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High Neutrophil–Lymphocyte Ratio and Delta Neutrophil–Lymphocyte Ratio Are Associated with Increased Mortality in Patients with Hepatocellular Cancer

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Abstract

Background

The neutrophil–lymphocyte ratio (NLR) has been proposed as a prognostic biomarker for cirrhosis and non-liver malignancies. We aimed to evaluate the prognostic value of NLR in a diverse cohort of patients with hepatocellular carcinoma (HCC).

Methods

We performed a retrospective study of patients diagnosed with HCC between 2008 and 2017 at two large US health systems. We used Cox proportional hazard and multivariable ordinal logistic regression models to identify factors associated with overall survival and response to first HCC treatment, respectively. Primary variables of interest were baseline NLR and delta NLR, defined as the difference between pre- and post-treatment NLR.

Results

Among 1019 HCC patients, baseline NLR was < 5 in 815 (80.0%) and ≥ 5 in 204 (20.0%). Patients with NLR ≥ 5 had a higher proportion of infiltrative tumors (36.2% vs 22.3%), macrovascular invasion (39.6% vs 25.5%), metastatic disease (20.6% vs 11.4%), and AFP > 200 ng/mL (45.6% vs 33.8%). Baseline NLR ≥ 5 was independently associated with higher mortality (median survival 4.3 vs 15.1 months; adjusted HR 1.70, 95%CI 1.41–2.06), with differences in survival consistent across BCLC stages. After adjusting for baseline covariates including NLR, delta NLR > 0.26 was also independently associated with increased mortality (HR 1.42, 95%CI 1.14–1.78). In a secondary analysis, high NLR was associated with lower odds of response to HCC treatment (20.2% vs 31.6%; adjusted OR 0.55, 95%CI 0.32–0.95).

Conclusions

In a large Western cohort of patients with HCC, high baseline NLR and delta NLR were independent predictors of mortality.

Impact

NLR is an inexpensive test that may be a useful component of future HCC prognostic models.

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Abbreviations

AASLD:

American Association for the Study of Liver Diseases

AFP:

Alpha-fetoprotein

ECOG:

Eastern Cooperative Oncology Group

EMR:

Electronic medical record

HBV:

Hepatitis B virus

HCC:

Hepatocellular carcinoma

HCV:

Hepatitis C virus

HR:

Hazard ratio

MELD:

Model for End-Stage Liver Disease

NAFLD:

Nonalcoholic fatty liver disease

NLR:

Neutrophil–lymphocyte ratio

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Funding

Dr. Singal’s research was supported by National Cancer Institute R01 CA222900 and R01 MD12565. Dr. Hoshida was supported by Cancer Prevention and Research Institute of Texas RR180016. Dr. Marrero was supported by NIH R01 CA237659. Dr. Rich was supported by the Texas Health Resources Clinical Scholar Award. This research was supported in part by NIH UL-1TR001105 and CTSA NIH UL-1 RR024982. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center, 5959 Harry Hines Blvd, POB 1, Suite 420, Dallas, TX, 75390-8887, USA

    Nicole E. Rich, Aarthi Parvathaneni, Mobolaji Odewole, Ana Arroyo, Arjmand R. Mufti, Thomas A. Kerr, Lafaine Grant, Shannan R. Tujios, Marlyn J. Mayo, William M. Lee, Yujin Hoshida, Jorge A. Marrero & Amit G. Singal

  2. Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX, USA

    Ahana Sen

  3. Division of Digestive and Liver Diseases, Comprehensive Transplant Center and Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA

    Ju Dong Yang

  4. Department of Radiology, UT Southwestern Medical Center, Dallas, TX, USA

    Takeshi Yokoo

  5. Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA

    Purva Gopal

  6. Children’s Research Institute, UT Southwestern Medical Center, Dallas, TX, USA

    Hao Zhu

  7. Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA

    Adam C. Yopp

  8. Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, TX, USA

    Amit G. Singal

Authors
  1. Nicole E. Rich
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Contributions

Drs. Singal and Rich had full access to all of the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis and were involved in study concept and design and analysis and interpretation of the data; Rich, Parvathaneni, Sen, and Odewole performed acquisition of the data; Rich, Parvathaneni, and Singal drafted the manuscript; all authors provided critical revision of the manuscript for important intellectual content; Singal obtained funding and has given administrative, technical, and material support and supervised the study. Amit Singal is the guarantor of the article.

Corresponding author

Correspondence to Nicole E. Rich.

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Conflict of interest

Jorge Marrero has served as a consultant for Glycotest and received research funding from AstraZeneca. Amit Singal has been on advisory boards and served as a consultant for Wako Diagnostics, Roche, Exact Sciences, Glycotest, GRAIL, Bayer, Eisai, BMS, Exelixis, AstraZeneca, Genentech, and TARGET-RWE. Ju Dong Yang has served as a consultant for Exact Sciences, Gilead Sciences, and Eisai. The other authors have no relevant conflicts of interest.

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Nicole E. Rich and Aarthi Parvathaneni have contributed equally to this work.

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Rich, N.E., Parvathaneni, A., Sen, A. et al. High Neutrophil–Lymphocyte Ratio and Delta Neutrophil–Lymphocyte Ratio Are Associated with Increased Mortality in Patients with Hepatocellular Cancer. Dig Dis Sci 67, 2666–2676 (2022). https://doi.org/10.1007/s10620-021-07001-6

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  • DOI: https://doi.org/10.1007/s10620-021-07001-6

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