Construction and Validation of a Novel Nomogram Predicting Recurrence in Alpha-Fetoprotein-Negative Hepatocellular Carcinoma Post-Surgery Using an Innovative Liver Function-Nutrition-Inflammation-Immune (LFNII) Score: A Bicentric Investigation

Abstract

Purpose

We developed a nomogram based on the liver function, nutrition, inflammation, and immunity (LFNII) score to predict recurrence-free survival (RFS) post-resection in patients with hepatocellular carcinoma (HCC) exhibiting alpha-fetoprotein (AFP) negativity (AFP ≤20 ng/mL).

Patients and Methods

Clinical data of 661 patients diagnosed with alpha-fetoprotein-negative hepatocellular carcinoma (AFP-NHCC) who underwent surgical resection at two medical centers between 2012 and 2021 were collected. A total of 462 and 199 patients served as the training and validation sets, respectively. Pre-operative blood markers were collected and analyzed for LFNII. The LFNII score was formulated using the least absolute shrinkage and selection operator Cox regression model. A nomogram model was developed using the training set to incorporate other relevant clinicopathological indicators and predict postoperative recurrence. Model discrimination was assessed using the receiver operating characteristic curve, calibration was evaluated using a calibration curve, and clinical applicability was assessed using clinical decision curve analysis. A comparison with liver cancer staging was performed using the nomogram model. Finally, a cohort study was conducted to validate our findings.

Results

We derived the LFNII scores from nine indicators. Elevated LFNII scores correlated with unfavorable clinicopathological features. The LFNII score area under the curve revealed superior predictive efficacy at 1-, 2-, and 5-year RFS intervals, with values of 0.675, 0.658, and 0.633, respectively. Multivariate Cox analysis revealed that a high LFNII score independently increased RFS risk in patients with AFP-NHCC. The C-index of the LFNII-nomogram model was 0.686 (95% confidence interval [CI], 0.651–0.721). The nomogram model’s clinical application value surpassed that of standard HCC staging systems.

Conclusion

The LFNII score-derived nomogram effectively predicted the RFS of patients with AFP-NHCC after curative resection.

Keywords:

• hepatocellular carcinoma
• alpha-fetoprotein-negative
• immunity
• inflammation
• nutrition
• recurrence-free survival

Abbreviations

AAR, aspartate aminotransferase to alanine aminotransferase; AFP, alpha-fetoprotein; AFP-NHCC, alpha-fetoprotein-negative hepatocellular carcinoma; ALB, albumin; ALBI, albumin-bilirubin score; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ATS, alpha-feto protein tumor burden score; AUC, area under the curve; BCLC, Barcelona Clinic Liver Cancer system; DCA, decision curve analysis; GAPR, gamma-glutamyl transpeptidase to alkaline phosphatase; GAR, gamma-glutamyl transpeptidase to aspartate aminotransferase; GGT, gamma-glutamyl transpeptidase; GLR, gamma-glutamyltransferase-to-lymphocyte ratio; HCC, hepatocellular carcinoma; KM, Kaplan–Meier; LASSO, least absolute shrinkage and selection operator; LFNII, liver function-nutrition-inflammation-immune; LMR, lymphocyte-to-monocyte ratio; LYMPH, lymphocyte; MLR, monocyte-to-lymphocyte ratio; MONO, monocyte; MVI, microvascular invasion; NEUT, neutrophil; NLR, neutrophil-to-lymphocyte ratio; NrLR, neutrophil times gamma-glutamyl transpeptidase-to-lymphocyte ratio; PALBI, modified albumin-bilirubin score; PLR, platelet-to-lymphocyte ratio; PLT, blood platelet count; RFS, recurrence-free survival; ROC, receiver operating characteristic; SII, systemic immune-inflammation index; SIRI, serum immune-to-inflammation ratio index; TBIL, total bilirubin.

Data Sharing Statement

All data generated or analyzed during this study are included in this article and the Supplementary Materials. Further inquiries can be directed to the corresponding authors.

Ethics Approval

The researchers obtained ethical permission from the Ethics Committees of the Cancer Hospital of the Chinese Academy of Medical Sciences and the Fifth Medical Center of the PLA General Hospital, with approval number 21/198-2869. This study was conducted in accordance with the principles outlined in the Declaration of Helsinki, and the research protocols were conducted in accordance with applicable standards and laws. Informed consent was obtained from all participants prior to their inclusion in the study.

Acknowledgments

The authors would like to thank the patients who participated in this study and the staff at the Department of Hepatobiliary Surgery of the Cancer Hospital, Chinese Academy of Medical Sciences, and The Fifth Medical Center of the PLA General Hospital for their support and cooperation.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or in all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The author(s) report no conflicts of interest in this work.

Additional information

Funding

This study was supported by the CAMS Innovation Fund for Medical Sciences (CIFMS; grant number 2021-I2M-1-066); CAMS Initiative for Innovative Medicine (grant number 2021-I2M-1-015); National Natural Science Foundation of China (grant numbers 81972311, 82141127); and Sanming Project of Medicine in Shenzhen (grant number SZSM202011010).