Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as predictors of tumor response in hepatocellular carcinoma after DEB-TACE

Abstract

Objectives: To investigate the predictive value of quantifiable imaging and inflammatory biomarkers in patients with hepatocellular carcinoma (HCC) for the clinical outcome after drug-eluting bead transarterial chemoembolization (DEB-TACE) measured as volumetric tumor response and progression-free survival (PFS).

Methods: This retrospective study included 46 patients with treatment-naïve HCC who received DEB-TACE. Laboratory work-up prior to treatment included complete and differential blood count, liver function, and alpha-fetoprotein levels. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were correlated with radiomic features extracted from pretreatment contrast-enhanced magnetic resonance imaging (MRI) and with tumor response according to quantitative European Association for the Study of the Liver (qEASL) criteria and progression-free survival (PFS) after DEB-TACE. Radiomic features included single nodular tumor growth measured as sphericity, dynamic contrast uptake behavior, arterial hyperenhancement, and homogeneity of contrast uptake. Statistics included univariate and multivariate linear regression, Cox regression, and Kaplan-Meier analysis.

Results: Accounting for laboratory and clinical parameters, high baseline NLR and PLR were predictive of poorer tumor response (p = 0.014 and p = 0.004) and shorter PFS (p = 0.002 and p < 0.001). When compared to baseline imaging, high NLR and PLR correlated with non-spherical tumor growth (p = 0.001 and p < 0.001).

Conclusions: This study establishes the prognostic value of quantitative inflammatory biomarkers associated with aggressive non-spherical tumor growth and predictive of poorer tumor response and shorter PFS after DEB-TACE.

Key points: • In treatment-naïve hepatocellular carcinoma (HCC), high baseline platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) are associated with non-nodular tumor growth measured as low tumor sphericity. • High PLR and NLR are predictive of poorer volumetric enhancement-based tumor response and PFS after DEB-TACE in HCC. • This set of readily available, quantitative immunologic biomarkers can easily be implemented in clinical guidelines providing a paradigm to guide and monitor the personalized application of loco-regional therapies in HCC.

Keywords: Hepatocellular carcinoma; Lymphocytes; Neutrophils; Platelet count; Radiomics.

Fig. 1

Study workflow and exclusion criteria. AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; BL, baseline; CBC, complete blood count; DBC, differential blood count; DEB-TACE, drug-eluting bead transarterial chemoembolization; ETB, enhancing tumor burden; ETV, enhancing tumor volume; F/U, follow-up; HCC, hepatocellular carcinoma; LI-RADS, Liver Imaging Reporting and Data System; OS, overall survival; PFS, progression-free survival; TB, tumor burden; TTV, total tumor volume; qEASL, quantitative European Association for the Study of the Liver

Fig. 2

Linear regression of tumor sphericity on baseline imaging and inflammatory markers prior to treatment. This graph demonstrates that more single nodular growth patterns of tumors, measured as increased tumor sphericity, correlate with low (a) neutrophil-to-lymphocyte ratio (NLR) (p = 0.001) and (b) platelet-to-lymphocyte ratio (PLR) (p < 0.001)

Fig. 3

Linear regression of inflammatory markers and tumor response according to qEASL. This graph demonstrates that low (a) neutrophil-to-lymphocyte ratio (NLR) and (b) platelet-tolymphocyte ratio (PLR) correlate with better tumor response according to quantitative European Association for the study of the Liver (qEASL) (p = 0.004,p = 0.001)

Fig. 4

Representative examples of HCC lesions with low (a) and high (b) tumor sphericity as assessed using radiomics feature analysis on baseline MRI. While low tumor sphericity indicative of extranodular and aggressive tumor growth (a) was associated with higher PLR, well-defined tumors with high sphericity (b) were associated with lower PLR. Additionally, patients with high PLR (a) revealed poorer tumor response after DEB-TACE (c, stable disease) as compared to patients with low PLR (d, partial response). White arrows indicate tumors

Fig. 5

a, b Kaplan-Meier analysis of NLR and PLR with PFS. a Patients with low NLR (separated by the mean of 3.22) did not demonstrate significant longer PFS compared to patients with high NLR (12.17 and 5.51 months, p = 0.187). b Patients with low PLR (< 113.1) showed longer PFS than patients with high PLR (15.5 and 5.51 months, p < 0.001). Dotted lines indicate the median PFS of the respective group