Urologic Oncology: Seminars and Original Investigations ] (2016) ∎∎∎–∎∎∎
Original article
Increased body mass index as a risk factor in localized prostate cancer treated by radical prostatectomy Maximilien C. Goris Gbenou, M.D.a,b,c,*, Alexandre Peltier, M.D.b,c, Claude C. Schulman, M.D., Ph.D.c,d, Roland van Velthoven, M.D., Ph.D.b,c a
b
Department of Urology, Valence Hospital, Valence, France Department of Urology, University Hospital—Jules Bordet Institute, Brussels, Belgium c Faculty of medicine, Université Libre de Bruxelles, Brussels, Belgium d Department of Urology, Edith Cavell Clinic, Brussels, Belgium
Received 14 July 2015; received in revised form 6 October 2015; accepted 20 December 2015
Abstract Background: The association between obesity and aggressive forms of prostate cancer is controversial. We compared preoperative body mass index (BMI) and prostate-specific antigen (PSA) levels as predictive risk factors for increased prostate weight and disease aggressiveness. Materials and methods: This retrospective review of 464 patients with localized prostate cancer who underwent radical prostatectomy between March 1999 and October 2006 examined relationships among clinicopathological variables (BMI, preoperative serum PSA, biopsy and pathologic Gleason score [GS], and whole prostate weight) using linear and multinomial logistic regression analysis. We used multivariate regression modeling adjusting for age, year of surgery, PSA or BMI, pathologic stage, and GS. Results: Median age of patients (51% cT1c, 69% pT2) was 61 years (41–76), mean BMI 26.50 kg/m2 (standard deviation ¼ 4.82), mean PSA 6.8 ng/ml (0.67–27.2), median prostate weight 51 g (12–200), median biopsy GS 6 (3–9), and median pathologic GS 7 (4–10). GS was upgraded in 227 patients (49%) from median GS 6 to 7 (P o 0.00001). Mean prostate weight was 47 ⫾ 13.7 g for BMI o 25 kg/m2 (n ¼ 170), 47 ⫾ 15 g for BMI 25 to 30 kg/m2 (n ¼ 224), and 59 ⫾ 26 g for BMI 4 30 kg/m2 (n ¼ 69) (P o 0.00184). Mean prostate weight was significantly higher for BMI 4 30 than BMI o 25 (47 ⫾ 13 g vs. 59 ⫾ 25 g, P o 0.00015). Mean PSA was significantly higher for BMI 4 30 than for all other patients combined (8.56 [95% CI: 6.94–10.18] vs. 8.34 [7.23–9.45]; P ¼ 0.001). PSA was positively associated with high biopsy GS for BMI Z 25 (P ¼ 0.048) and BMI Z 30 (P ¼ 0.009) but not for BMI r 25 (P ¼ 0.151). BMI Z 30 was associated with higher pT stage (odd ratio ¼ 1.279 [1.5–1.56]; P ¼ 0.015). In multivariate analyses, higher BMI was associated with higher prostate weight (P ¼ 0.036) and pT stage (P ¼ 0.008), and higher PSA with higher biopsy GS (P ¼ 0.002). Neither BMI nor PSA was associated with GS upgrading. Conclusions: Higher BMI was associated with higher prostate weight and PSA, as well as with higher pT stage and pathologic GS in men undergoing radical prostatectomy, providing further evidence that obese men are more likely to have aggressive cancer. BMI thus constitutes an additional risk factor besides PSA. r 2016 Elsevier Inc. All rights reserved.
Keywords: Prostate cancer; Prostate weight; Obesity; BMI; Risk factors; Radical prostatectomy
1. Introduction The relationship between obesity and prostate cancer risk is controversial but is supported by mounting evidence. A Corresponding author. Tel.: þ33-64-759-5336; fax: +33-47-575-7270. E-mail address: [email protected] (M.C. Goris Gbenou). *
http://dx.doi.org/10.1016/j.urolonc.2015.12.009 1078-1439/r 2016 Elsevier Inc. All rights reserved.
recent review of 23 prospective cohort studies has provided compelling cumulative data for a strong positive association between obesity and fatal prostate cancer [1]. In a metaanalysis of 17 cohort studies, obesity was not significantly correlated with prostate cancer incidence but was significantly correlated with an increased risk of aggressive prostate cancer and prostate cancer-associated mortality
2
M.C. Goris Gbenou et al. / Urologic Oncology: Seminars and Original Investigations ] (2016) 1–6
[2]. In a prospectively studied cohort of 404,576 men followed up for 16 years, significant trends of increasing risk were observed for deaths from prostate cancer in men with higher body mass index (BMI) values [3]. Furthermore, a dose-response meta-analysis of 25 prospective studies of localized and advanced prostate cancer has suggested that obesity may have a decreased risk for localized prostate cancer and an increased risk for advanced prostate cancer [4]. A higher BMI in men undergoing radical prostatectomy (RP) has been associated with a variety of factors including advanced, high-grade or upstaged disease or both [4,5], a greater percentage of the prostate involved with cancer, an increased tumor volume, extracapsular extension, and positive margins in several studies [6–9] including a recent study in a cohort of men eligible for active surveillance [10]. It has also been associated with enlarged prostates as determined by ultrasound [11]. However, prostate volume tends to underestimate prostate weight [12]. Kopp et al. [13] examined the relationship between preoperative BMI and whole prostate weight in a cohort of 16,325 patients who underwent RP and concluded that obesity is associated with a higher likelihood of an increased prostate weight. The present study measured preoperative BMI and prostate-specific antigen (PSA), prostate weight, and Gleason score (GS) (biopsy and specimen) in patients with localized prostate cancer undergoing RP in a single institution. A direct comparison was made of PSA and BMI as potential risk factors for enlarged prostates and aggressive cancers.
2. Materials and methods 2.1. Patients Approval for the study was obtained from the Jules Bordet Institute review board. Patients who underwent RP between March 1999 and October 2006 were identified in the institute's prospectively collected prostate cancer database. Prostate cancer had been diagnosed by transrectal biopsy in patients with elevated PSA or with a suspicious digital rectal examination or both. RP was performed by experienced surgeons using a reproducible laparoscopic or robot-assisted technique. The database includes information on patient age, height, weight, clinical stage, grade of cancer on diagnostic biopsies, preoperative PSA levels, prostate weight, and surgical specimen pathology. BMI was calculated using World Health Organization and National Institutes of Health definitions. Patients for whom a preoperative BMI value was available were selected and classified into 3 groups: BMI o 25 kg/m2, 25 to 30 kg/m2 (overweight), and 430 kg/m2 (obese), respectively. The histopathology technique has been described previously [14].
2.2. Statistical analysis Categorical and continuous variables were compared using the chi-square test and Student's t test, respectively. Linear and logistic multinomial regression analysis was used to examine relationships between preoperative BMI or PSA and clinicopathological variables (prostate weight at RP, biopsy and pathologic GS, and pT stage). Relationships between potential prognostic variables were analyzed using bivariate Pearson correlation. Multivariate regression modeling adjusting for age, year of surgery, PSA or BMI, pathologic stage, and GS was used. Friedman chi-square statistic and Kendall coefficient of concordance were calculated for BMI categories. P ¼ 0.05 was considered significant. Statistical analyses were performed using version 22 of Statistical Package for the Social Sciences (SPSS) (IBM Corporation, NY).
3. Results A total of 464 consecutive men who underwent RP during the study period and for whom BMI values could
Table 1 Patient characteristics No. of pts Mean BMI—kg/m2 (⫾SD) BMI o 25—n (%) BMI ¼ 25–30—n (%) BMI 4 30—n (%)
464 26.50 ⫾ 4.82 171 (37) 224 (48) 69 (15)
Median age—years (range) Mean age ⫾ SDa—years Mean preoperative serum PSA—ng/ml ⫾ SD Median preoperative serum PSA—ng/mL (range) Clinical stage cT1—n (%) Clinical stage Z cT2—n (%) Median RP specimen weight—g (range) RP wt o 50 g—n (%) RP wt Z 50 g—n (% Median biopsy Gleason score (range) Mean biopsy Gleason score ⫾ SD Gleason score upgradeb—n (%) Median pathologic Gleason score (range)
61 (41–76) 61.24 ⫾ 6.3 8.41 ⫾ 6.6 6.8 (0.67–27.2) 237 (51) 227 (49) 51 (12–200) 107 (48.6) 113 (51.4) 6 (3–9) 5.87 ⫾ 1.17 227 (49) 7 (4–10)c
Mean pathologic Gleason score ⫾ SD GS o 7—n (%) GS Z 7—n (%) Unspecified (previous radiation or hormone therapy)—n (%) Stage pT2—n (%) Stage Z pT3—n (%)
6.56 ⫾ 1.04 346 (75) 99 (21) 19 (4.1) 316 (68) 148 (32)
No. ¼ number; pts. ¼ patients; SD ¼ standard deviation. a Mean age ⫾ SD by BMI category: 60.93 ⫾ 6.22 (normal), 61.66 ⫾ 6.46 (overweight), and 61.48 ⫾ 6.42 (obese). b Percentage upgrade by BMI category: 38.6% (66/171) (normal), 46.8% (105/224) (overweight), and 27.5% (19/69) (obese). c Significant difference between biopsy and pathologic Gleason score (P o 0.00001).
M.C. Goris Gbenou et al. / Urologic Oncology: Seminars and Original Investigations ] (2016) 1–6
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Fig. Linear regression analyses showing prostate weight as a function of BMI. (A) Total population described by the equation y ¼ 50.25 þ 0.14*x. (B) Men with a BMI o 25 kg/m2 (y ¼ 48.29 þ 0.16*x). (C) Men with a BMI of 25 to 30 kg/m2 (y ¼ 19.73 þ 1.28*x). (D) Men with a BMI 430 kg/m2 (y ¼ 17.61 þ 2.37*x). (Color version of figure is available online.)
be calculated were included in the analysis. Patient data are presented in Table 1. Median age was 61 years (range: 45–76), mean BMI was 26.50 kg/m2 (standard deviation ¼ 4.82), and median PSA was 6.8 ng/ml (range: 0.67–27.2). In total, 51% had nonpalpable disease (cT1) and 69% organ-confined (pT2) disease. Median RP specimen weight was 51 g (range: 12–200). GS was upgraded in 227 (49%) patients from median GS 6 to 7 (P o 0.00001). There was no significant difference in mean age or percentage disease upgrade among the 3 BMI categories (normal, overweight, and obese) (Table 1). Mean preoperative PSA was significantly higher in obese men (BMI 4 30 kg/m2) than in normal men (BMI o 25 kg/m2) (8.56 ng/ml [95% CI: 6.94–10.18] vs. 8.34 ng/ml [95% CI: 7.23–9.45]; P o 0.001). Mean prostate weight was also significantly higher in obese men than normal men (59 ⫾ 25 g vs. 47 ⫾ 13 g; P o 0.00015). However, there was no significant difference in mean prostate weight
between overweight men (BMI ¼ 25–30 kg/m2) and normal men (47 ⫾ 15 g vs. 47 ⫾ 13 g; P ¼ 1.000, respectively). The Friedman analysis of variance Chisquare statistic for mean prostate weight according to BMI grouping (N ¼ 66, df ¼ 3) was 14.976 (P o 0.001) and Kendall coefficient of concordance was 0.075, with average rank r ¼ 0.061. Several statistical analyses were performed as follows: (1) in a linear regression plot of prostate weight vs. BMI, the coefficient was 0.14 for the total population (y ¼ 50.24 þ x*0.14) (Fig. A). It increased from 0.16 to 1.28 to 2.37 with BMI group (Fig. B–D, respectively). A BMI of o25 kg/m2 was negatively associated with prostate weight (standardized “beta” regression coefficient of -0.215, P ¼ 0.001) whereas BMIs of 25 to 30 and 430 kg/m2 were positively associated with prostate weight (standardized “beta” coefficients of 0.114, P ¼ 0.015 and 0.127, P ¼ 0.007, respectively); (2) in linear regression analyses, preoperative PSA was positively associated with a
M.C. Goris Gbenou et al. / Urologic Oncology: Seminars and Original Investigations ] (2016) 1–6
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Table 2 Pearson correlation evaluating potential risk factors in localized prostate cancer in 464 men
Age r P N
Age
PSA
Biopsy GS
BMI
Specimen wt (g)
pT stage
Specimen GS
1
0.053 0.253 464
0.113 0.016* 451
0.012 0.794 464
0.081 0.082 456
0.018 0.693 464
0.082 0.085 445
1
0.211 0.000** 451
0.036 0.437 464
0.062 0.183 456
0.037 0.432 464
0.239 0.000** 445
1
0.005 0.908 451
0.043 0.367 441
0.006 0.899 447
0.367 0.000** 428
0.137 0.003** 456
0.143 0.002** 464
0.029 0.535 445
1
0.072 0.127 452
0.075 0.119 435
1
0.019 0.692 441
464
PSA r P N
0.053 0.253 464
464
Biopsy GS r P N
0.113* 0.016 451
0.211** 0.000 451
451
BMI r P N
0.012 0.794 464
0.036 0.437 464
0.005 0.908 451
1
Specimen wt (g) r 0.081 P 0.082 N 456
0.062 0.183 456
0.043 0.367 441
0.137 0.003** 456
456
pT stage r P N
0.018 0.693 464
0.037 0.432 464
0.006 0.899 447
0.143 0.002** 464
0.072 0.127 452
464
Specimen GS r P N
0.082 0.085 445
0.239 0.000** 445
0.367 0.000** 428
0.029 0.535 445
0.075 0.119 435
0.019 0.692 441
464
1 445
r ¼ Pearson correlation coefficient ranging from 1 (perfect negative linear relationship) to þ1 (perfect positive linear relationship). N ¼ number of patients. * P ¼ 0.05. ** P ¼ 0.01.
high biopsy GS in patients with a BMI Z 25 kg/m2 (P ¼ 0.048) and Z30 kg/m2 (P ¼ 0.009) but not in patients with a BMI r 25 kg/m2 (P ¼ 0.151); (3) in a multinomial linear regression analysis, obesity (BMI Z 30 kg/m2) was significantly associated with higher pT stage (odds ratio: 1.279 [95% CI: 1.5–1.56]; P ¼ 0.015); (4) in a bivariate Pearson correlation analysis, BMI was positively correlated with preoperative specimen weight (P ¼ 0.003) and pT stage (P ¼ 0.002) but not with initial PSA (P ¼ 0.437) nor with biopsy GS (P ¼ 0.908) or pathologic GS (P ¼ 0.535) (Table 2); (5) in multivariate regression analysis, with either BMI or PSA as the dependent variable, preoperative BMI was positively associated with higher pT stage (P ¼ 0.008), prostate weight (0.032), and pathologic GS (P ¼ 0.042), whereas PSA was associated with higher biopsy GS only (0.002) (Table 3). Neither BMI nor PSA was significantly associated with age or GS upgrading.
Table 3 BMI and PSA as potential risk factors in multivariate regression analyses Parameter
Dependent variable (preop)
Age
PSA BMI
5.918 1.413
0.132 0.087
0.717 0.768
Whole prostate weight
PSA BMI
100.887 75.209
2.248 4.646
0.135 0.032
Biopsy Gleason score
PSA BMI
438.384 46.845
9.767 2.894
0.002 0.090
Pathologic Gleason score PSA BMI
126.918 67.331
2.828 4.159
0.093 0.042
Upgraded Gleason score PSA BMI
50.970 23.436
1.136 1.448
0.287 0.230
pT stage
93.704 79.388
2.113 7.051
0.147 0.008
PSA BMI
Mean square F value P value
M.C. Goris Gbenou et al. / Urologic Oncology: Seminars and Original Investigations ] (2016) 1–6
4. Discussion This retrospective study of a cohort of 464 patients with localized prostate cancer undergoing RP has highlighted an association between increasing BMI and higher prostate weight and also between increasing BMI and aggressive disease (high pathologic GS score and pT stage). Preoperative PSA level was significantly associated with biopsy GS only. Surprisingly, neither preoperative BMI nor PSA was associated with GS upgrading maybe because of unavailable scores in 4.1% of patients with a history of radiation or hormone therapy or because the incidence of upgraded disease is 4.5-fold lower for large (450 ml) prostates [15]. Our findings support the already reported relationships between obesity and both prostate weight and high-grade cancer observed in large patient cohorts. A relationship between preoperative BMI and increased prostate weight was established in a cohort of 16,325 patients [13] and a relationship between elevated BMI and increased prostate size, pathologic GS and tumor volume in a cohort of 14,293 patients [16]. Several studies have reported a relationship between obesity and increased risk of high-grade cancer (or possibly reduced risk of low-grade cancer) [17] in men undergoing RP: (1) both Amling [18] and Freedland et al. [19] found an association between obesity (BMI 4 30 mg/kg2 and 435 mg/kg2, respectively) and higher-grade tumors, and higher rates of disease recurrence after RP ; (2) Capitanio et al. (n ¼ 1,275) found that BMI was independently associated with tumor volume in a multivariable analysis [20]; and (3) Freedland et al. [19] (n ¼ 1106) found that obesity was associated with higher-grade tumors, a trend toward increased risk of positive surgical margins, and higher biochemical failure rates; a BMI Z 35 kg/m2 was associated with a higher risk of failure than a BMI between 30 and 35 kg/m2. The effect of BMI on PSA is controversial. An association between obesity and lower PSA levels has been highlighted, with no effect of BMI on the association between PSA level and tumor volume [16]. It has been suggested that PSA hemodilution in larger plasma volumes might explain the apparently lower PSA levels despite the larger prostates in obese men [20]. Our study confirmed that obese men had heavier prostates but detected higher and not lower mean PSA values. These mean PSA values in obese men were better correlated with GS than were mean PSA values in patients with BMI r 25 kg/m2. BMI thus provides additional prognostic information to PSA in obese patients but other more efficient markers are needed, in particular in nonobese patients. We did not evaluate the effect of obesity on disease recurrence or mortality. Obesity in patients who underwent RP has emerged as a significant independent predictor of risk of prostate cancer recurrence in several multivariate studies. Independent predictors for risk of recurrence in registry study by Bassett et al. [21] (n ¼ 2,131) were an increasing BMI (P ¼ 0.028), an increasing PSA level (P o 0.0001), and Gleason grade (P o 0.0001). In
5
prospective study by Strom et al. [22] (n ¼ 526), the independent predictors were a higher BMI at diagnosis and GS. In retrospective multi-institutional pooled analysis by Amling et al. [23] (n ¼ 3,162), obesity was associated with both higher Gleason grade tumors (P o 0.001) and a higher recurrence rate (P ¼ 0.027). However, BMI was not associated with biochemical failure in a cohort of 2,687 patients with low-risk and intermediate-risk prostate cancer [24] nor in 230 men eligible for active surveillance after RP (P ¼ 0.950) [15]. A limitation of our study is the lack of evaluation of the periprostatic fatty tissue resected during RP, which could affect prostate weight. Any detected effect would need to be taken into account in future studies. We did not investigate tumor volume, extracapsular extension, lymph node metastasis (although no association has been detected [25]), or preoperative hormone levels (e.g., changes in testosterone [26], sex-hormone binding globulin, and estrogen levels, respectively). Obesity is associated with manifold hormonal changes that might influence disease aggressiveness [27]. Metabolic syndrome-related factors might also affect disease aggressiveness and would require study.
5. Conclusions Our data indicate a strong association between obesity and higher prostate weight, disease stage and preoperative PSA, and provide further evidence for obese men undergoing RP having more aggressive cancers. PSA did not correlate with high GS because of its poor performance in nonobese patients. BMI is a parameter that needs to be evaluated in all prospective randomized studies of localized prostate cancer treatments. References [1] Golabek T, Bukowczan J, Chlosta P, Powroznik J, Dobruch J, Borowka A. Obesity and prostate cancer incidence and mortality: a systematic review of prospective cohort studies. Urol Int 2014;92:7– 14. [2] Zhang X, Zhou G, Sun B, Zhao G, Liu D, Sun J, et al. Impact of obesity upon prostate cancer-associated mortality: a meta-analysis of 17 cohort studies. Oncol Lett 2015;9:1307–12. [3] Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003;348:1625–38. [4] Discacciati A, Orsini N, Wolk A. Body mass index and incidence of localized and advanced prostate cancer—a dose-response metaanalysis of prospective studies. Ann Oncol 2012;23:1665–71. [5] Bassett JK, Severi G, Baglietto L, MacInnis RJ, Hoang HN, Hopper JL, et al. Weight change and prostate cancer incidence and mortality. Int J Cancer 2012;131:1711–9. [6] Freedland SJ, Banez LL, Sun LL, Fitzsimons NJ, Moul JW. Obese men have higher-grade and larger tumors: an analysis of the duke prostate center database. Prostate Cancer Prostatic Dis 2009;12:259– 63. [7] Gross M, Ramirez C, Luthringer D, Nepomuceno E, Vollmer R, Burchette J, et al. Expression of androgen and estrogen related
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[18] Amling CL. The association between obesity and the progression of prostate and renal cell carcinoma. Urol Oncol 2004;22:478–84. [19] Freedland SJ, Aronson WJ, Kane CJ, Presti JC Jr., Amling CL, Elashoff D, et al. 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. J Clin Oncol 2004;22:446–53. [20] Grubb RL 3rd, Black A, Izmirlian G, Hickey TP, Pinsky PF, Mabie JE, et al. Serum prostate-specific antigen hemodilution among obese men undergoing screening in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol Biomarkers Prev 2009;18:748–51. [21] Bassett WW, Cooperberg MR, Sadetsky N, Silva S, DuChane J, Pasta DJ, et al. Impact of obesity on prostate cancer recurrence after radical prostatectomy: data from CaPSURE. Urology 2005;66:1060–5. [22] Strom SS, Wang X, Pettaway CA, Logothetis CJ, Yamamura Y, Do KA, et al. Obesity, weight gain, and risk of biochemical failure among prostate cancer patients following prostatectomy. Clin Cancer Res 2005;11:6889–94. [23] Amling CL, Riffenburgh RH, Sun L, Moul JW, Lance RS, Kusuda L, et al. Pathologic variables and recurrence rates as related to obesity and race in men with prostate cancer undergoing radical prostatectomy. J Clin Oncol 2004;22:439–45. [24] Ly D, Reddy CA, Klein EA, Ciezki JP. Association of body mass index with prostate cancer biochemical failure. J Urol 2010;183: 2193–9. [25] Briganti A, Karakiewicz PI, Chun FK, Suardi N, Gallina A, Abdollah F, et al. Obesity does not increase the risk of lymph node metastases in patients with clinically localized prostate cancer undergoing radical prostatectomy and extended pelvic lymph node dissection. Int J Urol 2009;16:676–81. [26] Brand JS, van der Tweel I, Grobbee DE, Emmelot-Vonk MH, van der Schouw YT. Testosterone, sex hormone-binding globulin and the metabolic syndrome: a systematic review and meta-analysis of observational studies. Int J Epidemiol 2011;40:189–207. [27] Tewari R, Rajender S, Natu SM, Dalela D, Goel A, Goel MM, et al. Diet, obesity, and prostate health: are we missing the link. J Androl 2012;33:763–76.
Original article
Increased body mass index as a risk factor in localized prostate cancer treated by radical prostatectomy Maximilien C. Goris Gbenou, M.D.a,b,c,*, Alexandre Peltier, M.D.b,c, Claude C. Schulman, M.D., Ph.D.c,d, Roland van Velthoven, M.D., Ph.D.b,c a
b
Department of Urology, Valence Hospital, Valence, France Department of Urology, University Hospital—Jules Bordet Institute, Brussels, Belgium c Faculty of medicine, Université Libre de Bruxelles, Brussels, Belgium d Department of Urology, Edith Cavell Clinic, Brussels, Belgium
Received 14 July 2015; received in revised form 6 October 2015; accepted 20 December 2015
Abstract Background: The association between obesity and aggressive forms of prostate cancer is controversial. We compared preoperative body mass index (BMI) and prostate-specific antigen (PSA) levels as predictive risk factors for increased prostate weight and disease aggressiveness. Materials and methods: This retrospective review of 464 patients with localized prostate cancer who underwent radical prostatectomy between March 1999 and October 2006 examined relationships among clinicopathological variables (BMI, preoperative serum PSA, biopsy and pathologic Gleason score [GS], and whole prostate weight) using linear and multinomial logistic regression analysis. We used multivariate regression modeling adjusting for age, year of surgery, PSA or BMI, pathologic stage, and GS. Results: Median age of patients (51% cT1c, 69% pT2) was 61 years (41–76), mean BMI 26.50 kg/m2 (standard deviation ¼ 4.82), mean PSA 6.8 ng/ml (0.67–27.2), median prostate weight 51 g (12–200), median biopsy GS 6 (3–9), and median pathologic GS 7 (4–10). GS was upgraded in 227 patients (49%) from median GS 6 to 7 (P o 0.00001). Mean prostate weight was 47 ⫾ 13.7 g for BMI o 25 kg/m2 (n ¼ 170), 47 ⫾ 15 g for BMI 25 to 30 kg/m2 (n ¼ 224), and 59 ⫾ 26 g for BMI 4 30 kg/m2 (n ¼ 69) (P o 0.00184). Mean prostate weight was significantly higher for BMI 4 30 than BMI o 25 (47 ⫾ 13 g vs. 59 ⫾ 25 g, P o 0.00015). Mean PSA was significantly higher for BMI 4 30 than for all other patients combined (8.56 [95% CI: 6.94–10.18] vs. 8.34 [7.23–9.45]; P ¼ 0.001). PSA was positively associated with high biopsy GS for BMI Z 25 (P ¼ 0.048) and BMI Z 30 (P ¼ 0.009) but not for BMI r 25 (P ¼ 0.151). BMI Z 30 was associated with higher pT stage (odd ratio ¼ 1.279 [1.5–1.56]; P ¼ 0.015). In multivariate analyses, higher BMI was associated with higher prostate weight (P ¼ 0.036) and pT stage (P ¼ 0.008), and higher PSA with higher biopsy GS (P ¼ 0.002). Neither BMI nor PSA was associated with GS upgrading. Conclusions: Higher BMI was associated with higher prostate weight and PSA, as well as with higher pT stage and pathologic GS in men undergoing radical prostatectomy, providing further evidence that obese men are more likely to have aggressive cancer. BMI thus constitutes an additional risk factor besides PSA. r 2016 Elsevier Inc. All rights reserved.
Keywords: Prostate cancer; Prostate weight; Obesity; BMI; Risk factors; Radical prostatectomy
1. Introduction The relationship between obesity and prostate cancer risk is controversial but is supported by mounting evidence. A Corresponding author. Tel.: þ33-64-759-5336; fax: +33-47-575-7270. E-mail address: [email protected] (M.C. Goris Gbenou). *
http://dx.doi.org/10.1016/j.urolonc.2015.12.009 1078-1439/r 2016 Elsevier Inc. All rights reserved.
recent review of 23 prospective cohort studies has provided compelling cumulative data for a strong positive association between obesity and fatal prostate cancer [1]. In a metaanalysis of 17 cohort studies, obesity was not significantly correlated with prostate cancer incidence but was significantly correlated with an increased risk of aggressive prostate cancer and prostate cancer-associated mortality
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M.C. Goris Gbenou et al. / Urologic Oncology: Seminars and Original Investigations ] (2016) 1–6
[2]. In a prospectively studied cohort of 404,576 men followed up for 16 years, significant trends of increasing risk were observed for deaths from prostate cancer in men with higher body mass index (BMI) values [3]. Furthermore, a dose-response meta-analysis of 25 prospective studies of localized and advanced prostate cancer has suggested that obesity may have a decreased risk for localized prostate cancer and an increased risk for advanced prostate cancer [4]. A higher BMI in men undergoing radical prostatectomy (RP) has been associated with a variety of factors including advanced, high-grade or upstaged disease or both [4,5], a greater percentage of the prostate involved with cancer, an increased tumor volume, extracapsular extension, and positive margins in several studies [6–9] including a recent study in a cohort of men eligible for active surveillance [10]. It has also been associated with enlarged prostates as determined by ultrasound [11]. However, prostate volume tends to underestimate prostate weight [12]. Kopp et al. [13] examined the relationship between preoperative BMI and whole prostate weight in a cohort of 16,325 patients who underwent RP and concluded that obesity is associated with a higher likelihood of an increased prostate weight. The present study measured preoperative BMI and prostate-specific antigen (PSA), prostate weight, and Gleason score (GS) (biopsy and specimen) in patients with localized prostate cancer undergoing RP in a single institution. A direct comparison was made of PSA and BMI as potential risk factors for enlarged prostates and aggressive cancers.
2. Materials and methods 2.1. Patients Approval for the study was obtained from the Jules Bordet Institute review board. Patients who underwent RP between March 1999 and October 2006 were identified in the institute's prospectively collected prostate cancer database. Prostate cancer had been diagnosed by transrectal biopsy in patients with elevated PSA or with a suspicious digital rectal examination or both. RP was performed by experienced surgeons using a reproducible laparoscopic or robot-assisted technique. The database includes information on patient age, height, weight, clinical stage, grade of cancer on diagnostic biopsies, preoperative PSA levels, prostate weight, and surgical specimen pathology. BMI was calculated using World Health Organization and National Institutes of Health definitions. Patients for whom a preoperative BMI value was available were selected and classified into 3 groups: BMI o 25 kg/m2, 25 to 30 kg/m2 (overweight), and 430 kg/m2 (obese), respectively. The histopathology technique has been described previously [14].
2.2. Statistical analysis Categorical and continuous variables were compared using the chi-square test and Student's t test, respectively. Linear and logistic multinomial regression analysis was used to examine relationships between preoperative BMI or PSA and clinicopathological variables (prostate weight at RP, biopsy and pathologic GS, and pT stage). Relationships between potential prognostic variables were analyzed using bivariate Pearson correlation. Multivariate regression modeling adjusting for age, year of surgery, PSA or BMI, pathologic stage, and GS was used. Friedman chi-square statistic and Kendall coefficient of concordance were calculated for BMI categories. P ¼ 0.05 was considered significant. Statistical analyses were performed using version 22 of Statistical Package for the Social Sciences (SPSS) (IBM Corporation, NY).
3. Results A total of 464 consecutive men who underwent RP during the study period and for whom BMI values could
Table 1 Patient characteristics No. of pts Mean BMI—kg/m2 (⫾SD) BMI o 25—n (%) BMI ¼ 25–30—n (%) BMI 4 30—n (%)
464 26.50 ⫾ 4.82 171 (37) 224 (48) 69 (15)
Median age—years (range) Mean age ⫾ SDa—years Mean preoperative serum PSA—ng/ml ⫾ SD Median preoperative serum PSA—ng/mL (range) Clinical stage cT1—n (%) Clinical stage Z cT2—n (%) Median RP specimen weight—g (range) RP wt o 50 g—n (%) RP wt Z 50 g—n (% Median biopsy Gleason score (range) Mean biopsy Gleason score ⫾ SD Gleason score upgradeb—n (%) Median pathologic Gleason score (range)
61 (41–76) 61.24 ⫾ 6.3 8.41 ⫾ 6.6 6.8 (0.67–27.2) 237 (51) 227 (49) 51 (12–200) 107 (48.6) 113 (51.4) 6 (3–9) 5.87 ⫾ 1.17 227 (49) 7 (4–10)c
Mean pathologic Gleason score ⫾ SD GS o 7—n (%) GS Z 7—n (%) Unspecified (previous radiation or hormone therapy)—n (%) Stage pT2—n (%) Stage Z pT3—n (%)
6.56 ⫾ 1.04 346 (75) 99 (21) 19 (4.1) 316 (68) 148 (32)
No. ¼ number; pts. ¼ patients; SD ¼ standard deviation. a Mean age ⫾ SD by BMI category: 60.93 ⫾ 6.22 (normal), 61.66 ⫾ 6.46 (overweight), and 61.48 ⫾ 6.42 (obese). b Percentage upgrade by BMI category: 38.6% (66/171) (normal), 46.8% (105/224) (overweight), and 27.5% (19/69) (obese). c Significant difference between biopsy and pathologic Gleason score (P o 0.00001).
M.C. Goris Gbenou et al. / Urologic Oncology: Seminars and Original Investigations ] (2016) 1–6
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Fig. Linear regression analyses showing prostate weight as a function of BMI. (A) Total population described by the equation y ¼ 50.25 þ 0.14*x. (B) Men with a BMI o 25 kg/m2 (y ¼ 48.29 þ 0.16*x). (C) Men with a BMI of 25 to 30 kg/m2 (y ¼ 19.73 þ 1.28*x). (D) Men with a BMI 430 kg/m2 (y ¼ 17.61 þ 2.37*x). (Color version of figure is available online.)
be calculated were included in the analysis. Patient data are presented in Table 1. Median age was 61 years (range: 45–76), mean BMI was 26.50 kg/m2 (standard deviation ¼ 4.82), and median PSA was 6.8 ng/ml (range: 0.67–27.2). In total, 51% had nonpalpable disease (cT1) and 69% organ-confined (pT2) disease. Median RP specimen weight was 51 g (range: 12–200). GS was upgraded in 227 (49%) patients from median GS 6 to 7 (P o 0.00001). There was no significant difference in mean age or percentage disease upgrade among the 3 BMI categories (normal, overweight, and obese) (Table 1). Mean preoperative PSA was significantly higher in obese men (BMI 4 30 kg/m2) than in normal men (BMI o 25 kg/m2) (8.56 ng/ml [95% CI: 6.94–10.18] vs. 8.34 ng/ml [95% CI: 7.23–9.45]; P o 0.001). Mean prostate weight was also significantly higher in obese men than normal men (59 ⫾ 25 g vs. 47 ⫾ 13 g; P o 0.00015). However, there was no significant difference in mean prostate weight
between overweight men (BMI ¼ 25–30 kg/m2) and normal men (47 ⫾ 15 g vs. 47 ⫾ 13 g; P ¼ 1.000, respectively). The Friedman analysis of variance Chisquare statistic for mean prostate weight according to BMI grouping (N ¼ 66, df ¼ 3) was 14.976 (P o 0.001) and Kendall coefficient of concordance was 0.075, with average rank r ¼ 0.061. Several statistical analyses were performed as follows: (1) in a linear regression plot of prostate weight vs. BMI, the coefficient was 0.14 for the total population (y ¼ 50.24 þ x*0.14) (Fig. A). It increased from 0.16 to 1.28 to 2.37 with BMI group (Fig. B–D, respectively). A BMI of o25 kg/m2 was negatively associated with prostate weight (standardized “beta” regression coefficient of -0.215, P ¼ 0.001) whereas BMIs of 25 to 30 and 430 kg/m2 were positively associated with prostate weight (standardized “beta” coefficients of 0.114, P ¼ 0.015 and 0.127, P ¼ 0.007, respectively); (2) in linear regression analyses, preoperative PSA was positively associated with a
M.C. Goris Gbenou et al. / Urologic Oncology: Seminars and Original Investigations ] (2016) 1–6
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Table 2 Pearson correlation evaluating potential risk factors in localized prostate cancer in 464 men
Age r P N
Age
PSA
Biopsy GS
BMI
Specimen wt (g)
pT stage
Specimen GS
1
0.053 0.253 464
0.113 0.016* 451
0.012 0.794 464
0.081 0.082 456
0.018 0.693 464
0.082 0.085 445
1
0.211 0.000** 451
0.036 0.437 464
0.062 0.183 456
0.037 0.432 464
0.239 0.000** 445
1
0.005 0.908 451
0.043 0.367 441
0.006 0.899 447
0.367 0.000** 428
0.137 0.003** 456
0.143 0.002** 464
0.029 0.535 445
1
0.072 0.127 452
0.075 0.119 435
1
0.019 0.692 441
464
PSA r P N
0.053 0.253 464
464
Biopsy GS r P N
0.113* 0.016 451
0.211** 0.000 451
451
BMI r P N
0.012 0.794 464
0.036 0.437 464
0.005 0.908 451
1
Specimen wt (g) r 0.081 P 0.082 N 456
0.062 0.183 456
0.043 0.367 441
0.137 0.003** 456
456
pT stage r P N
0.018 0.693 464
0.037 0.432 464
0.006 0.899 447
0.143 0.002** 464
0.072 0.127 452
464
Specimen GS r P N
0.082 0.085 445
0.239 0.000** 445
0.367 0.000** 428
0.029 0.535 445
0.075 0.119 435
0.019 0.692 441
464
1 445
r ¼ Pearson correlation coefficient ranging from 1 (perfect negative linear relationship) to þ1 (perfect positive linear relationship). N ¼ number of patients. * P ¼ 0.05. ** P ¼ 0.01.
high biopsy GS in patients with a BMI Z 25 kg/m2 (P ¼ 0.048) and Z30 kg/m2 (P ¼ 0.009) but not in patients with a BMI r 25 kg/m2 (P ¼ 0.151); (3) in a multinomial linear regression analysis, obesity (BMI Z 30 kg/m2) was significantly associated with higher pT stage (odds ratio: 1.279 [95% CI: 1.5–1.56]; P ¼ 0.015); (4) in a bivariate Pearson correlation analysis, BMI was positively correlated with preoperative specimen weight (P ¼ 0.003) and pT stage (P ¼ 0.002) but not with initial PSA (P ¼ 0.437) nor with biopsy GS (P ¼ 0.908) or pathologic GS (P ¼ 0.535) (Table 2); (5) in multivariate regression analysis, with either BMI or PSA as the dependent variable, preoperative BMI was positively associated with higher pT stage (P ¼ 0.008), prostate weight (0.032), and pathologic GS (P ¼ 0.042), whereas PSA was associated with higher biopsy GS only (0.002) (Table 3). Neither BMI nor PSA was significantly associated with age or GS upgrading.
Table 3 BMI and PSA as potential risk factors in multivariate regression analyses Parameter
Dependent variable (preop)
Age
PSA BMI
5.918 1.413
0.132 0.087
0.717 0.768
Whole prostate weight
PSA BMI
100.887 75.209
2.248 4.646
0.135 0.032
Biopsy Gleason score
PSA BMI
438.384 46.845
9.767 2.894
0.002 0.090
Pathologic Gleason score PSA BMI
126.918 67.331
2.828 4.159
0.093 0.042
Upgraded Gleason score PSA BMI
50.970 23.436
1.136 1.448
0.287 0.230
pT stage
93.704 79.388
2.113 7.051
0.147 0.008
PSA BMI
Mean square F value P value
M.C. Goris Gbenou et al. / Urologic Oncology: Seminars and Original Investigations ] (2016) 1–6
4. Discussion This retrospective study of a cohort of 464 patients with localized prostate cancer undergoing RP has highlighted an association between increasing BMI and higher prostate weight and also between increasing BMI and aggressive disease (high pathologic GS score and pT stage). Preoperative PSA level was significantly associated with biopsy GS only. Surprisingly, neither preoperative BMI nor PSA was associated with GS upgrading maybe because of unavailable scores in 4.1% of patients with a history of radiation or hormone therapy or because the incidence of upgraded disease is 4.5-fold lower for large (450 ml) prostates [15]. Our findings support the already reported relationships between obesity and both prostate weight and high-grade cancer observed in large patient cohorts. A relationship between preoperative BMI and increased prostate weight was established in a cohort of 16,325 patients [13] and a relationship between elevated BMI and increased prostate size, pathologic GS and tumor volume in a cohort of 14,293 patients [16]. Several studies have reported a relationship between obesity and increased risk of high-grade cancer (or possibly reduced risk of low-grade cancer) [17] in men undergoing RP: (1) both Amling [18] and Freedland et al. [19] found an association between obesity (BMI 4 30 mg/kg2 and 435 mg/kg2, respectively) and higher-grade tumors, and higher rates of disease recurrence after RP ; (2) Capitanio et al. (n ¼ 1,275) found that BMI was independently associated with tumor volume in a multivariable analysis [20]; and (3) Freedland et al. [19] (n ¼ 1106) found that obesity was associated with higher-grade tumors, a trend toward increased risk of positive surgical margins, and higher biochemical failure rates; a BMI Z 35 kg/m2 was associated with a higher risk of failure than a BMI between 30 and 35 kg/m2. The effect of BMI on PSA is controversial. An association between obesity and lower PSA levels has been highlighted, with no effect of BMI on the association between PSA level and tumor volume [16]. It has been suggested that PSA hemodilution in larger plasma volumes might explain the apparently lower PSA levels despite the larger prostates in obese men [20]. Our study confirmed that obese men had heavier prostates but detected higher and not lower mean PSA values. These mean PSA values in obese men were better correlated with GS than were mean PSA values in patients with BMI r 25 kg/m2. BMI thus provides additional prognostic information to PSA in obese patients but other more efficient markers are needed, in particular in nonobese patients. We did not evaluate the effect of obesity on disease recurrence or mortality. Obesity in patients who underwent RP has emerged as a significant independent predictor of risk of prostate cancer recurrence in several multivariate studies. Independent predictors for risk of recurrence in registry study by Bassett et al. [21] (n ¼ 2,131) were an increasing BMI (P ¼ 0.028), an increasing PSA level (P o 0.0001), and Gleason grade (P o 0.0001). In
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prospective study by Strom et al. [22] (n ¼ 526), the independent predictors were a higher BMI at diagnosis and GS. In retrospective multi-institutional pooled analysis by Amling et al. [23] (n ¼ 3,162), obesity was associated with both higher Gleason grade tumors (P o 0.001) and a higher recurrence rate (P ¼ 0.027). However, BMI was not associated with biochemical failure in a cohort of 2,687 patients with low-risk and intermediate-risk prostate cancer [24] nor in 230 men eligible for active surveillance after RP (P ¼ 0.950) [15]. A limitation of our study is the lack of evaluation of the periprostatic fatty tissue resected during RP, which could affect prostate weight. Any detected effect would need to be taken into account in future studies. We did not investigate tumor volume, extracapsular extension, lymph node metastasis (although no association has been detected [25]), or preoperative hormone levels (e.g., changes in testosterone [26], sex-hormone binding globulin, and estrogen levels, respectively). Obesity is associated with manifold hormonal changes that might influence disease aggressiveness [27]. Metabolic syndrome-related factors might also affect disease aggressiveness and would require study.
5. Conclusions Our data indicate a strong association between obesity and higher prostate weight, disease stage and preoperative PSA, and provide further evidence for obese men undergoing RP having more aggressive cancers. PSA did not correlate with high GS because of its poor performance in nonobese patients. BMI is a parameter that needs to be evaluated in all prospective randomized studies of localized prostate cancer treatments. References [1] Golabek T, Bukowczan J, Chlosta P, Powroznik J, Dobruch J, Borowka A. Obesity and prostate cancer incidence and mortality: a systematic review of prospective cohort studies. Urol Int 2014;92:7– 14. [2] Zhang X, Zhou G, Sun B, Zhao G, Liu D, Sun J, et al. Impact of obesity upon prostate cancer-associated mortality: a meta-analysis of 17 cohort studies. Oncol Lett 2015;9:1307–12. [3] Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003;348:1625–38. [4] Discacciati A, Orsini N, Wolk A. Body mass index and incidence of localized and advanced prostate cancer—a dose-response metaanalysis of prospective studies. Ann Oncol 2012;23:1665–71. [5] Bassett JK, Severi G, Baglietto L, MacInnis RJ, Hoang HN, Hopper JL, et al. Weight change and prostate cancer incidence and mortality. Int J Cancer 2012;131:1711–9. [6] Freedland SJ, Banez LL, Sun LL, Fitzsimons NJ, Moul JW. Obese men have higher-grade and larger tumors: an analysis of the duke prostate center database. Prostate Cancer Prostatic Dis 2009;12:259– 63. [7] Gross M, Ramirez C, Luthringer D, Nepomuceno E, Vollmer R, Burchette J, et al. Expression of androgen and estrogen related
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