Are left ventricular muscle area and radiation attenuation associated with overall survival in advanced pancreatic cancer patients treated with chemotherapy?

Clinical Radiology xxx (xxxx) xxx

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Are left ventricular muscle area and radiation attenuation associated with overall survival in advanced pancreatic cancer patients treated with chemotherapy? Q. Cai a, c, 1, Y. Mao a, b, 1, Q. Yang a, c, H. Wen a, c, Y. Lv a, c, **, R. Zhang a, c, * a State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China b Department of Hepato-biliary-pancreatic Oncology, Sun Yat-Sen University Cancer Center, No. 651 Dongfeng Road East, 510060, Guangzhou, China c Department of Radiology, Sun Yat-Sen University Cancer Center, No. 651 Dongfeng Road East, 510060, Guangzhou, China

art icl e i nformat ion Article history: Received 27 May 2019 Accepted 12 November 2019

AIM: To evaluate whether cardiac muscle area and radiation attenuation, determined using pre-chemotherapy computed tomography (CT), are associated with therapeutic response and overall survival (OS) in chemotherapy-treated advanced pancreatic cancer (APC) patients. MATERIALS AND METHODS: Ninety-eight chemotherapy-treated APC patients who underwent pre-chemotherapy CT between 2009 and 2018 were considered. Left ventricular muscle area (LVMA) and left ventricular muscle radiation attenuation (LVMRA) were measured using pre-chemotherapy arterial-phase CT. OS and progression-free survival (PFS) were analysed using KaplaneMeier curves. Univariate and multivariate Cox regression analyses were performed to analyse potential factors affecting OS and PFS. RESULTS: Patients with low LVMRA, low LVMA at baseline CT, and multiple metastases had a significantly shorter median OS than patients with high LVMRA, high LVMA, and without multiple metastases (8.8 versus 14 months, p¼0.017; 12.2 versus 18.1 months, p¼0.038; 7.3 versus 13.5 months, p<0.001, respectively). Patients with low LVMRA and distant metastasis had a shorter median PFS than patients with high LVMRA and those without distant metastasis (4.9 versus 8.3 months, p¼0.032; 5.4 versus 9.9 months, p¼0.002, respectively). Moreover, the mean LVMRA was the highest in the partial response group (p¼0.028). CONCLUSION: LVMRA could well predict PFS and OS in chemotherapy-treated APC patients. Ó 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

* Guarantor and correspondent: R. Zhang, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China. Tel./fax: þ011 0086 020 87343221. ** Guarantor and correspondent: Y. Lv, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China. Tel.: þ011 0086 020 87343478; fax: þ011 0086 020-8734. E-mail addresses: [email protected] (Y. Lv), [email protected] (R. Zhang). 1 Q. Cai and Y. Mao contributed equally to this work.

Introduction Pancreatic cancer is the fourth leading cause of cancer deaths and its incidence is rising.1 At the time of diagnosis, approximately 60% of patients had advanced pancreatic

https://doi.org/10.1016/j.crad.2019.11.003 0009-9260/Ó 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Please cite this article as: Cai Q et al., Are left ventricular muscle area and radiation attenuation associated with overall survival in advanced pancreatic cancer patients treated with chemotherapy?, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.003

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cancer (APC), because of which surgical treatment was not suitable.2 Chemotherapy, such as FOLFIRINOX (FOL, folinic acid; F, fluorouracil; IRIN, irinotecan; OX, oxaliplatin), or gemcitabine therapy, is the main treatment for APC patients. Unfortunately, the anti-tumour efficacy of chemotherapy is limited and the median overall survival (OS) of treated patients is only 6e9 months.3,4 Early prediction of the effects of chemotherapy in APC patients would help guide clinical practices; however, the optimal markers for predicting outcomes in chemotherapy-treated APC patients remain unknown. Thus, it is extremely important to determine a useful marker for predicting outcomes in chemotherapy-treated APC patients. Most APC patients experienced cachexia during tumour progression,5 which was associated with a reduced response to chemotherapy and poor OS in patients with different cancers, including pancreatic cancer.6e8 A severe loss of muscle mass is a more recently recognised indicator of cachexia.6 Interestingly, various studies have indicated that the muscle mass at the level of the third lumbar vertebrae (L3), quantified by the cross-sectional muscle area and radiation attenuation, which means average density on computed tomography (CT), is associated with chemotherapy response and OS in different cancers9e11; however, a recent study indicated that the mass of the heart is more susceptible to cancer cachexia than is the skeletal muscle.12 Anush also reported that the progressive decrease in the body weight of individuals with cancer was accompanied by wasting of the cardiac muscle.13 Thus, the cardiac muscle may be a surrogate marker for cachexia; however, to the authors’ knowledge, no study has explored the relationship between cardiac muscle mass, assessed by CT, and the chemotherapy response/OS of APC patients. Therefore, the purpose of this retrospective study was to explore whether cardiac muscle area and radiation attenuation, measured using pre-chemotherapy CT, are associated with therapeutic response and survival in APC patients receiving chemotherapy.

Materials and methods Patient selection This retrospective study was approved by the institutional review board, who deemed that the requirement for informed consent could be waived. A total of 324 patients diagnosed with pancreatic cancer between 1 January 2009 and 1 January 2018 were reviewed. APC patients treated with FOLFIRINOX/gemcitabine as first-line therapy and for whom data from at least one CT examination that included the heart at diagnosis were available for analysis were included in this study. APC patients included patients with locally advanced disease and distant metastases. The exclusion criteria were as follows: patients who underwent surgical treatment (n¼127); patients who underwent chemotherapy prior to the baseline CT examination (n¼53); patients who did not undergo follow-up examinations after chemotherapy (n¼8); patients for whom the time interval was >3 months between the first follow-up CT after chemotherapy and the baseline CT (n¼3); patients for whom CT phases were incomplete or images were not available (n¼5); patients who received surgical treatment after chemotherapy (n¼17); patients with incomplete clinical data (n¼3); and patients with a follow-up of <1 year and who were alive at the last follow-up (n¼10). Finally, 98 APC patients who underwent chemotherapy and received CT examinations before chemotherapy were enrolled in this study. The flow chart of patient selection is shown in Fig 1.

Data collection All of the data were retrieved from medical records at the Sun Yat-sen University Cancer Center. The clinical and imaging parameters included age, sex, height, weight, body mass index (BMI), hypertension, diabetes, primary tumour location, primary tumour size, presence of distant metastasis, and presence of metastases within multiple different

Figure 1 Flowchart of the patient selection process. Please cite this article as: Cai Q et al., Are left ventricular muscle area and radiation attenuation associated with overall survival in advanced pancreatic cancer patients treated with chemotherapy?, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.003

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organs. Furthermore, laboratory data including carbohydrate antigen 19-9 (CA19-9) and C-reaction protein (CRP) levels within a week of initial diagnostic CT were recorded.

Definition of cachexia The common definition of cachexia in cancer patients is weight loss >5% or weight loss >2% in patients already symptomatic by virtue of having BMI <20 kg/m2.14 In this study, patients were divided into two groups according to BMI: BMI <20 kg/m2 and BMI 20 kg/m2.

Measurement of cardiac muscle parameters The pre-chemotherapy arterial-phase CT images (section thickness: 5 mm) were retrieved retrospectively from the institutional picture archiving and communication system (PACS, Centricity 4.0; GE Healthcare, Barrington, IL, USA) for analysis. A radiologist with 10 years of experience in abdominal imaging identified a single axial section in which the interventricular septum and left ventricular wall were adequately displayed. The semi-automated GE Reformat post-processing tool provided by the GE PACS workstation (Centricity Radiology RA1000; GE Medical Healthcare, Little Chalfont, UK) was used to measure the left ventricular muscle area (LVMA) and radiation attenuation (LVMRA). The “Measurement area” button was used to outline the left ventricular wall border manually excluding the papillary muscle. When the density window setting was between 30 and þ150 HU, the area of the left ventricle muscle with a

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density between 30 and 150 HU was depicted. Then the cross-sectional area and mean density of the outlined tissue were calculated using the semi-automated GE Reformat post-processing tool. The measurement process of LVMA and LVMRA is shown in Fig 2.

Evaluation of chemotherapy response The evaluation of chemotherapy response was performed within 2e3 months after the start of the first cycle of chemotherapy by a single radiologist with 10 years of experience in abdominal imaging, based on the new response evaluation criteria in solid tumours (RECIST 1.1).15 The treatment response is classified as partial response (PR), progressive disease (PD), and stable disease (SD). PR is defined as a decrease in the maximum diameter of the target tumour lesion by >30% compared to that on baseline CT. PD is defined an increase in the maximum diameter of the target tumour lesion by >20%; SD is defined as a decrease or increase in the maximum diameter of the target tumour lesion by <30% or <20%, respectively.

Endpoints The endpoint, OS, was defined as the time interval (in months) from the date of diagnosis to the date of death or the date of the last follow-up. Progression-free survival (PFS) was defined as the time interval (in months) from the date of diagnosis to the date of the first radiologically

Figure 2 The measurement process of LVMA and LVMRA. (a) The axial section was selected to measure LVMA/LVMRA. (b) The region of interest (ROI) was delineated manually along the left ventricular wall border excluding the papillary muscle. (c) When the density window setting was between þ30 and þ150 HU, the area of the left ventricle muscle with a density between 30 and 150 HU was depicted (the shaded green area on the CT image). (d) The cross-sectional area and mean density of the shaded green area on the CT image were calculated by the semi-automated GE Reformat post-processing tool. Please cite this article as: Cai Q et al., Are left ventricular muscle area and radiation attenuation associated with overall survival in advanced pancreatic cancer patients treated with chemotherapy?, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.003

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documented disease progression based on RECIST 1.1.15 Follow-up was continued until 31 December 2018.

Statistical analysis Optimal cut-off values of LVMRA, LVMA, and CRP were determined using the X-tile software,16 which is widely used in calculating the optimal cut-off values that show the most significant predictive power for OS.17e19 For continuous variables, data are expressed as mean  standard deviation (SD) and compared using Student’s t-test. Differences between the two groups were compared using the Chi-squared test. A Cox proportional hazards model was used for univariate and multivariate analyses. Patients’ clinical end points were calculated using the KaplaneMeier method and compared by the log-rank test. All factors with a p-value <0.05 in the univariate analysis were included in the multivariate analysis. Hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were estimated from the Cox regression analysis.

Results Patient characteristics A total of 98 APC patients were enrolled in this study, including 57 men and 41 women. Representative CT images are shown in Fig 3. The median age of the patients was 56.5 years (range, 21e77 years). In this retrospective study, 59 of the 98 (60.2%) patients had distant metastases at diagnosis, and 18 (18.4%) patients had metastases within multiple

different organs at diagnosis. In assessments of chemotherapy response, 20 of the 98 (20.4%) patients showed PR, 61 (62.2%) patients showed SD, and 17 (17.4%) patients showed PD. Patient characteristics are shown in Table 1.

The cut-off values determined by X-tile In the present study, the cut-off values for LVMRA, LVMA, and CRP that showed the most significant predictive power for OS were 912 mm2, 85.2 HU, and 1.2 ng/ml, respectively. Based on these cut-off values, patients were divided into two subgroups: low LVMRA (85.2 HU) and high LVMRA (>85.2 HU), low LVMA (912 mm2) and high LVMA (>912 mm2), and low CRP (1.2 ng/ml) and high CRP (>1.2 ng/ml).

Survival analysis The 1- and 3-year OS rates were 55.7% and 14.9%, respectively, while the 1- and 3-year PFS rates were 24.5% and 3.3%, respectively. The KaplaneMeier method showed that patients with a low LVMRA had a significantly shorter median OS than those with a high LVMRA (8.8 versus 14 months, p¼0.017, Fig 4a) and a shorter median PFS (4.9 versus 8.3 months, p¼0.032, Fig 4d). Patients with a low LVMA had a significantly shorter median OS than those with a high LVMA (12.2 versus 18.1 months, p¼0.038, Fig 4b). There were no significant differences in PFS between patients in the two LVMA-based groups. Moreover, patients without metastases within multiple different organs had a significantly higher median OS than those with metastases within multiple different organs (13.5 versus 7.3 months, p<0.001, Fig 4c). Patients with distant metastasis had a

Figure 3 (a) Patient 1. A 49-year-old man with APC. The histogram showed that LVMRA and LVMA of the patient were 78.6 HU and 759 mm2, respectively. The shaded green area on the CT image represents the area of the left ventricle muscle with a density between 30 and 150 HU. CT examination before chemotherapy showed that the primary tumour was located in the tail of the pancreas (yellow triangle), and the patient had multiple metastases in the liver (not shown). After chemotherapy, the size of the pancreatic lesion had not changed much (yellow triangle), and the partial intrahepatic metastases were slightly larger than those before chemotherapy (not shown). The patient developed ascites after chemotherapy (red triangle). (b) Patient 2. A 60-year-old man with APC. The histogram showed that LVMRA and LVMA of the patient were 105.9 HU and 996 mm2, respectively. The shaded green area on the CT image represents the area of the left ventricle muscle with a density between 30 and 150 HU. CT examination before chemotherapy showed that the primary tumour was located in the tail of the pancreas (yellow triangle) and the patient had multiple metastases in the liver (green triangle). After chemotherapy, the size of the pancreatic lesion was smaller (yellow triangle) and intrahepatic metastases were smaller than those before chemotherapy (green triangle). Please cite this article as: Cai Q et al., Are left ventricular muscle area and radiation attenuation associated with overall survival in advanced pancreatic cancer patients treated with chemotherapy?, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.003

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shorter median PFS than those without distant metastasis (5.4 versus 9.9 months, p¼0.002, Fig 4e).

Table 1 Patient and tumour characteristics. Variables Gender Female Male Age (years) 65 >65 Hypertension Absent Present Tumour size (cm) 4 >4 CA19-9 (U/ml) 4000 >4000 CRP (ng/ml) 1.2 >1.2 Distant metastasis Absent Present Metastases within multiple different organs Absent Present Chemotherapy response PR SD PD

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n (%) 41 (41.8) 57 (58.2) 84 (85.7) 14 (14.3) 85 (86.7) 13 (13.3) 51 (52.0) 47 (48.0) 79 (80.6) 14 (19.4) 27 (27.6) 71 (72.4) 39 (39.8) 59 (60.2) 80 (81.6) 18 (18.4) 17 (17.3) 61 (62.2) 20 (20.5)

CA19-9, carbohydrate antigen 19-9; CRP, C-reaction protein; PR, partial response; SD, stable disease; PD, progressive disease.

Prognostic factors for OS and PFS in APC patients who underwent chemotherapy Table 2 shows the findings of the univariate and multivariate analyses of the factors associated with OS and PFS in APC patients who underwent chemotherapy. Multivariate logistic regression analysis showed that LVMA (912 versus >912 mm2: HR ¼ 0.447; 95% CI ¼ 0.223e0.896, p¼0.023), LVMRA (85.2 versus >85.2 HU: HR ¼ 0.494; 95% CI ¼ 0.295e0.829, p¼0.008), and the presence of metastases within multiple different organs at baseline CT (no versus yes: HR ¼ 3.125; 95% CI ¼ 1.684e5.797, p<0.001) were significant predictors of OS. The LVMRA (85.2 versus >85.2 HU: HR ¼ 0.543; 95% CI ¼ 0.345e0.854, p¼0.008) and presence of distant metastasis at baseline CT (no versus yes: HR ¼ 2.149; 95% CI ¼ 1.367e3.378, p¼0.001) were also significant predictors of PFS.

Association between CRP levels and OS/LVMRA As shown in Fig 5a, patients with low CRP levels had higher OS than patients with high CRP levels (16.5 versus 11.5 months, p¼0.045). Fig 5b shows that patients with low LVMRA had significantly higher CRP levels than those with high LVMRA (higher CRP%: low versus high LVMRA: 87.9% versus 64.6%, p¼0.015).

Figure 4 KaplaneMeier curves for OS and PFS. (a) Patients with low LVMRA had a significantly shorter median OS than those with high LVMRA (8.8 versus 14 months, p¼0.017). (b) Patients with low LVMA had a significantly shorter median OS than those with a high LVMA (12.2 versus 18.1 months, p¼0.038). (c) Patients without metastases within multiple different organs had a significantly higher median OS than those with metastases within multiple different organs (13.5 versus 7.3 months, p<0.001). (d) Patients with low LVMRA had a shorter median PFS than those with high LVMRA (4.9 versus 8.3 months, p¼0.032). (e) Patients with distant metastasis had a shorter median PFS than those without distant metastasis (5.4 versus 9.9 months, p¼0.002). Please cite this article as: Cai Q et al., Are left ventricular muscle area and radiation attenuation associated with overall survival in advanced pancreatic cancer patients treated with chemotherapy?, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.003

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Table 2 Univariate and multivariate analyses of prognostic factors for overall survival (OS) and progression-free survival (PFS) in unresectable/distant metastasis pancreatic cancer patients underwent chemotherapy. Characteristics

OS Univariate

p-Value Multivariate

Gender Female 0.005 Male Age 65 0.122 n.d. >65 Hypertension Absent 0.396 n.d. Present Tumour size (cm) 4 0.555 n.d. >4 LVMA (mm2) 912 0.043 1 (reference) >912 0.447 (0.223e0.896) LVMRA (HU) 85.2 0.019 1 (reference) >85.2 0.494 (0.295e0.829) CA19-9 (U/ml) 4000 0.032 n.d. >4000 CRP (ng/ml) 1.2 0.045 >1.2 Distant metastasis Absent 0.360 n.d. Present Metastases within multiple different organs Absent 0.001 1 (reference) Present 3.125 (1.684e5.797)

PFS

p-Value

Univariate

Multivariate

NS

0.08

n.d.

n.d.

n.d.

0.514

n.d.

n.d.

n.d.

0.842

n.d.

n.d

n.d.

0.875

n.d.

n.d.

0.023

0.267

n.d.

n.d.

0.008

0.031

1 (reference) 0.543 (0.345e0.854)

0.008

n.d.

0.665

n.d.

n.d.

NS

0.055

n.d.

n.d.

n.d.

0.022

1 (reference) 2.149 (1.367e3.378)

0.001

<0.001

0.003

NS

LVMA, left ventricular muscle area; LVMRA, left ventricular muscle radiation attenuation; CA19-9, carbohydrate antigen 19-9; CRP, C-reaction protein.

Association between LVMRA and chemotherapy response

Influence factors of LVMA/LVMRA

As shown in Fig 5c, the mean LVMRA was higher in the PR group than that in the SD and PD groups (mean LVMRA: PR versus SD: 99.34 versus 89.85 HU, p¼0.024; PR versus PD: 99.34 versus 88.22 HU, p¼0.028).

The correlation between LVMA and BMI was significantly positive (r¼0.422, p<0.001, Fig 6a) whereas that between LVMRA and BMI was significantly negative (r¼0.420, p<0.001, Fig 6b). Patients with a BMI <20 kg/m2

Figure 5 Association between LVMRA and chemotherapy response. (a) Patients with a high CRP level had a significantly shorter median OS than those with a low CRP level (16.5 versus 11.5 months, p¼0.045). (b) Patients with low LVMRA had a significantly higher CRP level than those with high LVMRA (higher CRP%: low versus high LVMRA: 87.9% versus 64.6%, p¼0.015). (c) Mean LVMRA was higher in the PR group than in the SD and PD groups (mean LVMRA: PR versus SD: 99.34 versus 89.85, p¼0.024; PR versus PD: 99.34 versus 88.22, p¼0.028). Please cite this article as: Cai Q et al., Are left ventricular muscle area and radiation attenuation associated with overall survival in advanced pancreatic cancer patients treated with chemotherapy?, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.003

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Figure 6 (a) LVMA positively correlated with a BMI (r¼0.422, p<0.001). (b) LVMRA negatively correlated with a BMI (r¼0.420, p<0.001). (c) Patients with a BMI <20 kg/m2 had a significantly lower LVMA than did those with a BMI 20 kg/m2 (724.9 versus 820.6 mm2, p¼0.012). (d) Patients with a BMI <20 kg/m2 had a higher LVMRA than did those with a BMI 20 kg/m2 (97.1 versus 87.9 HU, p¼0.004). * 0.01
had a significantly lower LVMA than did those with a BMI 20 kg/m2 (724.9 versus 820.6 mm2, p¼0.012, Fig 6c). Patients with a BMI <20 kg/m2 had a higher LVMRA than did those with a BMI 20 kg/m2 (97.1 versus 87.9 HU, p¼0.004, Fig 6d).

Male patients had a significantly higher LVMA than did female patients (836.3 versus 717.2 mm2, p¼0.001, Fig 7a). Further, male patients had a significantly lower LVMRA than did female patients (86.9 versus 97.1 HU, p¼0.001, Fig 7b). There was no significant difference in LVMA and

Figure 7 Male patients had a significantly higher LVMA than did female patients (836.3 versus 717.2 mm2, p¼0.001). (b) Male patients had significantly lower LVMRA than did female patients (86.9 versus 97.1 HU, p¼0.001). (c) There was no significant difference in LVMA between patients with and without diabetes. (d) There was no significant difference in LVMRA between patients with and without diabetes. ** 0.001
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LVMRA between patients with and without diabetes (Fig 7c, d).

Discussion The present study found that low LVMRA was associated with poorer OS and shorter PFS. In addition, LVMA was an independent prognostic factor for OS. Patients with partial response showed higher LVMRA. Cachexia was common during tumour progression, with 50e80% of cancer patients developing cachexia.14 Studies have shown that cachexia is responsible for decreased response to chemotherapy and poorer clinical outcome in different cancers.6e8 Some studies have also shown that the levels of multiple tumour progression-related inflammatory factors, such as tumour necrosis factor-alpha (TNF-a), are elevated in cachexia patients.20 TNF-a is a master regulator of inflammation and a key player in the cytokine network that can stimulate the production of other cytokines and promote tumour angiogenesis to cause chemoresistance.21 In addition, cachexia is often accompanied by weight loss and reduced food intake, which can decrease the dosage of chemotherapeutics.22 Thus, considering the same tumour burden, patients with weight loss would receive lower dosages of chemotherapeutics, and this may interfere with the chemotherapeutic effect. In general, cachexia is a complex multifactorial syndrome accompanied by various metabolic alterations and systemic inflammation, which work together to cause chemotherapy resistance and need to be studied further.23 Various studies have indicated that the skeletal muscle area and radiation attenuation obtained from CT were associated with chemotherapy response and OS in different cancers.9e11 As heart mass was more susceptible to cancer cachexia than skeletal muscle,12 the present study investigated whether cardiac muscle area and radiation attenuation measured using pre-chemotherapy CT were associated with therapeutic response and survival in APC patients receiving chemotherapy. The present study found that low LVMRA was associated with a shorter OS and PFS in APC patients, which was consistent with the results of previous studies in skeletal muscle.24,25 Low muscle radiation attenuation reflects the accumulation of intramuscular triglyceride, which contributes to muscle weakness in a sense.26 Intramuscular triglyceride accumulation has been shown to be correlated with heart failure,27 which was associated with poor clinical outcome. Moreover, low skeletal muscle radiation attenuation has also been reported to be associated with systemic inflammation, a hallmark of cachexia.28 Patients with low LVMRA had significantly higher CRP levels, which is associated with systemic inflammation.29 There is increasing evidence showing that systemic inflammation promotes tumorigenesis, favours angiogenesis, and enhances tumour spread, all of which are associated with a poor clinical outcome.30 In the present study, patients with high CRP levels had poorer OS than those with low CRP levels (Fig 5a), which was similar to the findings of a previous study.31

Interestingly, patients with a PR presented higher LVMRA (Fig 5c). These data indicate that LVMRA may predict response to chemotherapy in APC patients. In addition to LVMRA, low LVMA was associated with poor outcome in APC patients. The exact mechanism underlying the correlation between LVMA and OS in APC patients remains elusive. In the present study, LVMA only influenced the OS in APC patients, not PFS, suggesting that LVMA may not have a direct impact on tumour biology, but rather affected survival as a host factor. Cardiac muscle atrophy, which was assessed by low LVMA, can lead to muscular contractile dysfunction, causing abnormal energy homeostasis, impaired cell growth, and immune dysfunction, leading to decreased survival.32,33 Moreover, there was no significant difference in the mean LVMA among the PD, SD, and PR groups. Considering the above findings, LVMRA, rather than LVMA, could better predict both PFS and OS in APC patients who underwent chemotherapy. Moreover, the present study explored the correlation between BMI and LVMA/LVMRA. Congruent with previous research, the present study found that the correlation between LVMA and BMI was significantly positive, which suggested that cancer patients with low BMI had decreased LVMA13; however, the relationship between muscle density and BMI remains controversial. A previous study on skeletal muscle density and prognosis in pancreatic cancer patients found no correlation between skeletal muscle density at L3 and BMI25; however, the present study found that LVMRA and BMI had a significantly negative correlation. The different metabolic processes of the cardiac muscle and skeletal muscle led to different results. Hence, the relationship between LVMRA and BMI needs further study. It has been reported that there are a range of factors associated with low skeletal muscle density including male sex,34 type 2 diabetes mellitus,35 and systemic inflammatory response36; however, whether these factors also affect cardiac muscle density remains unclear. In the present study, male patients had a lower LVMRA than did female patients; this finding was similar to that in a previous study on skeletal muscle34; however, there was no significant difference in LVMA and LVMRA between patients with and without diabetes. This study had several limitations. First, there was a difference in the values of LVMA and LVMRA between male and female patients in the present study; however, due to the relatively small number of patients in our study, we did not classify them into those with low and high LVMA/ LVMRA according to the cut-off values for men and women respectively and further study is needed. Second, as this was a retrospective study conducted in a single institution, there could be selection and verification biases. Third, LVMA and LVMRA was measured only from a single axial section. Further volumetric analysis should be undertaken. Fourth, the present study did not explore whether LVMA and LVMRA changed between the pre-chemotherapy and posttreatment CT, which was worth further exploration in the future. Fifth, studies have shown that TNF-a is a key mediator of inflammatory response; however, as this was a retrospective study, TNF-a data of most patients could not

Please cite this article as: Cai Q et al., Are left ventricular muscle area and radiation attenuation associated with overall survival in advanced pancreatic cancer patients treated with chemotherapy?, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.003

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be obtained. Further studies could investigate the relationship between TNF-a and LVMRA. Nevertheless, detailed data were recorded and LVMRA was found to be able to predict both PFS and OS in APC patients who underwent chemotherapy. A prospective study would enable better evaluation of prognostic factors in APC patients who underwent chemotherapy. In conclusion, the present results suggested that LVMRA was associated with OS and PFS in APC patients receiving chemotherapy. Moreover, LVMA was a predictor of OS. Therefore, our study suggests that simple and rapid analysis of a single CT image may be valuable for pre-chemotherapy risk assessment in patients with APC.

Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Please cite this article as: Cai Q et al., Are left ventricular muscle area and radiation attenuation associated with overall survival in advanced pancreatic cancer patients treated with chemotherapy?, Clinical Radiology, https://doi.org/10.1016/j.crad.2019.11.003