Sarcopenia is associated with an increased inflammatory response to surgery in colorectal cancer

doi:10.1016/j.clnu.2015.07.005

Clinical Nutrition

Volume 35, Issue 4, August 2016, Pages 924-927

https://doi.org/10.1016/j.clnu.2015.07.005 Get rights and content

Summary

Background & aims

Sarcopenia in gastrointestinal cancer has been associated with poor clinical outcome after surgery. The effect of low muscle mass on the inflammatory response to surgery has not been investigated, however skeletal muscle wasting in the context of cachexia is associated with a hyperinflammatory state at baseline. Knowledge on this matter can provide new insight into the detrimental effects of sarcopenia on postoperative recovery, possibly leading to novel therapeutic strategies. The aim of this study was to evaluate whether low muscle mass is associated with increased inflammation after resection of colorectal malignancies.

Methods

Eighty-seven consecutive patients undergoing elective resection of a primary colorectal tumor were enrolled. Muscle mass was assessed on routine preoperative computed tomography (CT) scans using image analysis by Osirix^® by measuring skeletal muscle at the third lumbar vertebra (L3) level. The effect of muscle mass on pre- and postoperative plasma concentrations of C-reactive protein (CRP), calprotectin and interleukin-6 (IL-6) was analyzed. Clinical outcome was assessed by HARM (HospitAl stay, Readmission, and Mortality) scores.

Results

Skeletal muscle mass was not predictive of plasma concentrations of CRP and IL-6. However, low skeletal muscle mass was significantly predictive of high plasma concentrations of calprotectin on postoperative days (POD) 2 through 5, reaching highest significance on POD4 (regression beta, −6.06; 95% confidence interval, −10.45 to −1.68; p = 0.007).

Conclusions

Low muscle mass in patients undergoing surgery for colorectal cancer was associated with an increased postoperative inflammatory response. This may be at least part of the explanation for the high incidence of postoperative complications in sarcopenic patients.

Introduction

Frailty in cancer patients has been associated with poor clinical outcome after colorectal surgery [1], [2], [3]. The syndrome of frailty is a state of increased vulnerability towards stressors, leading to an increased risk of developing adverse health outcomes [4]. The definitions and biological characteristics of frailty are subject to debate, however weight loss and skeletal muscle wasting are well accepted as prominent features of frailty. Indeed, skeletal muscle wasting or sarcopenia is associated with prolonged length of hospital stay and postoperative infections after colorectal surgery and negatively affects cancer outcomes following resection of colorectal liver metastases [5], [6].

The mechanism by which sarcopenia is associated with impaired postoperative outcome is unknown. A hyperinflammatory response to surgery can be postulated. Although differences in inflammatory response to surgery between sarcopenic and non-sarcopenic patients have not been investigated, skeletal muscle wasting in the context of cachexia is associated with a hyperinflammatory state at baseline [7], [8]. Increased inflammatory responses may decrease wound healing and lengthen hospital stay. Moreover, in colorectal surgery impaired wound healing of the gut may manifest as anastomotic leakage, involving significant mortality and health care costs.

This study evaluated whether low muscle mass was associated with increased inflammation after resection of colorectal malignancies by measuring inflammatory markers in plasma.

Section snippets

Patients and sample collection

Patients who underwent colorectal surgery at Maastricht University Medical Center, Maastricht, The Netherlands and Orbis Medical Center, Sittard-Geleen, The Netherlands were eligible for inclusion in this prospective observational study during the period from January 2011 to September 2013. The study was approved by the medical ethical committee of Maastricht University Medical Center and conducted according to the revised version of the Declaration of Helsinki (October 2008, Seoul). The

Patients

Eighty-seven patients were enrolled, of whom 56 were males. Mean age was 65.6 (SD, 11.9) years. Mean L3 index was 50.5 (7.6) cm²/m² in men and 39.7 (5.2) cm²/m² in women. General characteristics of patients were listed in Table 1.

CRP

The interaction term of L3 index and time showed significance of p = 0.20 in predicting CRP concentrations. However, average marginal effects showed no significant regression coefficients of L3 index and CRP concentrations at any time point.

Calprotectin

The interaction term of L3

Discussion

This study showed an increased inflammatory response in patients with low skeletal muscle mass after colorectal surgery as measured by plasma concentrations of calprotectin. Calprotectin is a heterodimeric peptide (36 kDa) constituting 60% of the cytosolic content of neutrophils and is released from neutrophils upon activation, which indicates importance in wound/suture healing [12]. The current results suggested that activation of this cell type was disturbed in sarcopenic patients, which may

Conflict of Interest

None.

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COVID-19 survivors experiencing high muscle mass loss during hospital stay fail to fully recover muscle health. In addition, greater muscle loss was associated with a higher frequency of post-acute sequelae of SARS-CoV-2 and greater total COVID-19-related health care costs 2 and 6 months after discharge. Altogether, these data suggest that the loss of muscle mass resulting from COVID-19 hospitalization may incur in an economical burden to health care systems.
Sarcobesity Index Predicts Poor Disease-Specific Survival After Resection for Colorectal Cancer
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We retrospectively analyzed 506 patients with stage I–III CRC who underwent surgery between January 2010 and December 2019. Preoperative computed tomography images were analyzed and the sarcobesity index (SI) was calculated for each patient as the VAT/SMA ratio. The optimal cutoff value for predicting survival was determined using time-dependent receiver operating characteristic analysis. Overall survival and disease-specific survival (DSS) were compared between SO (SI > 1.25) and non-SO (SI ≤ 1.25) patients. The rates and modes of recurrence were also compared between the two groups.
Three hundred (59.3%) patients were identified to be sarcobese. No differences in short-term outcomes and administration of adjuvant chemotherapy were found, except for a longer length of stay in patients with SO. In a univariable analysis, SO was associated with a worse 5-y overall survival and DSS, considering the whole population and stages II and III separately. A multivariable analysis confirmed SO to be an independent risk factor for DSS (hazard ratio 2.29; 95% confidence interval 1.13-4.62, P = 0.02). Although the overall recurrence rate did not differ between the groups, a significantly higher rate of recurrence at multiple sites was observed in patients with SO (P = 0.01).
The SI, defined as per the VAT/SMA ratio, seems to be a reliable tool for identifying patients with worse DSS after potentially curative surgery for stage I-III CRC.
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Citation Excerpt :
IL-6 and TNF-α are associated with the loss of muscle mass in older men and women [28]. However, the significant association of IL-6 or TNF-α with sarcopenia was not identified in later studies, especially in cancer patients [13,16,29,30]. On the other hand, TNF-α was reported to be associated with chemotherapy [31] or cancer-induced sarcopenia [30].
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We used the %FINDCUT SAS macro to determine the cutpoints of the skeletal muscle index (SMI) to define sarcopenia in colorectal cancer patients. Immunohistochemical staining was performed to detect high and low IL-23 expression in cancer samples. Clinicopathological features were also recorded. The prognosis of the 5-year disease-free survival and overall survival were analyzed using univariate and multivariate methods.
A total of 114 patients with colorectal cancer were enrolled. The mean age was 63.2 years. Forty-six (40%) patients were female. Sarcopenia was defined as less than 50 cm²/m² for men and 32 cm²/m² for women and 52(46%) patients were defined as having sarcopenia. Sarcopenia was significantly associated with poor 5-year disease-free survival and overall survival (p = 0.003 and p = 0.001, respectively). Multivariate adjustment demonstrated that sarcopenia was an independent predictor of the 5-year disease-free survival (hazard ratio = 1.827, p = 0.024) and overall survival (hazard ratio = 3.669, p < 0.001). A lower SMI was detected in patients with high IL-23 expression (p = 0.045). After grouping the patients with sarcopenia and IL-23 expression, the patients with sarcopenia and high IL-23 expression had the worst disease-free survival (p = 0.013) and overall survival (p = 0.007).
This is the first study to explore the significant association between IL-23 expression and sarcopenia in colorectal cancer. Sarcopenia combined with IL-23, as an inflammatory marker, significantly predicted poor survival.
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Sarcopenia, a multi-faceted skeletal muscle disorder in the older population, has poor health outcomes. Some previous observational studies investigated the association between circulating inflammatory markers and sarcopenia components to evaluate chronic inflammation as a risk factor for sarcopenia in the elderly population. Nevertheless, the association between circulating C-reactive protein (CRP) and hs-CRP, as the recognized markers of systemic inflammation and components of sarcopenia, is unclear. This meta-analysis aimed to investigate the association of muscle strength, muscle mass, and muscle function with two serum inflammatory markers, circulating C-reactive protein (CRP) and high-sensitive CRP (hs-CRP).
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Sarcopenia is a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength with or without increased fat mass and is a risk factor for adverse outcomes such as physical disabilities, poor quality of life, and death.7–10 Recent studies have reported that sarcopenia increases postoperative complications or decreases overall survival (OS) in gastrointestinal malignancies.11–14 Sarcopenic obesity (SO), a concept derived from sarcopenia, represents a high visceral adipose tissue-to-skeletal muscle ratio.15
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Original articleSarcopenia is associated with an increased inflammatory response to surgery in colorectal cancer

Summary

Background & aims

Methods

Results

Conclusions

Introduction

Section snippets

Patients and sample collection

Patients

CRP

Calprotectin

Discussion

Conflict of Interest

Am J Surg

Am J Surg

Clin Nutr

Clin Nutr

Lancet

Lancet

Clin Nutr

J Visc Surg

Clin Nutr

Crit Rev Oncol Hematol

Functional compromise reflected by sarcopenia, frailty, and nutritional depletion predicts adverse postoperative outcome after colorectal cancer surgery

Ann Surg

From bedside to bench: research agenda for frailty

Sci Aging Knowledge Environ

Sarcopenia is associated with postoperative infection and delayed recovery from colorectal cancer resection surgery

Br J Cancer

Body composition and outcome in patients undergoing resection of colorectal liver metastases

Br J Surg

Original article
Sarcopenia is associated with an increased inflammatory response to surgery in colorectal cancer