The impact of sarcopenia and myosteatosis on outcomes of unresectable pancreatic cancer or distal cholangiocarcinoma

Clinical Nutrition xxx (2015) 1e7

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Clinical Nutrition journal homepage: http://www.elsevier.com/locate/clnu

Original article

The impact of sarcopenia and myosteatosis on outcomes of unresectable pancreatic cancer or distal cholangiocarcinoma Katie E. Rollins a, 1, Nilanjana Tewari a, 1, Abigail Ackner a, Amir Awwad b, Srinivasan Madhusudan c, Ian A. Macdonald d, Kenneth C.H. Fearon e, Dileep N. Lobo a, * a

Gastrointestinal Surgery, National Institute for Health Research, Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University Hospitals and University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK Division of Radiological and Imaging Sciences, University of Nottingham, Nottingham University Hospitals, Queen's Medical Centre, Nottingham NG7 2UH, UK c Academic Oncology, University of Nottingham, School of Medicine, Nottingham University Hospitals, City Hospital Campus, Nottingham NG5 1PB, UK d Metabolic Physiology Group, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK e Department of Clinical and Surgical Sciences, University of Edinburgh, Royal Infirmary, Edinburgh EH16 4SA, UK b

a r t i c l e i n f o

s u m m a r y

Article history: Received 10 July 2015 Accepted 22 August 2015

Background & aims: Patients with pancreatic cancer have a poor prognosis, are often cachectic, and frequently demonstrate features of systemic inflammation, which may contribute to the phenomenon of myosteatosis. Analysis of body composition from CT scans has been used to study sarcopenia and its association with prognosis in a number of types of cancer, particular in combination with obesity. It has also been suggested that myosteatosis, defined as attenuated mean skeletal muscle Hounsfield units (HU), is associated with reduced survival in cancer. This study aimed to assess the association between body composition (sarcopenia and myosteatosis) and outcome in patients with unresectable pancreatic cancer. Methods: All patients diagnosed with unresectable pancreatic cancer at Nottingham University Hospitals NHS Trust between 2006 and 2013 were considered for the study. A total of 228 patients were included retrospectively. Body composition was assessed using cross-sectional CT analysis to calculate a skeletal muscle index (SMI) for sarcopenia and use mean skeletal muscle HU for myosteatosis. Results: The prevalence of sarcopenia in the whole patient group at baseline was 60.5% (138/228). Overall, patients who were sarcopenic had no significant difference in overall survival versus those who were not (p ¼ 0.779). However, patients who were overweight/obese and sarcopenic had a significantly lower survival (p ¼ 0.013). Of the 58 patients who were overweight or obese and sarcopenic, 32 were also myosteatotic. The prevalence of myosteatosis overall at baseline was 55.3% (126/228) and this was associated with significant reduction in overall survival (p ¼ 0.049). Univariate Cox regression revealed myosteatosis but not sarcopenia to be predictive of reduced survival, however this relationship was lost on multivariate testing. Myosteatosis was associated with significantly greater levels of systemic inflammation (white cell count, neutrophil-lymphocyte ratio and C-reactive protein), anaemia and worsening of baseline blood urea. This relationship was not seen with sarcopenia. Conclusions: This is the largest study on the association between body composition and survival in patients with unresectable pancreatic cancer and has shown that although sarcopenia alone did not have a bearing on survival, the presence of myosteatosis was associated significantly with the presence of systemic inflammation and reduced survival. © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Keywords: Pancreatic cancer Cholangiocarcinoma Sarcopenia Myosteatosis Survival Inflammation

Abbreviations: CRP, C-reactive protein; CT, computed tomography; DICOM, digital imaging and communications in medicine; ESR, erythrocyte sedimentation rate; HU, Hounsfield units; NLR, neutrophilelymphocyte ratio; SMI, skeletal muscle index; WHO, World Health Organisation. * Corresponding author. Tel.: þ44 115 8231149; fax: þ44 115 8231160. E-mail address: [email protected] (D.N. Lobo). 1 Joint first authors. http://dx.doi.org/10.1016/j.clnu.2015.08.005 0261-5614/© 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Please cite this article in press as: Rollins KE, et al., The impact of sarcopenia and myosteatosis on outcomes of unresectable pancreatic cancer or distal cholangiocarcinoma, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.08.005

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K.E. Rollins et al. / Clinical Nutrition xxx (2015) 1e7

1. Introduction Pancreatic ductal adenocarcinoma and distal cholangiocarcinoma are aggressive types of cancer with overall 5-year survival rates of less than 5%. The 5-year survival for patients treated with surgical resection is 4e8% and most patients with unresectable disease die within 9e15 months of diagnosis [1,2]. Pancreatic ductal adenocarcinoma is associated with both local and systemic inflammation, with previous studies demonstrating increased resting energy expenditure, most pronounced in those with increased acute phase response [3]. As a consequence, the prevalence of sarcopenia, severe weight loss [4] and cancer cachexia in this frail patient cohort is high [5], which is linked in part to poor survival [6,7]. Analysis of body composition from CT scans has been used to document the prevalence of both sarcopenia and myosteatosis and their association with prognosis in a number of different types of cancer [8e16]. Sarcopenia refers to a decrease in muscle mass, and resultant low muscularity which is quantifiable using cross sectional imaging [17]. CT-based cut-offs for the definition of sarcopenia have previously been established using regression equations from a heterogeneous group of cancer patients [11,16]. Sarcopenia is associated with poor clinical outcomes including increased risk of infection, loss of function and increased mortality [18]. In addition, sarcopenic patients have an increased risk of chemotherapy-related toxicity [8e10]. Recent evidence, however, has suggested that the relationship between sarcopenia and cancer outcomes may be mostly relevant in overweight or obese patients [12]. However, other studies have suggested that sarcopenia may not have a bearing on clinical outcome [18,19]. Myosteatosis is the process of infiltration of lipid into both the inter- and intramyocellular compartments [20,21] and can be estimated by the attenuation of skeletal muscle Hounsfield units (HU) on CT scanning. The conventional lower cut off for the normal attenuation of skeletal muscle is 30 HU [21,22], which is estimated to be two standard deviations below the mean skeletal muscle HU of young healthy people. There are a range of factors associated with attenuated muscle density including obesity [23], increasing age [24], male gender [25], type 2 diabetes mellitus [26], inactivity [27] and malignancy. Myosteatosis has also been linked to the host systemic inflammatory response [28], particularly neutrophilelymphocyte ratio (NLR) in patients with colorectal cancer, but this relationship is not yet understood fully. Attenuated skeletal muscle density is prognostic of reduced survival independently in patients with malignancy of the lung and gastrointestinal tract [29]. The aims of this retrospective study, examining the role of measures of body composition in patients with unresectable pancreatic cancer and distal cholangiocarcinoma, were to examine the relationship between sarcopenia, myosteatosis, markers of systemic inflammation and survival. 2. Methods All patients diagnosed with unresectable pancreatic ductal adenocarcinoma and distal cholangiocarcinoma managed at Nottingham University Hospitals NHS Trust between 2006 and 2013 were considered for the study. Patients with at least one abdominal

CT scan taken at diagnosis and available for analysis were included. For patients in the palliative chemotherapy (gemcitabine-based throughout the duration of the study) group, a follow-up CT after commencement of chemotherapy, at a minimum of 60 days after the baseline CT, was also analysed. Blood results from within a week of the initial diagnostic CT scan were also collated. Patients with ampullary and duodenal carcinomas, neuroendocrine tumours or gastrointestinal stromal tumours were excluded. All patients had a diagnosis of cancer based upon histology and/or cytology; however, the precise tumour type (pancreatic ductal adenocarcinoma or distal cholangiocarcinoma) was not always known. Patient data were extracted from the electronic records of the Nottingham Information System and recorded by an investigator with no involvement in patient care. Missing data on patient height and weight were obtained from review of hospital case notes and data on survival by contacting the patients' General Practitioners. The conduct of the study was approved by the audit department of Nottingham University Hospitals and the need to obtain informed consent from patients was waived.

2.1. Body composition analysis Electronic copies of CT scans taken routinely for clinical reasons were obtained from the hospital Picture Archiving and Communication System. Once accessed, the scans were anonymised, and one CT image slice at the third lumbar vertebra (L3) level was selected in Digital Imaging and Communications in Medicine (DICOM) format. The images were analysed by a single trained investigator using SliceOmatic 5.0 software (TomoVision, Montreal, Canada) to calculate the surface area of the specific tissue types: skeletal muscle tissue, visceral adipose tissue and subcutaneous/ intramuscular adipose tissue. Within the L3 region are the following muscles: psoas, erector spinae, quadratus lumborum, transversus abdominus, external and internal obliques and rectus abdominus. SliceOmatic software relies on the variation in radiodensity of the different tissue types to identify and, thereby, quantify the surface area of the tissue present. The different tissue radiodensities are represented by specific HU thresholds: 29 to þ150 for skeletal muscle [13], 150 to 50 for visceral adipose tissue [14] and 190 to 30 for subcutaneous and intramuscular adipose tissue [15]. Once the tissues were identified, the cross-sectional surface area (cm2) of each tissue was calculated by the software [9]. Any change in tissue area was expressed as absolute change (cm2). The mean HU measurement of all skeletal muscle within the L3 cross-section was recorded as a measure of myosteatosis, which was defined operationally as a mean skeletal muscle radiodensity of <33 HU in those with a BMI 25 and <41 HU in those with a BMI < 25 across the axial orthogonal view [29]. These data were used to estimate whole body stores of fat-free mass (FFM) and fat mass (FM) using regression equations [16] as follows:

Total body fat­free mass ðFFMÞ ðkgÞ i h  ¼ 0:3  skeletal muscle area at L3 cm2 þ 6:06

i h  Total body fat mass ðFMÞ ðkgÞ ¼ 0:042  total adipose tissue area at L3 cm2 þ 11:2

Please cite this article in press as: Rollins KE, et al., The impact of sarcopenia and myosteatosis on outcomes of unresectable pancreatic cancer or distal cholangiocarcinoma, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.08.005

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The cross sectional area of skeletal muscle was normalised for patient height by calculating the skeletal muscle index (SMI) (cm2/ m2). Patients were classified as sarcopenic according to established cut offs [29]; L3 SMI < 41 cm2/m2 for women and <43 cm2/m2 for men with a BMI < 25 and <53 for men with a BMI  25. Patients with a BMI less than 20 kg/m2 were classified as underweight, between 20 and less than 25 kg/m2 as normal BMI, between 25 and less than 30 kg/m2 as overweight and those with a BMI 30 kg/m2 were classified as obese. The presence of sarcopenia and myosteatosis was also correlated with haemoglobin, renal function tests and markers of inflammation (white cell count, NLR, albumin, Creactive protein and erythrocyte sedimentation rate) as well as World Health Organisation (WHO) performance status [30] at the time of diagnosis as quantified by a consultant oncologist at clinical review and the number of regular medications taken by the patient at baseline. 2.2. Statistical analysis Data were analysed using GraphPad Prism v6 (GraphPad, La Jolla, CA, USA) and SPSS v 22 software (IBM SPSS Statistics, Armonk, NY, USA). Data are shown as mean ± SD or median [interquartile range (IQR)] according to data type (parametric or non-parametric, respectively). Those patients who underwent palliative chemotherapy had body composition analysed before and after chemotherapy, and the difference in body composition measures were assessed using paired t-testing. Those who underwent best supportive treatment only underwent only one assessment of body composition, and this single measure was correlated with outcome in this group. KaplaneMeier survival curves were constructed for survival outcomes in all patient groups, with comparison of the curves performed using a Log-Rank ManteleCox analysis. Correlation between blood results and skeletal muscle index as a measure of sarcopenia and mean skeletal muscle HU as a measure of myosteatosis was assessed using Pearson's correlation coefficient. Univariate and multivariate analyses were performed using Cox regression modelling to calculate hazard ratios and 95% confidence intervals for overall survival. All analyses were performed using two-tailed testing and differences were considered significant at p < 0.05. 3. Results A total of 228 patients were found suitable for the study and their demographic data are shown in Table 1. 3.1. Change in body composition In the palliative chemotherapy group, there was a significant decrease in cross-sectional area of skeletal muscle, visceral adipose tissue and subcutaneous adipose tissue between the baseline and follow-up CT scans (Table 2). SMI and mean skeletal muscle HU tended to decrease between the two time points. 3.2. Prevalence of sarcopenia and myosteatosis The prevalence of sarcopenia in the whole patient group at baseline was 61% (138/228), with 58/228 (25%) being both sarcopenic and overweight/obese. The prevalence of myosteatosis overall was 55% (n ¼ 126/228), with the majority of these patients being in the group managed with best supportive care (91 versus 35 patients who received palliative chemotherapy). The prevalence of sarcopenia and myosteatosis and the combination of these composition markers in the patient cohort is shown in Fig. 1.

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Table 1 Baseline demographic data. No Palliative chemotherapy chemotherapy group (n ¼ 98) group (n ¼ 130) Age (years), Mean ± SD

64.8 ± 8.7

72.9 ± 11.1

Gender, n (%) Male Female

55 (56.1) 44 (44.9)

69 (53.1) 61 (46.9)

WHO performance status 0 1 2 3 4

25 45 6 1 0

2 23 21 27 2

Number of medications 0e5 6e10 >11

64 18 4

41 35 9

Diabetes mellitus, n (%) Type I Type II

0 18 (18.4)

0 24 (18.5)

Stage of disease, n (%) Locally advanced Metastatic

60 (61.2) 38 (38.8)

54 (41.5) 76 (58.5)

BMI (kg/m2), Mean ± SD Underweight (BMI < 18.5 kg/m2), n (%) Normal (BMI 18.5e24.9 kg/m2), n (%) Overweight/obese (BMI  25 kg/m2), n (%)

23.2 ± 5.7 7 (7.1) 59 (60.2) 32 (32.7)

25.7 ± 5.8 22 (16.9) 43 (33.1) 65 (50)

Estimated total fat-free mass (kg), Mean ± SD 42.5 ± 8.7 Estimated total fat mass (kg), Mean ± SD 20.5 ± 8.7 Sarcopenic, n (%) 60 (61.2) Overweight/obese and sarcopenic, n (%) 20 (20.4) Myosteatotic, n (%) 35 (35.7)

34.21 ± 4.3 11.6 ± 7.1 78 (60.0) 38 (29.2) 91 (70.0)

Values are numbers with percentages in brackets unless otherwise indicated.

3.3. Survival analyses At the time of analysis, the entire patient cohort had died. Median survival was 5.8 months from index CT scan for the whole patient group and significantly lower in those who did not have chemotherapy (2 versus 10 months, p < 0.001). The difference in survival remained significant after confounding variables such as age, gender, performance status and the presence of metastatic disease were taken into consideration. Patients were divided into subgroups according to stage of disease i.e. locally advanced or metastatic. In each subgroup, the administration of chemotherapy was associated with better survival than no chemotherapy (p < 0.0001). In the whole patient cohort, there was no significant reduction in survival in those who had sarcopenia diagnosed from the baseline CT scan (p ¼ 0.779) (Fig. 2a). At the time of the prechemotherapy scan, 60/98 (61.2%) of the patients receiving chemotherapy were sarcopenic, whereas this was 69/98 (70.4%) at

Table 2 Change in measures of body composition on CT. Tissue

Baseline CT

Skeletal muscle (cm2) Visceral adipose (cm2) Subcutaneous adipose (cm2) Skeletal muscle index (cm2/m2) Skeletal muscle mean HU

121.3 82.4 149.8 42.2 40.1

± ± ± ± ±

29.3 60.1 90.6 8.6 7.4

Follow-up CT 113.9 70.9 122.8 39.8 39.0

± ± ± ± ±

25.2 56.3 87.9 8.0 8.4

p <0.001 0.001 <0.001 0.060 0.054

All values are Mean ± SD. p values in bold font are statistically significant.

Please cite this article in press as: Rollins KE, et al., The impact of sarcopenia and myosteatosis on outcomes of unresectable pancreatic cancer or distal cholangiocarcinoma, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.08.005

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K.E. Rollins et al. / Clinical Nutrition xxx (2015) 1e7

Fig. 1. Prevalence of sarcopenia and myosteatosis.

the time of the post-chemotherapy CT scan. Sarcopenia at baseline did not affect survival in this group (p ¼ 0.675) (Fig. 2b) however its presence on the post chemotherapy CT scan was associated with a significantly reduced survival (p ¼ 0.030) (Fig. 2c). Overall, there were 58 patients in the whole cohort who were either overweight or obese and sarcopenic. These patients had a significantly shorter duration of survival (p ¼ 0.013) (Fig. 2d). Of these overweight or obese patients, 32 were both sarcopenic and myosteatotic. There were small numbers in each group with sarcopenic obesity, thus a separate subgroup analysis was not conducted. The presence of myosteatosis at the baseline CT scan was associated with a significant reduction in survival in the whole patient cohort (p ¼ 0.049) (Fig. 3). Those who were myosteatotic had a reduced median survival when compared with those who were not myosteatotic (117 days versus 254 days, p ¼ 0.077). In those patients who received palliative chemotherapy, at the time of the prechemotherapy scan 36% (n ¼ 35/98) of the patients were myosteatotic.

The presence of myosteatosis, but not that of sarcopenia was associated with reduced overall survival. Survival rates in those who were both myosteatotic and sarcopenic (median survival 114 days) and those who were myosteatotic but not sarcopenic (median survival 131 days) were lower than in those who were sarcopenic but not myosteatotic (median survival 280.5 days) and nonsarcopenic and non-myosteatotic (median survival 229 days) (p ¼ 0.003). Univariate and multivariate models using Cox regression analysis are shown in Table 3. Factors significantly predictive of overall survival on univariate analysis were NLR, C-reactive protein, presence of myosteatosis, increasing age and presence of metastatic rather than locally advanced disease. When these variables were applied to a multivariate model, NLR, C-reactive protein and the presence of metastatic disease remained significant. Poorer WHO performance status was associated with lower mean skeletal muscle HU at baseline i.e. the prevalence of myosteatosis was greater in those with this poor functional status; mean HU was 41.6 (SD 7.1) in patients with a performance status of zero versus 18.1 (SD 0.3) in those with a performance status of 4 (p < 0.0001). 3.4. Chemotherapy tolerance and toxicity The presence of sarcopenia did not impact significantly upon rates of completion of a full 6 cycle course of palliative chemotherapy [31.7% (n ¼ 19/60) versus 43.2% (n ¼ 16/37) in those who were not sarcopenic, p ¼ 0.281]. This also had no significant effect upon the incidence of chemotherapy-related toxicity [16.7% (n ¼ 10/60) in those who were sarcopenic versus 24.3% (n ¼ 9/37) in those who were not sarcopenic, p ¼ 0.432]. The presence of myosteatosis similarly did not impact upon patients' ability to complete the full course of chemotherapy (37.1% versus 35.5% in those not myosteatotic, p ¼ 0.830) nor on the incidence of toxicity (28.6% versus 19.4%, p ¼ 0.322).

Fig. 2. Kaplan Meier survival curves for the presence and absence of sarcopenia (a) in the whole palliative patient cohort, (b) in those receiving palliative chemotherapy prior to chemotherapy, (c) in those receiving palliative chemotherapy following chemotherapy, (d) in the whole patient cohort by the presence of sarcopenia with overweight/obese.

Please cite this article in press as: Rollins KE, et al., The impact of sarcopenia and myosteatosis on outcomes of unresectable pancreatic cancer or distal cholangiocarcinoma, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.08.005

K.E. Rollins et al. / Clinical Nutrition xxx (2015) 1e7

Fig. 3. Survival by presence and absence of myosteatosis in the whole patient cohort.

3.5. Correlation with blood variables The blood results for those patients who were sarcopenic versus those who were not sarcopenic demonstrated no significant difference for any of the variables considered (Table 4). There was no significant correlation between any of the measures and skeletal muscle index (SMI). In contrast, patients with myosteatosis had a significantly lower haemoglobin and albumin, and significantly higher inflammatory markers (white cell count, NLR and C-reactive protein) and blood urea when compared with those without myosteatosis (Table 4). There was no significant difference in the serum creatinine and erythrocyte sedimentation rate (ESR) between the two groups. However, ESR values were available for only 45 patients. 4. Discussion This is the largest study to date on the impact of body composition on survival in patients with unresectable pancreatic cancer

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and distal cholangiocarcinoma and has shown that although sarcopenia alone did not have a bearing on survival, the presence of myosteatosis was associated significantly with the presence of systemic inflammation and reduced survival. The presence of neither sarcopenia nor myosteatosis had a significant impact upon rates of completion of full course palliative chemotherapy or incidence of chemotherapy-related toxicity. Myosteatosis, but not sarcopenia, correlated significantly with increasing systemic inflammation, anaemia and blood urea. The degree of skeletal muscle attenuation, as quantified by mean skeletal muscle HU of the cross sectional L3 slice, also significantly decreased with increasing WHO performance status, i.e. the prevalence of myosteatosis was greater in those with poor functional status. Myosteatosis, but not sarcopenia was significantly predictive of mortality in univariate but not multivariate modelling. The presence of metastatic disease at presentation, a NLR > 3 [28], and a CRP  10 mg/l were significant on univariate and multivariate testing, but increasing age and presence of myosteatosis were only significant on only univariate testing. Recent literature has suggested that myosteatosis may be a negative prognostic marker in cancer [29]. In a series of 1473 consecutive patients with lung and abdominal cancer, the presence of low muscle attenuation was a significant negative predictor [29], corroborating the results of the present study. This relationship has not been investigated previously in patients with pancreatic cancer and distal cholangiocarcinoma. The relationship between the presence of myosteatosis and host systemic inflammatory response in a large series of patients with colorectal cancer found a direct association between the two factors [28]. High NLR was an independent predictor of reduced muscle mass in this series, and previous studies have shown an association between high NLR and poorer survival [31,32]. Similarly, studies have suggested an association between elevated CRP and poor survival, specifically in pancreatic cancer [33,34]. Low serum albumin concentration was also an independent predictor of low muscle mass [28], which the findings of the present study corroborate. A previous study of patients with pancreatic cancer demonstrated that patients who were anaemic at baseline had accelerated loss of

Table 3 Uni- and multivariate Cox regression models demonstrating the hazard ratio for overall survival. N ¼ 151 with complete data. Factor

Univariate

Haemoglobin Neutrophilelymphocyte ratio (NLR) (<3 or 3) C-reactive protein (<10 mg/l or 10 mg/l) Sarcopenia Myosteatosis Gender Age Local or metastatic disease

Multivariate

HR (95% CI)

p

HR (95% CI)

p

0.99 2.10 1.60 1.05 1.35 0.94 1.02 1.83

0.377 <0.001 0.010 0.739 0.027 0.630 0.002 <0.001

1.01 2.04 1.52 1.10 1.36 0.83 1.01 1.80

(1.00e1.01) (1.37e3.05) (1.04e2.22) (0.77e1.58) (0.92e2.00) (0.58e1.18) (0.99e1.03) (1.24e2.59)

0.142 <0.001 0.030 0.607 0.120 0.303 0.326 0.002

Not myosteatotic (mean), n ¼ 161

p

(0.99e1.00) (1.58e2.78) (1.12e2.28) (0.80e1.37) (1.04e1.76) (0.72e1.22) (1.01e1.04) (1.40e2.38)

p values in bold font are statistically significant.

Table 4 Blood results by presence or absence of sarcopenia and myosteatosis, n ¼ 228. Sarcopenic (mean), n ¼ 154 Haemoglobin (g/l) White cell count (109 cells/l) Neutrophil lymphocyte ratio Albumin (g/l) Blood urea (mmol/l) Serum creatinine (mmol/l) C-reactive protein (mg/l) Erythrocyte sedimentation rate (mm/h)

120.7 10.4 7.9 31.3 6.0 87.9 52.1 28.9

± ± ± ± ± ± ± ±

21.1 8.8 17.5 6.2 3.8 43.8 73.0 22.8

Not sarcopenic (mean), n ¼ 74 125.2 9.7 6.1 31.9 5.5 83.2 58.0 27.6

± ± ± ± ± ± ± ±

24.8 4.6 5.7 7.0 2.9 35.4 67.7 22.2

p

Myosteatotic (mean), n ¼ 67

0.158 0.495 0.345 0.515 0.373 0.406 0.620 0.847

117.6 11.1 8.5 30.2 6.5 87.4 75.8 31.0

± ± ± ± ± ± ± ±

24.7 9.4 17.9 6.4 3.9 37.9 88.1 22.9

128.5 8.9 5.6 32.9 4.8 84.4 42.6 22.7

± ± ± ± ± ± ± ±

18.4 3.6 6.6 6.8 2.5 43.9 55.9 20.4

0.0003 0.031 0.012 0.0028 0.0003 0.588 0.046 0.243

p values in bold font are statistically significant.

Please cite this article in press as: Rollins KE, et al., The impact of sarcopenia and myosteatosis on outcomes of unresectable pancreatic cancer or distal cholangiocarcinoma, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.08.005

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muscle mass [35], but these authors did not investigate the presence of myosteatosis. Congruent with previous research, our study has demonstrated that sarcopenia is widely prevalent in patients with advanced pancreatic cancer. Overall, we did not see a significant association between sarcopenia and survival, either in those undergoing best supportive care or palliative chemotherapy. In order to ascertain whether the degree of reduction of SMI had an impact upon survival, the cohort was divided into quartiles. Those in the bottom quartile (SMI 22.1e36.5 cm2/m2) had a median survival of 194 days, in the second quartile (SMI 36.6e41.6 cm2/m2) 162 days, in the third quartile (SMI 41.7e47.5 cm2/m2) 150 days and the fourth quartile (SMI 47.6e75.4 cm2/m2) 180 days. Equally, when quartiles were separated by gender, there was no consistency in survival rates by SMI. The lack of a relationship between sarcopenia and survival may reflect the issue that the former is not a dynamic measure of actual muscle loss, and may be influenced by the patients' constitutional level of muscularity. In a previous study on body composition in pancreatic cancer, the documented median BMI at the time of diagnosis was 20.7 kg/ m2, falling to 17.7 kg/m2 near to the time of death [4]. The median BMI in our patient cohort was 23.95 kg/m2 (IQR 21.7e27.7), comparable with that found in more recent literature [12]. Obesity, in particular increase in visceral fat, has been associated with complications after pancreaticoduodenectomy [36] and abbreviated survival in pancreatic cancer [37]. The present study found that the presence of sarcopenia at baseline was not associated with a reduction in overall survival. However, when the presence of sarcopenia combined with being overweight or obese was considered, this was associated with a significant reduction in survival (p ¼ 0.013). It is unclear what the underlying relationship between myosteatosis and systemic inflammation is. As with the lipotoxic hypothesis in type II diabetes, it may be that the infiltration of lipid into both the inter- and intramyocellular compartments has overall toxic effects and drives the presence of insulin resistance which, in turn, may exacerbate systemic inflammation [38,39]. On the other hand, it is possible that the presence of increasing systemic inflammation, in this case due to the inflammatory nature of pancreatic cancer [3], leads to the development of myosteatosis [40]. Whether myosteatosis is a direct contributor to shortened survival or is a marker for some other direct cause cannot be determined from the present analysis. This study has some limitations. We were only able to include patients in the study who had digital CT scans available for analysis. This excluded all patients who had been diagnosed with pancreatic cancer prior to 2006, when the scans began to be stored electronically. In addition, the chemotherapy cohort included only patients who had at least one baseline scan and one after a minimum of 60 days. Some patients may have experienced chemotherapy toxicity or disease progression and, therefore, had no further imaging beyond this point. The prevalence of sarcopenia and myosteatosis is unknown in this group, and our analysis may have excluded some of the patients with poorest survival. We noted better survival in those who underwent palliative chemotherapy compared with those who received no chemotherapy and this certainly reflects stage of disease and patient fitness. However, as none of our patients underwent surgical resection of the pancreatic tumour, full pathological staging was not possible and we could not, therefore, correct for this as a potential confounding factor. In addition, this study was retrospective and carries the limitations of such studies, despite efforts made to ensure the data were as complete and accurate as possible. Despite these limitations, this is the largest study on body composition to date in patients with advanced pancreatic cancer

and distal cholangiocarcinoma and has established a significant association between the presence of myosteatosis, systemic inflammation and reduced survival. Furthermore, it reinforces the concept that sarcopenia in overweight or obese individuals is associated with poor prognosis in unresectable disease. Conflict of interest The authors have no conflicts of interest to declare. Author contributions All authors contributed to the  conception and design, or analysis and interpretation of data  drafting the article or revising it critically for important intellectual content  and final approval of the version to be published.

Funding KER was funded by a European Society for Clinical Nutrition and Metabolism (ESPEN) Research Fellowship. The funders had no role in the design, execution and writing up of the study. References [1] Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet 2011;378:607e20. [2] Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004;350:1200e10. [3] Falconer JS, Fearon KC, Plester CE, Ross JA, Carter DC. Cytokines, the acutephase response, and resting energy expenditure in cachectic patients with pancreatic cancer. Ann Surg 1994;219:325e31. [4] Wigmore SJ, Plester CE, Richardson RA, Fearon KC. Changes in nutritional status associated with unresectable pancreatic cancer. Br J Cancer 1997;75: 106e9. [5] Fearon KC, Voss AC, Hustead DS. Definition of cancer cachexia: effect of weight loss, reduced food intake, and systemic inflammation on functional status and prognosis. Am J Clin Nutr 2006;83:1345e50. [6] Ozola Zalite I, Zykus R, Francisco Gonzalez M, Saygili F, Pukitis A, Gaujoux S, et al. Influence of cachexia and sarcopenia on survival in pancreatic ductal adenocarcinoma: a systematic review. Pancreatology 2015;15:19e24. [7] Bachmann J, Heiligensetzer M, Krakowski-Roosen H, Buchler MW, Friess H, Martignoni ME. Cachexia worsens prognosis in patients with resectable pancreatic cancer. J Gastrointest Surg 2008;12:1193e201. [8] Baracos VE, Reiman T, Mourtzakis M, Gioulbasanis I, Antoun S. Body composition in patients with non-small cell lung cancer: a contemporary view of cancer cachexia with the use of computed tomography image analysis. Am J Clin Nutr 2010;91:1133Se7S. [9] Prado CM, Baracos VE, McCargar LJ, Mourtzakis M, Mulder KE, Reiman T, et al. Body composition as an independent determinant of 5-fluorouracil-based chemotherapy toxicity. Clin Cancer Res 2007;13:3264e8. [10] Prado CM, Baracos VE, McCargar LJ, Reiman T, Mourtzakis M, Tonkin K, et al. Sarcopenia as a determinant of chemotherapy toxicity and time to tumor progression in metastatic breast cancer patients receiving capecitabine treatment. Clin Cancer Res 2009;15:2920e6. [11] Prado CM, Lieffers JR, McCargar LJ, Reiman T, Sawyer MB, Martin L, et al. Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a populationbased study. Lancet Oncol 2008;9:629e35. [12] Tan BH, Birdsell LA, Martin L, Baracos VE, Fearon KC. Sarcopenia in an overweight or obese patient is an adverse prognostic factor in pancreatic cancer. Clin Cancer Res 2009;15:6973e9. [13] Mitsiopoulos N, Baumgartner RN, Heymsfield SB, Lyons W, Gallagher D, Ross R. Cadaver validation of skeletal muscle measurement by magnetic resonance imaging and computerized tomography. J Appl Physiol 1998;85: 115e22. [14] Vehmas T, Kairemo KJA, Taavitsainen MJ. Measuring visceral adipose tissue content from contrast enhanced computed tomography. Int J Obes 1996;20: 570e3. [15] Kvist H, Sjostrom L, Tylen U. Adipose-tissue volume determinations in women by computed-tomography e technical considerations. Int J Obes 1986;10: 53e67.

Please cite this article in press as: Rollins KE, et al., The impact of sarcopenia and myosteatosis on outcomes of unresectable pancreatic cancer or distal cholangiocarcinoma, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.08.005

K.E. Rollins et al. / Clinical Nutrition xxx (2015) 1e7 [16] Mourtzakis M, Prado CMM, Lieffers JR, Reiman T, McCargar LJ, Baracos VE. A practical and precise approach to quantification of body composition in cancer patients using computed tomography images acquired during routine care. Appl Physiol Nutr Metabol 2008;33:997e1006. [17] Tsai S. Importance of lean body mass in the oncologic patient. Nutr Clin Pract 2012;27:593e8. [18] Awad S, Tan BH, Cui H, Bhalla A, Fearon KC, Parsons SL, et al. Marked changes in body composition following neoadjuvant chemotherapy for oesophagogastric cancer. Clin Nutr 2012;31:74e7. [19] Dalal S, Hui D, Bidaut L, Lem K, Del Fabbro E, Crane C, et al. Relationships among body mass index, longitudinal body composition alterations, and survival in patients with locally advanced pancreatic cancer receiving chemoradiation: a pilot study. J Pain Symptom Manage 2012;44:181e91. [20] Miljkovic I, Zmuda JM. Epidemiology of myosteatosis. Curr Opin Clin Nutr Metab Care 2010;13:260e4. [21] Aubrey J, Esfandiari N, Baracos VE, Buteau FA, Frenette J, Putman CT, et al. Measurement of skeletal muscle radiation attenuation and basis of its biological variation. Acta Physiol (Oxf) 2014;210:489e97. [22] Goodpaster BH, Thaete FL, Kelley DE. Composition of skeletal muscle evaluated with computed tomography. Ann N Y Acad Sci 2000;904:18e24. [23] Lee S, Kuk JL, Davidson LE, Hudson R, Kilpatrick K, Graham TE, et al. Exercise without weight loss is an effective strategy for obesity reduction in obese individuals with and without type 2 diabetes. J Appl Physiol 2005;99:1220e5. [24] Anderson DE, D'Agostino JM, Bruno AG, Demissie S, Kiel DP, Bouxsein ML. Variations of CT-based trunk muscle attenuation by age, sex, and specific muscle. J Gerontol A Biol Sci Med Sci 2013;68:317e23. [25] Kalichman L, Hodges P, Li L, Guermazi A, Hunter DJ. Changes in paraspinal muscles and their association with low back pain and spinal degeneration: CT study. Eur Spine J 2010;19:1136e44. [26] Kelley DE, McKolanis TM, Hegazi RA, Kuller LH, Kalhan SC. Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. Am J Physiol Endocrinol Metab 2003;285:E906e16. [27] Taaffe DR, Henwood TR, Nalls MA, Walker DG, Lang TF, Harris TB. Alterations in muscle attenuation following detraining and retraining in resistancetrained older adults. Gerontology 2009;55:217e23. [28] Malietzis G, Johns N, Al-Hassi HO, Knight SC, Kennedy RH, Fearon KC, et al. Low muscularity and myosteatosis is related to the host systemic inflammatory response in patients undergoing surgery for colorectal cancer. Ann Surg 2015. http://dx.doi.org/10.1097/SLA.0000000000001113 [Epub ahead of print], PMID: 25643288.

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[29] Martin L, Birdsell L, Macdonald N, Reiman T, Clandinin MT, McCargar LJ, et al. Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index. J Clin Oncol 2013;31: 1539e47. [30] Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649e55. [31] Malietzis G, Giacometti M, Kennedy RH, Athanasiou T, Aziz O, Jenkins JT. The emerging role of neutrophil to lymphocyte ratio in determining colorectal cancer treatment outcomes: a systematic review and meta-analysis. Ann Surg Oncol 2014;21:3938e46. [32] Ben Q, An W, Wang L, Wang W, Yu L, Yuan Y. Validation of the pretreatment neutrophilelymphocyte ratio as a predictor of overall survival in a cohort of patients with pancreatic ductal adenocarcinoma. Pancreas 2015;44:471e7. [33] Martin HL, Ohara K, Kiberu A, Van Hagen T, Davidson A, Khattak MA. Prognostic value of systemic inflammation-based markers in advanced pancreatic cancer. Intern Med J 2014;44:676e82. [34] Szkandera J, Stotz M, Absenger G, Stojakovic T, Samonigg H, Kornprat P, et al. Validation of C-reactive protein levels as a prognostic indicator for survival in a large cohort of pancreatic cancer patients. Br J Cancer 2014;110:183e8. [35] Di Sebastiano KM, Yang L, Zbuk K, Wong RK, Chow T, Koff D, et al. Accelerated muscle and adipose tissue loss may predict survival in pancreatic cancer patients: the relationship with diabetes and anaemia. Br J Nutr 2013;109:302e12. [36] House MG, Fong Y, Arnaoutakis DJ, Sharma R, Winston CB, Protic M, et al. Preoperative predictors for complications after pancreaticoduodenectomy: impact of BMI and body fat distribution. J Gastrointest Surg 2008;12:270e8. [37] Mathur A, Hernandez J, Shaheen F, Shroff M, Dahal S, Morton C, et al. Preoperative computed tomography measurements of pancreatic steatosis and visceral fat: prognostic markers for dissemination and lethality of pancreatic adenocarcinoma. HPB Oxf 2011;13:404e10. [38] Miljkovic I, Cauley JA, Wang PY, Holton KF, Lee CG, Sheu Y, et al. Abdominal myosteatosis is independently associated with hyperinsulinemia and insulin resistance among older men without diabetes. Obes (Silver Spring) 2013;21: 2118e25. [39] Shaw CS, Clark J, Wagenmakers AJ. The effect of exercise and nutrition on intramuscular fat metabolism and insulin sensitivity. Annu Rev Nutr 2010;30:13e34. [40] Miljkovic I, Kuipers AL, Kammerer CM, Wang X, Bunker CH, Patrick AL, et al. Markers of inflammation are heritable and associated with subcutaneous and ectopic skeletal muscle adiposity in African ancestry families. Metab Syndr Relat Disord 2011;9:319e26.

Please cite this article in press as: Rollins KE, et al., The impact of sarcopenia and myosteatosis on outcomes of unresectable pancreatic cancer or distal cholangiocarcinoma, Clinical Nutrition (2015), http://dx.doi.org/10.1016/j.clnu.2015.08.005