Accumulating evidence suggests that obesity is associated with tumor progression in prostate cancer (PCa) patients after radical prostatectomy (RP). We conducted a retrospective multicenter study to determine the effect of body mass index (BMI) on the clinicopathological characteristics and biochemical recurrence of PCa in Japanese men who underwent RP.
The medical records of 1257 men with PCa treated by RP without neoadjuvant therapy at four medical institutes between 2001 and 2009 were retrospectively reviewed. Patients were categorized into four groups using the World Health Organization (WHO) BMI classification and BMI quartiles. Associations of the various BMI categories with clinicopathological characteristics and biochemical recurrences were statistically evaluated. Biochemical recurrence was defined as a PSA level of >0.2 ng ml–1.
Of the 1257 patients, 230 (18.3%) experienced biochemical recurrence during the median follow-up period of 49 months. The median BMI was 23.8 kg m–2, and 1.4% patients were underweight, 65.4% were of normal weight, 30.9% were overweight and 2.4% were obese (WHO classification). Preoperative PSA levels and PSA density (PSAD) tended to decrease as BMI increased. Pathological characteristics did not differ significantly among BMI categories. As per the WHO classification and quartile categories, biochemical recurrence rate was comparable among the BMI groups. After adjusting for other pre- and postoperative covariables, multivariate Cox proportional hazards analysis revealed that a high BMI did not have an independent impact on biochemical recurrence-free survival.
Underweight Japanese PCa patients treated by RP had higher preoperative PSA levels and PSAD. High BMI was not associated with adverse pathological findings or increased biochemical recurrence rate in Japanese PCa patients treated with RP. Racial differences may exist in the relationship between obesity and outcomes of RP in PCa patients.
Obesity is a major public health issue and is associated with both an increased risk of death and aggressive phenotypes of several cancers, including prostate cancer (PCa).1 A large meta-analysis of 27 prospective studies observed a nonstatistically significant association between body mass index (BMI) and PCa risk.2 However, recent meta-analyses suggested differing associations of obesity with various PCa subtype.3, 4 In particular, obesity had a dual effect on PCa, with a decreased risk for localized PCa and an increased risk for advanced PCa, presumably because of the cancer’s etiologic heterogeneity.3, 4 In addition, obesity correlates with a number of clinical variables, including serum PSA level and prostate volume, in patients with prostatic disease.5, 6, 7 Several studies from western countries have shown that obesity predisposes to recurrent PCa with more aggressive pathological features and/or higher biochemical recurrence rates after radical prostatectomy (RP).8, 9, 10, 11, 12, 13, 14 In addition, obese men were reported to be at greater risk of developing higher-grade tumors after surgery in low-risk PCa matched the criteria of active surveillance programs.15
The prevalence of obesity is increasing in Asia because of westernization of diet and lifestyle. However, there is a vast difference in the proportion of BMI between Asian and Western populations. The relationship of BMI with clinicopathological characteristics and treatment outcome in PCa patients treated by RP remains largely unknown in Asia, including Japan. These modifiable lifestyle factors may help us to improve patient outcomes if the relationship becomes evident.
We conducted a multicenter study to investigate the impact of BMI on clinicopathological features and biochemical recurrences in Japanese PCa patients treated by RP.
Materials and methods
A total of 1269 consecutive patients with clinically localized PCa underwent RP between January 2000 and December 2009 at Akita University (276 patients), Tohoku University (334 patients), Hirosaki University (363 patients) and the Miyagi Cancer Center (296 patients). The study was approved by each institution’s review board, and all patients signed informed consent forms. No patient had a history of prostate surgery, neoadjuvant hormonal therapy or radiation therapy. Of the 1269 patients, 12 (0.9%) were excluded from further analysis because of missing BMI data. RP was achieved using either the open (1156 patients) or the laparoscopic approach (101 patients). Pathological evaluation of biopsy and surgical specimens was performed according to the Gleason grading system and the 2002 TNM classification.
BMI (kg m–2) was calculated as weight (kg) divided by the square of height (m). The patients were categorized into four groups on the basis of the World Health Organization (WHO) BMI classification (underweight (<18.5 kg m–2), normal weight (18.5–24.99 kg m–2), overweight (25.00–29.99 kg m–2) and obese (⩾30 kg m–2)) and the BMI quartiles (<22.2, 22.2–23.7, 23.8–25.5 and ⩾25.6 kg m–2). The association of the various BMI categories with clinicopathological characteristics and biochemical recurrence was examined. The date of biochemical recurrence was defined as that when the serum PSA level exceeded 0.2 ng ml–1, when salvage radiation was performed because PSA levels did not decrease below 0.2 ng ml–1 after surgery, or when adjuvant or salvage therapy was initiated even if PSA did not exceed 0.2 ng ml–1. PSA density (PSAD) was obtained by dividing serum PSA levels by the individual prostate volumes measured using a transrectal or abdominal ultrasound.
We assessed differences in clinicopathological characteristics between each BMI group using analysis of variance for continuous variables and the χ2 test for categorical variables. The maximum contrast method was introduced to elucidate dose–response relationships using the SAS/MULTTEST. Odds ratios for pathological outcomes were also estimated for each BMI category using multiple logistic regression analysis after adjusting for patient age (continuous variable), PSA level (continuous variable), clinical stage (>T2 vs others) and biopsy findings (Gleason score⩾4+3 vs others). Biochemical recurrence-free survival was determined using the Kaplan–Meier method and the log-rank test. To identify independent prognostic factors, multivariate analysis was performed using the Cox proportional hazards regression model with age, PSA level, BMI, extracapsular tumor extension, positive surgical margins, pathological Gleason score, seminal vesicle invasion and lymph node involvement as variables. With the exception of BMI, the variables included in the multivariate analysis were significant in the univariate analysis. BMI was used as a continuous variable for the Cox proportional hazard regression model. All statistical analyses were performed using the SPSS software package, version 19.0 (SPSS, Chicago, IL, USA). All reported P-values were two-sided with statistical significance considered at P<0.05.
BMI and patient characteristics
Patient characteristics are shown in Table 1. In total, 1257 PCa patients (mean age at diagnosis, 66.0 years (range, 45–83)) were entered in this study. The mean preoperative serum PSA level was 9.9 ng ml–1 (range, 0.5–98 ng ml–1). The median BMI was 23.8 kg m–2 (range, 17.2–34.1 kg m–2), and 1.4% (17/1257) patients were underweight, 65.4% (822/1257) were of normal weight, 30.9% (388/1257) were overweight and 2.4% (30/1257) were obese (WHO classification). The median prostate volume was 32.0 g (range, 2.3–118.0 g), and the median PSAD was 0.38 ng ml–1 g–1 (range, 0.024–7.9 ng ml–1 g–1). The mean age was significantly higher in the underweight group than in the other groups (P=0.020). When patients were categorized on the basis of the WHO classification for BMI, the preoperative PSA level and PSAD tended to decrease as BMI increased by the maximum contrast method (P=0.0083 and P=0.025, respectively).
BMI and pathological outcomes
Pathological characteristics did not differ significantly among the BMI categories by the WHO classification and BMI quartiles (Table 1). When the patients were grouped by the WHO classification, there was no significant increased risk of adverse pathological findings in the higher BMI groups compared with the normal group after adjusting for age, PSA levels, clinical stage and biopsy Gleason score (Table 2). Similarly, when the patients were grouped by BMI quartiles, there was no significant increased risk of adverse pathological findings in the higher BMI groups compared with the lowest quartile group after adjusting for age, PSA levels, clinical stage and biopsy Gleason score (Table 3).
BMI and biochemical recurrence
Of the 1257 patients, 230 (18.3%) experienced biochemical recurrence during a median follow-up period of 49 months. Biochemical recurrence was observed in 1 of 17 (5.9%) patients in the underweight group, 152 of 822 (18.5%) patients in the normal weight group, 74 of 388 (19.1%) patients with the overweight group and 3 of 30 (10.0%) patients in the obese group. Kaplan–Meier analysis indicated no statistically significant difference in the incidence of biochemical recurrence between groups classified according to the WHO classification (P=0.465) or the BMI quartile classification (P=0.954). Figure 1 shows the results of Kaplan–Meier analysis for the incidence of biochemical recurrence in the groups classified according to the BMI quartiles. As presented in Table 4, BMI was not a significant prognostic factor for postoperative biochemical recurrence after adjusting for pre- and postoperative variables (Table 4). Preoperative PSA level, extraprostatic extension, positive surgical margins, pathological Gleason score, seminal vesicle invasion and lymph node involvement were all statistically significant predictors of an increased risk of biochemical recurrence after RP in a model including pre- and postoperative factors (Table 4).
As per our knowledge, this is the largest retrospective study that explored the relationship of BMI with clinicopathological characteristics and outcomes after RP in Japanese PCa patients. We demonstrated that preoperative PSA levels and PSAD tended to decrease as BMI increased. However, BMI did not have any impact on postoperative pathological outcomes and adds no prognostic value in Japanese patients treated by RP for clinically localized PCa.
Contrary to the results of studies from the United States,16, 17 we found no significant relationship between biochemical recurrence and BMI in this study. However, our results were similar to those from other countries such as the Netherlands and Korea,18, 19 which demonstrated that higher BMI was not significantly associated with a higher biochemical recurrence rate. The reason for this discrepancy may be explained by differences in the BMI profiles of patients entered in these studies. Compared with patients of studies from the United States, our patients had a significantly lower rate of both overweight and obesity.20 In the North American series, 17–34% patients8, 21 had a high BMI (⩾30), whereas only 2.4% patients in our series fell into this BMI category. Recent evidence suggests that a high BMI (⩾30) may be significant with respect to the adverse pathology of PCa in the United States.12, 21 Although we found that a linear increase in the BMI had no significant influence on the aggressive phenotype of PCa, we could not accurately assess the impact of BMI (⩾30) on the aggressiveness of PCa because of the small number of obese patients in our study. Furthermore, PCa patients in Japan simply may not demonstrate sufficient significant biological alterations of obesity compared with those in the United States. Although we used the two classification systems to evaluate the relationship between the BMI and clinicopathological outcomes, a population-based BMI cutoff point may be required to delineate the relationship.22 In addition, the pre- and postoperative duration of overweight and obesity, which could not be evaluated in this study, may have a significant influence on biochemical recurrence. In two small retrospective studies on Japanese PCa patients treated using RP, BMI was an independent predictor of biochemical recurrence when patients were divided into two groups according to mean cutoff values for BMI (cutoff BMI, 26.5 kg m–2).23, 24 However, when we used this value to divide our study population into two groups (cutoff BMI, 26.5 kg m–2), BMI had no effect on biochemical recurrence (P=0.636 using the log-rank test). Although the number of patients in the previous reports was relatively small, as compared with that in our study, the discrepancy may also have resulted from the varying inclusion criteria for surgery, follow-up duration or quality of surgery. A nationwide study is required to validate the effects of high BMI (⩾30) on the Japanese population.
The impact of BMI on pathological findings in our study was also discrepant from that reported in other studies. Our results suggested that a higher BMI was not associated with adverse pathological findings in Japanese PCa patients treated by RP. Similarly, Isbarn et al.25 analyzed data from 1538 European men treated by RP and demonstrated that their BMI was unrelated to the pathological findings as per multivariate analysis. In contrast, Siddiqui et al.21 performed a prospective cohort study that included 5313 men treated by RP and found that obese men appeared to have adverse pathological features at the time of RP. Lee et al.18 revealed that a higher BMI was associated with extracapsular tumor extension and positive surgical margins in Korean men who underwent RP; however, they indicated that BMI did not affect other adverse pathological factors such as Gleason scores and seminal vesicle invasion. Although the discrepancy may be explained by the lack of severe obesity in our population or selection bias for RP as mentioned above, the difference in racial background may further affect pathological characteristics and outcomes. Whether or not there was any difference in genetic background or dietary lifestyle between the Japanese patients in our study and the Korean patients in the previous study18remains unclear.
Both population-based studies26, 27 and studies of patients with clinically localized PCa treated by RP5 have found that obese men have lower PSA levels compared with nonobese men. Hemodilution and low androgenic activity are reported to have an inverse relationship with obesity and serum PSA levels.5, 28 In our study, although there was no significant association between BMI and PSA levels (r=−0.011, P=0.207), serum PSA levels tended to decrease as BMI increased, and the PSA level was higher in the underweight group than in the other groups (Table 1). To the best of our knowledge, there have been no studies focusing on the impact of underweight status on clinical outcomes in PCa patients. Although the hemodilution theory and age differences between the treatment groups are reliable explanations for the positive association between BMI and PSA levels in our study, it will be intriguing to assess the specific effects of underweight status on clinical variables, including serum PSA levels, in other populations. Recently, the PSA mass, defined as the absolute amount of PSA protein in the circulation, was reported to be associated with visceral adipose tissue deposition in PCa patients who underwent RP.29 PSA mass was also found to be associated with PSA recurrence in clinically localized PCa patients.30 As the effects of plasma volume can be avoided by the concept of PSA mass, it may be valuable to assess the effects of BMI on PSA mass in the future.
This study has several limitations. First, this was a retrospective study. Patients unsuitable for surgery such as those with severe obesity, low performance status and/or other complications might have been excluded at the surgeon’s discretion. Second, the duration of follow-up was too short to clarify the impact of BMI on prognosis. Therefore, a future validation study with a longer follow-up period is required. Third, the validity of presurgical BMI for the assessment of the effects of obesity on clinicopathological characteristics and outcome after RP in PCa patients remains controversial. Park et al.29 reported that visceral obesity, as measured by computed tomography, was associated with prostate enlargement and production of PSA. Furthermore, while BMI was measured once just before the operation in this study, several reports suggested that BMI in early and middle–late adulthood as well as weight changes before and after surgery were risk factors for biochemical recurrence and/or advanced phenotype of PCa in PCa patients treated by RP.31, 32 Therefore, other factors that are related to long-term obesity should be assessed in future analyses as predictors of clinical outcome. Finally, because of the multicenter nature of this study, differences in surgical quality and the lack of a central pathologist may have caused an unexpected bias regarding the relationship of BMI with clinicopathological characteristics and outcomes.
In this retrospective multicenter study including 1257 Japanese PCa patients who underwent RP, preoperative PSA levels and PSAD tended to decrease as BMI increased. However, high BMI was not associated with adverse pathological findings or an increased biochemical recurrence rate.
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The authors declare no conflict of interest.
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