Author Affiliations: Department of Liver Surgery (Li Y, Yi HM, Wang GY, Yang Y and Jiang N) and Department of Medical Oncology (Ruan DY), The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China

Corresponding Author: Nan Jiang, MD, PhD, Department of Liver Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China (Tel:+86-20-85252177; Fax:+86-20-85252276; Email: njiang163@ 163.com)

 

© 2015, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(15)60412-X

Published online September 9, 2015.

 

Acknowledgments: We thank Professor Jin-Xin Zhang from Department of Medical Statistics and Epidemiology, Sun Yat-Sen University for his technical assistance.

Contributors: JN proposed the study. LY, RDY and JN performed the research and wrote the first draft. LY and RDY collected and analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. LY and RDY contributed equally to this article. JN is the guarantor.

Funding: This study was supported by grants from the Guangdong Natural Science Foundation (S2013010016023), National Natural Science Foundation of China (81572368), Science and Technology Planning Project of Guangdong Province, China (2014A020212084), the Fundamental Research Funds for the Central Universities (12ykpy47 and 12ykpy43), National 12th Five-Year Science and Technology Plan Major Projects of China (2012ZX10002017-005).

Ethical approval: Not needed.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

BACKGROUND: No staging systems of hepatocellular carcinoma (HCC) are tailored for assessing recurrence risk. We sought to establish a recurrence risk scoring system to predict recurrence of HCC patients receiving surgical curative treatment (liver resection or transplantation).

 

METHODS: We retrospectively studied 286 HCC patients with preserved liver function receiving liver resection (n=184) or transplantation (n=102). Independent risk factors were identified to construct the recurrence risk scoring model. The recurrence free survival and discriminatory ability of the model were analyzed.

 

RESULTS: Total tumor volume, HBsAg status, plasma fibrinogen level were included as independent prognostic factors for recurrence-free survival and used for constructing a 3-factor recurrence risk scoring model. The scoring model was as follows: 0.758×HBsAg status (negative: 0; positive: 1)+0.387×plasma fibrinogen level (≤3.24 g/L: 0; >3.24 g/L: 1)+0.633×total tumor volume (≤107.5 cm³: 0; >107.5 cm³: 1). The cut-off value was set to 1.02, and we defined the patients with the score ≤1.02 as a low risk group and those with the score >1.02 as a high risk group. The 3-year recurrence-free survival rate was significantly higher in the low risk group compared with that in the high risk group (67.9% vs 41.3%, P<0.001). In the subgroup analysis, liver transplantation patients had a better 3-year recurrence-free survival rate than the liver resection patients in the low risk group (80.0% vs 64.0%, P<0.01). Additionally for patients underwent liver transplantation, we compared the recurrence risk model with the Milan criteria in the prediction of recurrence, and the 3-year recurrence survival rates were similar (80.0% vs 79.3%, P=0.906).

 

CONCLUSION: Our recurrence risk scoring model is effective in categorizing recurrence risks and in predicting recurrence-free survival of HCC before potential surgical curative treatment.

 

(Hepatobiliary Pancreat Dis Int 2015;14:477-484)

 

KEY WORDS: hepatocellular carcinoma; liver resection; liver transplantation; total tumor volume; plasma fibrinogen

Globally, hepatocellular carcinoma (HCC) is one of the most common cancers and causes 695 900 deaths annually.^[1] Recurrence, which is seen in approximately 70% of the patients within 5 years, is the primary cause of poor survival of HCC patients after surgical curative treatment, either liver resection (LR) or liver transplantation (LT). Many factors including large tumor burden, micro and major vascular invasion, poor histological differentiation and multifocal disease are associated with HCC recurrence.^[2-4] Various tumor staging systems are currently available to predict prognosis, but they have major limitations. The American Joint Committee on Cancer (AJCC) Tumor-Node-Metastasis (TNM) staging system does not consider liver function.^[5] The OKUDA staging system considers tumor burden and liver function, but not major vascular invasion and distant metastases,^[6] two prominent features critical for choosing treatment after surgery. The Cancer of the Liver Italian Program (CLIP) staging system has better performance in survival prediction,^{[7, 8]} however, it is skewed and lacks resolution.^[9] The Barcelona Clinic Liver Cancer (BCLC) system combines disease staging with treatment strategy and has been used in Europe and the USA, but it discriminates poorly survival of very early or far advanced cancer stage patients.^[10]

 

LR offers a cost-effective choice for patients with resectable tumor and preserved liver function while LT remains a rational therapeutic option in selected patients with HCC.^[11] The Milan criteria have been widely used for assessing candidacy for LT, which has yielded favorable survival outcomes.^{[12, 13]} However, many investigators consider this classification too restrictive, unduly denying access to a substantial number of patients who expect to benefit from LT. Several alternative schemes such as the University of California San Francisco (UCSF) criteria and the Hangzhou criteria have been proposed to expand the selection of candidates whose tumors remain at a reasonable size.^{[14, 15]} But like the Milan criteria, the UCSF criteria also exclude all patients with more than three lesions, the Hangzhou criteria need histopathologic grade which sometimes is not available for preoperative assessment. More importantly, both the tumor staging systems and the LT selection criteria are used in HCC patients for overall survival, which may not be adequate for predicting postoperative recurrence.

 

Total tumor volume (TTV) has been used recently as a comprehensive measure of tumor burden to predict prognosis of HCC patient receiving LT.^{[16, 17]} However, to date, few studies have specifically investigated the predictive accuracy of recurrence risk in HCC patients based on TTV along with other prognostic parameters. Besides tumor burden, the impact of tumor microenvironment has been evaluated in various malignancies. A specific association between the hemostatic system and cancer has been recognized previously.^[18] Zhu et al^[19] demonstrated that the expression of fibrinogen mRNA was significantly higher in the cancer tissues of patients with HCC. The neutrophil-to-lymphocyte ratio (NLR) which represents the imbalance of systemic inflammatory response has been demonstrated as a predictor of poor prognosis in cancer patients.^{[20, 21]} Whether these novel markers could predict the recurrence of HCC is still unknown. In this retrospective study, we analyzed the preoperative prognostic factors of HCC patients received curative surgical treatments (LR and LT). Our aims were 1) to set up a simple and practical model to discriminate the recurrence risk based on TTV; 2) to provide a new strategy and approach for making optimal clinical decision.

 

 

We retrospectively reviewed the medical records of patients with pathologically proven HCC who received LR or LT between September 2003 and September 2010 in our institution. The selection criteria were as follows: 1) no extrahepatic tumor or lymph node metastasis; 2) no positive surgical margin upon LR; 3) no perioperative period death; 4) newly diagnosed HCC without any neoadjuvant therapy; and 5) preserved liver function (Child-Turcotte-Pugh class A). All the patients were potentially available for both LR and LT regarding patients' personal choice and financial situations.

 

Preoperative diagnosis of HCC was based on alpha-fetoprotein (AFP) and characteristic radiological features using at least two of the following imaging methods: ultrasonography, computed tomography (CT) or magnetic resonance imaging (MRI). A lesion was considered HCC when it demonstrated an arterial enhancement with washout on delayed images or when a significant increase in size was documented. Preoperative data including demographic information and baseline clinicopathologic characteristics were retrieved. TTVs calculated as the sum of the volumes of all tumors using a standard equation: tumor volume (cm³)=4/3×3.14×r³ (r=the maximum radius of each measurable tumor nodule).^[16]

 

The follow-up was once every 3 months for the first 3 years, and every 6 months thereafter and consisted of physical examination, routine blood chemistry, serum AFP, chest X-ray and abdominal ultrasound. In patients with suspicious lesions upon ultrasound or elevated AFP, further examinations (contrast-enhanced ultrasound, CT or MRI) were conducted to confirm or to rule out recurrence. The primary endpoint was recurrence-free survival (RFS), defined as the time from the date of surgery to the date of the first recurrence or last follow-up in patients with no recurrence. Immunosuppressive agents after LT included calcineurin inhibitor (cyclosporine A or tacrolimus) and/or rapamycin, and glucosteroid (discontinued within 3 months).

 

Categorical data were expressed as number and percentage. Continuous variables were expressed as mean and standard deviation unless specified otherwise. Predictive factors for recurrence were examined using a step-forward analysis that included a univariate analysis, followed by a multivariate analysis that included factors with at most 0.1 P value in univariate analysis using a Cox's regression model. Factors deemed as independent recurrence risk factors were used to construct a mathematical model. RFS was examined using the Kaplan-Meier method. A receiver operating characteristic (ROC) analysis was performed to find the cut-off value. All statistical analyses were performed using the SPSS 16.0 for Windows (SPSS Inc, Chicago, IL) or the MedCalc version 11.4 (The MedCalc software). Statistical significance was set at P<0.05.

 

 

A total of 286 HCC patients were included in this study, 184 (64.3%) underwent LR and 102 (35.7%) received LT. The characteristics of the patients are summarized in Table 1. The majority of the patients were male (n=261, 91.3%). The mean age was 47.6 years old (range 12-73). The majority of the patients (n=251, 87.8%) were positive for HBsAg and hepatic cirrhosis was present in 69.9% (n=200) of them. Vascular invasion was found in a minority of the patients (n=55, 19.2%). The patients in the LR group and the LT group were comparable in demographic and baseline characteristics.

 

The median follow-up time was 23 months (range 1-132). A total of 141 (49.3%) patients experienced tumor recurrence, mostly within the first 3 years (n=124, 87.9%). The RFS rates were 72.4% and 56.6% at 1 and 3 years, 72.3% and 55.4% for patients underwent LR, 72.5% and 58.8% for those received LT, respectively. No significant difference in the RFS rate was observed between LR and LT (P=0.302).

 

The median value of TTV was 41.67 cm³. The optimal cut-off value for TTV determined by the ROC analysis was 107.5 cm³ and 31.8% of the patients (n=91) were beyond this volume. For pretreatment plasma fibrinogen, the median level was 2.98 g/L and the cut-off value was 3.24 g/L. The plasma fibrinogen level over 3.24 g/L was found in 38.5% of the patients (n=110). For preoperative NLR, the cut-off value was 2.32, and 45.5% of the patients (n=130) were beyond this ratio.

 

Upon univariate analysis, lower RFS was associated with HBsAg positivity, elevated plasma fibrinogen level, elevated preoperative NLR, vascular invasion and larger TTV (Table 2). Multivariate regression analysis revealed three independent prognostic predictors of poor RFS: HBsAg positivity (HR: 2.134; 95% CI: 1.095-4.159; P=0.026), plasma fibrinogen >3.24 g/L (HR: 1.473; 95% CI: 1.012- 2.144; P=0.043) and TTV >107.5 cm³ (HR: 1.883; 95% CI: 1.251-2.834; P=0.002; Fig. 1).

 

The three independent factors identified with multivariate analysis were included in the final model. The scoring model was as follows: 0.758×HBsAg status (negative: 0; positive: 1)+0.387×plasma fibrinogen level (≤3.24 g/L: 0; >3.24 g/L: 1)+0.633×TTV(≤107.5 cm³: 0; >107.5 cm³: 1). The associated parameter estimates (regression coefficients or weights) and P values of the variables are shown in Table 3. The ROC curve analysis showed that the AUC of scoring was 0.658 (95% CI: 0.600-0.713; P<0.001). The cut-off score was 1.02 with a sensitivity of 55.32% and a specificity of 70.34% (Fig. 2A). Patients were divided into the high recurrence risk group (model score >1.02) and the low recurrence risk group (model score ≤1.02). The 1-, 3-year RFS rates of the low recurrence risk group and high recurrence risk group were 81.2% and 60.3%, 67.9% and 41.3%, respectively (P<0.001; Fig. 2B).

 

We further evaluated the RFS rates of patients who had undergone LR and those who had received LT stratified by the risk groups according to the recurrence risk model. In the overall analysis that included all subjects, the RFS rate was not significantly different between HCC patients who had received LR and those who had had LT (Table 2). A subgroup analysis revealed that the RFS rate was significantly higher in the LT patients than in the LR patients of the low risk group, and the 3-year RFS rates were 80.0% and 64.0%, respectively (P<0.01; Fig. 3A); but it was not observed in the high risk group (45.2% vs 37.3%; P=0.524).

 

Forty patients were in the low risk group and 29 patients who had undergone LT were within the Milan criteria. The 1-, 3-year RFS rates were 90.0% vs 82.8%, and 80.0% vs 79.3%, respectively (P=0.381, P=0.906; Fig. 3B) in this group. The 3-year RFS rate AUC of the risk scoring model was higher than that within the Milan criteria (67.1% vs 62.0%).

 

 

Currently available staging systems for HCC are based on clinical and pathological findings and are limited in their usefulness for predicting recurrence. In this study, we investigated prognostic risk factors based on the preoperative clinical information, established a recurrence prediction system for those of potentially surgical curable patients; this system is valuable to bedside decision-making.

 

Recurrence after HCC removal is associated with tumor size, the number of tumor nodules, major vascular invasion and liver function status. In all currently available staging systems, tumor burden is estimated as a composite of the maximum diameter of the biggest tumor nodule and the number of tumor nodules. TTV, a simplified measure of tumor burden, is a feasible prognostic predictor for HCC patients undergoing locoregional therapy.^[22] Toso et al^[16] set the cut-off value of TTV to 115 cm³ to predict the outcomes; this value was later confirmed by a larger database analysis.^[17] Our data indicated that TTV>107.5 cm³ is an independent prognostic predictor of poor RFS. A TTV of 107.5 cm³ corresponding to a single nodule of 6 cm in the maximum diameter was used as the cut-off value. Compared to the traditional approach, TTV achieves a higher accuracy of pre-transplant radiological staging and is not limited by tumor number.^[16]

 

Chronic hepatitis B infection is seen in a significant proportion of HCC patients worldwide.^[23] Up to 80% of HCC cases are attributed to chronic HBV infection in China.^[24] Consistently, HBsAg was also positive in the majority of our patients (87.8%). HCC patients with active hepatitis B have a significantly higher risk of recurrence after curative surgery.^[25] We also found that positive HBsAg status was an independent risk factor of tumor recurrence.

 

Fibrinogen, a 340-kDa glycoprotein synthesized by hepatocytes and converted to fibrin by activated thrombin, is one of the important coagulation factors.^[26] The hemostatic system plays a critical role in maintaining vascular integrity and also appears to contribute significantly to vascular development, tissue repair, inflammatory processes, cell adhesion and trans-endothelial cell migration. This spectrum of biological functions has made the hemostatic system components prime candidates as tumor progression factors.^[27] Recent studies^[28-30] indicated that elevated plasma fibrinogen levels are associated with tumor progression and other poor outcomes in several types of malignancies. Kinoshita et al^[31] found that an elevated plasma fibrinogen level is associated with a larger tumor size, the presence of vascular invasion and higher CLIP scores in patients with HCC. Similar to several previous studies, our data indicated that elevated plasma fibrinogen remained a significant risk factor for HCC recurrence and patients with plasma fibrinogen level over 3.24 g/L had a lower 3-year RFS rate (44.5%) than those below 3.24 g/L (64.2%).

 

The advantage of our system is that it does not require any additional histological examinations and can be clinically applicable as a marker for the recurrence prediction of patients with HCC. Based on these factors, our recurrence risk scoring model showed increasing recurrence rate upon progression from low score to high score and we defined the risk group by the cut-off value of 1.02. The 1-, 3-year survival rates of HCC patients with survival scores of less than 1.02 were 81.2% and 67.9% respectively after surgery. Our model had a specificity of 0.703 for the prediction of first year recurrence. The equation produces a prognostic score which is objective and specific for predicting HCC recurrence after surgery.

 

Patients with potentially curable HCC should be treated surgically,^[32] but optimal type of surgery remains controversial.^[33-35] A previous study reported a higher RFS rate after LT for single HCC at <5 cm with underlying cirrhosis.^[36] For patients with early stage HCC meeting the Milan criteria, the prognosis after LT is comparable to that for benign liver disease; a fraction of patients beyond the Milan criteria may also benefit from LT. However, the option of LT is limited by tumor burden and more so by a lack of donors.^[37] As such, LR remains a choice from the cost-effectiveness perspective.^[11] In our study, the patients within the Milan criteria showed much higher 3-year RFS rate than those beyond the Milan criteria (79.3% vs 50.7%, P<0.05). However only less than 1/3 patients (29/102) were within the Milan criteria. This may be the reason that no significant difference in the RFS rate was observed between LR and LT. But in a subgroup analysis, we noticed a longer RFS after LT (relative to LR) in low risk patients, which may be due to removal of both detectable and undetectable tumor lesions, particular in patients with an underlying liver disease or unresectable tumor. This indicated the recurrence risk scoring model helps assess the patients who benefit most from liver transplantation. Owing to limited organ supply, LR as the primary treatment, followed by salvage LT, if necessary, has been advocated.^[38] We demonstrated that LT is the ideal choice for low risk patients. The prognosis of high risk patients was not significantly different between patients receiving LR and LT, indicating that after both surgeries the intensive examination should be strongly recommended.

 

For LT patients, the recurrence risk scoring model was comparable with the Milan criteria but more patients were selected (40 vs 29 patients). This indicated that the scoring model may open an access to a substantial number of patients who are expected to benefit from LT.

 

The current study should be interpreted with caution due to its retrospective nature and regional high prevalence of HBV infection in the study sample. The validity of the new model requires a larger population.

 

In conclusion, we identified preoperative prognostic risk factors and established an effective recurrence prediction system for potentially surgical curable HCC patients. With this staging system, we can preoperatively predict the patients' outcome after surgery with clinically available markers, such as TTV, plasma fibrinogen and HBsAg status. 

 

 

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