Usefulness of the cachexia index as a prognostic indicator for patients with gastric cancer

Abstract Aim Cachexia is associated with the morbidity and mortality of cancer patients. The cachexia index (CXI) is a novel biomarker of cachexia associated with the prognosis for certain cancers. This study analyzed the relationship between CXI with long‐term outcomes of gastric cancer patients. Methods We included 175 gastric cancer patients who underwent curative gastrectomy at our hospital between January 2011 and October 2019. The CXI was calculated using skeletal muscle index, serum albumin level, and neutrophil‐to‐lymphocyte ratio. The prognostic value of CXI was investigated by univariate and multivariate Cox hazard regression models adjusting for potential confounders. Results In the multivariate analyses, tumor location (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.11–0.49; p < 0.01), disease stage (HR, 15.4; 95% CI, 4.18–56.1; p < 0.01), and low CXI (HR, 2.97; 95% CI, 1.01–8.15; p = 0.03) were independent and significant predictors of disease‐free survival. Disease stage (HR, 9.88; 95% CI, 3.53–29.1; p < 0.01) and low CXI (HR, 4.07; 95% CI, 1.35–12.3; p < 0.01) were independent and significant predictors of overall survival. The low CXI group had a lower body mass index (p = 0.02), advanced disease stage (p = 0.034), and a lower prognostic nutritional index (p < 0.01). Conclusions Cachexia index is associated with a poor prognosis for gastric cancer, suggesting the utility of comprehensive assessment using nutritional, physical, and inflammatory status.


| INTRODUC TI ON
Gastric cancer is the fourth most prevalent malignancy worldwide and the second leading cause of cancer-related deaths. 1 Although advances in treatment have improved the prognosis of early-stage cancer, 2 advanced cancer still has a high recurrence rate and a poor prognosis. 1 Therefore, the investigation of preoperative biomarkers to predict therapeutic outcomes is critically important for clinical decision-making.
Cancer cachexia, a multifactorial syndrome defined as ongoing loss of skeletal muscle mass with or without a decrease in fat mass, is associated with approximately 30% of cancer-related deaths. 3 It is also characterized by systemic inflammation, progressive weight loss, and malnutrition that cannot be fully evaluated by one of these components due to its complexity. Recently, a new parameter called the cachexia index (CXI) 4,5 has been proposed and is gaining recognition as a potentially comprehensive measure of the state of cachexia.
The CXI is composed of parameters such as the skeletal muscle index (SMI), serum albumin level, and neutrophil-to-lymphocyte ratio (NLR). Further, the CXI has been reported to be able to predict the prognosis for several malignancies. 5,6 However, the utility of the CXI as a prognostic factor in gastric cancer patients has not been reported. Therefore, we here investigated the prognostic value of the CXI in gastric cancer patients.

| Patients
In this study, all patients who underwent laparoscopic or robotic gastrectomy at the Department of Surgery, International University of Health and Welfare Hospital between January 2011 and October 2019 were included in the study. Patients with remnant gastric cancer and locally advanced unresectable tumors were excluded and the remaining 175 eligible patients were enrolled in this study. We retrospectively collected clinical and laboratory data, including computed tomography (CT) scan results, using the hospital's electronic patient record system.

This study was approved by the appropriate Research Ethics
Committee at the International University of Health and Welfare Hospital (approval no. 22-B-7) and was conducted in accordance with the Declaration of Helsinki. The requirement for informed consent was waived considering the study design and anonymization of data.

| Treatment and follow-up
Distal or total gastrectomy was performed as the standard procedure. Gastrectomy was performed with D1 plus lymph node dissection for early gastric cancer, and D2 lymph node dissection for advanced cancer. Tumor-node-metastasis (TNM) classification was quoted from the latest version of the Japanese Classification of Gastric Carcinoma (the 5th edition). 7 Postoperative complications were defined as grade III of Clavien-Dindo classification or higher that occurred within 30 postoperative days. Patients with stage II or III received adjuvant chemotherapy according to the Japanese gastric cancer treatment guidelines, 8 if the general condition was judged to be tolerated. The patients were followed up every 3 months to check for the recurrence by performing blood tests, including those for tumor markers, after the operation.
Moreover, CT was performed at least every 6 months after the operation.

| CXI and nutritional assessment
The CXI was calculated as follows: SMI × serum albumin level (g/dL) / NLR. 5,6 In this equation, based on a previously described method, to calculate the SMI we used the minor and major diameters of the right iliopsoas muscle of the L3 vertebra level, which were measured using preoperative CT. 6 The SMI was calculated as follows: iliopsoas minor axis (cm) × major axis (cm) × / height squared (cm 2 / m 2 ). 9,10 The cutoff values of SMI and CXI were determined by a receiver-operating characteristic curve using the survival status at the 3-year follow-up in strata of sex, considering the differences in the skeletal muscle between males and females. According to the cutoff values, all the patients were divided into the low and high CXI groups. The NLR was defined as the neutrophil count divided by the lymphocyte count. 11,12 The Prognostic Nutritional Index (PNI) was calculated as 10 × serum albumin level (g/dL) + 0.005 × lymphocyte count. 13 The cutoff values of albumin and PNI were determined by a receiver-operating characteristic curve using the survival status at the 3-year follow-up.

| Statistical analysis
All statistical analyses were performed using STATA version 14 (Stata Corporation). All p-values were two-sided, and we used the two-sided α level of 0.05. The data are expressed as medians, ranges, and ratios. Continuous and categorical variables were compared using the Mann-Whitney U-test or chi-square test, as appropriate. The endpoint, which was overall survival (OS), was defined as time from the date of surgery until the date of death from any cause or the last follow-up date for the living patients.
Disease-free survival (DFS) was defined as time from the date of surgery to the date of gastric cancer relapse, the last follow-up date, or death.
Univariable and multivariable Cox proportional hazards regression models were conducted to estimate hazard ratio (HR) and 95% confidence intervals (CIs) for DFS and OS. A multivariate analysis was performed for factors with p < 0.05 in the univariate analysis.
The Kaplan-Meier method was used to estimate cumulative survival probabilities, and the differences between groups were compared using the log-rank test.

| DISCUSS ION
In this study, we found that a low CXI was associated with worse survival of gastric cancer patients. Notably, this survival association was consistent in both early and advanced stage of gastric cancer. Our results suggest the importance of assessing cancer cachexia even in the early stage. Moreover, CXI may help to evaluate cancer cachexia comprehensively and provide better predictive value for long-term outcomes.
Cancer cachexia is a syndrome characterized by reduction of muscle mass and anorexia, which is frequently seen in patients with advanced cancer. It has been proposed that inflammatory cytokines produced by tumors have a profound effect on cachexia. An increase in interleukin-6 or tumor necrosis factorα causes loss of appetite, muscle atrophy, and increased energy consumption that leads to cachexia. Several studies have suggested that myokines produced by skeletal muscles might have anti-cancer effects. 14,15 Therefore, decreased myokine levels caused by cancer cachexia might be associated with a poor prognosis. Cachexia has also been associated with reduced chemotherapeutic effects, increased side effects, and treatment interruptions, resulting in poor outcome in cancer patients. 16,17 In this study, 49% of early gastric cancer patients showed low CXI. Abbreviations: HR, hazard ratio; CI, confidence interval; CEA, carcinoembryonic antigen; CA19-9, carbohydrate antigen 19-9; SMI, skeletal muscle mass index; PNI, prognostic nutritional index; NLR, neutrophil-to-lymphocyte ratio; CXI, cachexia index.  We acknowledge the potential limitation of this study. This study was principally limited by its small sample size and single-center retrospective design, which might have caused a selection bias. In addition, the cut-off value of CXI was determined using data from a single center, which may lack generalizability. Therefore, although this is the first study to investigate the relationship between the CXI findings and clinical outcomes in gastric cancer patients, our findings need to be validated by large-scale studies.
In conclusion, the CXI might be a valuable factor for predicting the DFS and OS of gastric cancer patients. Our results suggest the utility of comprehensive assessment using nutritional, physical, and inflammatory status in gastric cancer patients.

AUTH O R CO NTR I B UTI O N S
KN and KH developed the main concept and designed the study.

ACK N OWLED G M ENTS
None.

JP21K08805 and by research grants from the Uehara Memorial
Foundation and Japanese Foundation for Multidisciplinary Treatment of Cancer.

CO N FLI C T O F I NTE R E S T
The authors declare that they have no conflicts of interest.