Author Affiliations: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine (Wang LY, Zheng SS, Xu X, Wang WL, Wu J, Zhang M, Shen Y, Yan S, Chen XH, Jiang TA and Chen F); Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Health, Zhejiang Province (Zheng SS, Xu X, Wang WL, Wu J, Zhang M, Shen Y, Yan S and Xie HY), Hangzhou 310003, China

 

Corresponding Author: Shu-Sen Zheng, MD, PhD, FACS, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Health, Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China (Tel: +86-571-87236601; Fax: +86-571-87236628; Email: shusenzheng@zju.edu.cn)

 

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

doi: 10.1016/S1499-3872(15)60335-6

Published online January 29, 2015.

 

 

Acknowledgements: We would like to thank Dr. Bill Thompson (Old Dominion University, USA) for proofreading this manuscript.

Contributors: ZSS proposed the study. WLY wrote the first draft. All authors contributed to the design and interpretation of the study and to further drafts. ZSS is the guarantor.

Funding: This study was supported by grants from National S&T Major Project (2012ZX10002017), the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (81121002) and the National Natural Science Foundation of China (81200331).

Ethical approval: This study was approved by the Committee of Ethics in Biomedical Research of Zhejiang University.

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: The prognostic prediction of liver transplantation (LT) guides the donor organ allocation. However, there is currently no satisfactory model to predict the recipients' outcome, especially for the patients with HBV cirrhosis-related hepatocellular carcinoma (HCC). The present study was to develop a quantitative assessment model for predicting the post-LT survival in HBV-related HCC patients.

 

METHODS: Two hundred and thirty-eight LT recipients at the Liver Transplant Center, First Affiliated Hospital, Zhejiang University School of Medicine between 2008 and 2013 were included in this study. Their post-LT prognosis was recorded and multiple risk factors were analyzed using univariate and multivariate analyses in Cox regression.

 

RESULTS: The score model was as follows: 0.114×(Child-Pugh score)-0.002×(positive HBV DNA detection time)+0.647×(number of tumor nodules)+0.055×(max diameter of tumor nodules)+0.231×lnAFP+0.437×(tumor differentiation grade). The receiver operating characteristic curve analysis showed that the area under the curve of the scoring model for predicting the post-LT survival was 0.887. The cut-off value was 1.27, which was associated with a sensitivity of 72.5% and a specificity of 90.7%, respectively.

 

CONCLUSION: The quantitative score model for predicting post-LT survival proved to be sensitive and specific.

 

(Hepatobiliary Pancreat Dis Int 2015;14:43-49)

 

KEY WORDS: HBV cirrhosis; hepatocellular carcinoma; liver transplantation; Hangzhou criteria; post-LT survival

Hepatitis B virus (HBV) infection remains a major cause of liver related morbidity and mortality globally with more than 240 million people infected, accounting for more than 780 000 deaths annually.^[1] In Eastern Asia, HBV is the first cause of liver cirrhosis and hepatocellular carcinoma (HCC). Fifty to fifty-five percent of HCC cases are attributed to chronic HBV infection worldwide, and up to 80% in China.^{[2, 3]} Eighty-four percent of liver transplantation (LT) recipients in liver transplantation centers had the history of HBV infection.

 

Several criterion such as Milan criteria and Hangzhou criteria are used to select recipients to prolong the survival time.^[4-9] Many scientists searched the risk factors of survival after liver transplantation in patients with HBV-related HCC. They found that tumor morphologic features, AFP level, histological differentiation and HCC recurrence could be used to predict post-LT survival.^{[4, 10-12]} It is well known that patients with AFP >400 ng/mL had poor prognosis.^[11] However, the ideal cut-off line of AFP value has not been defined. Furthermore, the detectable AFP mRNA in blood indicated that the tumor is poorly differentiated.^{[13, 14]} However, no quantitative model for predicting post-LT survival has been established. We therefore tried to analyze the risk factors and to derive a mathematical model to predict post-LT survival.

 

 

Ethical approval was obtained from the Committee of Ethics in Biomedical Research of Zhejiang University. The current regulations of the Chinese Government and the Declaration of Helsinki were strictly followed for each organ donation and transplant performed at our center. Written informed consent from each donor and recipient were obtained.

 

From 2008 to 2013, 238 HCC patients with HBV-related cirrhosis received LT at the Liver Transplant Center, First Affiliated Hospital, Zhejiang University School of Medicine. All recipients received a post-LT HBV prophylaxis of anti-viral nucleoside analogues and hepatitis B immunoglobulin. They were followed up with liver image changes and AFP levels. The clinical and pathological results of all recipients were retrospectively analyzed, and the post-LT prognosis of all patients was recorded. The baseline demographics and clinical characteristics of the liver transplant recipients are shown in Table 1.

 

All data were obtained from the clinical records of recipients. In order to determine which variables were independent predictors of survival and to develop the final post-LT survival prediction model, 15 potential predictors were screened. The following predictors were selected based on previous studies and clinical experience: gender, age, body mass index (BMI), pre-LT diabetes, waiting time for transplant, pre-LT intervention (yes or no), MELD scores, Child-Pugh scores, number of tumor nodules, max diameter of tumor nodules, total diameter of tumor nodules, microvascular invasion (yes or no), preoperative AFP levels, tumor differentiation grades, positive HBV DNA detection time (days between LT and positive HBV DNA detection).

 

The Cox proportional hazard regression models was used to identify the association of factors with prognosis. First, a univariate analysis was used to evaluate the potential value of risk factors. Then, candidate variables (P value <0.10) were entered into a multivariate analysis. A prognostic model was established from the multivariate Cox proportional hazards analysis: [(regression coefficients β1)×(variable 1)+(regression coefficients β2)×(variable 2)+(regression coefficients β3)×(variable 3)+...]. We also calculated the area under the receiver-operator curve (AUC) and the sensitivity and specificity of an optimal cut-off point for the model score.

 

Survival curves were estimated using the Kaplan-Meier method, and differences were evaluated by the log-rank test. The statistically significant variables from the univariate analysis were also evaluated using the Cox regression analysis to determine the risks for post-LT survival. When the multivariate analysis was applicable or continuous covariates were involved, the Cox proportional hazards regression model was used to determine the effect of covariates, and a stepwise model selection tool was used to construct the final multivariate model. Hazard ratios (HRs) and 95% CIs were estimated using the Cox proportional hazards regression model. A P<0.05 was considered statistically significant. All data were analyzed using SPSS software version 16.0.

 

 

With a mean follow-up of 983 days, the 1-year survival rate of recipients within the Hangzhou criteria was significantly higher than that of recipients beyond the Hangzhou criteria (86.0% vs 64.0%, P<0.001). Also, the 3-year survival rate of recipients within the Hangzhou criteria was higher than that of recipients beyond the Hangzhou criteria (77.2% vs 30.9%, P<0.001). The results were similar for the 5-year survival rate (within the Hangzhou criteria 71.8% vs beyond the Hangzhou criteria 21.4%, P<0.001). These results are shown in Fig. 1.

 

The univariate analysis showed that 10 variables were significant risk factors for survival of the recipients: positive HBV DNA detection time, waiting time for transplant, MELD scores, Child-Pugh classification, number of tumor nodules, maximum diameter of tumor nodules, total diameter of tumor nodules, microvascular invasion (yes or no), preoperative AFP levels, and tumor differentiation grades. All of the predictors that were tested for inclusion were hazard ratio, 95% CI, and P values from univariate analyses (Table 2). All of the identified survival risk factors were then analyzed by multivariate Cox regression. The analysis was a composite derived from 10 imputed data sets in the final model, and variables included in the final model are shown in Table 3. The positive HBV DNA detection time, Child-Pugh score, number of tumor nodules, max diameter of tumor nodules, preoperative AFP levels, and tumor differentiation grades were significant predictors for survival in HBV cirrhosis-related HCC recipients. The variables used, the associated parameter estimates (regression coefficients or weights), and P values from the final model are shown in Table 3. Other variables were analyzed but not included in the final model-building process. The prognostic index from the model was the sum of the variables, each multiplied by its weight. A positive weight attached to a prognostic factor indicated higher mortality, and a negative weight indicated a lower mortality. These parameters were the same for the prognostic index. The post-LT survival could be calculated by the following survival score equation: 0.114×(Child-Pugh score)-0.002×(positive HBV DNA detection time)+0.647×(number of tumor nodules)+0.055×(max diameter of tumor nodules)+0.231×lnAFP+0.437×(tumor differentiation grade). The receiver operating characteristic (ROC) curve was constructed for the scoring model (Fig. 2) and the AUC was calculated. The ROC curve analysis showed that the AUC was 0.887 (95% CI 0.845-0.930, P<0.001). The cut-off score was 1.27 with a sensitivity of 72.5% and a specificity of 90.7%. The 1-, 3-, and 5-year survival rates of recipients with survival scores less than 1.27 were 94.6%, 86.1%, and 77.1%, respectively. Only 19.6% (27/138) of the Hangzhou criteria recipients' survival scores were over 1.27 (Fig. 3). Patients with survival score of less than 1.27 had more favorable outcomes. Overall survival for all recipients and for recipients within the Hangzhou criteria are shown in Fig. 3.

 

To investigate the predictive value of preoperative AFP levels in tumor differentiation, a scatter diagram was constructed (Fig. 4A). Preoperative AFP levels were related to tumor differentiation in recipients with diameters of <5 cm sono-nodule. Because preoperative AFP is a significant prognostic factor for recipients' post-LT recurrence and post-LT survival, ROC curve analysis was performed on the predictive value of preoperative AFP in post-LT prognosis (Fig. 4B, C). The ROC curve analysis showed that the AUC was 0.710 and 0.731 for preoperative AFP in predicting post-LT recurrence and post-LT survival, and an preoperative AFP level of 325.3 ng/mL was the cut-off value. Recipients with AFP levels above 325.3 ng/mL had high post-LT recurrence and poor survival rates. AUC, P values and 95% CI were collected (Table 4).

 

 

In Asia, liver transplantation offers a feasible therapy for HBV cirrhosis-related HCC. The Milan, UCSF, Barcelona, and "up-to-seven" criterion are all used to predict patients' survival in patients with HCC after LT. We proposed our candidate selection criteria as the Hangzhou criteria for patients with HCC.^[4] Our criteria are to identify recipients that do not meet the Milan criteria but have favorable post-LT outcomes. In this study, the 1-, 3-, and 5-year survival rates of HBV cirrhosis-related HCC recipients within the Hangzhou criteria were 86.0%, 77.2%, 71.8%, which are comparable to other published studies adapted either the Hangzhou or Milan criteria.^{[7, 15-17]} These rates were all significantly higher than those that did not meet the Hangzhou criteria. As recipients beyond the Milan criteria increase over time, the number of such transplants also increases. Gao et al^[6] reported that the Milan criteria should be the preferred criteria for LT. However, the consensus is that the Milan criteria are too restrictive, and LTs can be performed safely in other carefully selected recipients.^{[18, 19]} In the present study, we demonstrated that survival rates in patients who met the Hangzhou criteria were similar to those who met the Milan criteria. The Hangzhou criteria only moderately expand the Milan criteria and could be accepted as the preferred criteria for LT.

 

During the past decade, studies^{[20, 21]} found that some indicators could predict post-LT survival. In this study, we selected variables based on a comprehensive assessment of previously reported clinical prognostic factors and added other new variables in order to derive a mathematical model for predicting post-LT survival in a more rational and effective manner. In this study, multiple factors for post-LT survival of HBV cirrhosis-related HCC recipients were chosen based on both tumor morphologic features (tumor size, tumor number, and max diameter of tumor nodules) and on tumor biology factors (preoperative AFP levels, tumor differentiation, and positive HBV DNA detection time). All these factors have been extensively studied in an effort to reduce post-LT recurrence and achieve better survival in order to use donor organs reasonably and effectively. The positive HBV DNA detection time, Child-Pugh score, number of tumor nodules, max diameter of tumor nodules, preoperative AFP levels, and tumor differentiation were significantly correlated with post-LT survival in HBV cirrhosis-related HCC recipients.

 

Positive HBV DNA detection time is a new predictive and characteristic risk factor for HBV cirrhosis-related HCC recipients' post-LT prognoses. The introduction of this new risk factor in the survival score formula was based on its characteristics related to liver injury and the recurrence of HCC. The recurrence of HBV also affects graft loss and death, consequently affecting post-LT recipients' survival.^[21-26]

 

Tumor differentiation associated with post-LT survival and recurrence of HCC has been recently reported. The post-LT survival rates have been reported to be higher in recipients with well-differentiated tumors than in those with poor-differentiated tumors.^{[4, 11, 27-29]} Our results showed that tumor differentiation based on tumor biology is a remarkable risk factor in prognosis. After analyzing the correlation between AFP levels and tumor differentiation, the results indicated that preoperative AFP levels are correlated with tumor differentiation for recipients with tumor diameter <5 cm sono-nodule.

 

The diagnostic accuracy of the survival score equation was quantified by the receiver operating characteristic area under the curve (ROC AUC). AUC reached a high level of 0.887 (95% CI 0.845-0.930, P<0.001). The post-LT survival could be quantitatively assessed by the survival score equation and the cut-off score of 1.27. The sensitivity and specificity were 72.5% and 90.7%, respectively. Such high specificity indicates high true-negative rate and low false-positive rate. Hence, if the survival score is below 1.27, there is a high probability that the recipient will have a good post-LT survival rate. Conversely, when the survival score is above 1.27, the recipient is unlikely to have a good post-LT survival rate.

 

The 1-, 3-, and 5-year survival rates of recipients with survival scores of less than 1.27 were 94.6%, 86.1%, and 77.1%, respectively. The equation produces a prognostic score that is an objective and sensitive tool for predicting post-LT survival of recipients and could encourage more rational and effective LT recipient selections. Additionally, the survival score equation helps assess the patients who benefit most from liver transplantation. The scoring model for predicting post-LT survival was specific and sensitive as a quantitative predictive model for LT recipients. The percentage of Hangzhou criteria recipients whose survival score was more than 1.27 was only 19.6%, indicating that the Hangzhou criteria can be the safe and preferred criteria for LT.

 

Preoperative AFP levels were significantly associated with post-LT recurrence and survival. This observation was similar to several previous studies.^{[4, 30, 31]} Several different cut-off values for AFP levels (100, 210, 400, and 1000 ng/mL) have been proposed.^[30-44] The AFP cut-off value of 400 ng/mL has been widely adopted for predicting HCC recurrence.^{[4, 30, 32-35]} A similar AFP cut-off value of 455 ng/mL has also been reported as a predictive parameter for post-LT survival.^[36] Other studies^[43-44] reported a much higher cut-off value that reaches 1000 ng/mL or greater. In this study, an AFP level of 325.3 ng/mL was the optimal cut-off value for predicting post-LT recurrence and survival in HBV cirrhosis-related HCC recipients.

 

In conclusion, HBV cirrhosis-related HCC recipients within the Hangzhou criteria have favorable survival rates after LT. The quantitative predictive scoring model proposed in our investigation was sensitive and specific for predicting post-LT survival in LT recipients.

 

 

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