Haiyan Zhang
Dan Li
Jing Li- Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Background: The Prognostic Nutritional Index (PNI), which reflects both nutritional and immune status, has emerged as a potential predictor of survival outcomes in cancer patients. However, its role in forecasting the prognosis of hepatocellular carcinoma (HCC) following curative hepatectomy remains unclear. To further investigate the association between PNI and survival outcomes in HCC patients, we conducted a systematic review and meta-analysis.
Methods: We performed a comprehensive search across Web of Science, PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure to identify studies evaluating the prognostic value of PNI in HCC following curative hepatectomy. Overall survival (OS), recurrence-free survival (RFS), and disease-free survival (DFS) were extracted as primary outcomes. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using fixed-effect or random-effect models. Additionally, heterogeneity, publication bias, and sensitivity analyses were performed to evaluate the consistency and robustness of the obtained results.
Results: This systematic review and meta-analysis included 19 studies comprising a total of 9,830 patients. The results indicated that higher PNI was significantly associated with longer overall survival (OS) (n = 6,812; HR = 1.60; 95% CI: 1.44–1.77; p < 0.001) and recurrence-free survival (RFS) (n = 8,529; HR = 1.48; 95% CI: 1.30–1.69; p < 0.001). There was significant heterogeneity among studies for RFS (I2 = 56.0%, p = 0.004). Subgroup analysis indicated that age, variations in PNI cutoff values and follow-up periods were the primary contributors to this heterogeneity. The trim-and-fill method indicated that publication bias did not impact the OS results, and Egger’s test found no publication bias for RFS (p = 0.104). Sensitivity analysis further confirmed the stability of these results.
Conclusion: Preoperative PNI is a significant prognostic indicator in HCC patients undergoing curative hepatectomy, with higher PNI correlating with improved survival outcomes.
Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024530150, identifier CRD42024530150.
1 Introduction
Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer, presenting a significant global health burden (1). Despite advancements in diagnostic and therapeutic strategies, the prognosis for HCC patients, especially those undergoing curative hepatectomy, remains variable and frequently uncertain (2). Therefore, identifying reliable prognostic factors for HCC is fundamentally crucial.
The prognosis of HCC is influenced by a number of factors, including tumor diameter, disease stage, liver function, alpha-fetoprotein (AFP), vascular invasion, cirrhosis, hepatitis B or C infection, alcoholic liver disease (1, 3). Notably, markers related to malnutrition and inflammation have proven to be reliable prognostic indicators. High levels of lymphocytes and tumor-infiltrating lymphocytes suggest a potent immune defense against cancer (4). In contrast, elevated neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios, along with programmed cell death-ligand 1 (PD-L1) expression, indicate inflammation and immune escape, which are associated with poorer cancer outcomes (5). Additionally, changes in body mass index, the prognostic nutritional index (PNI), serum albumin (ALB), and C-reactive protein levels crucially reflect a patient’s nutritional and immune status. These indicators significantly impact cancer prognosis by revealing insights into malnutrition, systemic inflammation, and survival expectations (6).
Among various prognostic indicators, PNI has emerged as a potential factor influencing the prognosis of cancer patients, including those with HCC (7). PNI is calculated based on ALB levels and total lymphocyte counts in the blood, with the formula as follow: PNI = 10 × ALB (g/dL) + 0.005 × total lymphocyte count (/mm3). Serum ALB, an acute-phase protein, has antioxidant and anti-inflammatory properties which can serve as an important indicator of both nutritional status and systemic inflammation (8). Lymphocytes play a vital role in cell-mediated immunity, inhibiting tumor cell proliferation and invasion through cytokine-mediated cytotoxicity (9, 10). Consequently, a low PNI serves as an indicator of insufficient nutritional and immune function in cancer patients. Various researches have shown that a low preoperative PNI is an independent negative prognostic factor for various digestive system neoplasms, including gastric and colorectal cancers (11), as well as for lung (12), breast (13), ovarian cancers (14), and gastrointestinal stromal tumors (15, 16).
However, the role of PNI in predicting prognosis for patients with HCC remains debated (17–19). Numerous studies suggested that a low PNI served as a prognostic indicator in patients with HCC following surgery (20–22). For example, the study of Hanxin Feng indicated that PNI was a significant prognostic markers for overall survival (OS), but not for disease-free survival (DFS) (23). Conversely, Xiaoxiao Fan’s study revealed that HCC patients with a PNI below 45 had a poor recurrence-free survival (RFS) rate, though this association did not extend to OS (20).
Moreover, multiple meta-analyses have identified the PNI as an independent risk factor for patients with liver cancer post-surgery (20, 24, 25). However, the previous meta-analyses only included studies published up to 2021. Since then, numerous studies on PNI in HCC had been published. Additionally, the value of PNI in peripheral blood may vary with different treatment methods, such as chemotherapy and immunotherapy, an aspect overlooked in previous analyses. In the systematic review, we analyzed the association between preoperative PNI in treatment-naive patients and cancer survival outcomes.
2 Materials and methods
2.1 Literature search
On April 3, 2024, a comprehensive literature search was conducted across Embase, PubMed, the Cochrane Library, Web of Science, and China National Knowledge Infrastructure (CNKI), without language restrictions. The search strategy incorporated keywords such as “PNI,” “HCC,” “prognosis,” “survival,” and “treatment outcome,” alongside their respective Medical Subject Headings (MeSH) terms. This meta-analysis was designed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
2.2 Study selection
Our systematic review aimed to address the following research question: What is the relationship between PNI and cancer survival in patients with HCC? We employed the PICOS (Patient, Intervention, Comparison, Outcome, and Study Design) framework to define selection criteria, as follows: “P” (patient)—patients diagnosed with HCC; “I” (intervention)—not applicable; “C” (comparison)—comparison between groups with high and low PNI; “O” (outcome)—relevant indicators to evaluate the association between preoperative PNI and prognostic outcomes on peripheral blood analysis; and “S” (study design)—prospective and retrospective study. According to the PICOS principles, the inclusion criteria were as follows: (1) Studies evaluated the association between various indicators and predictive outcomes, including PNI; (2) the patients were categorized into high and low PNI groups based on PNI values; (3) studies reported the prognosis of PNI value using multivariate Cox regression analysis. The exclusion criteria were as follows: (1) reviews, case reports, letters, editorials, and meeting abstracts; (2) full text was not available; (3) animal or in vitro experiments rather than clinical studies; (4) absence of preoperative PNI measurements prior to curative liver resection; (5) patients who received antitumor therapy before surgery or biopsy, as well as these whose treatment history were unclear; (6) studies that did not directly provide hazard ratios (HR) and 95% confidence intervals (CI).
2.3 Data extraction
Three investigators independently extracted data following consistent criteria, with any disagreements resolved through consensus. The data collected included the publication year, first author’s name, country, median age, gender, number of patients, outcome endpoints, PNI cut off value, median follow-up period, and method for estimating HRs with CIs. This meta-analysis focused on three outcome endpoints: OS, RFS, and DFS.
2.4 Quality assessment
Three investigators independently assessed the quality of included studies using the Quality in Prognostic Studies (QUIPS) tool. The assessment encompassed: study participation, study attrition, prognostic factor measurement, outcome measurement, study confounding, and statistical analysis. Studies were classified as having a low risk of bias if more than four of these six criteria demonstrated a low risk of bias. Conversely, studies with two or more criteria showing a high risk of bias were categorized as high risk of bias. Studies that did not meet either threshold were classified as having a moderate risk of bias.
2.5 Statistical analysis
Statistical analysis was conducted using RevMan 5.4 (Informer Technologies, Los Angeles, CA, USA) and Stata version 14.0 (Stata Corporation, College Station, TX, USA). Pooled HRs and 95% CIs for OS, RFS, and DFS were calculated to evaluate the association between PNI and survival outcomes. Heterogeneity was assessed by the I2 value derived from the Q test, with p < 0.05 or I2 > 50% indicating significant heterogeneity. Effect models were selected based on the I2 and p values: a random-effects model was applied if I2 > 50% or p < 0.05; otherwise, a fixed-effect model was applied. Publication bias was evaluated with Egger’s test and the trim-and-fill method. Sensitivity analysis was performed to assess the stability of results by sequentially excluding individual studies.
3 Results
3.1 Study selection
A total of 1,035 papers were initially identified. After removing duplicate literature and reading the title, abstract, and full text according to the study’s inclusion and exclusion criteria, ineligible publications were excluded. Ultimately, 19 studies were identified, comprising 9,830 patients with HCC who underwent curative resection (7, 20, 23, 26–41). These studies were published between 2016 and 2024. The flow diagram for the study selection is presented in Figure 1.
Figure 1. Flow diagram of study selection.
3.2 Study characteristics and quality assessment
Table 1 in the meta-analysis presents the characteristics of the included studies, all of which were conducted in Asia, including 14 from China, 1 from Korea, and 4 from Japan, totaling 19 studies. Notably, in one study (40), the correlation between OS and PNI was separately discussed for patients with TNM stage I and TNM stage II. The sample sizes ranged from 100 to 2020 participants, with all studies being retrospective in design. Thirteen studies evaluated the impact of the PNI on OS, 12 on RFS, and 3 on DFS. The studies revealed that the median age of participants ranged from 49.63 to 70.46 years, with a higher prevalence of male participants. The majority of patients were in the early stages of disease, with 7,950 patients classified under the Barcelona Clinic Liver Cancer (BCLC) staging system as stages 0/A and 1,550 in advanced stages B/C/D. Most patients were affected by hepatitis B virus (HBV) or hepatitis C virus (HCV), and all underwent curative surgical excision. Follow-up periods varied, with median durations from 1.9 to 5.3 years. The median cut off values for PNI ranged from 44.35 to 53.95. Preoperative routine blood examinations were conducted, and HRs were calculated using multivariate regression analysis in all studies. According to the QUIPS checklist, 17 studies were assessed as having a low risk of bias, while 2 studies exhibited a moderate risk of bias.
Table 1. Characteristics of studies included in the meta-analysis.
3.3 The relation between PNI and OS in HCC patients
Thirteen studies were included in the meta-analysis of OS. A fixed effect model was used to calculate the pooled HRs and 95% CIs, as the heterogeneity test reported a p value of 0.08 and I2 value of 37.1%. The results showed that patients with higher PNI had significantly longer OS (n = 6,812, HR = 1.60; 95% CI: 1.44–1.77; p < 0.001) (Figure 2).
Figure 2. Forest plot of HR with 95% CI for correlation between expression of PNI and OS.
3.4 The relation between PNI and RFS in HCC patients
A total of 12 studies reported the effects of PNI on RFS in the meta-analysis. Besides, 3 articles discussed DFS, which has a similar definition to RFS. Therefore, the HR of DFS was combined with RFS to obtain the final HR for the total 15 studies. A random effects model was used to calculate the pooled HRs and 95% CIs due to the relatively high heterogeneity (I2 = 56.0%, p = 0.004). Our results demonstrated that a higher PNI was associated with improved survival outcomes (n = 8,529, HR = 1.48, 95% CI: 1.30–1.69, p < 0.001) (Figure 3).
Figure 3. Forest plot of HR with 95% CI for correlation between expression of PNI and RFS.
Subgroup analyses of RFS were conducted based on several potential factors (age, sample sizes, cut off value of PNI, follow-up periods, and study quality) to investigate the heterogeneity (Table 2). The result indicated that age, cut off value of PNI and follow-up period were likely contributors to heterogeneity. The heterogeneity for studies with age < 60 (HR =1.41, 95% CI: 1.20–1.66, p < 0.001), PNI cut off value > 46 (HR = 1.41, 95% CI: 1.15–1.73, p = 0.001), and follow-up period >3 years (HR = 1.31, 95% CI: 1.04–1.64, p = 0.019) was notably high, with I2 values of 59.1, 63.1 and 59.4%, respectively. In contrast, no significant heterogeneity was observed for studies with age ≥ 60 (HR =1.47, 95% CI: 1.13–1.91, I2 = 0), PNI cut off value ≤46 (HR = 1.56, 95% CI: 1.35–1.80, I2 = 31.6%), or a follow-up period ≤3 years (HR = 1.64; 95% CI: 1.34–2.00; I2 = 0).
Table 2. Subgroup analysis of RFS included in the meta-analysis.
3.5 Publication bias and sensitivity analysis
Publication bias between studies was conducted using Egger’s test. Results indicated publication bias was found between PNI and OS (p = 0.001), while no publication bias was detected between PNI and RFS (p = 0.104) (Figure 4b). To further evaluate publication bias for OS, the trim-and-fill method was applied. The addition of six missing studies did not alter the overall effect (HR = 1.495; 95% CI: 1.361–1.642; p < 0.001) (Figure 4a), indicating that publication bias for OS did not impact the results and could be ignored. Sensitivity analysis demonstrated that no single study significantly influenced the conclusions of this meta-analysis (Figure 5).
Figure 4. Result of Publication bias. (a) Funnel diagram of OS after filled six studies. (b) Egger’ s test of RFS.
Figure 5. Consequence of sensitivity analysis. (a) OS. (b) RFS.
4 Discussion
PNI was first proposed by Buzby et al. (42), and later validated by Onodera et al. (43) to predict the surgical risk in gastrointestinal malignancy. Due to its convenience and efficiency, the PNI has been investigated widely, with numerous studies demonstrating that a low PNI is an independent prognostic factor for both short-term postoperative complications and long-term outcomes across various cancers, such as gastric cancer (44), colorectal cancer (44), lung cancer (45), oral cancer (46), biliary tract cancer (47), and so on. In HCC, the PNI was first proposed as a potential prognostic maker by Pinato et al. (48), and its role in HCC treatment and prognosis continues to expand. Pretreatment PNI had been studied across diverse HCC patient groups, including these treated with curative therapies, radiofrequency ablation, microwave ablation (49), sorafenib (50), anti-PD1 therapy (51) and liver transplantation (52). More recently, researches have begun to explore the implications of post-treatment PNI (53). As studies on this topic continue to emerge, there is an urgent need to summarize and analyze the extensive research data to draw meaningful conclusions.
In this review, we comprehensively summarized the literature to date, providing supportive evidence for the prognostic significance of PNI in predicting outcomes for HCC patients following curative hepatectomy. This systematic review and meta-analysis included 19 studies with a total of 9,830 patients. The results indicated that the higher PNI was associated with significantly longer OS (n = 6,812, HR = 1.60; 95% CI: 1.45–1.77; p < 0.001) and RFS (n = 8,529, HR = 1.48, 95% CI: 1.30–1.68, p < 0.001), consistent with the previous meta-analyses (20, 24, 25). In the meta-analyses conducted by Guangliu Wu (24) and Xiaoxiao Fan (20), it remained unclear whether the patients received systemic antitumor therapy prior to hepatectomy, and the timing of PNI testing was ambiguous. Notably, Guangliu Wu’s study did not clarify whether PNI was assessed preoperatively or postoperatively (24), and the most recent literature in Xiaoxiao Fan’s study dated back to 2017 (20). Another related meta-analysis suggested that a lower preoperative PNI significantly predicted worse OS and DFS across HCC patients undergoing surgical resection, transcatheter arterial chemoembolization, and non-surgical treatment (25). In our meta-analysis, we only included treatment-naive patients prior to surgery to eliminate the effect of antitumor treatment on PNI. Moreover, the literature included in this paper is relatively new and up to 2024, which provides a more comprehensive understanding of the relationship between PNI and survival outcomes.
The significant statistical heterogeneity was found in RFS. Although the factors of heterogeneity of PNI are very complex, the results of subgroup analyses could partially explain these heterogeneous factors. Subgroup analysis demonstrated that there were significant differences in age, cut-off values of PNI, and follow-up period. Firstly, heterogeneity generation is related to the age. Generally, the elderly are more susceptible to malnutrition due to decreased physiologic function and metabolic level, which in turn may influence PNI. Particularly, the related research also showed that poor nutritional status in HCC patients over 65 years was associated with worse prognoses (54). Consistently, broad age range from 49.6 to 70.5 median years was observed in our study, which may contribute to the heterogeneity. Secondly, the cut off value significantly influences the delineation of specific groupings, which were closely associated with the calculated method. Indeed, three different sources of cut-off value were involved among all the included articles with “previous literature” (7, 20, 29), “survminer” package (30, 35), and ROC data. Thirdly, the follow-up period is also a source of heterogeneity. One study focused on the psoas muscle index (PMI), an indicator similar to PNI, indicated that PMI was an independent prognostic factor for 1-year treatment outcomes but not effective for predicting 6-month outcomes (55). Unfortunately, the absence of precise median follow-up times in six of the studies included in this paper limited the potential for further in-depth analysis. Additionally, differences in multivariate analysis models may also contribute to heterogeneity, as models based on different postoperative inflammatory indicators and clinicopathological factors exhibit varying HRs and 95% CIs (30).
The PNI incorporates measurements, such as ALB levels and lymphocyte count, that reflect both nutritional and immunological status. ALB (56) helps regulate blood volume and pressure, crucial for transporting nutrients, hormones, and immune cells (56). It’s also linked to cancer prognosis, particularly in patients with HCC (57, 58). Lymphocytes, another part of the PNI, can prevent tumor growth and recurrence by supporting immune function (59). Additionally, a low PNI is associated with poor survival rates in metastatic intrahepatic cholangiocarcinoma (ICC) (6). Moreover, it also helps predict outcomes for patients undergoing immunotherapy (60), targeted therapy (50), and radiochemotherapy (61, 62).
There are several reasons why a low preoperative PNI may be associated with a poor prognosis in patients with HCC following curative hepatectomy. Firstly, the PNI serves as an indicator of nutritional status. A low preoperative PNI suggests a compromised nutritional state, which negatively impacts prognosis. Secondly, the study of Pinato noted that PNI correlated significantly with raised AFP, liver functional reserve, and the presence of portal vein thrombosis, suggesting that a high-risk PNI correlated with a more aggressive disease phenotype (48). Additionally, both ALB levels and lymphocyte counts could explain the phenomenon. ALB levels are linked to liver function and have been correlated with survival outcomes across various cancer types, including HCC. The lymphocyte count, an accessible and cost-effective biomarker of inflammation, plays a crucial role in assessing immune function and infection status.
Besides the PNI, patient prognosis may also be influenced by other factors, such as TNM staging (63), BCLC staging (26), age, sex (64), follow-up time (55). The study found that while PNI did not predict OS in HCC cases generally (HR = 1.855, 95% CI: 0.927–3.711; p = 0.081), it was an independent prognostic factor for OS in HCC patients who underwent curative hepatectomy at TNM stage I (HR = 2.305, 95% CI: 1.008–5.268; p = 0.048) (20). Unfortunately, most of the articles included in this study did not provide staging information, leaving insufficient data for further analysis. Across all 19 studies included, the number of BCLC (0/A) stage patients was greater than that of BCLC (B/C/D) stage patients, and the number of male patients was greater than that of female patients, which makes the conclusions of this paper more applicable to early-stage male liver cancer patients. Notably, most of the patients included had HBV, and antiviral treatment had a considerable impact on the conclusions, as it is known to produce biochemical and virological improvements in chronic HBV patients, including elevated serum ALB levels and increased peripheral T-lymphocyte counts (65). Studies shown that the use of antiviral treatment was associated with higher PNl (66). However, the included studies did not specify whether patients received HBV treatment or provide details of the treatment regimen, limiting the investigation of the relationship between antiviral treatment and PNI.
There were limitations in this meta-analysis. Firstly, we were unable to perform a subgroup analysis for each TNM stage and gender because of the limited number of included studies. Secondly, the cut off value of PNI was not completely consistent between studies, leading to the potential sources of heterogeneity. Finally, all the studies included were retrospective studies, lacking the prospective study. Additionally, all the studies are based in Asia. The lack of research from Europe and America means that the conclusions are only applicable to Asian patients.
5 Conclusion
In summary, this meta-analysis and systematic review endeavor to provide a definitive assessment of the prognostic significance of the preoperative PNI in HCC patients undergoing curative hepatectomy. Moreover, based on the conclusion, we speculated that HCC patients could benefit from preoperative treatment, such as enteral nutrition support and preoperative non-steroid anti-inflammatory drugs, to help HCC patients reach a satisfied PNI value.
Data availability statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.
Author contributions
HZ: Writing – original draft, Software, Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – review & editing. DL: Writing – review & editing, Validation. JL: Data curation, Formal analysis, Funding acquisition, Investigation, Project administration, Resources, Writing – original draft, Writing – review & editing.
Funding
The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was financially supported by Research Projects of Biomedical Center of Hubei Cancer Hospital (Grant number: 2022SWZX10).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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Keywords: prognostic nutritional index, hepatocellular carcinoma, survival, prognosis, meta-analysis
Citation: Zhang H, Li D and Li J (2024) Prognostic significance of preoperative prognostic nutritional index in hepatocellular carcinoma after curative hepatectomy: a meta-analysis and systemic review. Front. Nutr. 11:1433528. doi: 10.3389/fnut.2024.1433528
Edited by:
Jean-Marc A. Lobaccaro, Université Clermont Auvergne, FranceReviewed by:
Wentao Wang, Sichuan University, ChinaQuanjun Lyu, The First Affliated Hosptial of Zhengzhou, China
Copyright © 2024 Zhang, Li and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jing Li, bGpfMDkyMzEzQDE2My5jb20=