Prognostic and clinicopathological significance of the Controlling Nutritional Status (CONUT) score in patients with lymphoma: a meta-analysis

Abstract

Objectives

The role of the Controlling Nutritional Status (CONUT) scores in predicting the prognosis of lymphoma cases has been extensively explored, with no consistent results. The present meta-analysis focused on accurately evaluating whether CONUT could be used to predict the prognosis of lymphoma cases and its clinicopathological value.

Design

The present meta-analysis was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The prognostic significance of CONUT to overall survival (OS) and progression-free survival (PFS) in lymphoma was estimated by calculating pooled HRs with 95% CIs. The relationship between CONUT and clinicopathological characteristics was measured based on pooled ORs with 95% CIs.

Data sources

PubMed, Web of Science, Embase and Cochrane Library databases were comprehensively searched from inception through 24 March 2023.

Statistical methods

Either a random-effects model or a fixed-effects model was selected depending on the level of heterogeneity among the included studies.

Results

This meta-analysis enrolled seven articles, containing 2060 patients with lymphoma. According to the pooled analysis, a higher CONUT score significantly predicted poor OS (HR=1.94, 95% CI 1.46 to 2.57, p<0.001) as well as poorer PFS (HR=1.51, 95% CI 1.04 to 2.20, p=0.031). Furthermore, according to the combined analysis, a higher CONUT score was significantly associated with Ann Arbor stages III–IV (OR=3.75, 95% CI 2.96 to 4.75, p<0.001), an Eastern Cooperative Oncology Group performance status of 2–4 (OR=5.14, 95% CI 3.97 to 6.65, p<0.001), high-intermediate/high National Comprehensive Cancer Network International Prognostic Index (OR=8.05, 95% CI 5.11 to 12.66, p<0.001), B symptoms (OR=4.97, 95% CI 2.89 to 8.52, p<0.001), extranodal disease (OR=3.25, 95% CI 2.24 to 4.70, p<0.001), bone marrow involvement (OR=4.86, 95% CI 3.25 to 7.27, p<0.001) and elevated lactate dehydrogenase levels (OR=3.21, 95% CI 2.37 to 4.34, p<0.001).

Conclusions

According to our results, higher CONUT scores were significantly associated with poor OS and PFS in lymphoma.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• We performed a meta-analysis of seven studies, totalling 2060 patients, to investigate the association between the Controlling Nutritional Status (CONUT) score and prognosis of patients with lymphoma.

• The relationships between CONUT scores and the clinicopathological characteristics of patients with lymphoma were determined in the stratified analysis.

• The various cut-off values for CONUT scores in the included studies might be a source of heterogeneity in the results.

Introduction

Lymphoma accounted for 627 439 new cases of patients with cancer and 283 169 cancer-related deaths worldwide in 2020.¹ Lymphomas are highly heterogeneous tumours that present with numerous clinical manifestations and are strikingly diverse genetically.² They are classified as either non-Hodgkin’s lymphomas (NHL) or Hodgkin’s lymphomas, with various subtypes under these two umbrella terms.³ Moreover, in the Western hemisphere, NHL is the most common type of haematological malignancy, with an incidence of about 13 per 100 000 people.⁴ Although aggressive B cell lymphomas can be cured with chemotherapy and immunotherapy, most indolent lymphomas are incurable; however, they often achieve durable remissions requiring lifelong monitoring.⁵ Several advances have been made in the treatment of lymphoma, including stem cell transplantation, adoptive cell therapy and targeted therapy. However, refractory or recurrent tumours have limited the survival of patients with lymphoma. Therefore, there is an urgent need to identify novel diagnostic and prognostic markers that allow for accurate and early identification of high-risk patient groups with lymphomas.

Furthermore, systemic inflammation and malnutrition are related to dismal prognoses in many cancers.^6–9 ‘Measures’ that represent the nutritional and inflammatory status of patients have been investigated as prognostic factors, including neutrophil to lymphocyte ratio,¹⁰ platelet to lymphocyte ratio,¹¹ C reactive protein to albumin ratio,¹² the Controlling Nutritional Status (CONUT) score¹³ and the Geriatric Nutritional Risk Index.¹⁴ CONUT scores are determined based on serum albumin content, peripheral lymphocyte count as well as total cholesterol content (online supplemental table S1). The CONUT system was first proposed in 2005 by Ignacio et al ¹⁵ and initially used as a screening approach to evaluating patients’ nutritional status. Additionally, CONUT is a significant prognostic factor in various types of cancer, such as breast cancer,¹⁶ hepatocellular carcinoma,¹⁷ urothelial carcinoma,¹⁸ colorectal cancer,¹⁹ hypopharyngeal cancer²⁰ and prostate cancer.²¹ The legitimacy of using CONUT scores while predicting the prognosis of lymphoma cases has been widely investigated but no consistent results can be obtained.^22–28 For instance, higher CONUT scores (usually ≥5) were reported to significantly predict the prognosis of lymphoma cases in some studies, whereas other scholars did not show a significant relationship between lymphoma prognosis and use of CONUT scores.²³ Therefore, through a comprehensive literature review, the present meta-analysis focused on identifying the precise role of CONUT scores when estimating lymphoma prognoses. Moreover, we also investigated the association of CONUT with the clinicopathological characteristics of lymphoma.

Materials and methods

Patient and public involvement

No patients were involved.

Study guideline

The meta-analysis was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.²⁹ The PRISMA checklist is shown in online supplemental table S2.

Literature search

We thoroughly searched PubMed, Web of Science, Embase and Cochrane Library databases from inception through 24 March 2023. To retrieve study literature related to the primary topic of our analysis, the following Medical Subject Headings (MeSH) terms were adopted and combined with text words, namely (controlling nutritional status or CONUT) and lymphoma. The detailed search strategies for each database are shown in online supplemental file 1. References in related articles were also reviewed, aiming to identify more work.

Study eligibility criteria

Studies conforming to the following criteria were included: (1) lymphoma confirmed by pathology; (2) reporting a relationship between CONUT scores and lymphoma survival outcomes; (3) providing enough information to predict HRs with 95% CIs; (4) a threshold was identified to stratify low and high CONUT scores; and (5) English studies. The following studies were excluded: (1) animal studies; (2) case reports, reviews, letters, conference abstracts and comments; and (3) studies with overlapped patients.

Data collection and quality evaluation

Two researchers (LL and LS) were responsible for collecting the data from the included articles, independently. Any discrepancy between them was resolved through mutual negotiation. The following data were collected from the qualified articles: first author, publication year, country, age, sample size, gender, study period, histology, study centre, cut-off value of CONUT, follow-up, survival outcomes and survival analysis, combined with HRs (95% CIs). In this meta-analysis, overall survival (OS) was the primary outcome, whereas progression-free survival (PFS) was the secondary outcome. Two researchers (LL and LS) were responsible for independently evaluating the quality of each enrolled study according to the Newcastle-Ottawa Scale (NOS).³⁰ The NOS uses three factors: selection, comparability and outcome, with scores ranging from 1 to 9. Studies with NOS scores ≥6 were designated to be of high quality.

Statistical analysis

The role of CONUT scores in OS and PFS in lymphoma was analysed by calculating pooled HRs with 95% CIs. The Cochran Q test and I² statistics were used to evaluate interstudy heterogeneity. An I² of >50% and Q test with p<0.10 indicated studies with high heterogeneity. A random-effects model was adopted for studies with high heterogeneity, whereas a fixed-effects model was used for studies with low heterogeneity. Subgroup analyses were also carried out to identify the source of heterogeneity. Associations between CONUT scores and clinicopathological factors were measured based on pooled ORs with 95% CIs. Funnel plots and the Begg’s test were visually inspected to assess for potential publication bias. Statistical analyses were completed with Stata V.12.0 software. P<0.05 (two-tailed) stood for statistical significance.

Results

Literature screening

During the original literature review, 122 articles were initially included and 86 studies remained after removing duplicate records (figure 1). Another 74 articles were eliminated during title and abstract screening, and the remaining 12 were further examined with full-text reading. Later, five studies that did not focus on CONUT (n=3), were meeting abstracts (n=1) and did not study lymphoma (n=1) were eliminated. Ultimately, seven studies were enrolled in the present meta-analysis, involving 2060 patients with lymphoma^22–28 (figure 1, online supplemental table S3).

Figure 1.

PRISMA flow diagram of this meta-analysis. CONUT, Controlling Nutritional Status; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Eligible study features

Online supplemental table S3 presents the baseline features of the seven enrolled articles. The publication years of these articles ranged from 2020 to 2023. Three studies were carried out in Japan,^{22 23 27} two in China^{26 28} and two in Turkey.^{24 25} The enrolled articles all used the English language and were of retrospective design,^22–28 with sample sizes between 81 and 615 patients (median: 266). Five were single-centre studies^{23–26 28} and two were multicentre trials.^{22 27} Four studies enrolled patients with diffuse large B cell lymphoma (DLBCL),^22–25 whereas the remaining three included extranodal NK/T cell lymphoma,²⁸ peripheral T cell lymphoma²⁷ and lymphoma cases.²⁶ Three studies adopted a CONUT cut-off value of ≥5,^{22 25 27} two used a cut-off of ≥2^{24 28} and the two remaining each chose a cut-off of ≥4²³ and ≥7.²⁶ All seven articles mentioned a relationship between CONUT scores and OS in lymphoma^22–28 and three proved a relationship between CONUT and PFS.^{23 24 28} Five articles provided HRs with 95% CIs based on multivariable regressions^23–27 and two offered the same based on univariable regressions.^{22 28} For all enrolled articles, the NOS scores ranged from 7 to 9, with a median of 8, suggesting high quality.

CONUT and OS in lymphoma

Seven articles, comprising 2060 cases,^22–28 provided a relationship between CONUT and OS in lymphoma. We employed a random-effects model due to heterogeneity (I²=90.7%, p<0.001). As seen in figure 2 and online supplemental table S4, a pooled HR of 1.94 (95% CI 1.46 to 2.57, p<0.001) was obtained, which indicated a significant association between high CONUT scores and poor OS of lymphoma cases. Furthermore, subgroup analyses based on various factors were conducted (online supplemental table S4). An elevated CONUT score was significantly correlated with poor OS in the following subgroups: studies from China (p=0.002), sample size of ≥200 (p=0.013), single-centre studies (p=0.003), cut-off value of ≥4 (p=0.003), cut-off value of ≥7 (p<0.001) and those that included DLBCL cases (p=0.013) (online supplemental table S4).

Figure 2.

Forest plot depicting the association between CONUT and OS in lymphoma according to various cut-off values. The cut-off values in the studies are as follows: ≥2 in Akgün Çağlıyan et al ²⁴ and Wu et al ²⁸; ≥4 in Nagata et al ²³; ≥5 in Matsukawa et al,²² Baysal et al ²⁵ and Nakamura et al ²⁷; and ≥7 in Liu et al.²⁶ Overall estimate should be interpreted with caution give the varying cut-offs used in the different studies. CONUT, Controlling Nutritional Status; OS, overall survival.

CONUT and PFS in lymphoma

Altogether, three articles, involving 1116 cases,^{23 24 28} provided evidence on the prognostic role of CONUT in PFS. Due to heterogeneity (I²=80.3%, p=0.006), we used a random-effects model. The combined data from these studies indicated that elevated CONUT scores were significantly associated with shortened PFS in lymphoma (HR=1.51, 95% CI 1.04 to 2.20, p=0.031; online supplemental table S4, figure 3). Based on the subgroup analysis, high CONUT scores still significantly predicted PFS, regardless of subtype (p<0.05; online supplemental table S4). Moreover, elevated CONUT scores were also significantly correlated with poor PFS in studies from China (p<0.001) and Turkey (p<0.001) (online supplemental table S4).

Figure 3.

Forest plot depicting the association between CONUT and PFS in lymphoma according to various cut-off values. The cut-off values in the studies are as follows: ≥2 in Akgün Çağlıyan et al ²⁴ and Wu et al ²⁸; and ≥4 in Nagata et al. ²³ Overall estimate should be interpreted with caution give the varying cut-offs used in the different studies. CONUT, Controlling Nutritional Status; PFS, progression-free survival.

CONUT and clinicopathological features

Five studies, comprising 1830 patients,22–24 27 28 reported a relationship between CONUT scores and the clinicopathological characteristics of lymphoma. According to the combined analyses in figures 4 and 5 and online supplemental table S5, higher CONUT scores were remarkably associated with Ann Arbor stages III–IV (OR=3.75, 95% CI 2.96 to 4.75, p<0.001), Eastern Cooperative Oncology Group performance status of 2–4 (OR=5.14, 95% CI 3.97 to 6.65, p<0.001), high to intermediate/high National Comprehensive Cancer Network International Prognostic Index (OR=8.05, 95% CI 5.11 to 12.66, p<0.001), B symptoms (OR=4.97, 95% CI 2.89 to 8.52, p<0.001), extranodal disease (OR=3.25, 95% CI 2.24 to 4.70, p<0.001), bone marrow involvement (OR=4.86, 95% CI 3.25 to 7.27, p<0.001) and elevated lactate dehydrogenase levels (OR=3.21, 95% CI 2.37 to 4.34, p<0.001). Nonetheless, CONUT scores were not significantly associated with gender (OR=1.04, 95% CI 0.71 to 1.53, p=0.823) in patients with lymphoma (figure 4, online supplemental table S5).

Figure 4.

Forest plots describing the correlation between CONUT and clinicopathological factors in lymphoma: (A) gender (male vs female); (B) Ann Arbor stage (III–IV vs I–II); (C) ECOG PS (2–4 vs 0–1); and (D) NCCN IPI (high-intermediate/high vs low/low-intermediate). CONUT, Controlling Nutritional Status; ECOG PS, Eastern Cooperative Oncology Group performance status; NCCN IPI, National Comprehensive Cancer Network International Prognostic Index.

Figure 5.

Forest plots describing the correlation between CONUT and clinicopathological factors in lymphoma: (A) presence of B symptoms (yes vs no); (B) extranodal disease (yes vs no); (C) bone marrow involvement (yes vs no); and (D) lactate dehydrogenase level (elevated vs normal). CONUT, Controlling Nutritional Status.

Publication bias

We created funnel plots with Begg’s test to examine possible publication bias for OS and PFS (online supplemental figure S1). Ultimately, the Begg’s test revealed an absence of significant publication bias for OS (p=0.230) and PFS (p=0.296).

Discussion

The effect of CONUT scores on the prognosis of lymphoma cases remains to be elucidated, according to prior investigations. This meta-analysis retrieved the most recent literature and collected data from seven eligible studies.^22–28 This meta-analysis showed that elevated CONUT scores significantly predict dismal OS and inferior PFS in patients with lymphoma. Moreover, a high CONUT score can also be considered a risk factor for aggressive tumour biology in lymphoma. To our knowledge, this meta-analysis is the first to explore whether CONUT could be used when predicting the prognosis of lymphoma cases and to assess its clinicopathological value.

CONUT scores can be calculated according to serum albumin content, total lymphocyte count and total cholesterol content. A high CONUT score can be caused by decreased albumin levels, low lymphocyte counts and low cholesterol levels. Therefore, the mechanisms of the prognostic value of CONUT in lymphoma patient survival can be explained by the following aspects. First, albumin is at its highest abundance in plasma, which occupies around 50% of all proteins.³¹ Serum albumin level is frequently used to represent nutritional status and is closely associated with inflammation.³² Several human defence mechanisms are impaired by malnutrition, including anatomical barriers, humoral and cellular immunity, and phagocytic function. Serum albumin levels can be used to determine the prevalence of malnutrition.³³ Hypoalbuminaemia can induce the activation of factors such as interleukin 1, interleukin 6 and tumour necrosis factor-α.^{34 35} A recent single-centre study showed that a low serum albumin level was a prognostic factor for an undesirable OS rate in patients with DLBCL.³⁶ Another multicentre study also reported that consecutive hypoalbuminaemia was a simple and effective adverse prognostic factor in patients with DLBCL treated with the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) regimen.³⁷ Second, lymphocytes are immune response cells which are essential for anticancer efficacy. Specifically, T lymphocytes recognise and kill tumour cells, thereby inhibiting proliferation and metastasis.³⁸ Lymphocyte loss in the tumour microenvironment hinders the natural antitumour ability of the body, leading to immunity tolerance and escape by tumour cells.³⁹ Furthermore, patients with lymphoma receiving chemotherapy could have low lymphocyte counts.³⁵ Additionally, as an essential component of the cell membrane, cholesterol contributes plasma membrane dimension, organisation and fluidity, maintaining cellular function.⁴⁰ Hypocholesterolaemia is significantly associated with lower levels of lymphocytes, total T cells and CD8+ cells, compared with hypercholesterolaemia.⁴¹ As serum cholesterol levels decrease, immune cells become unable to fight cancer cells due to the higher levels of cholesterol in cancer cell membranes.⁴² Hence, high CONUT scores are typically associated with tumour invasion and metastasis, along with dismal survival outcomes.

Recently, numerous meta-analyses have been conducted to explore whether CONUT scores can be used to predict the prognosis of various tumour types.^43–45 Peng et al ⁴³ showed that CONUT scores have a prognostic value for OS in patients with glioblastoma in their meta-analysis of 1406 cases. Xue et al ⁴⁴ reported that a high CONUT score predicted dismal OS, cancer-specific survival (CSS) and recurrence-free survival (RFS) in upper tract urothelial carcinoma and renal cell carcinoma in their meta-analysis of 5410 cases. Another recent meta-analysis reported that higher CONUT scores had an unfavourable impact on OS, disease-free survival, CSS and PFS in lung cancer, relative to those with low CONUT scores.⁴⁵ Ma et al ⁴⁶ performed a meta-analysis enrolling 2294 patients and proved that higher CONUT scores remarkably predict the well-known dismal OS in pancreatic cancer. Additionally, as reported by Takagi et al, ⁴⁷ higher CONUT scores predicted dismal OS, CSS and RFS in patients with colorectal cancer undergoing surgery. Therefore, the results of our meta-analysis were consistent with prior work on other cancers. We also analysed a meta-analysis that explored the prognostic role of CONUT scores in patients with haematological malignancies by Lu et al.⁴⁸ Six studies were included in their meta-analysis and three investigated DLBCL. All three studies^22–24 were included in the current meta-analysis, where we focused on lymphoma. Additionally, we analysed the association between CONUT scores and eight clinicopathological features in lymphoma which were not explored in the previous meta-analysis.⁴⁸ Our meta-analysis included 2060 patients, which was more than that in the meta-analysis by Lu et al.⁴⁸ Therefore, this study’s novelty, comprehensiveness and large sample size were strengths compared with the meta-analysis by Lu et al.⁴⁸

Certain limitations should be noted in this meta-analysis. First, significant heterogeneity in the HRs for OS and PFS existed. For example, the HRs and 95% CIs from various countries were different from each other, which may be due to selection bias, sample size and study period. Therefore, we performed a subgroup analysis based on study country to explore its impact on the overall results. Although we used a random-effects model for this analysis, the source of heterogeneity could not be precisely traced. Second, our enrolled articles were of retrospective design, possibly introducing selection bias. Third, the threshold for CONUT scores were different between the included articles. Therefore, large-scale prospective studies should be conducted for further validation.

Conclusions

In summary, this meta-analysis provides concrete evidence that higher CONUT scores are significantly related to inferior OS and PFS in lymphoma.

Data availability statement

Data are available upon reasonable request. The data that support the findings of this study are available from the corresponding author upon reasonable request.

Ethics statements

Patient consent for publication

Not required.

Ethics approval

The ethics committee and institutional review board waived a formal approval for the present work since it is based on published studies.