Abstract
Background/Aim: Recently, preoperative inflammatory, immune, and nutritional statuses have attracted attention as prognostic factors in post-curative gastrectomy patients with gastric cancer (GC). The usefulness of the C-reactive protein-albumin-lymphocyte (CALLY) index as a prognostic factor in patients with various cancers, has been reported. However, reports on the clinical significance of the CALLY index in patients with GC after gastrectomy remain inadequate. In this prospective study, we focused on the preoperative CALLY index and investigated its usefulness as a prognostic factor in patients with GC. Patients and Methods: This study included 459 patients who underwent gastrectomy for GC between December 2013 and November 2017 at Kanagawa Cancer Center, Kanagawa, Japan. The preoperative CALLY index was calculated based on the preoperative blood test data. Patients were divided into high- and low-CALLY groups. The associations of the preoperative CALLY scores with clinicopathological factors, overall survival (OS), and recurrence-free survival (RFS) after gastrectomy for GC were evaluated. Results: The low-CALLY group was significantly older, had higher venous invasion, and a more progressive pStage than did the high-CALLY group. OS and RFS after gastrectomy in the low-CALLY group were significantly worse than those in the high-CALLY group (77.9% vs. 88.9%; p<0.001 and 73.8% vs. 87.1%; p<0.001, respectively). In the multivariate analysis, a low CALLY score was an independent prognostic factor of worse OS and RFS. Conclusion: Preoperative CALLY levels may be a useful prognostic predictor in patients with GC after curative gastrectomy.
Gastric cancer (GC) ranks fifth in terms of new cancer cases and third in terms of cancer-related deaths, worldwide (1). Despite recent advances in treatment modalities, such as endoscopy, surgery, and chemotherapy, the outcomes of patients with GC remain poor (2). Therefore, from a clinical perspective, a simple prediction of post-treatment prognosis using pre-treatment blood tests may facilitate planning of nutritional therapy, surgery, and chemotherapy and may improve the outcomes of cancer treatment. Preoperative inflammation, immunity, and nutritional status have recently received increased attention in relation to cancer outcomes and prognosis, and although various tools have been reported for nutritional and inflammatory status assessment (3-12), further exploration of new nutritional and inflammatory status metrics for patients with GC is warranted.
The C-reactive protein (CRP)-albumin-lymphocyte index (CALLY) was first reported by Iida et al. as a combined measure of immune function, inflammation, and nutritional status, and is a useful prognostic biomarker for patients with hepatocellular carcinoma (HCC) (13). To date, the prognostic potential of the CALLY has been reported for several cancer types (14-16). However, the use of preoperative CALLY as a prognostic factor in patients with GC who have undergone gastrectomy has rarely been reported (17).
Therefore, the purpose of this study was to determine the prognostic impact of preoperative CALLY, determined using preoperative and perioperative blood tests in patients with GC who were scheduled for radical surgery.
Patients and Methods
Institutional Review Board Statement. This prospective study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Kanagawa Cancer Center (approval number: 25Research-20) before study initiation. Prior to surgery, written informed consent was obtained from each patient for the use of anonymized clinical data.
Patients. Between December 2013 and November 2017, 459 patients with GC were enrolled. The registration criteria were as follows: i) GC proven by pathological diagnosis, ii) gastrectomy, achieving R0 resection, with radical lymph node resection as the initial treatment for GC, iii) age>20 years, and iv) Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. In principle, pStage II patients received S-1 monotherapy, while pStage III patients received S-1 plus docetaxel or capecitabine plus oxaliplatin therapy, for one year.
Analysis of the associations of CALLY scores with clinicopathological factors and survival. CALLY scores were calculated using the preoperative blood test data, as follows:
The cutoff value of 3.28 was determined by receiver operating characteristic (ROC) curve analysis. Patients with GC were divided into high- and low- CALLY groups based on this cutoff value. We analyzed the associations between CALLY and clinicopathological factors and survival.
Statistical analyses. Continuous variables are presented as mean and standard deviation and were analyzed nonparametrically using the Mann-Whitney U-test. Categorical variables were compared using the χ2 test or Fisher’s exact test, as appropriate. Overall survival (OS) and recurrence-free survival (RFS) were evaluated using the Kaplan-Meier method and log-rank tests. Variables identified as significant (p<0.05) in univariate analysis were considered candidates for multivariate COX regression analysis, and results are presented as hazard ratios (HRs) with 95% confidence intervals (CIs). Statistical significance was set at p<0.05.
All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (R Foundation for Statistical Computing, Vienna, Austria).
Results
Relationship between CALLY and clinicopathological factors. Table I shows the relationship between preoperative CALLY scores and clinicopathological factors in patients with GC. Overall, 459 patients with GC were divided into high-(n=362) and low-CALLY score (n=97) groups according to their preoperative CALLY scores (Table I). Patients in the low-CALLY group were older (p=0.018), had more venous invasion (p=0.036), and were more likely to be pStage II/III (p=0.019) than were those in the high-CALLY group.
Clinicopathological comparisons between low- and high-CALLY score groups.
Relationship of CALLY scores with OS and RFS. The 5-year OS of the low-CALLY score group was significantly worse than that of the high-CALLY score group (77.9% vs. 88.9%, p<0.001) (Figure 1). Similarly, the 5-year RFS of the low-CALLY score group was significantly worse than that of the high-CALLY score group (73.8% vs. 87.1%, p<0.001) (Figure 2).
Kaplan-Meier 5-year overall survival (OS) curve according to CALLY score. The OS of the low-CALLY score group is significantly lower than that of the high-CALLY score group.
Kaplan-Meier 5-year relapse-free survival (RFS) according to CALLY score. The RFS of the low-CALLY score group is significantly lower than that of the high-CALLY score group.
Univariate and multivariate analyses of survival. Table II and Table III show the results of univariate and multivariate analyses of OS and RFS in patients with GC who underwent curative resection. On the multivariate analyses, pStage (HR=2.59, 95%CI=1.35-4.97, p=0.004), and CALLY scores (HR=1.96, 95%CI=1.19-3.23, p=0.008) were independent prognostic factors predicting OS (Table II). Furthermore, on the multivariate analyses, lymphatic invasion status (HR=1.86, 95%CI=1.11-3.13, p=0.02), pStage (HR=2.42, 95%CI=1.33-4.40, p=0.004), and CALLY (HR=1.69, 95%CI=1.06-2.70, p=0.03) were independent prognostic factors predicting RFS (Table III).
Univariate and multivariate analyses of clinicopathological factors and preoperative CALLY for overall survival.
Univariate and multivariate analyses of clinicopathological factors and preoperative CALLY for relapse-free survival.
Discussion
Peri-treatment immune and nutritional statuses have attracted attention as prognostic factors for patients with cancer (18, 19). CALLY is a novel inflammatory nutrition-related indicator in patients with various cancers (14-16). However, the usefulness of the CALLY as a prognostic predictor in patients with GC has not been adequately studied. Hence, in this study, we investigated the usefulness of the CALLY as a novel prognostic factor in patients with GC after surgery. Survival analysis showed that the OS and RFS in the low-CALLY score group were significantly worse than those of patients in the high-CALLY score group. In addition, the CALLY was shown to be an independent prognostic factor impacting OS and RFS.
The usefulness of the CALLY as a prognostic predictor in patients with various cancers has been reported. In particular, after transarterial chemoembolization, HCC patients with low CALLY scores had significantly worse median OS than did those with high CALLY scores. Furthermore, multivariate analysis showed that the CALLY is an independent prognostic factor in OS of these patients (20). In non-small cell lung cancer, patients with low CALLY scores had significantly worse OS than did those with high CALLY scores. In that study, multivariate analysis showed that the CALLY was an independent risk factor for prognosis (21). An observational study of 1396 patients with colorectal cancer (CRC) showed that the CALLY was an independent prognostic factor for OS (22). These reports support the results of the present study.
It is hypothesized that the mechanism by which the CALLY is a useful prognostic factor for patients with GC after curative resection may be its composition of CRP, albumin, and lymphocytes, which are associated with inflammatory, immunological, and nutritional status (18, 19, 23-25). The CRP level is associated with inflammation (26). In cancer patients, higher CRP levels indicate higher levels of cytokines and chemokines associated with angiogenesis, cancer progression, and metastasis (27). Several CRP-related prognostic markers have been reported in patients with GC after surgery (28, 29). On the other hand, albumin levels are associated with nutritional status (30). Several albumin-based prognostic factors have been reported to be useful for the assessment of nutritional status in patients with GC (31-33). Further, inflammation play a critical role in antitumor immune functions and can support the cancer cells by the signals within the cancer microenvironment (18). In patients with GC, the nutritional index, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio have been reported to be prognostic factors in combination with lymphocytes (4).
From a clinical point of view, the CALLY is a simple and useful indicator that can be calculated from preoperative blood tests of patients with GC. In addition, the preoperative use of the CALLY may predict a poor prognosis in patients with compromised nutritional and immunological statuses. Thus, aggressive nutritional therapy (34), neoadjuvant chemotherapy (35, 36), or more aggressive adjuvant chemotherapy (37) may be considered for this population with a low CALLY score and associated poor prognosis.
Study limitations. First, this was a single-center study. Prospective multicenter studies are required to determine the usefulness of the CALLY. Second, few reports have described the CALLY as a prognostic factor, and the optimal cutoff value remains unknown. Therefore, determining a clinically relevant cutoff for the CALLY requires further investigation.
Conclusion
Preoperative CALLY scores may be a useful prognostic predictor in patients with GC who have undergone curative surgery. In particular, nutritional and perioperative chemotherapy should be considered in patients with a low CALLY score.
Acknowledgements
The Authors thank all patients, their families, and the site staff for their participation in this study.
Footnotes
Authors’ Contributions
IH and TO contributed to the study concept and design. Data collection and literature searches were performed by IH, MT, SO, JO, SN, YM, KK, TA, TY, NY, AS, YR, T. Ogata, and TO. Data were analyzed by IH and TO. All investigators interpreted the data. The article and figures were drafted by IH and TO. The article has been revised and approved by all the investigators. All Authors actively participated in this study.
Conflicts of Interest
The Authors declare that they have no conflicts of interest in relation to this study.
- Received November 24, 2023.
- Revision received December 27, 2023.
- Accepted December 28, 2023.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
