William J. Aronson

Impact of Obesity on Biochemical Control After Radical Prostatectomy for Clinically Localized Prostate Cancer: A Report by the Shared Equal Access Regional Cancer Hospital Database Study Group

PURPOSEnGiven the limited information regarding the impact of obesity on treatment outcomes for prostate cancer, we sought to examine the relationship between body mass index (BMI) and cancer control after radical prostatectomy (RP).nnnPATIENTS AND METHODSnWe compared clinicopathologic and biochemical outcome information across BMI groups from 1,106 men treated with RP between 1988 and 2002. Multivariate analysis was used to determine if BMI significantly predicted adverse pathology or biochemical recurrence.nnnRESULTSnObesity was related to year of surgery (P <.001) and race (P <.001), with black men having the highest obesity rates. Obese patients had higher biopsy and pathologic grade tumors (P <.001). On multivariate analysis, BMI > or = 35 kg/m(2) was associated with a trend for higher rates of positive surgical margins (P =.008). Overweight patients (BMI, 25 to 30 kg/m(2)) had a significantly decreased risk of seminal vesicle invasion (P =.039). After controlling for all preoperative clinical variables including year of surgery, BMI > or = 35 kg/m(2) significantly predicted biochemical failure after RP (P =.002). After controlling for surgical margin status, BMI > or = 35 kg/m(2) remained a significant predictor of biochemical failure (P =.012). There was a trend for BMI > or = 35 kg/m(2) to be associated with higher failure rates than BMI between 30 and 35 kg/m(2) (P =.053).nnnCONCLUSIONnThe percentage of obese men undergoing RP in our data set doubled in the last 10 years. Obesity was associated with higher-grade tumors, a trend toward increased risk of positive surgical margins, and higher biochemical failure rates among men treated with RP. A BMI > or = 35 kg/m(2) was associated with a higher risk of failure than a BMI between 30 and 35 kg/m(2).

Defining the ideal cutpoint for determining PSA recurrence after radical prostatectomy

OBJECTIVESnTo determine the ideal cutpoint for defining prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP). Although various cutpoints have been used, a recent study suggested that 0.4 ng/mL may be the most appropriate.nnnMETHODSnA retrospective survey of 358 men undergoing RP at the West Los Angeles Veterans Affairs Medical Center between 1991 and 2001 was undertaken. The 3-year and 5-year risk of PSA recurrence was estimated by Kaplan-Meier analyses using various cutpoints of postoperative PSA to define recurrence: greater than 0.1, greater than 0.2, greater than 0.3, greater than 0.4, and greater than 0.5 ng/mL. The 1 and 3-year risk of PSA progression after a detectable PSA level (PSA rising to a higher cutpoint) was evaluated for each definition of PSA recurrence using Kaplan-Meier analyses. Multivariate analysis using a Cox proportional hazards model was used to determine the clinical variables that were significant independent predictors of PSA recurrence at each cutpoint.nnnRESULTSnFor patients with a detectable postoperative PSA value from 0.11 to 0.2 ng/mL, the 1 and 3-year risk of PSA progression was 64% (95% confidence interval [CI] 46% to 82%) and 93% (95% CI 74% to 99%), respectively. For patients with a PSA value from 0.21 to 0.3 ng/mL, the 1 and 3-year risk of PSA progression was 86% (95% CI 69% to 97%) and 100% (95% CI 87% to 100%), respectively. The use of higher PSA cutpoints to define recurrence resulted in a lower 5-year risk of PSA recurrence. The 5-year risk of PSA recurrence using a greater than 0.1 ng/mL cutpoint resulted in a 43% (95% CI 36% to 50%) risk of recurrence compared with only 23% (95% CI 18% to 30%) for a greater than 0.5 ng/mL cutpoint. In multivariate analysis, PSA and biopsy Gleason score were significant independent predictors of biochemical recurrence, regardless of the definition of PSA recurrence used (P <or=0.002).nnnCONCLUSIONSnPSA and biopsy Gleason score were significant predictors of biochemical failure, regardless of the definition of failure used. However, the definition of PSA recurrence dramatically affected the perceived success of therapy. Patients with a postoperative PSA value greater than 0.2 ng/mL are at very high risk of developing an additional rise in PSA. On the basis of this finding, a PSA value greater than 0.2 ng/mL is an appropriate cutpoint to define PSA recurrence after RP.

Time trends in biochemical recurrence after radical prostatectomy: results of the SEARCH database

OBJECTIVESnTo determine whether in the prostate-specific antigen (PSA) era stage and/or grade migration of patients treated with radical prostatectomy (RP) has occurred. We also examined whether the biochemical recurrence rates after RP have changed with time.nnnMETHODSnA total of 1654 patients from the Shared Equal Access Regional Cancer Hospital (SEARCH) database were analyzed for time trends in age, preoperative PSA level, clinical stage, biopsy Gleason score, prostatectomy Gleason grade, pathologic stage, margin status, and recurrence rates after RP. Results were stratified into three 4-year blocks of time between 1988 and 2002 for analysis.nnnRESULTSnThe preoperative PSA level, patient age, tumor stage, rate of capsular penetration, and lymph node involvement decreased with time. Both biopsy and pathologic Gleason grade steadily increased with time. The positive margin rate and incidence of seminal vesicle involvement remained stable. On multivariate analysis, only serum PSA level (P <0.001) and biopsy Gleason score (P <0.001) were significant independent predictors of the time to recurrence after RP. The year of surgery was not a significant independent predictor of biochemical recurrence after RP in multivariate analysis.nnnCONCLUSIONSnDespite lower stage and lower PSA levels with time, we found no improvement in PSA recurrence rates over time. This may reflect lead-time bias in detecting PSA recurrence by the use of more sensitive PSA assays in recent years.

Comparison of percentage of total prostate needle biopsy tissue with cancer to percentage of cores with cancer for predicting PSA recurrence after radical prostatectomy: results from the SEARCH database

OBJECTIVESnTumor volume in the prostate needle biopsy is an important prognosticator for patients with prostate cancer. However, the best method to measure tumor volume in the prostate needle biopsy is unknown. We compared the total percentage of biopsy tissue with cancer to the percentage of cores positive for their ability to predict adverse pathologic findings and biochemical failure after radical prostatectomy (RP).nnnMETHODSnA retrospective survey of 355 patients from the Shared Equal Access Regional Cancer Hospital database treated with RP between 1990 and 2002 was undertaken. Multivariate analysis was used to compare the percentage of cores and percentage of tissue with cancer to the standard clinical variables of age, prostate-specific antigen (PSA) level, biopsy Gleason score, and clinical stage for their ability to predict positive surgical margins, non-organ-confined disease, seminal vesicle invasion, and time to PSA recurrence after RP.nnnRESULTSnOn multivariate analysis, the percentage of tissue with cancer significantly predicted non-organ-confined disease and seminal vesicle invasion, but the percentage of cores did not significantly predict any of the pathologic features examined. In separate multivariate analysis, only the percentage of tissue with cancer, but not the percentage of cores with cancer, significantly predicted PSA failure. Moreover, when compared in the same multivariate analysis, only the percentage of tissue with cancer (hazard ratio 8.25, 95% confidence interval 3.06 to 22.22, P <0.001) was a significant predictor. The area under the receiver operating curves for predicting PSA failure was significantly greater for the percentage of tissue with cancer (0.697) than for the percentage of cores (0.644, P = 0.022). Cutpoints for the percentage of tissue with cancer (less than 20%, 20% to 40%, and greater than 40%) and the percentage of cores (less than 34%, 34% to 50%, greater than 50%) both provided significant preoperative risk stratification for biochemical failure, although the percentage of tissue with cancer cutpoints provided better risk stratification (higher hazard ratios and lower P value). Cutpoints for the percentage of tissue with cancer but not the percentage of cores positive further stratified patients who were at low (P = 0.041), intermediate (P = 0.002), and high (P = 0.023) risk on the basis of the PSA level and biopsy Gleason score.nnnCONCLUSIONSnThe percentage of tissue with cancer was better than the percentage of cores at predicting advanced pathologic features and PSA recurrence after RP. Unlike the percentage of cores, the percentage of tissue with cancer cutpoints further stratified low, intermediate, and high-risk patients on the basis of PSA level and biopsy Gleason score. Although the percentage of tissue with cancer is a slightly more cumbersome measurement than the percentage of positive cores, it provided statistically and clinically superior preoperative risk stratification for biochemical failure after RP.

Effect of Isocaloric Low-Fat Diet on Prostate Cancer Xenograft Progression to Androgen Independence

An isocaloric low-fat diet has been shown to slow androgen-sensitive Los Angeles Prostate Cancer-4 (LAPC-4) tumor growth in a mouse xenograft model. LAPC-4 cells were injected into male severe combined immunodeficient mice. After palpable tumors developed, the mice were divided into three groups, high-fat intact, high-fat castration, and low-fat castration. Tumor latency (18 versus 9 weeks; P < 0.001) and mouse survival (20.8 ± 1.3 versus 13 ± 0.7 weeks; P < 0.01) were significantly longer in the low-fat castration versus high-fat castration group. Reduced dietary fat intake delayed conversion from androgen-sensitive to -insensitive prostate cancer and significantly prolonged survival of severe combined immunodeficient mice bearing LAPC-4 xenografts.

Risk factors for male osteoporosis

Hypogonadism from long-term androgen deprivation therapy (ADT), either by bilateral orchiectomy or administration of gonadotropin-releasing hormone (GnRH) agonists, causes significant and accelerated bone loss that may increase the risk of bone fractures in men with prostate cancer. Recent reports, as well as new data from our institution, have shown a high prevalence of pre-existing osteopenia and osteoporosis in men with prostate cancer before receiving ADT, and this is of great concern because of the risk of further bone loss during ADT. Data from these studies suggest the urgent need for clinical guidelines for screening, prevention, and treatment of these cases. This article reviews the prevalence and risk factors associated with osteoporosis in men and addresses risk factors in men with prostate cancer not receiving ADT. Considerations for the patient selection and timing of bone densitometry will also be discussed.

Natural history of persistently elevated prostate specific antigen after radical prostatectomy: results from the SEARCH database.

PURPOSEnWe examined natural history, predictors of biochemical recurrence and all cause mortality in patients with persistently elevated prostate specific antigen after radical prostatectomy in the Shared Equal Access Regional Cancer Hospital cohort.nnnMATERIALS AND METHODSnWe reviewed data on 1,156 men treated with radical prostatectomy after 1997. Prostate specific antigen persistence was defined as failure to achieve prostate specific antigen less than 0.03 ng/ml within 6 months postoperatively. Disease-free and overall survival was compared between men with and without persistence using the log rank test. Predictors of biochemical recurrence and all cause death were analyzed using the Cox model.nnnRESULTSnA total of 291 men (25%) had persistence, which was associated with increased biochemical recurrence and all cause death (p <0.001 and 0.041, respectively). In patients with persistence 1 and 5-year biochemical recurrence-free survival was 68% and 36%, significantly lower than 95% and 72%, respectively, in men without persistence. Ten-year overall survival in patients with vs without persistence was 63% vs 80%. In men with persistence independent predictors of prostate specific antigen recurrence were higher prostate specific antigen nadir (HR 2.19, p <0.001), positive surgical margins (HR 1.75, p = 0.022) and high pathological Gleason score (8-10 vs 2-6 HR 2.40, p = 0.026). Independent predictors of overall mortality were a higher prostate specific antigen nadir (HR 1.46, p = 0.013) and seminal vesicle invasion (HR 3.15, p = 0.047).nnnCONCLUSIONSnProstate specific antigen persistence is associated with increased biochemical recurrence and overall mortality. In men with persistence the prostate specific antigen nadir is an independent predictor of recurrence and mortality. Thus, prostate specific antigen persistence and nadir are important tools for early postoperative risk stratification.

What are the Factors Associated With Short Prostate Specific Antigen Doubling Time After Radical Prostatectomy? A Report From the SEARCH Database Group

PURPOSEnShort prostate specific antigen doubling time following recurrence after radical prostatectomy portends a poor prognosis in men with prostate cancer. We determined which demographic and clinicopathological variables were predictive of a short prostate specific antigen doubling time in a cohort of men with clinically localized prostate cancer treated with radical prostatectomy.nnnMATERIALS AND METHODSnData on 856 men from the Shared Equal Access Regional Cancer Hospital database who underwent radical prostatectomy for node negative prostate cancer between 1988 and 2003 were included in the analysis. We used logistic regression analysis to determine the independent factors associated with a short prostate specific antigen doubling time of less than 9 months vs a longer doubling time of 9 months or greater, or no recurrence. The variables analyzed were patient age, race, logarithmically transformed preoperative prostate specific antigen, body mass index, year of surgery, pathological Gleason sum, extraprostatic extension, surgical margin status and seminal vesicle invasion.nnnRESULTSnOn multivariate analysis higher preoperative prostate specific antigen (OR 2.20, 95% CI 1.52-3.19, p <0.001), pathological Gleason sum 8-10 (OR 4.70, 95% CI 2.11-10.43, p <0.001) and 7 (OR 2.11, 95% CI 1.09-4.08, p = 0.026), tumors with extraprostatic extension and/or positive surgical margins (OR 2.08, 95% CI 1.48-3.91, p = 0.023), and seminal vesicle invasion (OR 3.26, 95% CI 1.48-7.21, p = 0.003) were independent predictors of a short prostate specific antigen doubling time. Based on these risk factors we developed a table to estimate the risk of recurrence with a prostate specific antigen doubling time of less than 9 months.nnnCONCLUSIONSnThe factors that are invariably used to predict overall biochemical recurrence following radical prostatectomy, including high prostate specific antigen, high grade and adverse pathological findings, also predict aggressive recurrence.

Preclinical Models Relevant to Diet, Exercise, and Cancer Risk

Metabolic syndrome was initially described as an aggregation of risk factors for the development of coronary artery disease with insulin resistance and compensatory hyperinsulinemia as the underlying factor. In an earlier review, we suggested that hyperinsulinemia may also lead to prostate cancer (PCa), the most common male cancer in industrialized nations. Furthermore, we suggested that diet and exercise, known to be important in the development of insulin resistance, may also be important in the development of PCa. When we placed men from the United States on a low-fat diet and/or exercise program, serum levels of insulin, free testosterone, estradiol and insulin-like growth factor (IGF)-1 were reduced while sex hormone-binding globulin (SHBG) and insulin-like growth factor binding protein (IGFBP)-1 were elevated. These in vivo serum changes directly impacted on androgen-dependent prostate cancer cell lines in vitro to reduce cell growth and induce apoptosis. The reduction in serum IGF-1 and increase in IGFBP-1 with diet and exercise appear to be the most significant, as these changes lead to an increase in tumor cell p53 protein and its down-stream effector p21, which are responsible for the reduction in cell growth and induced apoptosis. Preliminary results from a clinical study with men on watchful waiting indicate that the observed in vitro effects of diet and exercise on prostate cancer cell growth also occur in vivo.

Predicting biochemical recurrence after radical prostatectomy for patients with organ-confined disease using p27 expression☆

OBJECTIVESnIt is unclear why men who undergo radical prostatectomy (RP) and are found to have pathologically organ-confined disease develop prostate-specific antigen (PSA) recurrences. We previously found that patients with less than 45% of cells in the prostate needle biopsy specimen (PNBx) staining positive for the cell cycle regulator p27 had a significantly increased risk of biochemical recurrence after RP. We sought to determine whether p27 staining in the PNBx specimen might serve as a molecular marker for PSA failure in the subset of patients who develop PSA recurrence despite organ-confined disease at RP.nnnMETHODSnThe PNBx specimens of 161 men treated with RP between 1991 and 2000 were examined for p27 expression using immunohistochemistry. The p27 cutpoint of less than 45% expression was used to define the high and low-risk categories. Patients were separated into two groups for analysis: organ-confined (pT2 and negative surgical margins) and non-organ-confined (pT2 with positive surgical margins, pT3, pT4, or lymph node involvement). The mean and median follow-up for patients with organ-confined and non-organ-confined disease was 47 and 43 months and 42 and 38 months, respectively. Multivariate Cox proportional hazards analysis was used to examine the preoperative clinical variables that were the strongest predictors of biochemical recurrence after RP among each group.nnnRESULTSnAmong organ-confined patients, p27 expression was the only significant independent predictor of the time to biochemical recurrence after RP (hazard ratio 5.15, 95% confidence interval 1.41 to 18.83, P = 0.013). Among patients with non-organ-confined disease, the percentage of biopsy tissue with cancer, biopsy Gleason score, and PSA level were independent predictors of PSA recurrence. p27 expression was not a significant independent predictor of PSA recurrence among men with non-organ-confined disease.nnnCONCLUSIONSnp27 expression in the PNBx was a significant independent predictor of PSA failure for patients with pathologically organ-confined disease, but not for those with non-organ-confined disease. Patients with organ-confined disease but low p27 expression had a greater than fivefold risk of developing PSA recurrence than were men with high p27 expression, suggesting that p27 may be a molecular marker associated with micrometastatic disease at the time of RP.