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  • Neutrophil-lymphocyte Ratio Plus Prognostic Nutritional Index Predicts the Outcomes of Patients with Unresectable Hepatocellular Carcinoma After Transarterial Chemoembolization

Neutrophil-lymphocyte Ratio Plus Prognostic Nutritional Index Predicts the Outcomes of Patients with Unresectable Hepatocellular Carcinoma After Transarterial Chemoembolization


For many malignancies, inflammation-based scores correlate with survival. The neutrophil-to-lymphocyte ratio (NLR) and prognostic nutritional index (PNI) are immunonutritional indices associated with postoperative outcomes in patients with hepatocellular carcinoma (HCC). We evaluated whether a combined preoperative NLR and PNI score was prognostically superior to either index alone in 793 patients with unresectable HCC after transarterial chemoembolization. Patient demographic, clinical, and pathological data were also collected and analysed. A receiver-operating characteristic (ROC) analysis was used to classify patients as follows: NLR-PNI 0 group (NLR ≤ 2.2 and PNI > 46), NLR-PNI 1 group (NLR > 2.2 or PNI ≤ 46) and NLR-PNI 2 group (NLR > 2.2 and PNI ≤ 46). Regarding 1-, 3-, and 5-year survival, the NLR-PNI score had superior discriminative abilities (i.e., higher area under the ROC curve), compared with either the NLR or PNI alone, and patients in the NLR-PNI 0, 1, and 2 groups had median survival times of 33 (95% confidence interval: 22.8–43.2), 14 (10.9–17.1), and 6 (9.9–14.1) months, respectively. In multivariate analyses, the Barcelona Clinic Liver Cancer, total bilirubin, vascular invasion, and NLR-PNI score adversely affected overall survival. In conclusion, the NLR-PNI score can improve the accuracy of prognoses for patients with unresectable HCC.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the third leading cause of cancer-related mortality worldwide1. Additionally, HCC was estimated to be the second leading cause of cancer-related death among men2. Currently, the prevalence of hepatitis B virus (HBV) infection in China is high, and more than 50% of HCC cases and deaths have been estimated to occur in this country2. However, a majority (60%) of patients with HCC have an advanced disease stage or liver decompensation at diagnosis and are therefore ineligible for curative therapies such as hepatic resection, liver transplantation, and frequency ablation. Rather, locoregional therapies such as transarterial chemoembolization (TACE) are widely used to treat unresectable intermediate and advanced HCCs3.

TACE exploits the progressive tumour angiogenesis and thus targets neoplastic tissue intra-arterially via the focused administration of chemotherapy administration, followed by the induction of acute ischemic damage with relative sparing of the surrounding tissue4. Evidence from randomized controlled trials has demonstrated the efficacy of TACE for improving overall survival (OS) by slowing disease progression5. However, studies have also shown that not all patients with unresectable HCC benefit from TACE. Therefore, it is crucial to differentiate between those patients who will and will not likely benefit from TACE.

The presence of an inflammatory response is considered pathogenic in the development of cancer-associated malnutrition, and leads to a poor performance status and increased mortality in cancer patients. Particularly, this is a concern for patients with HCC in China because the majority of HCC cases are consequent to an underlying chronic HBV infection, and the concomitant underlying illness and cirrhosis may contribute to an impaired nutritional status6. Researchers have expressed increasing interest in the role of systemic inflammation as a predictor of the outcomes of patients with HCC. Apart from objective markers of systemic inflammation, such as the C-reactive protein (CRP) and albumin (ALB) levels, various combinations of haematological components of the systemic inflammatory response have widely investigated, including the neutrophil to lymphocyte ratio (NLR) and prognostic nutritional index (PNI). However, the predictive abilities of the NLR and PNI regarding the post-TACE outcomes of patients with HCC remain unclear. Huang et al.7 revealed that an elevated NLR was associated with poor overall survival (OS) among patients undergoing TACE, and Pinato et al.6, who first proposed the PNI, proved that a lower score is an independent and externally validated predictor of poor OS in patients with HCC. However, Kinoshita et al.8 suggested that neither the NLR nor the PNI correlated with the outcomes of HCC. In addition, He et al.9 confirmed that the NLR and PNI are less powerful predictive systems that for patients receiving TACE for unresectable HCC.

To date, few studies have evaluated the relationship between the NLR and PNI to predict the outcomes of intermediate to advanced HCC, especially in a prognostic model based on a combination of these indices. Therefore, it remains unclear whether a combination of inflammation-based scores could better reflect the systemic inflammatory state. The present study investigated whether a combination of the NLR and PNI would be a useful prognostic predictor of the postoperative outcomes of TACE-treated patients with unresectable HCC.

Patients with newly diagnosed intermediate-to-advanced HCC who received TACE as an initial therapy at the Department of Liver Surgery, West China Hospital, Sichuan University (Chengdu, China) between January 2007 and December 2013 were enrolled in this study. The diagnosis of HCC was based on the diagnostic criteria used by the American Association for the Study of the Liver10. Patients who fulfilled all of the following criteria were included: (1) no treatment before TACE; (2) Child–Pugh liver function of A or B; (3) follow-up period ≥1 month; and (4) HCC was deemed unresectable by a liver cancer multidisciplinary team comprising surgeons, oncologists, radiologists, and interventional radiologists. Patients were excluded if they underwent hepatic resection, radio-frequency treatment, liver transplantation, or another appropriate treatment for HCC during the follow-up period. This study was approved by the Institutional Review Board (IRB) of the West China Hospital, Sichuan University. Informed written consent was obtained from all individual participants included in the study. All the methods used in this study were carried out according to the approved guidelines.

Clinicopathologic variables, including demographic parameters; full blood counts; ALB, total bilirubin (TB), alpha-fetoprotein (AFP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels; prothrombin time (PT); international normalized ratio (INR); tumour staging information (including number of focal lesions and maximum diameter of contrast-enhancing lesions); Child–Turcotte–Pugh class; Model for End-stage Liver Disease (MELD) score; and Barcelona Clinic Liver Cancer (BCLC) stage11, were collected at the time of referral to our department, prior to treatment.

The NLR was defined as the absolute neutrophil count divided by the lymphocyte count12. The PNI was calculated as follows: albumin (g/L) + 0.005 × absolute lymphocyte count (mm3)13. The NLR and PNI cut-off values were determined using receiver operating characteristic (ROC) curves according to the patients’ OS status.

A new inflammation-based score system, the NLR-PNI score, was then generated by combining the NLR score with the PNI score. The NLR-PNI score was calculated from pre-TACE data as follows: patients with both an elevated NLR and a decreased PNI were allocated a score of 2, those with either an elevated NLR or a decreased PNI were allocated a score of 1, and those with a decreased NLR and an elevated PNI were allocated a score of 0.

A uniform treatment protocol was applied to each patient. TACE was performed through the femoral artery via the Seldinger technique with local anaesthesia. After arteriography of the celiac trunk and superior mesenteric artery to visualize arterial vascularization of the liver, body surface-dependent doses of the chemotherapeutic agents 5-fluorouracil (800–1000 mg) and epirubicin-adriamycin (30–40 mg) were injected. Subsequently, lipiodol (Lipiodol Ultra-Fluide; Andre Guerbet Laboratories, France) and polyvinyl alcohol foam (PVA) embolization particles (Cook, Bloomington, IN, USA, 100–500 μm in diameter) were injected as selectively as possible into the hepatic segmental artery at the target tumour location. The embolization agent doses ranged from 5 to 30 mL and were determined based on the tumour location, size, and number.

One month after TACE, all patients underwent blood cell tests, liver function tests, AFP measurements, computed tomography or magnetic resonance imaging, and chest radiography to evaluate tumour responses. If elevated tumour marker levels (AFP), diminished lipiodol, enlarged lesions, or new nodules were observed, the patients were readmitted for angiography and treatment within an interval of 1.5–3.0 months. If a patient either could not tolerate the procedure because of a decline in his/her clinical status or presented with a complete response, TACE was terminated. The starting point of the survival analysis was defined as the day of the initial treatment. The end of follow-up was recorded as either December 31, 2013 (the last follow-up) or…