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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 1  |  Page : 84-89

Preablation neutrophil-to-lymphocyte ratio as an independent prognostic factor in locally advanced hepatocellular carcinoma patients following radiofrequency ablation


1 Department of Ultrasound, Qingdao Municipal Hospital, The Affiliated Hospital of Qingdao University, Qindao, China
2 Department of Ultrasound, Weifang People's Hospital, Weifang, Shandong, China

Date of Web Publication8-Mar-2018

Correspondence Address:
Dr. Xia Li
Department of Ultrasound, Qingdao Municipal Hospital, The Affiliated Hospital of Qingdao University, 1# Jiaozhou Road, Qindao
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_835_17

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 > Abstract 

Background and Aims: Neutrophil-to-lymphocyte ratio (NLR), as an inflammation-based marker, plays critical roles in hepatocellular carcinoma (HCC). This study was aimed to investigate the prognostic value of preablation NLR in locally advanced HCC patients following radiofrequency ablation (RFA) and to determine an optimal cutoff value for NLR.
Materials and Methods: From September 2008 to May 2017, 402 locally advanced HCC patients treated with RFA were retrospectively evaluated. Several prognostic factors including NLR was assessed with univariate and multivariate analysis. The optimal cutoff value of NLR was determined with a maximally selected log-rank test. Other prognostic factors influenced the overall survival (OS) were also evaluated.
Results: Based on the univariate analysis of 16 prognostic factors for OS, the type of hepatitis, a-fetoprotein (AFP), NLR, alanine aminotransferase, aspartate aminotransferase, and serum albumin were identified as independent prognostic factors; and based on multivariate analysis of 6 prognostic factors for OS, AFP, and NLR were identified (P < 0.05). A NLR of 2.2 was determined to be the optimal cutoff value (area under the curve = 0.855, P < 0.001). In a comparison between the high NLR group and the low NLR group, there was a difference of 7 months in the median OS (24 vs. 31 months, P < 0.001).
Conclusions: Preablation NLR was a valuable predictor in locally advanced HCC patients treated with RFA. NLR ≥2.2 indicated a poor prognosis. These findings suggested that preablation NLR may be a convenient, easily-obtained, low cost, and reliable biomarker with prognostic potential for HCC patients.

Keywords: Locally advanced hepatocellular carcinoma, neutrophil-to-lymphocyte, radiofrequency ablation


How to cite this article:
Tan W, Sun W, Li X, Zhao L, Wang C, Zang A, Kong X. Preablation neutrophil-to-lymphocyte ratio as an independent prognostic factor in locally advanced hepatocellular carcinoma patients following radiofrequency ablation. J Can Res Ther 2018;14:84-9

How to cite this URL:
Tan W, Sun W, Li X, Zhao L, Wang C, Zang A, Kong X. Preablation neutrophil-to-lymphocyte ratio as an independent prognostic factor in locally advanced hepatocellular carcinoma patients following radiofrequency ablation. J Can Res Ther [serial online] 2018 [cited 2019 Nov 14];14:84-9. Available from: http://www.cancerjournal.net/text.asp?2018/14/1/84/226766


 > Introduction Top


Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most frequent cause of cancer-associated mortality worldwide. It indicated the poor prognosis of HCC.[1],[2] With the improvement of imaging diagnosis, the incidence of locally advanced HCC has been increasing. The standard treatments for unresectable locally advanced HCC have been transarterial chemoembolization (TACE), radiofrequency ablation (RFA), microwave ablation, laser ablation (LA), and cryoablation.[3],[4] RFA has become one main modality of locoregional therapy because of its effectiveness and safety for small HCC (D ≤5.0 cm), with a 3-year survival rate of 62%–77%,[5] a low treatment complication rate of 8%–9%, and a low treatment mortality rate of 0%–0.5%.[6] Recently, increasing evidence has shown that the presence of systemic inflammation was correlated with poorer survival in some cancer patients.[7],[8],[9],[10],[11],[12] Several studies have shown that the pretherapy neutrophil-to-lymphocyte ratio (NLR) was an independent predictor for prognosis in HCC patients treated with liver transplantation, surgical resection, TACE, thermal ablation, and sorafenib.[13],[14],[15],[16] The NLR (neutrophil count to the lymphocyte count) has been a useful and readily available indicator in clinic that reflected the potential balance between neutrophil-associated pro-tumor inflammation and lymphocyte-dependent antitumor immune function.[17],[18],[19],[20] The elevated NLR may represent a trend toward increased protumor inflammation and decreased antitumor immune function.[21] However, the optimal cutoff value of NLR was approximately ranged from 1.0 to 5.0, which was too wide to be applied in clinic.[22],[23],[24] In addition, to the best of our knowledge, seldom study was performed on the prognostic role of NLR in locally advanced HCC patients following RFA.

In this study, we aimed to investigate the preablation NLR as a prognostic factor in locally advanced HCC patients treated with RFA and to determine the optimal cut-off value for determining NLR. In addition, the correlations between NLR and patients' clinicopathological features were also assessed. Furthermore, a simple preablation prognostic system would be established, which may assist in the selection of patients who would benefit most from RFA.


 > Materials and Methods Top


Patients population

This research was approved by the Medical Ethics Committee of our hospitals. Written informed consent was obtained from all the participating patients.

From September 2008 to May 2017, 402 locally advanced HCC patients (299 male and 103 female, aged 18–92 years, mean ± standard deviation: 51.7 ± 10.6 years) were enrolled in this study, with a total of 1098 HCC nodules detected by either conventional ultrasound (US) or contrast-enhanced US (CEUS)/computed tomography (CT)/magnetic resonance imaging (MRI). All patients received curative ablation. The mean diameter of lesions in our study was 2.9 ± 1.0 cm (ranged from 1.0 to 5.0 cm). The previous treatment of patients included surgical (83 cases, 20.6%), TACE (96 cases, 23.9%), and ablation (radiofrequency, microwave, cryoablation, and LA) (223 cases, 55.5%). The types of virus infections included hepatitis B virus (HBV) (262 patients, 65.2%), hepatitis C virus (HCV) (64 patients, 15.9%), HBV + HCV (10 patients, 2.5%), and without virus infection (66 patients, 16.4%). Liver cirrhosis was observed in 313 patients (77.9%). The differentiation degree was classified by high level (51 cases, 12.7%), middle level (334 cases, 83.1%), and low level (17 cases, 4.2%). The Child-Pugh score was evaluated as A (382 cases, 95.0%) and B (20 cases, 5.0%). The NLR is the ratio of the neutrophil count to the lymphocyte count. The final diagnosis of HCC was determined by pathological examination of surgical specimens or biopsy specimens.

The inclusion criteria were listed as follows: (1) Nonresectable locally advanced HCC or patient refused to receive surgery; (2) age of ≥18 years; (3) Eastern Cooperative Oncology Group performance status of 0 or 1; (4) single HCC lesion ≤5 cm; (5) more than two nodules, with a maximum diameter ≤3 cm; (6) absence of portal vein thrombosis or extrahepatic metastases; (7) without serious blood coagulation disorders; (8) a follow-up of at least 3 months after RFA treatment. The exclusion criteria were listed as follows: (1) severe cardiopulmonary disease; (2) serious renal function failure; (3) severe liver function failure, such as uncontrollable ascites, hepatic encephalopathy, and serious esophageal gastric varices; and (4) active or severe infection which may affect preablation NLR.

Ablation procedure

All treatments were performed after hospitalization. An enhanced CT or MRI scan of the abdomen and pelvis were performed within 1 month before the treatment for all patients, as well as the electrocardiogram. Serum laboratory tests were performed in 1 week before the treatment. CEUS was regularly performed to confirm tumor coverage and tumor number before RFA.[25]

Real-time US systems, LOGIC-E9 (GE Healthcare, Milwaukee, WI, USA) were applied for scanning with 3.5–5.0 MHz convex probes for ablation procedures. Before RFA, an US/CEUS-guided biopsy was performed with an automatic biopsy gun and a 18G cutting needle under local anesthesia with 1% lidocaine. During each biopsy, 2–3 punctures were performed. Subsequently, the antennas were percutaneously inserted into the tumor and placed in the desired location under the guidance of US or CEUS.

After the patients were consciously sedated and locally anesthetized, RFA was performed percutaneously by US guidance. Tumors were ablated through multiple overlapping insertions (2–4) by single electrode with a 1.0- or 3.5-cm exposed tip (ValleyLab, Burlington, MA). Emission time was lasted for 12 or 30 min by a 200W generator set. Complete ablation was defined as the ablation zone coverage a 0.5–1.0 cm width margin of the normal liver parenchyma surrounding the tumor if the ablation zone could be enlarged. Or else, a shaped ablation was performed. To completely ablate the tumor close to the bile duct, gallbladder, or bowel, ethanol was injected into the marginal tumor tissue through a 21G percutaneous transhepatic cholangiography needle during the ablation. When the hyperecho overlapped in the whole lesion, the electrode was withdrawn. The needle tracks were routinely cauterized to avoid bleeding and tumor seeding.[26],[27]

Follow-up

The enhanced images were obtained at 7-day after RFA and the complete ablation was defined as no-enhancement in any area of the lesion. Subsequently, patients were followed with repeat US and CT/MRI every 2–3 months during the 1st year and every 4–6 months in the following years. The period of follow-up was ranged from 3 to 60 months. Residual tumor, local progression, and new tumors were retreated if another RFA session could be tolerated by the patient.

Statistical analysis

The data were analyzed with SPSS for Windows (Version 21.0, SPSS Inc, Chicago, IL, USA). Variables statistically significant in the univariate analysis were involved into a multivariable Cox proportional hazards analysis. The prognostic value of preablation NLR was assessed taking into account of the effects from confounding factors. The optimal cutoff value of NLR was determined by receiver operating characteristic (ROC) curve analysis. Independent Chi-square tests were applied to compare categorical variables. Continuous variables were compared by unpaired t-tests. The overall survival (OS) curves were analyzed by the Kaplan-Meier method and compared with the log-rank test. P < 0.05 indicated statistically significant.


 > Results Top


Correlation between neutrophil-lymphocyte ratio and overall survival following radiofrequency ablation by univariate and multivariate analysis in locally advanced hepatocellular carcinoma patients

To determine whether preablative NLR was correlated with prognosis after RFA in locally advanced HCC patients, both univariate and multivariate analyses were performed. On univariate analysis of 16 prognostic factors for OS, the type of hepatitis, a-fetoprotein (AFP), NLR, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and serum albumin (ALB) were identified as independent prognostic factors (P< 0.05). Then, the six independent prognostic factors were further evaluated with multivariate Cox proportional hazard model analysis. AFP and NLR were identified as independent prognostic factors (P< 0.05) [Table 1]. The results suggested that NLR was an independent prognostic factors for OS in locally advanced HCC patients following RFA.
Table 1: Univariate and multivariate analysis of clinical factors in relation to survival of locally advanced hepatocellular carcinoma patients

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Selection of the optimal cutoff value of neutrophil-lymphocyte ratio for predicting overall survival after locally advanced hepatocellular carcinoma patients receiving radiofrequency ablation

To analyze preablative NLR value for predicting OS after locally advanced HCC patients receiving RFA, a time-dependent ROC curve was performed. An NLR of 2.2 was considered the optimal cutoff value to predict the prognosis after RFA (area under the ROC was 0.855, P < 0.001) [Figure 1]. Therefore, NLR was determined as a risk factor for prognosis, with a cutoff value of 2.2. All patients were divided into either a low (NLR <2.2) NLR group (n = 152) or a high (NLR ≥2.2) NLR group (n = 250). The results indicated that high NLR was observed in 62.2% (250/402) patients in locally advanced HCC, which may be inclined to a poor prognosis [Figure 2].
Figure 1: Receiver operating curves analysis for neutrophil-lymphocyte ratio predicating prognosis in locally advanced hepatocellular carcinoma patients following radiofrequency ablation neutrophil-lymphocyte ratio = 2.2 was considered to be evaluated (area under the receiver operating characteristic = 0.855; P < 0.001)

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Figure 2: Comparison of overall survival in the low (neutrophil-lymphocyte ratio <2.2) and high (neutrophil-lymphocyte ratio ≥2.2) neutrophil-lymphocyte ratio groups. The overall survival was significantly higher in the low neutrophil-lymphocyte ratio group than in the high neutrophil-lymphocyte ratio group in locally advanced hepatocellular carcinoma patients following radiofrequency ablation (P < 0.001)

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Comparisons of the overall survival between low- and high-neutrophil-lymphocyte ratio groups of locally advanced hepatocellular carcinoma

To compare the difference of OS between the low- and high-NLR groups in locally advanced HCC, the differences of basic clinical parameters were first eliminated between the two groups. A total of 15 clinical parameters were compared between the low NLR and high NLR groups [Table 2], [Table 3], [Table 4]. No significantly difference was found in gender, age, type of hepatitis, differentiation, Child-Pugh, cirrhosis, number of tumor, size of tumor, and prothrombin time between the two groups. While, significant difference was detected in pretreatments, AFP, cholinesterase (CHE), AST, ALT, and ALB. The results suggested that high NLR was negatively associated with these 6 clinical factors.
Table 2: Comparison of clinical parameters of locally advanced hepatocellular carcinoma patients between the low- and high-neutrophil-lymphocyte ratio groups

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Table 3: Comparison of clinical parameters of locally advanced hepatocellular carcinoma patients between the low and high NLR groups

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Table 4: Comparison of clinical parameters of locally advanced hepatocellular carcinoma patients between the low and high NLR groups (continued)

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During the follow-up period (median: 27 months), a comparison between the high NLR group and the low NLR group was performed with a significant difference. Seven months difference in the median OS was detected (24 months in high NLR group versus 31 in low NLR group, P < 0.001). The results suggested that high NLR (≥2.2) indicated a poor prognosis in locally advanced HCC patients.


 > Discussion Top


It reported that the development of cancers including HCC was closely related with the balance of inflammation and immunity status, and the liver was an immune organ itself.[28] HCC commonly occurs on the background of chronic liver disease, which induces chronic inflammation and impaired immunity. NLR was a useful, easy available clinic indicator that reflected systemic inflammatory response in some cancers.[29],[30],[31] A high level of neutrophil was related to the release of chemokines and interleukins, which promoted tumor growth and metastasis in HCC.[32] Lymphocytes was related to T lymphocyte-mediated antitumor response,[33] and a low level of lymphocyte reflected a weak lymphocyte-mediated immune response to tumor.[22] Previous studies have shown that a higher NLR was correlated with adverse survival outcomes in patients with various solid tumors.[7],[8],[11],[16]

RFA has emerged as one of the standard treatments for HCC patients according to the Barcelona-clinic liver cancer group.[3],[34] This technique was designed to induce tumor destruction by delivering a high frequency alternating current through an active needle-electrode introduced into the neoplastic tissue.[35] The resultant movement generated frictional heating which leads to cell death by means of coagulative necrosis. Cellular death would be instantaneously observed at temperatures above 60°C.[36] Increasing number of studies demonstrated that RFA treatment released tumor antigen to prime the immune system and to induce antitumor immunity.[37],[38],[39] The present retrospective study with a relatively large cohort of locally advanced HCC patients suggested that high preablation NLR was associated with poor survival, confirmed by both univariate and multivariate analysis. The results suggested that NLR and AFP were independent prognostic factors for predicting OS in locally advanced HCC patients receiving RFA. AFP was a useful factor for predicting prognosis in many studies which have been verified. However, NLR has not been analyzed as a representative index of immunity status in locally advance HCC patients. In this study, by ROC analysis, the optimal cutoff value of NLR was verified as 2.2. Moreover, 62.2% locally advanced HCC patients with high NLR may indicate a poor immunity status. The ratio was similar to that of in the prior report in recurrent HCC patients after thermal ablation.[15]

In the comparison of OS between the low and high NLR groups in locally advanced HCC, pretreatments, AFP, CHE, AST, AL, and ALB were verified as potential influence factors. However, in univariate and multivariate analysis, these factors were not considered as influence factors for prognosis. Thus, after eliminating the differences of basic clinical parameters between the two groups, the prognosis was differenced significantly in HCC patients in low and high NLR groups. In locally advanced HCC patients, prolonged survival time of 7 months was observed. This result may not only assist clinician in predicting HCC patients' survival before and after ablation but also reminding the clinician to perform timely adjuvant treatment to improve the prognosis of patients with preablation NLR of ≥2.2.

The results of present study should be interpreted with caution considering several limitations. First, this study was limited by the retrospective nature of the analysis and based on patients at seldom institutions. Second, C-reactive protein as another important inflammation index was not analyzed in this study. In addition, the mechanism of the relationship between NLR and prognosis in locally advanced HCC patients was not examined and analyzed. Therefore, multicenter prospective studies would be conducted to confirm and further perfect the findings demonstrated in this study.


 > Conclusions Top


The results of this study suggest that preablation NLR was a valuable predictor in locally advanced HCC patients treated with RFA. NLR cutoff of ≥2.2 indicated a poor prognosis, and this value may remind clinician to perform timely adjuvant treatment to improve the prognosis for patients with preablation high NLR. These findings suggested that preablation NLR may be a convenient, easily-obtained, low cost, and reliable biomarker with prognostic potential for locally advanced HCC patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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