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Originally published as JCO Early Release 10.1200/JCO.2004.04.181 on December 22 2003 © 2004 American Society of Clinical Oncology. 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 GroupFrom the Department of Urology, The Johns Hopkins School of Medicine, Baltimore, MD; Department of Urology and Department of Biostatistics, UCLA School of Medicine; Department of Surgery, Veterans Administration Greater Los Angeles Healthcare System, Los Angeles; Urology Section, Department of Surgery, Veterans Administration Medical Center San Francisco; Department of Urology, University of California San Francisco School of Medicine, San Francisco; Department of Urology, Stanford University School of Medicine, Palo Alto; Department of Urology, San Diego Naval Hospital, San Diego, CA; and Section of Urology, Medical College of Georgia, Augusta, GA. Address reprint requests to Stephen J. Freedland, MD, Department of Urology, The Johns Hopkins School of Medicine, 600 N Wolfe St, Baltimore, MD 21287-2101; e-mail: sfreedl1{at}jhmi.edu.
PURPOSE: Given 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). PATIENTS AND METHODS: We 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.
RESULTS: Obesity 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
CONCLUSION: The 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
Obesity is a major public health problem, and has been associated with multiple chronic diseases including coronary artery disease, hypertension, and diabetes [1-3]. It is estimated that more than 30% of the adult US population is obese [4]. Obesity has also been linked to several types of cancer, including breast and colon [5]. The relationship between obesity and prostate cancer (CaP) is less clear, with some studies showing an increased and others showing a decreased risk [6-9]. There are several potential mechanisms by which obesity could lead to CaP, including increased serum levels of insulin-like growth factor 1 and estrogenic compounds, and decreased sex hormone–binding globulin [10-12]. Although some studies suggest that obese men are more likely to develop androgen-independent disease and more likely to die from CaP [13-16], others found conflicting results [17,18]. Although the majority of men newly diagnosed with CaP will have early-stage disease, little is known about the impact of obesity on outcomes of primary therapy for clinically localized disease. Although several studies found increased body mass index (BMI) was associated with advanced pathology [19,20] and higher Gleason scores [19,21] among men treated with radical prostatectomy (RP), no studies have examined the relationship between obesity and biochemical failure after primary therapy. We sought to determine the impact of obesity on adverse pathologic findings and biochemical recurrence after RP among a racially diverse population with clinically localized CaP. To accomplish this, we used the multicenter Shared Equal Access Regional Cancer Hospital (SEARCH) database [22]. The SEARCH database contains clinical, pathologic, and biochemical follow-up data from men treated with RP at five equal access medical centers.
After obtaining institutional review board approval from each institution, data from 1,752 consecutive patients (excluding patients treated with preoperative androgen deprivation or radiation therapy) treated with RP from 1988 to 2002 at the West Los Angeles, Palo Alto, San Francisco (CA), and Augusta (GA) Veteran’s Administration Medical Centers (VAMCs), and the San Diego Naval Medical Center (CA), were combined into the SEARCH database. This database includes information on patient age, race, height, weight, clinical stage, grade of cancer on diagnostic biopsies, preoperative prostate-specific antigen (PSA) levels, surgical specimen pathology (tumor grade, stage, and surgical margin status), and follow-up PSA levels for a mean and median of 46 and 33 months (range, 1 to 174 months) as listed in Table 1. Patients without data regarding height or weight were excluded (n = 643). These 643 excluded patients were, in general, higher risk than those in the cohort included for analysis, and had significantly higher biopsy Gleason scores and PSA values, although the absolute differences were slight. They were also older, more likely to be treated in earlier years, and more likely to have clinical stage T2 tumors than the cohort analyzed. Because we sought to examine the impact of obesity on patients with clinical localized disease, patients with clinical T3 disease (n = 3) were excluded, resulting in a study population of 1,106 patients: 646 patients were treated at the San Diego Naval Medical Center, 351 patients were treated at the West Los Angeles VAMC, 95 patients were treated at the Augusta VAMC, and 14 patients were treated at the Palo Alto VAMC.
The prostatectomy specimens were sectioned in accordance with each institution's protocol [23-26]. Biochemical recurrence (PSA failure) was defined as a single PSA more than 0.2 ng/mL or two values at 0.2 ng/mL. Patients with no follow-up data (n = 47) were included for the evaluation of differences in preoperative and pathologic characteristics, but not biochemical recurrence.
BMI (weight in kilograms divided by height in meters squared) was examined as a continuous and a categoric variable using the National Institutes of Health definitions of normal weight (< 25 kg/m2), overweight ( Because the year of surgery was strongly correlated with BMI (Spearman, year of surgery v BMI, r = 0.138; P < .001) and was therefore a potential confounder when BMI was analyzed as a predictor of PSA outcome, year of surgery was forced to remain in the multivariate model for predicting PSA failure irrespective of the P value. To control for the potential confounding effect of the year of surgery, a standardized 3-year risk of PSA recurrence was determined using the Kaplan-Meier survivor estimate adjusting for year of surgery by standardizing the data to the first year of data collection, 1988. All clinical (age, clinical stage, PSA, BMI, and biopsy Gleason score) and pathologic variables (surgical Gleason score, pathologic stage, extracapsular extension rates, margin status, seminal vesicle invasion, and lymph node positivity) were similar between the centers, and therefore data for all centers were combined for analysis. All statistical analyses were performed using STATA software, version 7.0 (Stata Corp, College Station, TX).
Table 1 demonstrates the clinical and pathologic characteristics of the study population segregated by preoperative BMI grouping. Obesity (BMI  30 kg/m2) was significantly related to race, with black men having the highest obesity rate (31%), followed by white men (21%), with nonwhite-nonblack men having the lowest rate (13%). When examining mean BMI (plus or minus standard deviation), a similar pattern was noted, with black men having the highest BMI values (28.2 ± 4.8 kg/m2), followed by white men (27.4 ± 4.4 kg/m2), and with nonwhite-nonblack men having the lowest BMI values (26.3 ± 3.4 kg/m2). Obese patients were younger with higher biopsy and pathologic Gleason scores. Over time, there was a steady increase in BMI (Spearman, year of surgery v BMI, r = 0.138; P < .001; Fig 1). For patients treated between 1988 and 1990, 12% were mildly obese and 1% were moderately or severely obese compared with 18% mildly obese and 8% moderately or severely obese among patients treated between 2000 and 2002.
Because we previously found Gleason scores also increased over time [27], we examined whether the relationship between BMI and Gleason score merely reflected the changing nature of patients undergoing RP over time. When linear regression analysis controlling for year of surgery was used, BMI grouping remained a significant predictor of both biopsy (P = .010) and pathologic Gleason score (P = .001).
Multivariate logistic regression analysis was used to determine if BMI, after adjusting for other preoperative clinical variables, was significantly associated with the adverse pathologic findings of positive surgical margins, extracapsular extension, and seminal vesicle invasion. Using BMI less than 25 kg/m2 as the referent category, BMI During a mean and median follow-up of 46 and 33 months, respectively, among men who did not experience disease recurrence, 304 patients (29%) developed a biochemical recurrence. Because year of surgery was highly correlated with BMI, we first sought to examine the potential confounding effect of year of surgery on the risk of PSA failure. There was a weak association between year of surgery and time to PSA failure, with more recently treated patients having higher failure rates, although this did not reach statistical significance (Cox model; hazard ratio [HR], 1.03 for each one more recent year; 95% CI, 1.00 to 1.07; P = .056). However, between 1988 and 1990, only 51 of 114 patients (45%) had preoperative PSA values obtained, reflecting an overall poor use of PSA testing. Given that using an end point of PSA recurrence requires PSA monitoring, it is possible that biochemical recurrences during this time were detected later because PSA levels were not monitored, resulting in an apparent survival benefit for patients treated during this time. Therefore, we performed an analysis in which we excluded patients treated between 1988 and 1990 and separately examined only men treated since 1990, and found no significant relationship between year of surgery and PSA failure (Cox model; HR, 1.01 for each one more recent year; 95% CI, 0.97 to 1.05; P = .676)
Using a log-rank survivorship analysis, BMI grouping was significantly correlated to PSA failure, with obese patients having higher recurrence rates (log-rank P = .007; Fig 2). When two-way comparisons were performed, overweight patients had similar outcomes as men with normal weight (P = .463). Mildly obese men had slightly worse outcomes than men with normal weight or overweight men, although this did not reach statistical significance (P = .080 v overweight; P = .294 v normal weight). Moderately and severely obese men had significantly higher PSA failure rates than normal weight (P = .003) and overweight men (P = .002). There was a trend for moderately and severely obese men to have higher recurrence rates than mildly obese men, although this did not reach statistical significance (P = .053). To further explore the relationship between BMI and PSA failure, patients were divided into groups by each 2.5 kg/m2 separation in BMI and the actuarial risk of early (3 year) PSA failure was determined after the data for year of surgery were standardized (Fig 3). It is clear from Figure 3 that the risk of PSA failure did not dramatically increase until BMI was
Using a multivariate Cox proportional hazards analysis, the significant predictors of time to PSA failure after RP were determined (Table 2). When BMI was examined as a continuous variable, biopsy Gleason (P < .001), PSA (P < .001), and BMI (P = .050) were all significant independent predictors of PSA failure. When BMI was examined as a categoric variable, moderately and severely obese patients (BMI 35 kg/m2) were at significantly increased risk of PSA failure relative to men with normal weight (P = .002). Regardless of whether BMI was examined as a categoric or continuous variable, there was a trend for decreased biochemical failure rates among more recently treated patients (HR, 0.96 for each one more recent year), although this did not reach statistical significance (P > .1).
Because BMI was weakly related to surgical margin status, we examined whether this alone could explain the higher recurrence rate among obese patients. On multivariate analysis, after controlling for all preoperative clinical factors along with surgical margin status and year of surgery, moderate and severe obesity (BMI 35 kg/m2) remained a significant independent predictor of PSA failure (P = .012).
Because the majority of patients in this study were treated at one center (646 [58%] of 1,106 patients at the San Diego Naval Hospital), we examined whether the results were similar when this center was excluded. When only patients not treated at the San Diego Naval Hospital were examined using multivariate analysis forcing year of surgery to remain in the model, moderate and severe obesity (BMI
Obesity is a major health problem that affects more than 30% of United States adults [4]. Similarly, CaP is a major health problem, with an estimated 189,000 new patients diagnosed in 2002 [28], the vast majority of whom will have clinically localized disease. Despite such high prevalence for both diseases, little is known about the relationship between obesity and outcomes among men with newly diagnosed clinically localized CaP. Given that extirpative surgery is one of the most common treatments for early-stage CaP, we sought to determine whether obesity affected outcomes for RP. Using a large, racially diverse, multi-institutional database of men with clinically localized CaP, we found that obese but not overweight men were at increased risk for PSA recurrence after RP. Furthermore, men with a BMI 35 kg/m2 were higher-risk for failure than men with a BMI between 30 and 35 kg/m2. Obesity is associated with the development of multiple chronic diseases, including coronary artery disease, hypertension, and diabetes [1-3]. Obesity has also been linked to several types of cancer, including breast and colon cancer [5]. The relationship between obesity and CaP is less clear. Although several large studies concluded that obesity was associated with an increased risk of developing CaP [6,9], others found an inverse relationship [7,8]. Likewise, controversy exists as to the relationship between obesity and survival among men with advanced disease [13-18]. However, the vast majority of men with newly diagnosed CaP will have clinically localized disease. Only a few studies examined the relationship between obesity and pathologic features after RP, finding that increased BMI was associated with more advanced disease and higher Gleason scores [19-21]. This is in agreement with the current study, in which obese men had higher Gleason scores and a trend toward a higher rate of positive surgical margins. There was a trend for moderately and severely obese men to have a higher incidence of positive surgical margins, whereas there were no differences in the incidence of extracapsular disease. The higher positive surgical margin rate among obese men in the absence of other findings associated with adverse pathologic features is likely related to iatrogenic positive surgical margins because of technical difficulty during surgical dissection of the prostate among obese men. Despite this, obesity remained an adverse predictor of PSA failure even after controlling for margin status. Thus, although technical difficulty in performing RP in obese men may partially explain the observed outcome differences, it cannot completely explain the higher failure rates among obese men. It should be noted that although we do not have data available on surgical approach for our patients, the majority of men in the current series were treated with retropubic RP. Whether alternative surgical approaches including laparoscopic or perineal RP would be associated with a similar discrepancy in margin status remains to be determined. In this study, we found that black men undergoing RP had significantly higher rates of obesity than white men. This is contrast to the general adult population, in which the rates of obesity are similar between black and white men [4]. It is unclear why black men in our series had higher rates of obesity. Whether this is reflective of CaP patients in general or merely patients at our centers who choose RP remains to be determined. We have previously shown using the SEARCH database that there were no racial differences in PSA recurrence rates after RP [22]. However, in the current study, which is limited to patients with available BMI data, but contains longer follow-up and the inclusion of one new center (Augusta VAMC), we found that black race was an adverse risk factor in univariate analysis. However, after controlling for other preoperative clinical variables, including BMI, race was not a significant predictor of PSA failure. Similarly, Amling et al [19] found that although both black race and obesity were correlated with high-grade disease in univariate analysis, after controlling for obesity in multivariate analysis, black race was no longer an independent predictor of high-grade cancer. Thus, it is possible that increased rates of obesity among black men may in part explain the differences in biochemical outcomes after RP noted in various studies [29,30]. Given the relationship between race, BMI, and PSA failure after RP, it is recommended that all future studies examining racial outcomes among CaP patients control for BMI. Moreover, given the disproportionate burden of CaP on black men, programs targeted to control obesity in the black community may be warranted.
Mean BMI values steadily increased with time. Indeed, the rate of obesity (BMI The fact that obesity was a significant risk factor for PSA failure and that the rate of obese men undergoing RP is increasing argues that men treated with RP today are at higher risk than in the past. Conversely, continued PSA screening has resulted in a stage migration toward earlier-stage disease [33], which may minimize the negative influence of increasing BMI. Indeed, in univariate analysis, year of surgery was an adverse predictor of PSA failure, possibly reflecting the increased BMI. However, after controlling for BMI grouping, there was a trend for year of surgery to be associated with better PSA outcomes. Additional studies are needed to examine the conflicting influence of continued PSA screening with its associated stage migration and the increasing incidence of obesity on PSA failure rates after RP. Several different biologic mechanisms may explain the observed worse outcomes among obese men. Obesity is known to be associated with higher serum insulin levels and insulin resistance, both of which have been associated with increased risks of developing CaP [34,35]. Abdominal obesity and hyperinsulinemia have also been associated with lower circulating levels of sex hormone–binding globulin, with a resultant increase in bioavailable testosterone, lower serum levels of insulin-like growth factor–binding protein 1, and higher circulating levels of insulin-like growth factor 1 and estradiol [10-12]. All of these changes have been linked to higher in vitro mitogenic activity of human CaP cell lines when cultured with patient serum [36,37]. The increased mitogenic activity and antiapoptotic effect of serum from obese men may lead to larger prostate tumor volumes, advanced pathology, and micrometastatic disease [38]. Obesity is also associated with increased serum fatty acid levels [34]. The fatty acid consumed in the greatest quantity in the Western diet is linoleic acid (omega-6 polyunsaturated fatty acid), which is a known growth factor for androgen-dependent and androgen-independent CaP cell lines as well as human CaP xenografts [39,40]. An increased ratio of omega-6 to omega-3 fatty acids may also exert proinflammatory effects and promote tumor cell invasion via activation of the cyclooxygenase and lipoxygenase enzymes and production of 2-series prostaglandins and hydroxyeicosatetraenoic acids, which are overexpressed in malignant relative to benign prostate tissue [41]. However, because serum levels of the various factors that have been linked to obesity were not obtained at the time of surgery on our patients, we are unable to comment on the exact biologic reason why obesity was associated with worse outcomes among our patients. It is important to emphasize that simply because obese men in the current study were at higher risk for biochemical recurrence after RP does not imply RP represents a poor treatment option for obese men. The fact that obesity was related to biochemical outcome independent of surgical technique (surgical margins status) argues that obese men may have an inherently more aggressive form of CaP. This would imply that obese men would be at higher risk for failure regardless of the treatment option chosen. Clearly, future studies are needed to determine the impact of obesity on outcomes following other management strategies for CaP, including radiation therapy, hormonal therapy, and watchful waiting. Limitations to the current study were that the mean follow-up was relatively short. More studies using diverse patient populations are needed to confirm these findings. In addition, other measures of obesity, such as waist-to-hip ratio and percent lean body fat, were not available on our patients.
In conclusion, the percentage of obese men undergoing RP in our database doubled in the last 10 years. Obesity was associated with higher Gleason scores and a trend toward an increased incidence of positive surgical margins after RP. After controlling for these factors as well as year of surgery, obesity was a significant independent predictor of PSA failure. Men with a BMI
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Joseph C. Presti Jr, AstraZeneca, Merck; Christopher J. Kane, AMS, AstraZeneca, Merck, TAP; Christopher L. Amling, TAP, AstraZeneca.
Supported in part by the Department of Veterans Affairs and a Center for Prostate Disease Research (CPDR) grant from the United States Army Medical Research and Material Command. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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ABSTRACT
INTRODUCTION
2 for categoric variables. Predictors of adverse pathologic features were examined using logistic regression models. Time to recurrence was compared across the groups using a log-rank survivorship analysis. For multivariate analysis, a forward-stepwise Cox proportional hazards model was used with P < .15 determining which variables were entered into the model at each step. The variable with the highest P value was successively deleted until only variables with P < .1 remained. 
