The prognostic role of Controlling Nutritional Status (CONUT) scores in patients with gastrointestinal stromal tumors

Background: The Controlling Nutritional Status (CONUT) score is associated with the postoperative outcomes in various types of tumors. The relationship between the CONUT score and prognosis in patients with gastrointestinal stromal tumors (GISTs) needs to be clarified. Methods: Patients with completely resected primary GISTs in the absence of imatinib adjuvant therapy were included. Recurrence-free survival (RFS) was estimated with the Kaplan-Meier method and compared using log-rank test. Prognostic factors were compared using a Cox proportional hazards model. Results: A total of 455 patients were included. The median age was 57 years and 222 (48.8%) patients were male. The most common location was stomach (n= 219, 48.1%), the median tumor size was 4.5 cm (range 0.4-40.0) and the median mitotic index was 2/50 HPFs (range 0-200). Recurrence/metastasis developed in 92 (20.2%) patients. Patients were assigned to three groups: 219 (48.1%) were in normal nutrition group (CONUT=0-1), 196 (43.1%) were in light undernutrition group (CONUT=2-4) and 40 (8.8%) were in moderate-severe undernutrition group (CONUT≥5). Primary tumor site, tumor size, mitotic index, tumor rupture and CONUT score were independent prognostic factors for RFS using multivariate analysis (p<0.05). Conclusions: The CONUT score was an independent prognostic factor for patients with completely resected GIST.

high-risk GISTs [3]. Risk stratification of patients diagnosed with GISTs is an essential part of postoperative treatment. Currently, primary tumor location, tumor size, mitotic index, and tumor rupture are recognized worldwide as parameters for stratifying the recurrence risk of GISTs. Several prognostic classification criteria have been established, based on these parameters, to assess the risk of recurrence [2,4]. The prognostic role of some other parameters such as Ki-67 labeling index, p16 expression, age, and gender, are under investigation and remain controversial [5][6][7][8][9].
Preoperative conditions, particularly those affecting inflammatory or nutritional status, affect the clinical outcomes of patients with cancer [10][11][12]. Inflammatory markers, such as the neutrophil to lymphocyte ratio (NLR), the lymphocyte to monocyte ratio (LMR), and the platelet to lymphocyte ratio (PLR), have been introduced to predict the prognosis of various malignant tumors [11,[13][14][15][16][17]. Recently, immune-nutritional status measures, such as the prognostic nutritional index (PNI) and the Controlling Nutritional Status (CONUT) score, have been reported to be associated with postoperative prognoses in a number of cancer types [10][11][12][18][19][20][21]. However, little research has addressed the association between immune-nutritional status parameters assessed by the CONUT score and outcomes for GIST patients. To our knowledge, this is the first study reporting the prognostic role of the CONUT score for patients with GISTs.

Patients inclusion
Patients with localized primary GISTs treated between January 2000 and December 2013 at the First Affiliated Hospital, Zhejiang University School of Medicine, were included.
Diagnosis was based on a combination of histopathological evaluation and positive immunohistochemical staining for CD117 and/or DOG-1. Demographic and clinicopathologic information was collected, including patient age, gender, tumor location, tumor size, and mitoses. Tumor size was measured after 10% formalin fixation. Tumor mitoses were calculated as the number of mitoses per 50 high-power microscopic fields (HPFs). The risk of recurrence/metastasis was calculated using the modified NIH consensus criteria [4]. Preoperative blood samples were collected and assayed within 2 weeks prior to surgery.
The exclusion criteria were (1) presence of hematological disorders, (2) history of any other malignancy or concurrent malignancy, (3) evidence of multiple/metastatic GISTs prior to or during surgery, (4) prescription of neoadjuvant or adjuvant therapy, (5) preoperative parenteral nutrition or blood transfusion treatment prior to blood sample collection, (6) survival <1 month postoperatively, and/or (7) incomplete clinical and laboratory data.

Follow-up strategy
All patients were followed up every 3-6 months for the first 2 years, every 6-12 months for the next 3 years, and annually thereafter. Postoperative follow-up procedures included routine peripheral blood tests, abdominal enhanced computed tomography (CT), and endoscopy or abdominal magnetic resonance imaging (MRI), if necessary.

Statistical analyses
Categorical data were analyzed using chi-square tests. Continuous data were analyzed using Kruskal-Wallis tests. RFS time was calculated from surgery to tumor recurrence/metastasis; patients alive at the time of last follow-up and those who died for any reason without GIST recurrence/metastasis were censored. RFS were estimated using the Kaplan-Meier method and compared using log-rank tests. Prognostic factors were compared using Cox proportional hazards models. Only variables associated at p<0.05 in univariate analysis were entered into the multivariate model. All statistical analyses were performed using SPSS software ver. 19.0 (SPSS, Chicago, IL, USA). Two-sided p-values <0.05 were considered to reflect statistical significance.

Correlation between CONUT scores and clinicopathologic characteristics
The relationships between CONUT scores and clinicopathologic characteristics are summarized in Table 2. Only four patients scored over 9, indicating severe undernutrition.
We combined their data with those exhibiting moderate undernutrition to form a moderate-severe undernutrition group (CONUT≥5) for analysis, as in a previous report [24].

Survival analysis, univariate and multivariate analyses
The last patient follow-up was completed in June 2019. Median follow-up time was 110.0 months (range 7.0-232.0 months). Recurrence/metastasis developed in 92 patients (20.2%). Overall, the 5-year and 10-year RFS rates were 84.2% and 79.1%, respectively.

Discussion
Tumor progression has been shown to be affected not only by the malignant features of tumor cells themselves but also by the immunological and nutritional status of the patient [25]. Various types of blood sample-derived biomarkers that can simply and inexpensively predict postoperative survival in tumor patients have been introduced; these include systemic inflammatory response indicators, such as NLR and PLR, and, more recently, immune-nutritional status measure, such as PNI and CONUT [10][11][12][13][14][15][16][17][18][19][20][21].
PNI is calculated from serum albumin and total peripheral lymphocyte counts. Serum albumin concentration is known to be a reliable indicator of both nutritional status and systemic inflammation [26]. However, it has also been reported to be easily influenced by changes in body fluid volume, such as those due to dehydration/fluid retention status, as well as by inflammation caused by chronic disease [27,28]. Total peripheral lymphocytes, which play an important role in the immune response to tumors, are known to indicate immunological and nutritional status [29]. A decrease in T-lymphocytes has been reported to correlate with poor prognosis, due to an inadequate immune response to cancer [30,31].
Total cholesterol concentration is an indicator of a patient's caloric reserves [32].
Cholesterol, an essential component of the cell membrane, is involved in numerous biochemical pathways potentially correlated with cancer initiation and progression, as well as in immune responses. Low serum cholesterol levels were reported to be associated with poorer prognosis in patients with various cancers [27,[33][34][35]. A more accurate evaluation may be obtained by reducing the importance of serum albumin concentration in the evaluation criteria, and including the consideration of total cholesterol [23].
CONUT scoring is a nutritional evaluation system that is easy to calculate from serum albumin, total lymphocyte count, and total cholesterol. First reported by Ignacio et al., it is useful for evaluating the nutritional and immune status of patients [23]. Undernutrition is a complex state, and the CONUT score enables evaluation of its different aspects: the patient's protein reserve, calorie depletion, and immune defenses. The CONUT score can reflect immunological and nutritional status, and may serve as a good immuno-nutritional marker, calculated from inexpensive and objective laboratory assays.
CONUT has proven to be a promising scoring system for predicting outcomes in cancer patients undergoing surgery [18,19,21,22]. However, no study has assessed the relationship between CONUT score and clinical outcome for GISTs. The present study has shown that recognized parameters such as primary tumor location, tumor size, mitotic index, and tumor rupture are effective for stratifying the recurrence risk of GISTs, and that the CONUT score is another independent scoring system that can predict outcomes in patients receiving complete GIST resection. Moderate-severe undernutrition (CONUT ≥5) was most likely to be seen in male patients, with non-gastric, larger GISTs. These patients suffered from hypoalbuminemia, lymphocytopenia, and hypocholesterolemia, preoperatively. CONUT ≥5 was significantly associated with poorer prognosis. Although these patients made up a relatively small fraction (8.8%) of the study cohort, they are worthy of attention. In clinical practice, patients with high CONUT scores should receive more effective adjuvant therapy, and a shortened follow-up interval. Furthermore, considering the promising results of targeted nutritional intervention, patients with high CONUT scores may benefit from preoperative nutritional interventions [36][37][38].
To our knowledge, this is the first study to show that the CONUT score is an independent prognostic factor for GIST patients receiving complete resection. Based on our findings, the preoperative CONUT score may be useful in the stratification of risk and in tailoring individualized treatments for GIST patients.
The present study has some limitations. First, this was a single-institution, retrospective study, and the number of cases was limited. Second, potential factors that affect inflammation-based and nutritional markers could not be excluded absolutely. Third, there is the potential for selection bias in the inclusion of patients in this study. With these limitations, the present study demonstrated that the CONUT score is a promising prognostic factor. Large-scale prospective validation studies are needed to confirm these findings.

Conclusions
The CONUT score was independently associated with RFS in patients with GIST undergoing complete resection. The estimation of the CONUT score is inexpensive and easily performed using available laboratory data from daily clinical practice; it may be useful for treatment decision-making and improving follow-up performance.

Declarations
Ethics approval and consent to participate: This study was approved by the institutional ethics committee of the First Affiliated Hospital, Zhejiang University School of Medicine (No. 2013-280). The consent obtained from the participants was verbal whic was approved by the ethics committee.

Availability of data and materials:
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Competing interests:
Authors have no conflict of interest to declare.   Figure 1 Recurrence-free survival by CONUT scores from univariable analysis. CONUT: Controlling Nutritional Status