Prognostic impact of abdominal adiposity, waist ... - Nature

International Journal of Obesity (2011) 35, 1421–1426 & 2011 Macmillan Publishers Limited All rights reserved 0307-0565/11 www.nature.com/ijo

ORIGINAL ARTICLE Prognostic impact of abdominal adiposity, waist circumference and body mass index in patients with intermediate-risk prostate cancer treated with radiotherapy T Zilli1, TV Nguyen1, J-P Bahary1, M Chagnon2, A Dufresne1 and D Taussky1 1 2

Department of Radiation Oncology, Centre Hospitalier de l’Universite´ de Montreál, Montreál, Que´bec, Canada and Department of Statistics, Universite´ de Montreál, Montreál, Que´bec, Canada

Objective: We tested the potential role of abdominal visceral (VAT) and subcutaneous (SAT) adipose tissues, waist circumference (WC) and body mass index (BMI) as prognostic factors in patients with intermediate-risk prostate cancer (clinical stage T1b-2b, and Gleason Score (GS) ¼ 7 and prostate-specific antigen PSA level o15 ng ml1, or GS p6 and PSA between 10 and 20 ng ml1) treated with ultrasound-based image-guided radiotherapy. Methods: VAT, SAT and WC (measured from planning abdominal computed tomography) and BMI were compared with clinical and pathologic factors using univariate analyses. Cox regression analyses were performed to evaluate whether obesity indices significantly predicted biochemical disease free-survival (bDFS). Results: Of the 112 eligible patients, 30 (27%) were obese. Median BMI at baseline was 27.5 kg m2 (range, 19.2–51.5 kg m2). Greater abdominal adiposity, WC and BMI were significantly associated with younger age at diagnosis and increased prostate volume (P ¼ 0.003 and P ¼ 0.002, respectively). No significant correlation between obesity measures and T-stage, GS, PSA or percentage of positive cores at biopsy was found. On Cox regression analyses, none of the obesity measures predicted for bDFS. No association was observed between obesity indices and surrogate markers of biochemical failure as PSA nadir (nPSA) or time to nPSA. Conclusions: Abdominal adiposity, WC and BMI are associated with younger age at diagnosis and greater prostate volume but not with an increased risk of biochemical failure in patients with intermediate-risk prostate cancer. International Journal of Obesity (2011) 35, 1421–1426; doi:10.1038/ijo.2010.279; published online 25 January 2011 Keywords: prostate cancer; radiation therapy; body mass index; abdominal fat.

Introduction The association between prostate cancer and obesity as a potential risk factor for adverse pathological features or poor clinical outcomes after curative treatments is not yet fully understood. Some studies of radical prostatectomy have shown that a greater body mass index (BMI) is associated with a pathologically more aggressive prostate disease process1,2 and with a higher rate of biochemical recurrence.1,3–5 Similarly, several studies of conventional

Correspondence: Dr D Taussky, Radiation Oncology Department, Montreal University Hospital, 1560, Sherbrooke St East H2L 4M1, Montreál, Que´bec, Canada. E-mail: [email protected] Received 15 July 2010; revised 31 October 2010; accepted 24 November 2010; published online 25 January 2011

external beam radiotherapy (EBRT), with or without androgen deprivation therapy (ADT) for patients with localized prostate cancer, have suggested that a high BMI is a strong predictor of biochemical relapse.6–9 Conversely, a similar association has not been found in other surgical series10,11 or in patients treated with permanent seed brachytherapy (BT).12–14 The reasons for adverse outcomes following EBRT in obese patients are not clear. Are they due to technical problems or do obese patients have a more aggressive disease process, as previous studies suggest? EBRT data date back to before the introduction of image-guided radiotherapy techniques (IGRT). IGRT represents one of the most important technological innovations in radiation oncology in the last years.15 IGRT could improve treatment accuracy in obese patients and potentially lead to improved outcomes. If outcomes following IGRT are poorer, then obesity itself would be the adverse factor.

Prognostic impact of obesity in prostate cancer T Zilli et al

1422 Visceral adipose tissue (VAT) is a more sophisticated measure of abdominal obesity than BMI. Recent epidemiological studies have found that abdominal adiposity, in particular the presence of a large VAT compartment, is an important risk factor for cancer development and results in poor prognosis.16–20 These findings suggest therefore that adipose tissue distribution may be an independent prognostic factor in patients treated curatively for localized prostate cancer. The prognostic significance of abdominal fat distribution in patients with prostate cancer treated with EBRT on Gleason score (GS), prostate-specific antigen (PSA) or clinical stage and outcomes, has not yet been studied. The objective of this study is therefore to study, with the help of sophisticated volumetric imaging measurements of abdominal fat distribution, the impact of modern IGRT techniques on clinical outcomes of obese prostate cancer patients. We further examined whether VAT and subcutaneous adipose tissue (SAT) provide prognostic information in patients with intermediate-risk prostate cancer treated with exclusive radiotherapy other than that offered by simpler anthropometric measures of obesity such as BMI and computed waist circumference (WC).

Materials and methods Patient characteristics and treatment Between March 2003 and September 2007, 147 patients with histologically confirmed localized prostate cancer were enrolled at the University Hospital of Montreal in a prospective multicenter phase III randomized trial of high dose (79.2 Gy in 44 fractions) vs standard dose (70.2 Gy in 39 fractions) three-dimensional conformal radiotherapy or intensity-modulated radiotherapy. Of these, 35 with a follow-up of less than 24 months were excluded from the analysis, leaving 112 subjects. Eligible patients included those with clinical stage T1b-2b (American Joint Commission on Cancer, Fifth Edition), and GS ¼ 7 and PSA level o15 ng ml1, or GS p6 and PSA between 10 and 20 ng ml1. None of the subjects had any regional nodal involvement (radiologically or histo-pathologically after nodal sampling or dissection) or

evidence of distant metastases, and all were required to have an ECOG Zubrod performance status of 0 or 1. Subjects were assessed by detailed medical history and physical examination, including a digital rectal examination and pretreatment serum PSA. Supplementary staging included a bone scan for patients with a PSA X10 ng ml1 and a GS ¼ 7 to exclude the presence of distant metastasis. The study was approved by the local institutional review board. No central pathological review of the histological specimens was necessary for the inclusion in the study. Prostate size was determined by the referring urologist by transrectal ultrasound. All patients underwent a multi-detector computed tomography (CT) scan of the pelvis for treatment planning purposes and were treated with megavoltage photon beams on the prostate and proximal bilateral seminal vesicles using three-dimensional conformal radiotherapy techniques. Daily setup verification was performed on all subjects using a trans-abdominal ultrasound-based repositioning system BAT (B-mode Acquisition and Targeting; NOMOS, Sewickley, PA, USA).21

Anthropometric measures of obesity BMI (defined as weight in kg divided by height in m2; kg m2) was categorized according to World Health Organizations definitions; normal weight, BMI o25 kg m2; overweight, 25–29.9 kg m2; obesity, X30 kg m2. Among the 112 subjects, the predominant ethnicity (490%) was FrenchCanadian. No patient was of Asian ethnicity. Weight and height were measured and recorded at the first clinical visit. Abdominal fat adiposity was measured retrospectively from the subjects’ radiotherapy planning CT images. VAT and SAT volumes were delineated manually by one single observer for each subject at the iliac crest level (L4–5 interspace) on three slices of 3 mm in thickness using the Eclipse (Varian Associates, Palo Alto, CA, USA) treatment planning system (Figure 1). The approximate WC was calculated on the planning CT with the formula used to calculate the circumference of an ellipse: 2p sqrt (latero-lateral abdominal diameter2) þ (anterior-posterior abdominal diameter2)/2. Abdominal diameters were measured at the level of the iliac crests.

Figure 1 Radiotherapy planning CT images. Abdominal visceral (a) and subcutaneous (b) adipose tissues volumes traced manually at the iliac crest level.

International Journal of Obesity


1423 Clinical follow-up and statistical analysis Subjects underwent routine follow-up every 3 months for the first 2 years, every 6 months for an additional 3 years and then annually thereafter. PSA measurement and digital rectal examination were performed at each visit and reported by the attending physician. Subjects were followed until death or date of most recent follow-up. Biochemical failure was defined using the Phoenix consensus criteria (PSA nadir (nPSA) þ 2 ng ml1).22 Anthropometric measures of abdominal obesity, as well as age, PSA level at diagnosis, maximal percentage of tumor involvement of the biopsy specimen and prostate volume were analyzed as continuous variables. Categorical variables included: BMI (o25 kg m2 vs 25–29.9 kg m2 vs X30 kg m2); clinical tumor stage (T1 vs T2); GS (p6 vs 3 þ 4 vs 4 þ 3); and percentage of positive cores at biopsy, defined as the number of cores with any amount of cancer divided by the number of total cores (o50 vs X50%). Clinical variables were compared across BMI groups and other anthropometric measures of obesity using analysis of variance or Student’s t-test for continuous variables and w2 or Fisher exact tests for categorical variables. Kaplan–Meier estimates were used to evaluate biochemical disease-free survival (bDFS) and overall survival rates. Differences between groups were compared with the log-rank test. Cox proportional regression analysis was performed to evaluate the effect of the analyzed obesity measurements on the risk of biochemical failure. The median follow-up was 43.4 months, ranging between 24 and 79 months. As the follow-up time was relatively short, we used PSA nadir levels (nPSA) and time to PSA nadir (TnPSA) as surrogate markers for bDFS. A greater nPSA level and shorter TnPSA after curative EBRT are predictive of subsequent biochemical recurrence as demonstrated by Ray et al.23 We analyzed PSA failures stratified in function of these two variables after categorization in the following subgroups: 0–0.49, 0.5–0.99; 41.0 ng ml1 and 0–11.9 and 12.0–23.9; and X24 months for nPSA and TnPSA, respectively. Anthropometric measures of obesity were subsequently compared with nPSA and TnPSA. Statistical tests were two sided and a P-value o0.05 was considered statistically significant. Statistical analyses were performed using the SPSS 17.0 statistic software package (SPSS Inc., Chicago, IL, USA).

Results Baseline clinical characteristics Among the 112 enrolled subjects, median age and BMI of the cohort were 71 years (range, 55–80 years) and 27.5 kg m2 (range, 19.2–51.5 kg m2), respectively. Twenty-four percent of the patients (n ¼ 27) were considered as having normal weight (BMI o25 kg m2), 49% (n ¼ 55) as overweight (BMI 25–29.9 kg m2) and 27% (n ¼ 30) as obese (BMI X30 kg m2). Mean (±s.d.) VAT, SAT and WC measures for the whole population were 170±83 cm3, 93±54 cm3 and 94±11 cm, respectively. No differences in terms of

BMI categories (P ¼ 0.429), continuous BMI (P ¼ 0.191), VAT (P ¼ 0.381), SAT (P ¼ 0.786) and WC (P ¼ 0.447) were observed between patients enrolled in the high dose (n ¼ 56) vs the standard dose (n ¼ 56) EBRT group. Baseline clinical and pathological characteristics and anthropometric measures of obesity of the study population are summarized in Table 1. Higher BMI (as a continuous and categorical variable), WC, and SAT showed a statistically significant inverse correlation with the age at prostate cancer diagnosis. In obese patients, the mean age at diagnosis was 66.6±5.7 years compared with 70.2±5.2 and 71.3±5.6 years for overweight and normal weight patients, respectively (P ¼ 0.003). A statistically significant correlation was also found between prostate volume and different obesity variables. The mean prostate volume increased from 34.7±9.7 cm3 in normal weight subjects to 50.6±20 cm3 in obese patients (P ¼ 0.002). Conversely, anthropometric measures of obesity were not correlated to PSA at diagnosis, to GS, to clinical T-stage categories, to percentage of positive cores at biopsy, or to percentage of tumor involvement in the biopsy specimen. Comparisons of clinical and pathologic factors with anthropometric measures of obesity are shown in Table 2.

Biochemical failure and surrogates of biochemical failure Biochemical failure occurred in 13 patients, of which four (14.8%), 5 (9.1%) and four (13.3%) patients were in the normal weight, in the overweight and in the obese group,

Table 1

Baseline clinical characteristics of analyzed patients (n ¼ 112) No

Age (years) Median Range PSA at diagnosis (ng ml1) Median Range

%

71 55–80

7.2 1.5–19.1

Clinical T-stage T1 T2

60 52

54 46

Gleason score p6 3+4 4+3

19 66 27

17 59 24

PPC o50% X50%

64 48

57 43

% Tumor involvement at biopsy Mean±s.d.

50±28

Prostate volume (cm3) (n ¼ 91) Median Range

37.2 15.3–98.5

Abbreviations: PPC, percentage of positive cores at prostate biopsy; PSA, prostate-specific antigen.



1424 respectively. The 4-year estimated bDFS and OS rates (±s.d.) for the cohort were 86.7±4.1% and 99.1±0.9%, respectively. No difference was observed between the two EBRT dose groups in terms of bDFS (86.6±6.5% vs 86.6±5.3% for the low dose and the high dose EBRT group, respectively, P ¼ 0.411). The actuarial 4-year bDFS was not statistically different (P ¼ 0.797) between the different weight groups: 86.3±7.5% (BMI p25 kg m2), 90.4±4.7% (BMI 25–29.9 kg m2) and 77.1±10.2% (BMI X30 kg m2). In univariate Cox regression analysis, none of the anthropometric measures for obesity were associated with an increased risk of biochemical failure (P-values between 0.324 and 0.998). Subjects who showed biochemical progression were more likely to have presented with a higher nPSA (1.38± 1.48 ng ml1 vs 0.47±0.36 ng ml1, P ¼ 0.0001) and a shorter TnPSA (15.1±12.1 months vs 31.5±14 months, P ¼ 0.0001) than those who did not progress. The 4-year estimated bDFS was significantly different among the nPSA and TnPSA categories (P ¼ 0.0001 for both variables), with patients with an nPSA comprised between 0–0.49 ng ml1 and a TnPSA X24 months showing the better outcome (Table 3). Univariate analysis showed that none of the anthropometric variables for obesity showed a statistically significant association with nPSA or TnPSA, regardless of whether they were analyzed as continuous or categorical variables (P-values between 0.245 and 0.982). Table 2

Discussion BMI is a useful indicator of overall adiposity but it cannot distinguish between adiposity and lean body mass, particularly in men with greater muscle mass. The distribution of adipose tissue can have an influence on prostate cancer incidence. There is to date only one study that observed a significantly higher risk of prostate cancer in men with an increased abdominal VAT.16 Another easily measurable but imprecise estimate of abdominal adipose tissue is WC.24 The quantitative measurement of abdominal fat distribution Table 3 PSA failures stratified according to PSA nadir and time to PSA nadir (n ¼ 112) PSA failure No (n ¼ 99) PSA nadir (ng ml 0–0.49 0.5–0.99 41.0

1

4-year bDFS (%)

P-value (log rank)

Yes (n ¼ 13)

) 61 (96.8) 31 (86.1) 7 (53.8)

2 (3.2) 5 (13.9) 6 (46.2)

96.2 84.4 42.3

0.0001

Time to PSA nadir (months) 0–11.9 6 (46.2) 12.0–23.9 25 (86.2) X24 68 (97.1)

7 (53.8) 4 (13.8) 2 (2.9)

28.8 66.5 97.0

0.0001

Abbreviations: bDFS, biochemical disease free-survival; PSA, prostate-specific antigen. Data between parentheses are percentage.

Clinical and pathologic factors stratified by obesity classes BMI o25 kg m2 n ¼ 27

BMI 25–29.9 kg m2 n ¼ 55

BMI X30 kg m2 n ¼ 30

P-value Categorical

Age (years) Mean±s.d.

Continuous

BMI

BMI

WC

SAT

VAT

71.3±5.6

70.2±5.2

66.6±5.7

0.003

0.0001

0.023

0.001

0.351

PSA at diagnosis (ng ml1) Mean±s.d. 7.4±2.7

7.9±3.2

8.5±3.4

0.410

0.412

0.132

0.269

0.310

Clinical T-stage (%) T1 T2

17 (63) 10 (37)

25 (45) 30 (55)

18 (60) 12 (40)

0.233 F

0.108 F

0.283 F

0.244 F

0.669 F

Gleason score (%) p6 3+4 4+3

6 (22) 15 (56) 6 (22)

7 (13) 34 (62) 14 (25)

6 (20) 17 (57) 7 (23)

0.839 F F

0.955 F F

0.650 F F

0.446 F F

0.493 F F

PPC (%) o50% X50%

13 (48) 14 (52)

34 (62) 21 (38)

17 (57) 13 (43)

0.500 F

0.259 F

0.271 F

0.258 F

0.415 F

49.4±25.3

50.6±30.0

0.882

0.714

0.941

0.905

0.879

40.4±16.1

50.6±20.0

0.002

0.0001

0.0001

0.005

0.013

% Tumor involvement at biopsy Mean±s.d. 52.8±31.4 3

Prostate volume (cm ) Mean±s.d.

34.7±9.7

Abbreviations: BMI, body mass index; PPC, percentage of positive cores at prostate biopsy; PSA, prostate-specific antigen; SAT, subcutaneous adipose tissue; VAT, visceral adipose tissue; WC, waist circumference.



1425 using CT is considered the gold standard.25 Multi-detector CT is considered a highly-accurate and reproducible method to reliably calculate both VAT and SAT.26,27 In this study, obese subjects (BMI X30 kg m2) were younger at diagnosis than patients with a lower BMI. Abdominal adiposity volumes and other anthropometric measures were generally found to be inversely correlated with age at diagnosis. These results are in agreement with other published studies.4,5,7,8 On the other hand, this analysis did not reveal an association between the different anthropometric measures of obesity and adverse pathological features of the tumor, such as PSA, T-stage, GS, percentage of positive cores at biopsy or tumor involvement at biopsy specimen, as observed in other studies.8,13,28 Radiotherapy series examining the relationship between obesity and risk of biochemical failure in patients with prostate cancer have reported conflicting results. Obesity has been identified as an independent risk factor for increased biochemical relapse after EBRT6–9 but not after permanent low-dose-rate BT.12–14 This might be because accurate dose delivery can be compromised in obese patients by spatial shifts in prostate position and setup errors greater than 10 mm29,30 whereas similar problems are not present in BT. Notably, none of the EBRT studies that explored the relationship between prostate cancer and obesity used image-guided techniques in delivering treatments.6–9 In the current study, using more sophisticated anthropometric measures of abdominal obesity than previous EBRT studies and treating patients with IGRT techniques, we were unable to show that obesity or a specific fat distribution predisposes towards a higher risk of biochemical failure. This was true at least in patients with intermediate-risk disease, despite the fact that ultrasonographic prostate localization could be limited by its poor image quality in obese patients31 and its accuracy compared with implanted fiducial markers is questioned.32 Nevertheless, the use of the ultrasound localization of the prostate can increase the precision in dose delivery when compared with patient setups with conventional bony matching. Without BAT localization, misses of the clinical target volume outside the planning target volume margin can occur in 23.3–41.8% of treatments using patient setup verification with portal images.33 As a result, this study suggests that the observed increase in biochemical failure in obese patients in previous EBRT studies may be more closely related to inaccurate dose delivery than to a more aggressive disease process. Moreover, it appears that measurements of abdominal adiposity do not provide supplemental prognostic information in intermediate-risk prostate cancer patients other than those offered by general obesity estimates. However, it is possible that differences in aggressiveness and clinical outcome might appear in a larger series of patients with other than intermediate-risk cancers and longer follow-up. Within our cohort, obesity was correlated with a larger prostate size, similarly to that reported in previous studies.34,35 Considering the similar biochemical failure rates

between obese and non-obese patients12–14 permanent seed BT has been suggested provocatively as the preferred treatment option in obese patients.12 Nevertheless, our findings show that patients with a BMI X30 kg m2 had significantly (P ¼ 0.002) larger prostates (mean volume, 50.6 cm3) than normal weight patients (mean volume, 34.7 cm3), which could make BT technically more challenging in obese men. Our analysis was based on a specific subgroup of patients with intermediate-risk prostate cancer only, treated in a single institution and followed prospectively. We believe that the analysis of such a narrowly defined subgroup eliminates other clinical and treatment related confounding factors and makes our study therefore more interesting. Some potential limitations of this study need, however, to be considered. First, findings should be interpreted within the context of the potential bias presented by a small cohort of patients with a relatively short follow-up period and few events. As a result, the relationship between obesity parameters and two significant predictive factors of subsequent biochemical failure such as nPSA and TnPSA were analyzed.23 We could not find that abdominal adiposity, WC and BMI were associated with these surrogate factors of subsequent PSA recurrence. Second, calculated estimations of WC from CT images using the formula of an ellipse rather than standard manual measurements in a standing position warrant further study. However, a similar approach, estimating the WC on CT images, was previously described by Maurovich-Horvat et al.36 They found that the quantification of anthropometric measures of obesity, such as WC, appears to be highly reliable using CT images. In conclusion, these findings suggest that abdominal fat distribution and other anthropometric measures of obesity are neither associated with adverse pathologic features in patients with intermediate-risk prostate cancer nor with a higher risk of biochemical failure when modern IGRT techniques are used. Further studies including patients with different prostate cancer risk classes and with longer followup periods are warranted to more accurately assess the effects of obesity on PSA recurrence using IGRT techniques.

Conflict of interest The authors declare no conflict of interest.

Acknowledgements Dr Thomas Zilli was supported in part by a Fellowship grant from Sanofi-Aventis.

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