Association of subcutaneous and visceral adipose tissue with overall survival in Taiwanese patients with bone metastases – results from a retrospective analysis of consecutively collected data

Background Growing evidence indicates that measures of body composition may be related to clinical outcomes in patients with malignancies. The aim of this study was to investigate whether measures of regional adiposity–including subcutaneous adipose tissue index (SATI) and visceral adipose tissue index (VATI)–can be associated with overall survival (OS) in Taiwanese patients with bone metastases. Methods This is a retrospective analysis of prospectively collected data. We examined 1280 patients with bone metastases who had undergone radiotherapy (RT) between March 2005 and August 2013. Body composition (SATI, VATI, and muscle index) was assessed by computed tomography at the third lumbar vertebra and normalized for patient height. Patients were divided into low- and high-adiposity groups (for both SATI and VATI) according to sex-specific median values. Results Both SATI (hazard ratio [HR]: 0.696; P<0.001) and VATI (HR: 0.87; P = 0.037)–but not muscle index–were independently associated with a more favorable OS, with the former showing a stronger relationship. The most favorable OS was observed in women with high SATI (11.21 months; 95% confidence interval: 9.434−12.988; P<0.001). Conclusions High SATI and VATI are associated with a more favorable OS in Taiwanese patients with bone metastases referred for RT. The question as to whether clinical measures aimed at improving adiposity may improve OS in this clinical population deserves further scrutiny.

Introduction Bone represents one of the most common sites for cancer spread, especially in patients with breast, prostate, or lung malignancies. [1,2] Bone metastases are a significant source of morbidity, decreased performance status, and impaired quality of life. Moreover, the presence of bone metastases typically portends a poor prognosis, with a median overall survival (OS) of 6−7 months. [3] Several factors-including clinical stage, patient demographics, and tumor histology-have been shown to affect the OS of patients with bone metastases. [4] Notably, sex disparities have been reported in the survival of patients with metastatic spread to the bone-with mortality rate ratios being significantly higher in males than in females for most malignancies. [5] Women also have a higher total adiposity than men, with a preponderance of subcutaneous adipose tissue. In contrast, men typically tend to accumulate visceral adipose tissue. [6] Subcutaneous and visceral adipose tissue indices (SATI and VATI, respectively) may influence the clinical outcomes of patients with cancer in a sex-dependent manner. [7] Previous studies have reported a significant prognostic impact of SATI and VATI in different solid tumors, including advanced renal cell carcinoma, hepatocellular carcinoma, and pancreatic cancer, [8][9][10] although there has been some discrepant findings and the therapeutic implications of these observations have not been fully elucidated [11].
The aim of this study was to investigate whether measures of regional adiposity-including SATI and VATI-can be associated with overall survival (OS) in Taiwanese patients with bone metastases who were referred for radiotherapy (RT).

Study patients
The present study was designed as a retrospective review of prospectively collected data and was conducted in a radiation oncology setting. Between March 2005 and August 2013, a total of 1654 Taiwanese patients with bone metastases were consecutively referred for RT to the Chang Gung Memorial Hospital. All of them had a histology-proven diagnosis of cancer and underwent computed tomography (CT) imaging within 30 days of the initial assessment. The diagnosis of bone metastases was based on the results of bone scintigraphy, X-ray, CT, or magnetic resonance imaging. Patients were excluded in presence of the following criteria: age <18 years, unavailable CT scans within two weeks before the start of RT, or lack of measures of weight and height within two weeks of enrolment. A total of 374 cases met the exclusion criteria, resulting in a final study sample of 1280 patients. The study protocol was reviewed and approved by the Institution Review Board of the Chang Gung Memorial Hospital (approval number: IRB: 201701224B0). Owing to the retrospective nature of the analysis, the need for informed consent was waived. Data collection from electronic medical records was supervised by an experienced nurse and a radiation oncologist.

CT-based body composition analysis
In keeping with previous methodology,[12] single-slice CT imaging at level L3 was used to analyze adiposity. SATI and VATI were identified according to Hounsfield units (HU) (from -190 to -30 HU for SATI and from -29 to 150 HU for VATI, respectively). The tissue cross-sectional areas (expressed in cm 2 ) were calculated automatically by the CT software after normalization for patient height. SATI, VATI, total adipose tissue, and skeletal muscle indexes were expressed in cm 2 m -2 . All adiposity measures were taken in the two weeks preceding the start of RT.

Variable definition
Owing to the lack of a commonly accepted standard, SATI, VATI, and skeletal muscle indices were dichotomized according to median values measured at L3. OS was defined as the time elapsed from the start of RT for bone metastases to the date of death. Body mass index (BMI) was categorized as follows: underweight (BMI <18.5 kg/m 2 ), normal weight (BMI: 18.5-24.99 kg/m 2 ), overweight (BMI: [25][26][27][28][29].99 kg/m 2 ), and obese (BMI �30 kg/m 2 ). Equivalent doses in 2-Gy fraction (EQD2Gy) were used to express different total radiation doses in terms of amount and number of fractions. The time to metastases (calculated from the time of diagnosis of primary cancer to the identification of distant metastases) was categorized in � 1 year versus >1 year. Metastases were considered multiple in presence of simultaneous involvement of at least two organs or different parts of skeleton (e.g., sternum and sacrum). The use of systemic therapy was investigated in the timeframe ranging from 1 month before RT to the date of the last follow-up. Other variables of interest were previously described. [13] The presence of comorbidities was dichotomized (yes versus no) according to the Charlson comorbidity index. Employment status was classified into three categories using the Registrar General's Social Class (RGSC) scheme, as follows: unemployed, low-wage employed, and high-wage employed. Education status was categorized as high versus low (junior high school and above versus elementary school and below). The patient's place of residence was dichotomized as either rural or urban (population density below or above 800 persons per km 2 , respectively). Risky oral habits were classified as follows: cigarette smoking (smoked �100 in lifetime versus < 100 cigarettes in lifetime and no current smoking), betel quid chewing (current/former versus never), and alcohol drinking (current/former versus never).

Statistical analysis
Continuous variables were compared using the Student's t-test, whereas the Pearson's chisquare test was used for categorical variables. The associations between the study variables (including indices of adiposity) and OS were investigated using univariate and multivariate Cox proportional hazard ratio analyses. Results were expressed as hazard ratios (HRs) with their 95% confidence interval (CIs). We also categorized patients according to SATI and VATI values (high versus low, with high values serving as references). Survival plots were constructed with the Kaplan-Meier method (log-rank test).Two-tailed P values <0.05 were considered statistically significant. Owing to the exploratory nature of the study, the Bonferroni's correction was not applied.

Patient characteristics
The general characteristics of the study patients are summarized in Table 1. Of the 1280 participants, 1237 were followed up until death, whereas the remaining 43 were censored on the date last known to be alive. The study cohort included 740 (57.8%) men and 540 (42.2%) women. The most common primary cancer site was the lung (35% in both sexes), and there were 897 (70%) patients with an ECOG performance status of 0−1. The interval between the diagnosis of primary cancer and the detection of metastases was 0.11 months in women (95% CI: 0−15.64 months) and 0.04 months (95% CI: 0−13.50 months) in men, respectively. Table 1 shows the results pertaining to adiposity indices. Men had higher skeletal muscle and VATI than women, whereas SATI was higher in women.

Survival analysis
The The results of univariate and multivariate analyses are presented in Table 2. The following variables were independently associated with OS in multivariate analysis: SATI, VATI, sex, performance status, primary tumor site, more than one metastatic site, ECOG performance status, EQD2Gy, systemic therapy, education, days of metastases treatment, and time to metastases (Table 2).

Prognostic significance of SATI and VATI
We subsequently examined the prognostic impact of SATI and VATI by classifying patients into high versus low categories. Kaplan-Meier analysis revealed no differences in OS between the high SATI/high VATI group (median survival: 9.37 months) and high SATI/low VATI group (median survival: 9.43 months; P = 0.303; Table 3). The lowest OS (3.97 months) was observed in the low SATI/low VATI group (Fig 1; Table 3).  (Fig 2; Table 4). Association of adiposity and survival in patients with bone metastases

Discussion
The results of this retrospective analysis of prospectively collected data can be summarized as follows: 1) high SATI and VATI were independently associated with a better OS in a sample of Taiwanese patients with bone metastases, with the former showing a stronger relationship; 2) the most favorable OS was observed in women with high SATI. Although we observed associations-and not prediction or causation-our study adds to the growing literature investigating adiposity in relation to clinical outcomes of patients with malignancies. [13][14][15] Currently, the association of indices of adiposity with the disease course of cancer patients remains controversial. Although adiposity seems to be positively correlated with OS in several solid tumors [16,17], poorer survival figures have been reported for obese patients with cancer-possibly because of an increased production of growth factors and inflammatory mediators from the adipose tissue. [18] In this regard, it should be noted that adipose tissue may serve as a nutrient replacement in patients with cancer, [15,19] but it can be also involved in tumor spread through adipokine-induced extracellular matrix remodeling. [20] Pai et al. [21] have previously shown that SATI is strongly related to distant metastasis-free survival, locoregional control, and OS in 881 patients with head and neck cancer. Ebadi et al. [5] also demonstrated that patients with low SATI and high VATI independently predicted mortality in a sample of patients with different solid malignancies. Herein, we show that VATI, and most prominently SATI, were significantly associated with OS in Taiwanese patients with bone metastases. Controversy still exists on the relationship between VATI and clinical outcomes in patients with solid tumors.[10, [22][23][24] The reasons whereby SATI appears to hold a stronger association with OS over VATI in our study remain to be elucidated. However, it is notable that-differently from visceral fat (which is an active endocrine organ)-subcutaneous fat is more strictly involved in lipid and energy storage and is characterized by a lower inflammatory environment [14,25,26].
The study was conducted in a radiation oncology setting. Bone metastases are not only the most common site of distant spread in patients with solid malignancies but they are also the most commonly identified by radiation oncologists. The question as to whether our findings may be applied to patients with metastases to other distant sites (e.g., liver or brain) remains open. We acknowledge several limitations of the present study. First, the study was conducted in an Asian population, and it is well-known that ethnic differences exist in measures of adiposity between Asian and Caucasian populations [27]. Therefore, our findings need to be independently replicated in other geographic areas. Second, we did not segment body fat in the whole CT volume. Nonetheless, there is published evidence suggesting that measures of adiposity obtained at the L3 level through a simplified CT protocol are well-correlated to those taken at other sites [28][29][30][31]. Third, all measures of adiposity were taken in the two week preceding the start of RT. Wu et al. [32] have recently demonstrated the prognostic importance of the time at which body adiposity is assessed. However, these data were not available in this study, and we were unable to run this analysis. Finally, this was a retrospective analysis of prospectively collected data which had an exploratory nature. The application of the Bonferroni's correction in this setting may be too conservative and was avoided. In any case, our results should be considered as preliminary and hypothesis-generating. Because we observed associations, we cannot claim any prognostic effect of adiposity indices in our population. Future longitudinal studies are required to clarify this issue further. Association of adiposity and survival in patients with bone metastases These limitations notwithstanding, we found that high SATI and VATI are associated with a more favorable OS in Taiwanese patients with bone metastases referred for RT. The question as to whether clinical measures aimed at improving adiposity may improve OS in this clinical population deserves further scrutiny.