprehensive retrospective chart review, prospective data collection and proactive followup. Univariate and multivariate statistical analyses were done of preoperative, operative, pathological and recurrence data by race. RESULTS Although the incidences of hypertension and diabetes, pretreatment prostate specific antigen (PSA) and serum creatinine measurements, elevated PSA as an indication for biopsy and clinical stage were greater in black men, the operative variables of blood loss, operative time and performance of a nerve sparing procedure were not different. The incidence of margin positivity was greater in black patients but pathological stage, Gleason score and seminal vesicle or nodal involvement were not different. Black race was an adverse prognostic factor for recurrence following radical prostatectomy after multivariate adjustment for pretreatment PSA and acid phosphatase, organ confinement status and tumor grade. CONCLUSIONS The poorer recurrence-free outcome for black patients even after multivariate adjustment suggests a potentially more aggressive variant of prostate cancer in this population, the etiology of which is unknown. Race should be a stratification factor in clinical trials, especially those including radical prostatectomy and using recurrence-free outcome as an end point.