Prognostic significance of the controlling nutritional status (CONUT) score in patients undergoing hepatectomy for hepatocellular carcinoma: a systematic review and meta-analysis

Background The clinical value of the controlling nutritional status (CONUT) score in hepatocellular carcinoma (HCC) has increased. The aim of this meta-analysis was to systematically review the association between the CONUT score and outcomes in patients undergoing hepatectomy for HCC. Methods Embase, Medline Ovid, Web of Science, Cochrane CENTRAL, and Google Scholar were systematically searched. Random effects meta-analyses were conducted to examine the prognostic value of the CONUT score in HCC patients. Results A total of five studies including 4679 patients were found to be eligible and analyzed in the meta-analysis. The CONUT score was significantly associated with overall survival (HR 1.78, 95%CI = 1.20–2.64, P = 0.004, I2 = 79%), recurrence-free survival (HR 1.34, 95%CI = 1.17–1.53, P < 0.001, I2 = 16%) and postoperative major complications (OR 1.85, 95%CI: 1.19–2.87, P = 0.006, I2 = 72%) in HCC patients. Moreover, the CONUT score was associated with the Child–Pugh classification, liver cirrhosis, ICGR15, and tumor differentiation. However, it was not associated with tumor size, tumor number, and microvascular invasion. Conclusions The CONUT score is an independent prognostic indicator of the prognosis and is associated with postoperative major complications and hepatic functional reserve in HCC patients.


Background
Hepatocellular carcinoma is a major cause of cancerrelated morbidity and mortality [1]. Despite advances in early diagnosis and personalized medicine, the clinical outcome of hepatocellular carcinoma (HCC) remains poor with high recurrence rate after curative treatment [2]. Therefore, the identification of accurate and reliable prognostic markers is necessary in HCC patients.
The controlling nutritional status (CONUT) score [3], calculated from serum albumin level, total cholesterol level, and total lymphocyte count, was originally developed as a nutritional assessment tool in Western Europe in 2005. The evidence regarding the influence of the CONUT score on prognosis in gastrointestinal cancers has been growing, particularly in Asian populations [4,5]. We have recently reported on the association between the CONUT score and postoperative complication risk in gastrointestinal and hepato-pancreato-biliary surgical oncology [6]. However, to the best of our knowledge, no study has systematically investigated the significance of the CONUT score on outcomes in patients with HCC. Surgical complication risk and cancer prognosis differ between cancers and procedures. Therefore the effect of the CONUT score in patients with specific cancers should be systematically examined separately.
We herein conducted this systematic review and metaanalysis to evaluate the association between preoperative CONUT score and outcomes in patients undergoing hepatectomy for HCC. Furthermore, the impact of the CONUT score on clinicopathological factors was identified score in HCC patients.

Search methodology
A systematic literature search was performed on July 4th 2019 in 5 publication repositories: Embase, Medline Ovid, Web of Science, Cochrane CENTRAL, and Google scholar. The full search for all repositories is appended to this article (Additional file 1: Table S1). The methods for developing our search have been detailed in a previous publication [6]. This study is reported according to the Preferred Reporting Items for Systematic Reviewers and Meta-Analyses (PRISMA) guidelines [7].

Criteria for the review
Inclusion criteria were the following: original article, patients undergoing hepatectomy for HCC; the preoperative assessment of the CONUT score; and reported postoperative outcomes. In the case of multiple publications by the same institute, the study focusing on longterm outcomes or the study with the last date of publication was included in the meta-analyses.
Titles, abstracts and full articles were screened independently by two investigators (KT and PD), according to the PRISMA guidelines. All original articles that met the criteria were included. From the included articles, year and country of study publication, study type, patient information, cut-off and prevalence of the CONUT score, and postoperative short-term and long-term outcomes were extracted. The methodological quality of each studies was evaluated based on the Newcastle-Ottawa quality assessment scale for cohort studies [8]. Studies with a total score with 6 or higher were considered high-quality studies [9].
The primary outcomes were overall survival (OS), defined as time from surgery to death or last follow-up, and recurrence-free survival (RFS), defined as time from surgery to recurrence or last follow-up/death. Secondary outcomes were postoperative complications and the clinicopathological parameters. Postoperative complications were graded based on the Clavien-Dindo classification (CDc) [10], with major complications defined as CDc ≥3. The clinicopathological parameters included the Child-Pugh classification (A versus B), the degree of liver cirrhosis, indocyanine green retention test after 15 min (ICGR15), and tumor characteristics (tumor size, tumor number [single versus multiple], tumor differentiation [well and moderate differentiated versus poorly differentiated], and microvascular invasion).

Statistical analysis
Random effects meta-analyses were conducted to estimate the average correlation of the CONUT score with OS and RFS. Random effects models were used, as the populations were heterogeneous and consisted of patients deriving from different countries and undergoing different treatment protocols. The pooled hazard ratio (HR) with 95% confidence interval (95%CI) and the mean difference (MD) for continuous variables with 95%CI were calculated using the inverse variance method. The pooled odds ratio (OR) for dichotomous variables was calculated using the Mantel-Haenszel method. Heterogeneity among studies was quantified by calculating the I 2 values and the Chi-square test, with P < 0.05 being statistically significant and I 2 values of 50% or more indicating the presence of heterogeneity. Potential publication bias for outcomes was examined using Funnel plots. Analyses were conducted using R 3.5.4 (cran.r-project.org) and Review Manager 5.3 (Cochrane Collaboration, 2014).

Reported outcomes
The literatures reporting the effects of the CONUT score on outcome in patients undergoing hepatectomy for HCC are summarized in Table 2.
Five studies reported data on OS and RFS [11,12,14,16,17]. The Kaplan-Meier curve showed that patients with preoperative high CONUT score had a significantly poorer prognosis in terms of OS and RFS than those with low CONUT score in all studies. In the multivariable analyses, preoperative CONUT score was identified as an independent predictor associated with OS in all five studies. Regarding RFS, three studies [11,14,16] showed a significant association between preoperative CONUT score and RFS in the multivariable analysis, whereas two studies [12,17] showed no significant association.

Discussion
This systematic review and meta-analysis investigated the prognostic value of the CONUT score in patients undergoing hepatectomy for HCC. The present study demonstrated that the CONUT score was associated with OS, RFS and the incidence of postoperative major complications in patients with HCC. Moreover, we found that the CONUT score was associated with the Child-Pugh classification, liver cirrhosis, ICGR15, and tumor differentiation, whereas it was not associated with tumor size, tumor number, and microvascular invasion.
Recent meta-analyses have shown that the nutritional status evaluated by the CONUT score and the prognostic nutritional index (PNI) was associated with prognosis of various cancers [4,5,18]. Regarding the prognostic value of such nutritional assessment tools in HCC patients, recent meta-analyses have reported the relationship between the PNI and prognosis [9,19]. However, the CONUT score has been reported to provide the most appropriate sensitivity and specificity in patients with HCC compared with other immune-nutritional parameters including the PNI [15,17]. To date, the effect of the CONUT score on prognosis in patients with HCC has not been examined systematically. Actually, previous studies on the CONUT score in HCC patients reported different outcomes in terms of RFS and postoperative complications, as is shown in Table 2. Therefore, our results would add the clinical evidence of the association between the CONUT score and outcome in patients with HCC.
The present meta-analysis indicates that the CONUT score is associated with the prognosis, the postoperative major complications and hepatic functional reserve in HCC patients. Patients with high CONUT score had a significantly worse OS and RFS, and had a higher incidence of postoperative major complications than those with low CONUT score in HCC patients after hepatectomy. These results are in line with discovered correlations between nutritional status markers like PNI and sarcopenia, and the prognosis and postoperative complications in gastrointestinal and hepatopancreatobiliary surgical oncology [18,20,21]. In addition, it should be noted that prognosis in patients with HCC depends on tumor stage as well as hepatic functional reserve [22,23]. Indeed, our meta-analysis demonstrated the relationship between the CONUT score and the Child-Pugh classification, liver cirrhosis, and ICGR15. Interestingly, Wang et al. reported that the CONUT score is an effective indicator predicting PHR in hepatitis B HCC patients [16]. Among tumor The biological mechanism explaining the correlation between the CONUT score and short-and long-term outcomes is unknown. In past studies, preoperative higher CONUT score was found to be associated with worse nutritional status as well as poorer immune functional status preoperatively [16]. In addition, postoperative immune functional status was worse in patients with preoperative higher CONUT score. Perioperative poor immune-nutritional status could in turn be related to a higher incidence of postoperative complications. Separate CONUT score parameters have been correlated with outcomes in HCC patients in past studies. Serum albumin, on itself a major indicator of nutritional status, is associated with prognosis and complication risk in patients following hepatectomy for HCC [24,25]. Total lymphocyte count is a surrogate marker of immunenutritional status in cellular and antiviral immunity and has been shown to correlate with prognosis [26,27]. Serum cholesterol level, reflecting a malnutritional and end stage liver function status, is a prognostic factor to predict postoperative HCC recurrence and OS in HCC patients as well [28].
Several limitations of the present study should be acknowledged. All the included studies were retrospective studies from Japan and China, using different cut-off values for the CONUT score, and with the different prevalence in patients with high CONUT score ranging from 9 to 49%. The number of included studies in the metaanalysis was small. Therefore, further studies are needed to identify the significance of the CONUT score and determine the most appropriate cut-off value to estimate the prognosis and complication risks in HCC patients.

Conclusions
The present study suggests that the CONUT score could be an indicator to predict the prognosis, postoperative complications and hepatic functional reserve in patients following hepatectomy for HCC.
Additional file 1: Table S1. Search strings and terms. Table S2. The Newcastle-Ottawa scale for quality assessment of include studies. Figure S1.