Abstract
Background: The usefulness of the controlling nutritional status (CONUT) score for preoperative nutritional assessment has been reported in resected colorectal and esophageal cancer, but not in lung cancer with obstructive lung disease. Patients and Methods: We retrospectively reviewed 109 patients with adenocarcinoma with obstructive pulmonary disease. We set 1 as the cut-off value for the CONUT score and classified patients into high (≥1) and low (0) CONUT groups. Results: Among 109 patients, 35 (32.1%) had low CONUT scores, and 74 (67.8%) had high CONUT scores. The high-CONUT group was significantly associated with a lower body mass index (p=0.025) and wild-type epidermal growth factor receptor mutation status (p=0.011). A multivariate analysis showed that the CONUT score was independently associated with disease-free and overall survival. Conclusion: The results of this study suggest that the CONUT score was an independent prognostic factor for disease-free and overall survival in patients with lung adenocarcinoma with obstructive lung disease.
- Controlling Nutritional Status (CONUT)
- lung cancer
- surgery
- disease-free survival
- overall survival
- obstructive lung disease
Lung cancer is the most common cancer worldwide and has a devastating prognosis (1). Although surgical procedures, chemotherapies and molecular-targeted therapies for lung cancer have improved, the clinical outcome remains poor. Therefore, various prognostic factors have been studied. One such factor that has recently attracted substantial attention is the nutritional and immunological status, which is closely related to the survival of patients with malignant disease (2). Not only sarcopenia, body mass index (BMI) and changes in body weight, but also the prognostic nutritional index have been reported to affect the surgical outcomes of lung cancer (3-5). The prognostic nutritional index (PNI), which is calculated from the serum albumin concentration and total peripheral lymphocyte count, has also been reported to be associated with the survival in patients with lung cancer (6-8). We previously reported that the PNI was useful for predicting the risk of postoperative recurrence in patients with stage I non-small cell lung cancer (NSCLC) (9).
Like the PNI, the Controlling Nutritional Status (CONUT) score, another nutritional marker, is an index calculated from the serum albumin concentration and total peripheral lymphocyte count, with the addition of the total cholesterol concentration (10). The PNI score was deemed to place too much emphasis on serum albumin concentration; the CONUT score, by contrast, reduces the importance of the serum albumin concentration and newly incorporates the total cholesterol concentration, thereby leading to a more accurate evaluation of the nutritional status. While the CONUT score has been reported to be useful for the preoperative nutritional assessment in patients with resected colorectal and esophageal cancer, we reported the efficiency of the CONUT score as a prognostic factor in patients with pathological stage I NSCLC (11-14).
In patients with lung cancer with obstructive lung impairment, the nutritional status is often abnormal due to cachexia and muscle wasting. Previous reports have shown that the simultaneous presence of lung cancer and obstructive lung impairment correlated with cachexia (15, 16). The serum albumin levels were also found to be correlated with the pulmonary function, and high levels of cholesterol were noted in patients with severe chronic obstructive pulmonary disease (COPD) (17, 18). Therefore, in the present study, we focused on patients with obstructive lung disease, as obstructive lung disease may affect the nutritional status, which should be reflected in the CONUT score.
The aim of this study was to evaluate the utility of the preoperative CONUT score in predicting the postoperative disease-free (DFS) and overall (OS) survival in patients with lung adenocarcinoma with obstructive lung disease.
Patients and Methods
From January 2003 to December 2012, 428 consecutive patients with primary lung adenocarcinoma underwent complete surgery at the Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University. We retrospectively selected 109 patients with adenocarcinoma and obstructive pulmonary disease whose preoperative spirometry showed a forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio of less than 70%. The histological diagnosis of the tumors was based on the criteria of the World Health Organization and the seventh edition of the TNM classification system of the American Joint Committee on Cancer. Preoperative variables, such as age, sex, smoking status, BMI, CONUT score, and carcinoembryonic antigen (CEA) and epidermal growth factor receptor (EGFR) status were evaluated. The EGFR status had been determined in tumor tissue using the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method (Mitsubishi Chemical Medicine, Tokyo, Japan) (19).
Follow-up. The patients were followed up every 3-4 months for the initial 2 years, every 6 months for the next 3 years, and annually thereafter. They underwent medical checkups and chest X-ray or computed tomography. All patients were followed-up until April 2016 or until their death.
DFS and OS. The primary and secondary outcomes were the DFS and OS, respectively. The OS was defined as the time from the day of surgery until the last follow-up or death. The DFS was defined as the time from the day of surgery to the date of the last normal follow-up for patients without recurrence, or to the date of the first detection of a recurring lesion for patients with recurrence. In patients with no evidence of recurrence, DFS was censored at the date of death or last follow-up.
CONUT evaluation. The CONUT score was calculated using the serum albumin concentration, peripheral lymphocyte count and the total cholesterol concentration (Table I). Preoperative blood samples were obtained routinely before surgery. To determine the cut-off value for the CONUT score, we used a receiver operating characteristic (ROC) curve. The curve identified an optimal CONUT cut-off value of 1 (area under the curve of 0.596; sensitivity of 0.6711 and specificity of 0.4375, as shown in Figure 1). Therefore, we set 1 as the cut-off value for the CONUT score in this study and classified patients into high CONUT (≥1) and low CONUT (0) groups.
Statistical analysis. Statistical analyses for the categorical factors were performed using Fisher's exact tests. The DFS and OS rates were estimated using the Kaplan–Meier method with the log-rank test. Univariate and multivariate analyses with a Cox proportional hazards model or logistic regression model were performed to assess the significant factors. We used the JMP Statistical Discovery software program (version 11.0; SAS Institute, Cary, NC, USA) for the statistical analyses. When a p-value was less than 0.05, we considered the results statistically significant.
Results
Patient characteristics. The patient characteristics are summarized in Table II. The patients ranged in age from 45 to 85 years (mean, 72 years). There were 76 men and 33 women. The median BMI was 22.3 kg/m2. Patients with high (≥20) and low BMI (<20) accounted for 78% (n=85) and 22% (n=24), respectively. The histological subtypes of adenocarcinoma were atypical adenomatous hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma and lepidic predominant in 15 cases (13.7%) and other types in the remainder (86.3%). Pathological stage I disease was confirmed in 74 patients (67.9%), and stage II, III or IV disease was confirmed in 35 patients (32.1%). Pathological N0 disease was confirmed in 90 patients (82.5 %), and N1 or N2 disease was confirmed in 19 patients (17.5 %). The EGFR status was available for 73 patients; of these, 41 (56.2%) had wild-type EGFR, and 33 (43.8%) had mutant EGFR.
Correlation between CONUT scores and other clinicopathological findings. The clinicopathological characteristics of the two CONUT groups are shown in Table III. The high-CONUT group was significantly associated with a lower BMI (p=0.025) and wild-type EGFR mutation status (p=0.011).
Survival analyses according to the CONUT score. The five-year DFS rates in the low- and high-CONUT groups were 72.0% and 48.1%, respectively (Figure 2A), with a significant difference between the groups (p=0.012). The 5-year OS rates in the low- and high-CONUT groups were 85.7% and 66.7%, respectively (Figure 2B), and there was a significant difference between the groups (p=0.041). However, when the cut-off score was set at 2, there was no significant association between the CONUT score and the DFS and OS (Figure 3).
Univariate and multivariate analyses for the relationship between DFS and clinicopathological factors. The correlations between DFS and clinicopathological factors are shown in Table IV. In the univariate analysis, the CONUT score, CEA, pathological tumor status, pathological nodal status, grade, pleural invasion and lymphatic vessel invasion were significantly positively associated with the DFS. A multivariate analysis showed that the CONUT score (p=0.004), pathological nodal status (p=0.012), grade (p=0.034) and lymphatic vessel invasion (p<0.001) were independently positively associated with the DFS.
Univariate and multivariate analyses for the relationship between OS and clinicopathological factors. The correlations between the OS and clinicopathological factors are shown in Table V. In the univariate analyses, age, the CONUT score, CEA, pathological tumor status, nodal status, grade, pleural invasion lymphatic vessel invasion and histological subtype were significantly positively associated with the OS. A multivariate analysis showed that age (p=0.001), the CONUT score (p=0.037), CEA (p=0.010), pathological tumor status (p=0.037), pathological nodal status (p=0.007) and grade (p=0.016) were independently positively associated with the OS.
Discussion
Many studies have investigated the prognostic significance of inflammatory markers and nutritional status, such as PNI and CONUT, in patients with cancer. Among these markers, the efficiency of CONUT score for predicting the likelihood of survival or other events has been increasingly reported not only in patients with heart failure or liver failure, but also those with cancer (20, 21). The CONUT score may also be useful in predicting the treatment outcomes such as the survival for patients with lung cancer; however, its utility has yet to be evaluated. We found that the CONUT score was useful for predicting postoperative survival in patients with stage I NSCLC (unpublished data). Furthermore, as in patients with lung cancer without any complications, the preoperative CONUT score is also expected to be useful in predicting the outcomes of treatment in patients with respiratory complications, such as COPD or interstitial pneumonia. In this study, the prognostic influence of the CONUT score was evaluated in 109 patients with adenocarcinoma with obstructive pulmonary disease. We found that the CONUT score was an independent prognostic factor for the DFS and OS, demonstrating the importance of the preoperative nutritional status in patients with lung cancer with obstructive pulmonary disease.
The need for preoperative nutritional intervention in patients with cancer should be emphasized. Several studies have demonstrated the significance of a good nutritional status prior to therapeutic intervention in patients with esophageal cancer, head and neck cancer and NSCLC (22-26). With regard to patients with lung cancer, a systematic review suggested that exercise and nutritional interventions may have beneficial effects on unintentional weight loss and physical strength in patients with advanced NSCLC (26). However, the optimum intervention for improving the nutritional status has yet to be established. Preoperative nutritional intervention based on the CONUT score may be a factor which could contribute to improved survival and should be assessed in future studies.
Although the CONUT score was found to be useful as a prognostic factor, it may also have other potential roles. For example, since the CONUT score includes the total lymphocyte count, it reflects the immune status and may, therefore, be a useful marker for immunotherapy.
Immunotherapy has emerged as a promising strategy for cancer treatment. Immune checkpoint inhibitors were recently shown to improve the prognoses in multiple types of cancer (27, 28). With regard to lung cancer, nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor, has been approved in many countries; programmed death-ligand 1 (PD-L1) expression is, therefore, expected to serve as a useful biomarker for predicting the antitumor efficacy of antibodies against PD-1 or PD-L1. However, studies are ongoing to identify other useful biomarkers, which is one of the greatest challenges in studies of immune checkpoint inhibitors. For example, the absolute lymphocyte count has been shown to be a specific biomarker of ipilimumab, which is an antibody targeting cytotoxic T-lymphocyte-associated antigen 4 for melanoma (29). If the CONUT score can be used as a predictive factor for nivolumab efficacy, it may serve as a convenient and noninvasive marker in the prediction of the efficacy of this compound. However, at present, such uses are entirely speculative and not based on any data; further investigations are therefore needed.
Several limitations associated with the present study warrant mention. This was a retrospective study conducted at a single Institute, and all enrolled patients had adenocarcinoma. Further studies including patients with not only adenocarcinoma but also squamous cell carcinoma should be performed to confirm our findings. The CONUT score is convenient and useful for evaluating both the immunological and nutritional status. The results of this study suggest that the CONUT score is an independent prognostic factor for DFS and OS in patients with lung adenocarcinoma with obstructive lung disease.
Acknowledgements
The Authors thank Brian Quinn for his critical comments on the manuscript.
- Received March 24, 2017.
- Revision received April 10, 2017.
- Accepted April 11, 2017.
- Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved