Patients who received TACE treatment for unresectable HCC from September 2009 to November 2011 at the Department of Hepatobiliary Surgery, Sun Yat-Sen University Cancer Canter (Guangzhou, China) were identified from our prospective database. The research was approved by the Institutional Review Board of Sun Yat-sen University Cancer Center, and written informed consent was obtained.

The diagnosis of HCC was based on the diagnostic criteria for HCC used by the American Association for the Study of the Liver guidelines[23]. HCC was diagnosed by at least two radiologic images showing characteristic features of HCC or one radiologic image showing characteristic features of HCC associated with elevated serum alpha-fetoprotein (AFP; ≥ 400 ng/mL) or histopathologic evidence. Patients that met all of the following criteria were included in analysis: (1) no previous treatment before TACE; (2) HBV positive; (3) HCV and HIV negative; (4) liver function Child-Pugh A or B; (5) follow-up period ≥ 3 mo; and (6) HCC was considered to be unresectable by our multidisciplinary team including surgeons, oncologists, radiologists, hepatologists, and pathologists. Unresectable disease was defined as extensive bilobular involvement of the liver by a large solitary lesion or by multiple lesions, or invasion of major blood vessels including the main portal vein, hepatic veins, inferior vena cava, and main hepatic artery. Patients with any of the following were excluded: (1) obstructive jaundice; (2) hepatic encephalopathy; (3) liver function Child-Pugh C; and (4) poor data integrity.

All the parameters were recorded and evaluated as possible predictors of survivals including sex, age, CRP, white blood cell count, neutrophil count, lymphocyte count, platelet count, AFP, alkaline phosphatase (ALP), alpha-L-fucosidase (AFU), total bilirubin level, albumin, tumor size and number, and tumor thrombus. The inflammation-based prognostic scores, including GPS, mGPS, NLR, PLR, PI, and PNI, were determined as described in Table 1.

TACE was performed using the protocol that we have previously reported[24]. A selective 5 Fr catheter was introduced into the hepatic artery and visceral angiography was carried out to assess the arterial blood supply to the liver. Depending on the size, location, and arterial supply of the tumor, the tip of the catheter was advanced into the right or left hepatic artery; if all the tumors were fed by one enlarged independent hepatic artery branch, the tip of catheter was introduced into this tumor-feeding artery. If the conventional catheter could not enter the hepatic artery because of technical reasons, a 2.9 Fr micro catheter (Terumo Corp., Tokyo, Japan) was used. Hepatic artery infusion chemotherapy was performed using carboplatin 300 mg (Bristol-Myers Squibb, New York, NY, United States). After that, chemolipiodolization was performed using epirubicin 50 mg (Pharmorubicin; Pfizer, Inc., New York, NY, United States), and mitomycin C 6 mg (Zhejiang Hisun Pharmaceutical Co. Ltd., Taizhou, China) mixed with 5 mL of Lipiodol (Lipiodol Ultra-Fluide; Andre’ Guerbet Laboratories, Aulnay-Sous-Bois, France). If the chemolipiodolized arterial territory did not show stagnant flow, pure Lipiodol was then injected. In some patients, we were unable to reach stasis in a tumor-feeding artery even with the injection of the maximum amount of iodized oil (25 mL) because of the large size of the tumor. Embolization was then performed in these patients with injection of absorbable gelatin sponge particles (Gelfoam; Hanzhou alc Ltd, China), 1-2 mm in diameter, through the angiographic catheter. This treatment regimen was used consistently, regardless of tumor type and size.

Patients were followed carefully after treatment. Patients underwent liver CT scans one month after TACE, and liver CT scans were performed at three-month intervals during the first two years, then every 6 mo thereafter with physical examination and blood tests for AFP and liver function. When metastasis was suspected, chest CT, bone scintigraphy, and biopsy if indicated were also performed to confirm metastasis. The end of follow-up was the time of last follow-up (December 2013) or death.

Another session of TACE was performed every 4-10 wk until CT scans and AFP levels suggested stabilization of the tumor, or until it was not technically feasible either because of hepatic artery occlusion or impaired liver function. Overall survival (OS) was defined as the interval between treatment and death or last follow-up of surviving patients. Causes of death were determined from death certificates, medical interviews, and radiologic findings.

The definition and calculation for all inflammation scores (GPS, mGPS, NLR, PLR, PNI, PI) are listed in Table 1, and the universal cutoff values reported by literatures were utilized in the present study. Comparisons between two groups were conducted using the Student’s t test for continuous data, and the χ² test for categorical data. The OS was calculated by the Kaplan-Meier method and compared by a log-rank test. The prognostic variables in predicting OS were assessed by multivariate Cox proportional hazards regression analysis. Variables that proved to be significant in the univariate analysis were subsequently tested with the multivariate Cox proportional hazard model using a forward selection method. The hazard ratio of survival by Cox proportional hazard model was calculated to compare the strength of predictors of survival. To evaluate the discriminatory ability of each scoring system and each staging, the receiver operating characteristics (ROC) curve and the area under the curve (AUC) were constructed at 6-mo, 12-mo, and 24-mo follow-up. The AUC was also used to assess the discrimination ability of the new combined scoring with other scorings. Results are given as mean ± SD. All statistical tests were two-sided, and a significant difference was considered at P < 0.05. All the statistical analyses were performed using SPSS 13.0 software (SPSS Inc., Chicago, IL, United States).

A total of 224 consecutive patients who met our criteria were included in this study. Patients’ baseline characteristics are summarized in Table 2. There were 199 male (89%) and 25 female (11%) patients with a median age of 53 years (range: 23-80 years). The majority of our patients had a good liver functional reserve with Child-Pugh A (93.0%).

Among the 224 patients, 126 (56%) patients had an elevated CRP level (> 10 mg/L), 40 (18%) had hypoalbuminemia (< 35 g/L), and 24 (11%) had both elevated CRP level and hypoalbuminemia. Sixty-eight (30%) patients had PLR ≥ 150; 116 (52%) patients had NLR ≥ 3; 70 (31%) patients had PNI > 45, and 109 (49%) patients were allocated to PI 1 or 2. The relationships between inflammatory scores and clinicopathologic features were analyzed (data not shown). Both GPS and mGPS were associated with tumor size, vascular invasion, AST, ALP, Child-Pugh grade, and Cancer of the Liver Italian Program (CLIP); NLR with age, tumor size, vascular invasion, AST, ALP, CLIP, and BCLC stage; PI with tumor size, AST, ALP, and CLIP, PLR with age, tumor size, and ALP; PNI with Child-Pugh grade only.

The median follow-up period was 390 d (range: 90-1527), and at the time of analysis, 198 patients had died. The one-, two-, and three-year OS was 38.4%, 18.3%, and 11.1% respectively, and the median OS was 390 d.

The univariate and multivariate analyses of prognostic factors for OS are shown in Table 3. In univariate analysis, age, neutrophil count, CRP, ALT, AST, ALP, AFU, diameter of the largest lesion, total bilirubin, AFP, tumor size, tumor number, vascular invasion, Child-Pugh score, and inflammatory scores including GPS, mGPS, NLR, and PI were associated with OS (all P < 0.05). The BCLC stage, CLIP score, and TNM stage were also confirmed as significant predictors of OS (all P < 0.001) (Figure 1).

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Figure 1 Kaplan-Meier survival curves for overall survival in 224 patients undergoing transarterial chemoembolization for hepatocellular carcinoma. A: Glasgow Prognostic Score (GPS); B: Modified GPS (mGPS); C: Prognostic Index (PI); D: Neutrophil-lymphocyte ratio (NLR); E: Tumor-node-metastasis (TNM); F: Barcelona Clinic Liver Cancer (BCLC); G: Cancer of the Liver Italian Program (CLIP); H: Combined score of the GPS and CILP.

Multivariate analysis showed that ALT, GPS, and CLIP were independent prognostic factors for OS (all P < 0.01). When GPS and CLIP were replaced by the combined scores, multivariate analysis showed that the combined GPS and CLIP scores (HR = 1.724, 95%CI: 1.347-2.285; P < 0.001) were independent prognostic factors for OS along with ALT.

The prognostic power of inflammation scores and staging systems was compared by means of AUC analysis. ROC curves were calculated for survival status at 6-mo, 12-mo, and 24-mo follow-up, and the AUC were compared to assess the discrimination ability of each inflammation scores and staging systems. The GPS consistently had a higher AUC value at 6 mo, 12 mo, and 24 mo in comparison with other inflammation-based prognostic scores (all P < 0.001), and the CLIP consistently had a higher AUC value at 6 mo, 12 mo, and 24 mo in comparison with TNM and BCLC staging systems (all P < 0.001) (Table 4, Figure 2).

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Figure 2 Comparisons of the area under the curve for outcome prediction. Comparisons among the inflammation scores, staging systems, and combined score of the Glasgow Prognostic Score (GPS) and Cancer of the Liver Italian Program (CLIP) at A, D: 6 mo; B, E: 12 mo; and C, F: 24 mo in patients with hepatocellular carcinoma after transarterial chemoembolization. BCLC: Barcelona Clinic Liver Cancer; mGPS: Modified Glasgow Prognostic Score; NLR: Neutrophil-lymphocyte ratio; PI: Prognostic Index; PLR: Platelet-lymphocyte ratio; PNI: Prognostic Nutritional Index; TNM: Tumor-node-metastasis.

We proposed a combined score of the GPS and CLIP score (Table 5). The combined score had a higher AUC of 0.777 (95%CI: 0.692-0.862) when compared to the CLIP score alone or the GPS alone. The survival curve showed that the combined score divided patients into subgroups more accurately (Table 4, Figure 2).

Hepatocellular carcinoma (HCC) is one of the most frequent cancers worldwide. When diagnosed, up to 70%-90% of HCCs are not suitable for curative treatment because of advanced tumor stage. Transarterial chemoembolization (TACE), as the main treatment for HCC, has demonstrated improved survival benefit for select patients, but is not suitable for all patients. The key point is stratifying and choosing the most suitable HCC patients. To this aim, the authors compared the prognostic ability of six inflammation scores, and then proposed a new score by combining the optimal inflammation score with the staging system to recruit patients who would most likely benefit from TACE in such a heterogeneous HCC population.

There is increasing interest in the role of systemic inflammation as a predictor of outcome in HCC. The current research hotspot is to compare six inflammation scores in HCC patients undergoing TACE.

Previous studies have found that the inflammation scores, including the Glasgow Prognostic Score (GPS), modified GPS, platelet-lymphocyte ratio, neutrophil-lymphocyte ratio, Prognostic Nutritional Index, and Prognostic Index, are associated with patient survival, but which one is most suitable for HCC patients undergoing TACE is still controversial. Furthermore, the prognostic ability for only one score to predict survival is still weak. So, in the present study, the authors compared the prognostic ability of six inflammation scores and three clinical staging systems, and then combined the optimal score (GPS) and clinical staging system [Cancer of the Liver Italian Program (CLIP)] together. The results showed that the combined score can improve the prognostic power; thus it can help the interventional physician to recruit patients for TACE.

Those patients with combined score > 3 would not benefit from TACE, other treatments, for example sorafenib or clinical trials, should be considered.

The authors made an interesting and useful study to improve the estimation of the prognosis in patients with hepatitis B virus-related HCC after TACE. The result shows GPS is superior to other inflammation scores and combined use of GPS and CLIP can improve the prognostic power for overall survival. According to the combined scores, it can select patients who would most likely benefit from TACE, and predict survival benefit in these patients.