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Prostate cancer detection: The impact of obesity on Asian men
Urologic Oncology: Seminars and Original Investigations 33 (2015) 266.e17–266.e22
Original article
Prostate cancer detection: The impact of obesity on Asian men Alvin Leea, Sing Joo Chiab,* a
Yong Loo Lin School of Medicine, National University of Singapore b Department of Urology, Tan Tock Seng Hospital
Received 10 January 2015; received in revised form 13 February 2015; accepted 9 March 2015
Abstract Objective: To evaluate the impact of body mass index (BMI) on prostate cancer detection in biopsy-naive men presenting to a single tertiary hospital in Singapore. Materials and methods: We retrospectively examined 458 men who underwent initial prostate biopsies between January 2012 and April 2014. Indications for biopsy were serum prostate-specific antigen level Z4.0 ng/ml, or digital rectal examination findings suspicious for malignancy, or both. Only men with serum prostate-specific antigen level o20 ng/ml were included. BMI categories were based on the World Health Organization recommendations (normal: o25.0, overweight: 25.0–29.9, and obese: Z30). Results: Of the 458 men included in our cohort, 125 (27.3%) men were positive for prostate cancer on biopsy, with 69 (15.1%) being clinically significant (Gleason Z7). Men with BMI Z25 kg/m2 (41.7%) were younger (67.2 vs. 68.8 y, P ¼ 0.030), had larger prostates (45.5 vs. 40.1 g, P ¼ 0.014), and were more likely to have a positive biopsy finding (34.6% vs. 22.1%, P ¼ 0.003). On multivariate analysis, being overweight or obese was associated with increased risk of having prostate cancer on biopsy (odds ratio [OR] ¼ 2.61, 95% CI: 1.58–4.30, P o 0.001 and OR ¼ 3.26, 95% CI: 1.37–7.73 P ¼ 0.007, respectively). The same trend was observed for clinically significant cancers but not for clinically insignificant cancers (OR ¼ 3.57, 95% CI: 1.87–6.82, P o 0.001 and OR ¼ 3.86, 95% CI: 1.33– 11.21, P ¼ 0.013 for being overweight and obese, respectively). Conclusion: Asian men with BMI Z25 kg/m2 are at greater risk of having a positive initial biopsy result. The BMI threshold (BMI Z25 kg/m2) for Asian men to be at increased risk of prostate cancer detection on initial biopsy is lower than that of Western populations (BMI Z30 kg/m2). r 2015 Elsevier Inc. All rights reserved.
Keywords: Body mass index; Obesity; Oncology; Prostate cancer; PSA
1. Introduction Over the past decade, the incidence of prostate cancer has risen dramatically to become the third commonest cancer in Singaporean men and is the fifth commonest cause of cancer mortality [1]. This has created an urgent need for more studies on prostate cancer diagnosis and treatment in Asian populations. Increasingly, obesity has become a more prevalent public health problem in Singapore and the rest of the world [2]. It has also been linked with various forms of cancer [3]. A case in point of this phenomenon is the significant Ethics review: DSRB 2010/00318. * Corresponding author. Tel.: þ65-6357-7668; fax: þ65-6357-3198. E-mail address: [email protected] (S.J. Chia). http://dx.doi.org/10.1016/j.urolonc.2015.03.011 1078-1439/r 2015 Elsevier Inc. All rights reserved.
association between obesity and prostate cancer mortality as observed in large cohort studies [4,5]. Obesity-related detection biases and biological mechanisms have been cited to be important contributory factors of the epidemiological association between obesity and aggressive prostate cancer [6,7]. Many studies have found that obese men had lower prostate-specific antigen (PSA) levels and larger prostates, thereby making current detection methods less sensitive [6,8–13]. The aim of our study is to evaluate the impact of body mass index (BMI) on prostate cancer detection in biopsynaive men presenting to a single tertiary hospital in Singapore. We hypothesize that obesity is a risk factor of prostate cancer detection in Asian men and that clinical factors associated obesity may obscure prostate cancer detection in our local population.
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2. Materials and methods In our study, we retrospectively analyzed 804 patients who underwent transrectal ultrasound (TRUS)-guided prostate biopsy in a single tertiary institution from January 2012 to April 2014. The indications for prostate biopsy were serum PSA level Z4.0 ng/ml or digital rectal examination (DRE) findings suspicious for malignancy or both. Only patients with PSA level o20 ng/ml were included in our study so as to exclude those with metastatic disease. Subjects who had previous prostate biopsy, prostate surgery, currently/previously on 5-alpha reductase inhibitors, or with a known diagnosis of prostate cancer were excluded from the study. All men had at least 1 or more serum PSA levels measured and were subjected to DRE. All PSA measurements were performed using PSA Hybritech Assay, and only the latest serum PSA levels were analyzed. BMI data were retrieved from our electronic database and were only used if they were measured within 1 year of their biopsy. BMI categories were based on World Health Organization (WHO) recommendations (normal: o25.0, overweight: 25.0–29.9, and obese: Z30) [14]. Prostatespecific antigen density (PSAD) was calculated by dividing the serum PSA level by the prostate volume. For the prostate biopsy, patients were placed in the left lateral position, and a TRUS-guided biopsy of the prostate was performed. The ultrasound scanner used was Siemens ACUSON X150. The prostate volume was measured using the ellipsoid formula (π/6 craniocaudal transverse anteroposterior length). Patients underwent either sextant biopsy, systematic 12-core biopsy, or 18-core biopsy depending on the performing clinician's evaluation of the prostate volume and DRE findings. The core specimens were examined by pathologists in the same institution. Prostate cancers with Gleason sum Z7 were considered clinically significant, whereas cancers with Gleason sum o7 were considered clinically insignificant. Statistical analysis was performed using IBM SPSS Version 20. T test, Kruskal-Wallis test, and Pearson chisquare test were used to evaluate any differences in continuous and categorical variables. Logistic regression analysis was used to examine the association between clinical variables and prostate cancer detection on biopsy. Differences were significant if P o 0.05. Ethics approval was obtained from domain-specific review board before commencement of the study. Domain-specific review board 2010/00318.
3. Results Complete data sets, including BMI, were available in 586/804 (72.9%) men who underwent first TRUS-guided prostate biopsy. Of 586 men, 458 (78.1%) had serum PSA level o20 ng/ml and were included in our study (Fig. 1). Out of the 458 men in our study, 418 (91.3%) were Chinese, whereas the other 40 (8.7%) were of other races
804 Men underwent initial prostate biopsy 218 Men excluded due to incomplete datasets 586 Men with complete datasets 128 Men excluded due to PSA 20ng/ml 458 Men with PSA < 20 ng/ml
25.0 kg/m2
BMI < 25.0 kg/m2
BMI
267 Men (58.3%)
191 Men (41.7%)
Fig. 1. Flowchart of men who were included in our study cohort.
such as Malay, Indian, or Caucasian. Mean BMI and age were 24.2 kg/m2(⫾3.7) and 68.1 (⫾8.0) years, respectively. Of 458 men, 267 (58.3%), 160 (34.9%), and 31 (6.8%) were normal weight, overweight, and obese, respectively. Moreover, 424 (92.6%) men underwent systematic 12-core biopsy, 1 (0.2%) underwent sextant biopsy, and 33 (7.2%) underwent 18-core biopsy. Overall, 125 (27.3%) men were positive for prostate cancer on biopsy, with 69 (15.1%) having clinically significant cancer. There was no difference in the mean BMI between those who had a positive biopsy and those who had a negative one (24.6 kg/m2 vs. 24.0 kg/m2, P ¼ 0.173). The men were divided into 2 groups based on their BMI category for comparison (Fig. 1). Of 458 men, 191 (41.7%) had BMI Z25 kg/m2 whereas 267 (58.3%) had BMI o25 kg/m2 (Table 1). Men with BMI Z25 kg/m2 were more likely to have prostate cancer found on biopsy (34.6% vs. 22.1%, P ¼ 0.003) and were more likely to have clinically significant cancers (21.5% vs. 10.5%, P ¼ 0.001). They were also younger (67.2 vs. 68.8 y, P ¼ 0.030), had larger prostates (45.5 vs. 40.1 g, P ¼ 0.014), and were more likely to have a hypoechoic lesion seen on TRUS (7.9% vs. 3.0%, P ¼ 0.019). There were no significant differences in serum PSA levels between the 2 groups; however, men with BMI Z25 kg/m2 had lower PSAD (0.14 vs. 0.17, P ¼ 0.001). Men with BMI Z25 kg/m2 were no more likely to have suspicious DRE findings (P ¼ 0.356) (Table 1). On univariate analysis, being overweight or obese conferred greater risk of having a positive biopsy finding (odds ratio [OR] ¼ 1.80, 95% CI: 1.16–2.78, P ¼ 0.009 and OR ¼ 2.23, 95% CI: 1.02–4.85, P ¼ 0.044) (Table 2). After adjustment for multiple clinical variables, being overweight or obese was associated with significantly increased odds of having prostate cancer on biopsy. The odds of having prostate cancer were greater in the overweight and obese group compared with the reference group (OR ¼ 2.61, 95% CI: 1.58–4.30, P o 0.001 and OR ¼ 3.26, 95% CI: 1.37–7.73 P ¼ 0.007, respectively) (Table 2). Other significant independent associations included patient age, serum PSA level, and prostate volume. The presence of suspicious DRE and hypoechoic lesions on TRUS were no longer significant independent risk factors
A. Lee, S.J. Chia / Urologic Oncology: Seminars and Original Investigations 33 (2015) 266.e17–266.e22
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Table 1 Clinical and pathological features of men undergoing prostate biopsy Patient characteristics
Total
BMI o 25.0 kg/m2
BMI Z 25.0 kg/m2
P value
Number (%) Mean age ⫾ SD, y Mean BMI ⫾ SD, kg/m2 Median PSA (IQR), ng/ml Median PV (IQR), g Median PSAD (IQR)
458 68.1 ⫾ 8.0 24.2 ⫾ 3.7 7.00 (5.37–10.0) 42.2 (30.0–59.3) 0.16 (0.11–0.25)
267 (58.3) 68.8 ⫾ 8.2 21.8 ⫾ 2.3 7.14 (5.57–10.2) 40.1 (28.0–55.4) 0.17 (0.12–0.26)
191 (41.7) 67.2 ⫾ 7.8 27.6 ⫾ 2.6 6.94 (5.09–9.39) 45.5 (33.0–65.5) 0.14 (0.10–0.21)
0.030a o0.001a 0.100b 0.014b 0.001b
DRE findings Suspicious (%) Normal (%)
96 (21.0) 362 (79.0)
52 (19.5) 215 (80.5)
44 (23.0) 147 (77.0)
0.356c
Hypoechoic lesion Yes (%) No (%)
23 (5.0) 435 (95.0)
8 (3.0) 259 (97.0)
15 (7.9) 176 (92.1)
0.019c
Biopsy outcome Prostate cancer (%) High risk Low risk Benign prostate (%)
125 (27.3) 69 (15.1) 56 (12.2) 333 (72.7)
59 (22.1) 28 (10.5) 31 (11.6) 208 (77.9)
66 (34.6) 41 (21.5) 25 (13.1) 125 (65.4)
0.003c 0.001c 0.634c
IQR ¼ inter quartile range; PV ¼ prostate volume; SD ¼ standard deviation. a T test. b Kruskal-Wallis test. c Chi-square test.
after multivariate adjustment. The same trend was observed when BMI was analyzed as a continuous variable (analysis not shown). When prostate cancers detected on biopsy were categorized into whether they were clinically significant or insignificant, men who were overweight or obese were not at higher risk of having clinically insignificant prostate cancer detected (analysis not shown). Overweight and obese men were still more likely to have clinically significant prostate cancer detected on biopsy compared with the reference group. (OR ¼ 3.57, 95% CI: 1.87–6.82, P o 0.001 and OR ¼ 3.86, 95% CI: 1.33–11.21, P ¼ 0.013, respectively) (Table 3). Men with PSAD o0.15 ng/ml/g were more likely to overweight/obese and have a negative biopsy finding (Table 4) compared with men with PSAD Z0.15 ng/ml/g. In men with PSAD o0.15 ng/ml/g, there were no differences in overall prostate cancer detection between men with BMI o25 kg/m2 and those with BMI Z25 kg/m2. However, in men with PSAD Z0.15 ng/ml/g, those with BMI Z25 kg/m2 had greater cancer detection rates (54.5% vs. 27.3%, P o 0.001) (Table 5 and Fig. 2). 4. Discussion Prostate cancer is one of the commonest cancers afflicting men today and increasingly so in westernized Asian countries such as Singapore. It now ranks as the third commonest cancer in men locally [1]. Despite the rising trend in the past two decades, prostate cancer incidence and mortality rates are still lower in Asian countries compared
to Western countries. An ageing population, greater awareness, biopsy methods, and lifestyle factors such as obesity and dietary intake are just some of the reasons cited that could possibly account for this upward trend [15]. Obesity is a growing health problem, affecting more than 300 million people in the world [2]. The prevalence of obesity in Singaporean men has risen from 6.4% in 2004 to 12.1% in 2010 [16]. In our series, only 6.8% were obese based on the WHO definitions. This value is higher than rates reported in both Korean (1.4%) and Japanese (1.7%) prostate cancer detection study cohorts [17,18]. Comparatively, obesity was markedly more prevalent in other Western studies. For instance, a study by Freedland et al. [8] Table 2 Univariate and multivariate logistic regression analysis of factors predicting prostate cancer detection on prostate biopsy Cancer detection
BMI ¼ 25–29.9 kg/m2 (overweight) OR 95% CI
Univariate BMI (crude)
1.80 1.16–2.78
Multivariate BMI Age PV PSA DRE Hypoechoic lesion
2.61 1.05 0.97 1.19 0.75 0.73
BMI Z 30 kg/m2 (obese)
P value OR 95% CI
P value
0.009 2.23 1.02–4.85 0.044
1.58–4.30 o0.001 3.26 1.37–7.73 0.007 1.02–1.09 0.001 0.96–0.98 o0.001 1.12–1.26 o0.001 0.42–1.33 0.321 0.26–2.05 0.544
PV ¼ prostate volume. Reference group ¼ BMI o 25 kg/m2.
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Table 3 Univariate and multivariate logistic regression analysis of factors predicting clinically significant prostate cancer detection on prostate biopsy Clinically significant cancer
BMI ¼ 25–29.9 (overweight) OR 95% CI
Univariate BMI (crude) Multivariate BMI Age PV PSA DRE Hypoechoic lesion
2.30 1.34–3.97 3.57 1.04 0.96 1.26 0.51 0.63
BMI Z 30 (obese) P value OR 95% CI 0.003 2.49 0.98–6.30
P value 0.054
1.87–6.82 o0.001 3.86 1.33–11.21 0.013 1.00–1.09 0.034 0.94–0.97 o0.001 1.17–1.36 o0.001 0.25–1.02 0.058 0.19–2.03 0.434
PV ¼ prostate volume. Reference group ¼ BMI o 25 kg/m2. Clinical significant cancers ¼ Gleason sum Z7.
reported an obesity prevalence of 28%, whereas in a study by Pruthi et al. [9], it was 26%. Despite suggestion of increased risk of all-cause mortality at lower BMI cutoffs in Asian men, we chose to preserve the traditional WHO definitions for comparison with other studies on obesity and prostate cancer detection [8,9,19]. We also only selected men with serum PSA level o20 ng/ml to exclude men whose BMI may have been altered owing to the deleterious effects of metastatic disease. On analysis of our clinical variables, we found that men with higher BMI (Z25 kg/m2) were younger and had larger prostate sizes [8,9,12]. Intriguingly, men with BMI Z25 kg/m2 were found to be associated with greater risk of prostate cancer detection on crude analysis, a finding that was not observed in other studies [8,9,12,18–20]. After adjusting for other clinical variables, our findings indicate that being overweight conferred a 161% increased risk of prostate cancer detection, whereas being obese conferred 226% increased risk. These findings further support current evidence in literature that being obese may obscure prostate cancer detection using contemporary biopsy methods. Park et al. [20] recently studied a biopsy population of 1,213 men in Korea and found that men with BMI Z25 kg/m2 were at 45% increased risk of having prostate cancer detected on biopsy. Masuda et al. [17] observed significant elevation in the risk of cancer at biopsy at BMI Z25 kg/m2 in a Japanese cohort whereas Freedland et al. [8] also observed a 98% increased risk in obese men after adjusting for lower PSA levels and larger prostate size in a Western cohort. We believe that the difference in crude and adjusted ORs can be explained by confounding factors such as serum PSA level [10,11], prostate volume [8,9,12], and age, which were anticipated to result in lower prostate cancer detection rates (detection bias) [13] in overweight/obese men. In a stark contrast, Lee et al. [18], in a cohort of 3,113 Korean men, and Pruthi et al. [9], in another Western study
of 500 men, found that higher BMI was associated with lower risk of both overall prostate cancer and clinically significant cancer detection. The reason for the discrepancy between these conflicting studies remains unknown for now. This suggests that the relationship between BMI and prostate cancer detection and development is complex and possibly influenced by factors that have yet to be clearly elucidated. Several prospective and retrospective studies have suggested that obese men were more likely to harbor clinically significant prostate cancer and were at higher risk of prostate cancer mortality and recurrence after primary treatment [4–6,8,17,21–24]. Both overweight and obese men in our cohort were observed to be at significantly increased risk of having clinically significant prostate cancer detected on biopsy, thereby further supporting the growing body of evidence that links obesity to cancer aggressiveness. Moreover, the adjusted odds ratios of having clinically significant prostate cancer detection were quite similar between overweight and obese men. The insulin/insulin-like growth factor-1 axis, sex hormones, and adipokine signaling pathway are 3 mechanisms commonly proposed to help explain the association between obesity and prostate cancer aggressiveness [6,7]. Other studies have reported that obese men were less likely to have clinically insignificant disease or have no significant association with clinically insignificant disease [4,25]. In our cohort, BMI had no significant association with clinically insignificant prostate cancer detection, even after adjusting for multiple clinical variables (analysis not shown). More importantly, we found that men in our cohort with BMI Z25 kg/m2 had significantly increased risks of both overall prostate cancer and clinically significant cancer detection, which were only observed in obese men with BMI Z30 kg/m2 in Western cohorts [8,12]. Moreover, 41.7% of the men in our cohort had BMI Z25 kg/m2 and hence, a significant proportion of men were affected by this increase in risk of having cancer on biopsy. This suggests that at the same BMI levels, there are inherent ethnic differences in body composition between Asian and Caucasian men, which may affect the way BMI interacts with prostate cancer detection and development. Unfortunately, the precise reason why cancer detection risk increases at comparatively lower BMI levels (BMI Z25 kg/m2) in Table 4 Relationship between obesity, PSAD, and overall prostate cancer detection
All men (n ¼ 458) BMI o25 kg/m2 BMI Z25 kg/m2 Positive biopsy result Negative biopsy result a
Chi-square test.
PSAD o 0.15 ng/ml/g
PSAD Z 0.15 ng/ml/g
102 103 32 173
165 88 93 160
(38.2) (53.9) (25.6) (52.0)
(61.8) (46.1) (74.4) (48.0)
P value
0.001a o0.001a
A. Lee, S.J. Chia / Urologic Oncology: Seminars and Original Investigations 33 (2015) 266.e17–266.e22 Table 5 Effect of BMI on the relationship between PSAD and overall prostate cancer detection Positive biopsy result
Negative biopsy result
Men with PSAD o0.15 ng/ml/g (n ¼ 205) BMI o25 kg/m2 14 (13.7) 18 (17.5) BMI Z25 kg/m2
88 (86.3) 85 (82.5)
Men with PSAD Z0.15 ng/ml/g (n ¼ 253) BMI o25 kg/m2 45 (27.3) 48 (54.5) BMI Z25 kg/m2
120 (72.7) 40 (45.5)
a
P value
0.459
o0.001a
Chi-square test.
Asian men has not been well studied. It has been previously suggested that this could be because Asians have a greater fat percentage at a specific BMI, leading to greater central obesity and its associated peripheral insulin resistance [17,26]. Hyperinsulinemia and raised circulating insulinlike growth factor-1 have also been positively associated with prostate cancer risk [6,7,27,28]. We must also acknowledge some important limitations of our study. Our study cohort was recruited from an unscreened population who were referred to a single tertiary institution for urological consult and thus, selection bias may be present. This limits comparison with other studies as well as generalizability of our findings to men at risk of prostate cancer. Hence, the relevance of our findings requires external validation. Also, BMI is merely an estimate of one's body fat composition. Perhaps, other anthropometric measures such as waist circumference (as a parameter of central adiposity and metabolic syndrome) could be analyzed. Importantly, our study is inadequate to assess the effect of duration of obesity and weight changes
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in association with prostate cancer incidence and detection. Whether higher BMI causes a delay in prostate cancer diagnosis remains unclear and requires further elucidation in prospective studies. Another limitation of our study is that there are many possible confounders (e.g., diet, exercise, other comorbidities like diabetes mellitus, and dyslipidemia) associated with obesity that have not been accounted for and should be considered in future studies. Our study provides more support to evidence that suggest that obese men are exposed to detection bias owing to lower PSA levels and larger prostate sizes. The idea of BMI-adjusted PSA cutoffs for prostate biopsy had been previously proposed [6], but it has not been reliably shown to help early diagnosis of cancer. Obese men with larger prostates may benefit from an increase in the number of cores biopsied, which may be guided by the use of a nomogram [29]. Another implication of BMI on prostate cancer detection is its effect on PSAD. Reduced PSA levels and larger prostate sizes observed in obese men results in decreased PSA density. Despite so, there were no differences in the cancer detection rates between overweight men or men with normal weight in those with PSAD o0.15 ng/ml/g. We observed that using the traditional cutoff of Z0.15 ng/ml/g, there was a significant difference in cancer detection rates between men with BMI Z25 kg/m2 and men with BMI o25 kg/m2. More than half the men with BMI Z25 kg/m2 who met this cutoff had a positive biopsy finding. PSA density could possibly be a useful tool for prostate cancer detection in men with higher BMI levels. Among a cohort of Singaporean men undergoing first multicore prostate biopsy in a single tertiary institution, men with BMI Z25 kg/m2 were of younger age, had larger prostates, and were at increased risk of overall prostate cancer detection, especially clinically significant cancer.
Fig. 2. Bar charts showing the effect of body mass index on cancer detection rate of prostate-specific antigen density.
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After adjusting for multiple clinical variables, men with BMI Z25 kg/m2 were associated with a greater risk of overall cancer detection. Clinically significant cancers followed the same trend whereas clinically insignificant cancer did not. The BMI threshold (BMI Z25 kg/m2) for Asian men to be at increased risk of prostate cancer detection on initial biopsy is lower than that of Western populations (BMI Z30 kg/m2). This strongly suggests that even overweight Asian men are exposed to detection bias, which may warrant some modification of biopsy criteria or methods.
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Original article
Prostate cancer detection: The impact of obesity on Asian men Alvin Leea, Sing Joo Chiab,* a
Yong Loo Lin School of Medicine, National University of Singapore b Department of Urology, Tan Tock Seng Hospital
Received 10 January 2015; received in revised form 13 February 2015; accepted 9 March 2015
Abstract Objective: To evaluate the impact of body mass index (BMI) on prostate cancer detection in biopsy-naive men presenting to a single tertiary hospital in Singapore. Materials and methods: We retrospectively examined 458 men who underwent initial prostate biopsies between January 2012 and April 2014. Indications for biopsy were serum prostate-specific antigen level Z4.0 ng/ml, or digital rectal examination findings suspicious for malignancy, or both. Only men with serum prostate-specific antigen level o20 ng/ml were included. BMI categories were based on the World Health Organization recommendations (normal: o25.0, overweight: 25.0–29.9, and obese: Z30). Results: Of the 458 men included in our cohort, 125 (27.3%) men were positive for prostate cancer on biopsy, with 69 (15.1%) being clinically significant (Gleason Z7). Men with BMI Z25 kg/m2 (41.7%) were younger (67.2 vs. 68.8 y, P ¼ 0.030), had larger prostates (45.5 vs. 40.1 g, P ¼ 0.014), and were more likely to have a positive biopsy finding (34.6% vs. 22.1%, P ¼ 0.003). On multivariate analysis, being overweight or obese was associated with increased risk of having prostate cancer on biopsy (odds ratio [OR] ¼ 2.61, 95% CI: 1.58–4.30, P o 0.001 and OR ¼ 3.26, 95% CI: 1.37–7.73 P ¼ 0.007, respectively). The same trend was observed for clinically significant cancers but not for clinically insignificant cancers (OR ¼ 3.57, 95% CI: 1.87–6.82, P o 0.001 and OR ¼ 3.86, 95% CI: 1.33– 11.21, P ¼ 0.013 for being overweight and obese, respectively). Conclusion: Asian men with BMI Z25 kg/m2 are at greater risk of having a positive initial biopsy result. The BMI threshold (BMI Z25 kg/m2) for Asian men to be at increased risk of prostate cancer detection on initial biopsy is lower than that of Western populations (BMI Z30 kg/m2). r 2015 Elsevier Inc. All rights reserved.
Keywords: Body mass index; Obesity; Oncology; Prostate cancer; PSA
1. Introduction Over the past decade, the incidence of prostate cancer has risen dramatically to become the third commonest cancer in Singaporean men and is the fifth commonest cause of cancer mortality [1]. This has created an urgent need for more studies on prostate cancer diagnosis and treatment in Asian populations. Increasingly, obesity has become a more prevalent public health problem in Singapore and the rest of the world [2]. It has also been linked with various forms of cancer [3]. A case in point of this phenomenon is the significant Ethics review: DSRB 2010/00318. * Corresponding author. Tel.: þ65-6357-7668; fax: þ65-6357-3198. E-mail address: [email protected] (S.J. Chia). http://dx.doi.org/10.1016/j.urolonc.2015.03.011 1078-1439/r 2015 Elsevier Inc. All rights reserved.
association between obesity and prostate cancer mortality as observed in large cohort studies [4,5]. Obesity-related detection biases and biological mechanisms have been cited to be important contributory factors of the epidemiological association between obesity and aggressive prostate cancer [6,7]. Many studies have found that obese men had lower prostate-specific antigen (PSA) levels and larger prostates, thereby making current detection methods less sensitive [6,8–13]. The aim of our study is to evaluate the impact of body mass index (BMI) on prostate cancer detection in biopsynaive men presenting to a single tertiary hospital in Singapore. We hypothesize that obesity is a risk factor of prostate cancer detection in Asian men and that clinical factors associated obesity may obscure prostate cancer detection in our local population.
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2. Materials and methods In our study, we retrospectively analyzed 804 patients who underwent transrectal ultrasound (TRUS)-guided prostate biopsy in a single tertiary institution from January 2012 to April 2014. The indications for prostate biopsy were serum PSA level Z4.0 ng/ml or digital rectal examination (DRE) findings suspicious for malignancy or both. Only patients with PSA level o20 ng/ml were included in our study so as to exclude those with metastatic disease. Subjects who had previous prostate biopsy, prostate surgery, currently/previously on 5-alpha reductase inhibitors, or with a known diagnosis of prostate cancer were excluded from the study. All men had at least 1 or more serum PSA levels measured and were subjected to DRE. All PSA measurements were performed using PSA Hybritech Assay, and only the latest serum PSA levels were analyzed. BMI data were retrieved from our electronic database and were only used if they were measured within 1 year of their biopsy. BMI categories were based on World Health Organization (WHO) recommendations (normal: o25.0, overweight: 25.0–29.9, and obese: Z30) [14]. Prostatespecific antigen density (PSAD) was calculated by dividing the serum PSA level by the prostate volume. For the prostate biopsy, patients were placed in the left lateral position, and a TRUS-guided biopsy of the prostate was performed. The ultrasound scanner used was Siemens ACUSON X150. The prostate volume was measured using the ellipsoid formula (π/6 craniocaudal transverse anteroposterior length). Patients underwent either sextant biopsy, systematic 12-core biopsy, or 18-core biopsy depending on the performing clinician's evaluation of the prostate volume and DRE findings. The core specimens were examined by pathologists in the same institution. Prostate cancers with Gleason sum Z7 were considered clinically significant, whereas cancers with Gleason sum o7 were considered clinically insignificant. Statistical analysis was performed using IBM SPSS Version 20. T test, Kruskal-Wallis test, and Pearson chisquare test were used to evaluate any differences in continuous and categorical variables. Logistic regression analysis was used to examine the association between clinical variables and prostate cancer detection on biopsy. Differences were significant if P o 0.05. Ethics approval was obtained from domain-specific review board before commencement of the study. Domain-specific review board 2010/00318.
3. Results Complete data sets, including BMI, were available in 586/804 (72.9%) men who underwent first TRUS-guided prostate biopsy. Of 586 men, 458 (78.1%) had serum PSA level o20 ng/ml and were included in our study (Fig. 1). Out of the 458 men in our study, 418 (91.3%) were Chinese, whereas the other 40 (8.7%) were of other races
804 Men underwent initial prostate biopsy 218 Men excluded due to incomplete datasets 586 Men with complete datasets 128 Men excluded due to PSA 20ng/ml 458 Men with PSA < 20 ng/ml
25.0 kg/m2
BMI < 25.0 kg/m2
BMI
267 Men (58.3%)
191 Men (41.7%)
Fig. 1. Flowchart of men who were included in our study cohort.
such as Malay, Indian, or Caucasian. Mean BMI and age were 24.2 kg/m2(⫾3.7) and 68.1 (⫾8.0) years, respectively. Of 458 men, 267 (58.3%), 160 (34.9%), and 31 (6.8%) were normal weight, overweight, and obese, respectively. Moreover, 424 (92.6%) men underwent systematic 12-core biopsy, 1 (0.2%) underwent sextant biopsy, and 33 (7.2%) underwent 18-core biopsy. Overall, 125 (27.3%) men were positive for prostate cancer on biopsy, with 69 (15.1%) having clinically significant cancer. There was no difference in the mean BMI between those who had a positive biopsy and those who had a negative one (24.6 kg/m2 vs. 24.0 kg/m2, P ¼ 0.173). The men were divided into 2 groups based on their BMI category for comparison (Fig. 1). Of 458 men, 191 (41.7%) had BMI Z25 kg/m2 whereas 267 (58.3%) had BMI o25 kg/m2 (Table 1). Men with BMI Z25 kg/m2 were more likely to have prostate cancer found on biopsy (34.6% vs. 22.1%, P ¼ 0.003) and were more likely to have clinically significant cancers (21.5% vs. 10.5%, P ¼ 0.001). They were also younger (67.2 vs. 68.8 y, P ¼ 0.030), had larger prostates (45.5 vs. 40.1 g, P ¼ 0.014), and were more likely to have a hypoechoic lesion seen on TRUS (7.9% vs. 3.0%, P ¼ 0.019). There were no significant differences in serum PSA levels between the 2 groups; however, men with BMI Z25 kg/m2 had lower PSAD (0.14 vs. 0.17, P ¼ 0.001). Men with BMI Z25 kg/m2 were no more likely to have suspicious DRE findings (P ¼ 0.356) (Table 1). On univariate analysis, being overweight or obese conferred greater risk of having a positive biopsy finding (odds ratio [OR] ¼ 1.80, 95% CI: 1.16–2.78, P ¼ 0.009 and OR ¼ 2.23, 95% CI: 1.02–4.85, P ¼ 0.044) (Table 2). After adjustment for multiple clinical variables, being overweight or obese was associated with significantly increased odds of having prostate cancer on biopsy. The odds of having prostate cancer were greater in the overweight and obese group compared with the reference group (OR ¼ 2.61, 95% CI: 1.58–4.30, P o 0.001 and OR ¼ 3.26, 95% CI: 1.37–7.73 P ¼ 0.007, respectively) (Table 2). Other significant independent associations included patient age, serum PSA level, and prostate volume. The presence of suspicious DRE and hypoechoic lesions on TRUS were no longer significant independent risk factors
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Table 1 Clinical and pathological features of men undergoing prostate biopsy Patient characteristics
Total
BMI o 25.0 kg/m2
BMI Z 25.0 kg/m2
P value
Number (%) Mean age ⫾ SD, y Mean BMI ⫾ SD, kg/m2 Median PSA (IQR), ng/ml Median PV (IQR), g Median PSAD (IQR)
458 68.1 ⫾ 8.0 24.2 ⫾ 3.7 7.00 (5.37–10.0) 42.2 (30.0–59.3) 0.16 (0.11–0.25)
267 (58.3) 68.8 ⫾ 8.2 21.8 ⫾ 2.3 7.14 (5.57–10.2) 40.1 (28.0–55.4) 0.17 (0.12–0.26)
191 (41.7) 67.2 ⫾ 7.8 27.6 ⫾ 2.6 6.94 (5.09–9.39) 45.5 (33.0–65.5) 0.14 (0.10–0.21)
0.030a o0.001a 0.100b 0.014b 0.001b
DRE findings Suspicious (%) Normal (%)
96 (21.0) 362 (79.0)
52 (19.5) 215 (80.5)
44 (23.0) 147 (77.0)
0.356c
Hypoechoic lesion Yes (%) No (%)
23 (5.0) 435 (95.0)
8 (3.0) 259 (97.0)
15 (7.9) 176 (92.1)
0.019c
Biopsy outcome Prostate cancer (%) High risk Low risk Benign prostate (%)
125 (27.3) 69 (15.1) 56 (12.2) 333 (72.7)
59 (22.1) 28 (10.5) 31 (11.6) 208 (77.9)
66 (34.6) 41 (21.5) 25 (13.1) 125 (65.4)
0.003c 0.001c 0.634c
IQR ¼ inter quartile range; PV ¼ prostate volume; SD ¼ standard deviation. a T test. b Kruskal-Wallis test. c Chi-square test.
after multivariate adjustment. The same trend was observed when BMI was analyzed as a continuous variable (analysis not shown). When prostate cancers detected on biopsy were categorized into whether they were clinically significant or insignificant, men who were overweight or obese were not at higher risk of having clinically insignificant prostate cancer detected (analysis not shown). Overweight and obese men were still more likely to have clinically significant prostate cancer detected on biopsy compared with the reference group. (OR ¼ 3.57, 95% CI: 1.87–6.82, P o 0.001 and OR ¼ 3.86, 95% CI: 1.33–11.21, P ¼ 0.013, respectively) (Table 3). Men with PSAD o0.15 ng/ml/g were more likely to overweight/obese and have a negative biopsy finding (Table 4) compared with men with PSAD Z0.15 ng/ml/g. In men with PSAD o0.15 ng/ml/g, there were no differences in overall prostate cancer detection between men with BMI o25 kg/m2 and those with BMI Z25 kg/m2. However, in men with PSAD Z0.15 ng/ml/g, those with BMI Z25 kg/m2 had greater cancer detection rates (54.5% vs. 27.3%, P o 0.001) (Table 5 and Fig. 2). 4. Discussion Prostate cancer is one of the commonest cancers afflicting men today and increasingly so in westernized Asian countries such as Singapore. It now ranks as the third commonest cancer in men locally [1]. Despite the rising trend in the past two decades, prostate cancer incidence and mortality rates are still lower in Asian countries compared
to Western countries. An ageing population, greater awareness, biopsy methods, and lifestyle factors such as obesity and dietary intake are just some of the reasons cited that could possibly account for this upward trend [15]. Obesity is a growing health problem, affecting more than 300 million people in the world [2]. The prevalence of obesity in Singaporean men has risen from 6.4% in 2004 to 12.1% in 2010 [16]. In our series, only 6.8% were obese based on the WHO definitions. This value is higher than rates reported in both Korean (1.4%) and Japanese (1.7%) prostate cancer detection study cohorts [17,18]. Comparatively, obesity was markedly more prevalent in other Western studies. For instance, a study by Freedland et al. [8] Table 2 Univariate and multivariate logistic regression analysis of factors predicting prostate cancer detection on prostate biopsy Cancer detection
BMI ¼ 25–29.9 kg/m2 (overweight) OR 95% CI
Univariate BMI (crude)
1.80 1.16–2.78
Multivariate BMI Age PV PSA DRE Hypoechoic lesion
2.61 1.05 0.97 1.19 0.75 0.73
BMI Z 30 kg/m2 (obese)
P value OR 95% CI
P value
0.009 2.23 1.02–4.85 0.044
1.58–4.30 o0.001 3.26 1.37–7.73 0.007 1.02–1.09 0.001 0.96–0.98 o0.001 1.12–1.26 o0.001 0.42–1.33 0.321 0.26–2.05 0.544
PV ¼ prostate volume. Reference group ¼ BMI o 25 kg/m2.
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Table 3 Univariate and multivariate logistic regression analysis of factors predicting clinically significant prostate cancer detection on prostate biopsy Clinically significant cancer
BMI ¼ 25–29.9 (overweight) OR 95% CI
Univariate BMI (crude) Multivariate BMI Age PV PSA DRE Hypoechoic lesion
2.30 1.34–3.97 3.57 1.04 0.96 1.26 0.51 0.63
BMI Z 30 (obese) P value OR 95% CI 0.003 2.49 0.98–6.30
P value 0.054
1.87–6.82 o0.001 3.86 1.33–11.21 0.013 1.00–1.09 0.034 0.94–0.97 o0.001 1.17–1.36 o0.001 0.25–1.02 0.058 0.19–2.03 0.434
PV ¼ prostate volume. Reference group ¼ BMI o 25 kg/m2. Clinical significant cancers ¼ Gleason sum Z7.
reported an obesity prevalence of 28%, whereas in a study by Pruthi et al. [9], it was 26%. Despite suggestion of increased risk of all-cause mortality at lower BMI cutoffs in Asian men, we chose to preserve the traditional WHO definitions for comparison with other studies on obesity and prostate cancer detection [8,9,19]. We also only selected men with serum PSA level o20 ng/ml to exclude men whose BMI may have been altered owing to the deleterious effects of metastatic disease. On analysis of our clinical variables, we found that men with higher BMI (Z25 kg/m2) were younger and had larger prostate sizes [8,9,12]. Intriguingly, men with BMI Z25 kg/m2 were found to be associated with greater risk of prostate cancer detection on crude analysis, a finding that was not observed in other studies [8,9,12,18–20]. After adjusting for other clinical variables, our findings indicate that being overweight conferred a 161% increased risk of prostate cancer detection, whereas being obese conferred 226% increased risk. These findings further support current evidence in literature that being obese may obscure prostate cancer detection using contemporary biopsy methods. Park et al. [20] recently studied a biopsy population of 1,213 men in Korea and found that men with BMI Z25 kg/m2 were at 45% increased risk of having prostate cancer detected on biopsy. Masuda et al. [17] observed significant elevation in the risk of cancer at biopsy at BMI Z25 kg/m2 in a Japanese cohort whereas Freedland et al. [8] also observed a 98% increased risk in obese men after adjusting for lower PSA levels and larger prostate size in a Western cohort. We believe that the difference in crude and adjusted ORs can be explained by confounding factors such as serum PSA level [10,11], prostate volume [8,9,12], and age, which were anticipated to result in lower prostate cancer detection rates (detection bias) [13] in overweight/obese men. In a stark contrast, Lee et al. [18], in a cohort of 3,113 Korean men, and Pruthi et al. [9], in another Western study
of 500 men, found that higher BMI was associated with lower risk of both overall prostate cancer and clinically significant cancer detection. The reason for the discrepancy between these conflicting studies remains unknown for now. This suggests that the relationship between BMI and prostate cancer detection and development is complex and possibly influenced by factors that have yet to be clearly elucidated. Several prospective and retrospective studies have suggested that obese men were more likely to harbor clinically significant prostate cancer and were at higher risk of prostate cancer mortality and recurrence after primary treatment [4–6,8,17,21–24]. Both overweight and obese men in our cohort were observed to be at significantly increased risk of having clinically significant prostate cancer detected on biopsy, thereby further supporting the growing body of evidence that links obesity to cancer aggressiveness. Moreover, the adjusted odds ratios of having clinically significant prostate cancer detection were quite similar between overweight and obese men. The insulin/insulin-like growth factor-1 axis, sex hormones, and adipokine signaling pathway are 3 mechanisms commonly proposed to help explain the association between obesity and prostate cancer aggressiveness [6,7]. Other studies have reported that obese men were less likely to have clinically insignificant disease or have no significant association with clinically insignificant disease [4,25]. In our cohort, BMI had no significant association with clinically insignificant prostate cancer detection, even after adjusting for multiple clinical variables (analysis not shown). More importantly, we found that men in our cohort with BMI Z25 kg/m2 had significantly increased risks of both overall prostate cancer and clinically significant cancer detection, which were only observed in obese men with BMI Z30 kg/m2 in Western cohorts [8,12]. Moreover, 41.7% of the men in our cohort had BMI Z25 kg/m2 and hence, a significant proportion of men were affected by this increase in risk of having cancer on biopsy. This suggests that at the same BMI levels, there are inherent ethnic differences in body composition between Asian and Caucasian men, which may affect the way BMI interacts with prostate cancer detection and development. Unfortunately, the precise reason why cancer detection risk increases at comparatively lower BMI levels (BMI Z25 kg/m2) in Table 4 Relationship between obesity, PSAD, and overall prostate cancer detection
All men (n ¼ 458) BMI o25 kg/m2 BMI Z25 kg/m2 Positive biopsy result Negative biopsy result a
Chi-square test.
PSAD o 0.15 ng/ml/g
PSAD Z 0.15 ng/ml/g
102 103 32 173
165 88 93 160
(38.2) (53.9) (25.6) (52.0)
(61.8) (46.1) (74.4) (48.0)
P value
0.001a o0.001a
A. Lee, S.J. Chia / Urologic Oncology: Seminars and Original Investigations 33 (2015) 266.e17–266.e22 Table 5 Effect of BMI on the relationship between PSAD and overall prostate cancer detection Positive biopsy result
Negative biopsy result
Men with PSAD o0.15 ng/ml/g (n ¼ 205) BMI o25 kg/m2 14 (13.7) 18 (17.5) BMI Z25 kg/m2
88 (86.3) 85 (82.5)
Men with PSAD Z0.15 ng/ml/g (n ¼ 253) BMI o25 kg/m2 45 (27.3) 48 (54.5) BMI Z25 kg/m2
120 (72.7) 40 (45.5)
a
P value
0.459
o0.001a
Chi-square test.
Asian men has not been well studied. It has been previously suggested that this could be because Asians have a greater fat percentage at a specific BMI, leading to greater central obesity and its associated peripheral insulin resistance [17,26]. Hyperinsulinemia and raised circulating insulinlike growth factor-1 have also been positively associated with prostate cancer risk [6,7,27,28]. We must also acknowledge some important limitations of our study. Our study cohort was recruited from an unscreened population who were referred to a single tertiary institution for urological consult and thus, selection bias may be present. This limits comparison with other studies as well as generalizability of our findings to men at risk of prostate cancer. Hence, the relevance of our findings requires external validation. Also, BMI is merely an estimate of one's body fat composition. Perhaps, other anthropometric measures such as waist circumference (as a parameter of central adiposity and metabolic syndrome) could be analyzed. Importantly, our study is inadequate to assess the effect of duration of obesity and weight changes
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in association with prostate cancer incidence and detection. Whether higher BMI causes a delay in prostate cancer diagnosis remains unclear and requires further elucidation in prospective studies. Another limitation of our study is that there are many possible confounders (e.g., diet, exercise, other comorbidities like diabetes mellitus, and dyslipidemia) associated with obesity that have not been accounted for and should be considered in future studies. Our study provides more support to evidence that suggest that obese men are exposed to detection bias owing to lower PSA levels and larger prostate sizes. The idea of BMI-adjusted PSA cutoffs for prostate biopsy had been previously proposed [6], but it has not been reliably shown to help early diagnosis of cancer. Obese men with larger prostates may benefit from an increase in the number of cores biopsied, which may be guided by the use of a nomogram [29]. Another implication of BMI on prostate cancer detection is its effect on PSAD. Reduced PSA levels and larger prostate sizes observed in obese men results in decreased PSA density. Despite so, there were no differences in the cancer detection rates between overweight men or men with normal weight in those with PSAD o0.15 ng/ml/g. We observed that using the traditional cutoff of Z0.15 ng/ml/g, there was a significant difference in cancer detection rates between men with BMI Z25 kg/m2 and men with BMI o25 kg/m2. More than half the men with BMI Z25 kg/m2 who met this cutoff had a positive biopsy finding. PSA density could possibly be a useful tool for prostate cancer detection in men with higher BMI levels. Among a cohort of Singaporean men undergoing first multicore prostate biopsy in a single tertiary institution, men with BMI Z25 kg/m2 were of younger age, had larger prostates, and were at increased risk of overall prostate cancer detection, especially clinically significant cancer.
Fig. 2. Bar charts showing the effect of body mass index on cancer detection rate of prostate-specific antigen density.
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After adjusting for multiple clinical variables, men with BMI Z25 kg/m2 were associated with a greater risk of overall cancer detection. Clinically significant cancers followed the same trend whereas clinically insignificant cancer did not. The BMI threshold (BMI Z25 kg/m2) for Asian men to be at increased risk of prostate cancer detection on initial biopsy is lower than that of Western populations (BMI Z30 kg/m2). This strongly suggests that even overweight Asian men are exposed to detection bias, which may warrant some modification of biopsy criteria or methods.
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