The Value Of Adjuvant Transarterial Chemoembolization And Risk Factors For Residual Tumor After Resection Of Hepatocellular Carcinoma

The Value of Adjuvant Transarterial Chemoembolization and Risk Factors for Residual Tumor after Resection of Hepatocellular CarcinomaSurgical resection has a major role in the treatment for hepatocellular carcinoma (HCC). With the advances in surgical techniques and perioperative management, the short-term outcome of liver resection has been dramatically improved over the last decade. The long-term prognosis, however, remains unsatisfactory because of the high frequency of tumor recurrence even after radical resection.Postoperative adjuvant transarterial chemoembolization (TACE) is widely applied with the hope of reducing recurrence rates and improving overall survival for HCC. However, the effect of adjuvant TACE in HCC patients after radical resection remains controversial.Almost all HCC has the possibility of recurrence in theory. Recurrence occurred soon after resection is thought to be related to the presence of residual tumor. Residual tumor can develop even after radical resection of HCC and is associated with a poor prognosis. Eradicating the residual tumor at its earlier period can improve the long-term outcome.We retrospectively analyzed the clinical data on 1924 consecutive HCC patients who underwent radical resection between January 2001 and April 2007 to explore the prognosis of patients at different risk of recurrence after adjuvant TACE for assessing whether this treatment should be more restrictive, and to identify the risk factors for residual tumor in HCC patients after radical resection for helping clinicians to determine rational strategies in surveillance, prevention and management of postoperative residual tumor.Part one:The Value of Adjuvant Transarterial Chemoembolization after Radical Resection of Hepatocellular CarcinomaObjective:To evaluate the effect of adjuvant TACE on prognosis after radical resection of HCC.Methods:We retrospectively analyzed the clinical data on 1924 consecutive HCC patients who underwent radical resection between January 2001 and April 2007. Patients underwent resection only were classified into control group, while those received adjuvant TACE after operation were classified into intervention group. Patients were further stratified into 4 groups, i.e. tumor<5cm with low or high risk factors for recurrence, as well as tumor> 5cm with low or high risk factors for recurrence. Low risk factors for recurrence was defined as single tumor without microscopic tumor thrombus, while high risk factors for recurrence was defined as 2-3 nodules or the presence of microscopic tumor thrombus. The effects of adjuvant TACE on survival and early (<2 year)/late (>2 year) recurrence were evaluated.Results:In the subgroup of patients with tumor> 5cm and presenting high risk factors for recurrence, adjuvant TACE showed an overall survival benefit with a hazard ratio (HR) of 0.65 [95% confidence interval (CI):0.47,0.88 (P=0.006)]. Patients in TACE group showed higher 3-,6-month recurrence rates as than comparison. For patients who remained recurrence free within the first 6 months after resection, there were no significant differences in recurrence rates at 9-,12-,18-and 24-month after operation between intervention group and control group in each stratum. Cox regression model suggested adjuvant TACE was not an independent risk factor for late recurrence; however, it had negative effect on survival [HR=1.60 (95% CI:1.06,2.40), P=0.024] for those patients (especially patients with tumor<5cm and presenting low risk factors for recurrence).Conclusions:The value of adjuvant TACE was mainly due to its therapeutic actions on residual tumor or early recurrence. It had no effect on postponing or preventing recurrence, but may benefit to detect residual tumor or early recurrence. It showed survival benefit in patients with tumor> 5cm and presenting high risk factor for recurrence; however, in the subgroup of patients with tumor≤5cm and presenting low risk factors for recurrence, it could be a harm rather than a benefit.Part two:Risk Factors for Residual Tumor after Resection of Hepatocellular CarcinomaObjective:To identify the clinicopathological risk factors correlated with the development of residual tumor in HCC patients after resection.Methods:We analyzed the clinical data from 766 HCC patients who underwent radical resection. Hepatic artery angiography was performed within 2 months after operation and followed by post-Lipiodol computed tomography (CT) 4 weeks later for all these 766 patients to monitor residual tumor. Recurrence within the first 3-month postoperative period was defined as residual tumor. Patients were divided into 2 groups:recurrence and recurrence free within the first 3 months after surgery. Risk factors for residual tumor were investigated among various clinicopathological variables.Results:A total of 63 (8.22%) patients were found to have residual tumor after surgery. Three independent factors associated with the development of residual tumor were identified by logistic model multivariately analysis:preoperative serum alpha-fetoprotein (AFP) level [odds ratio (OR)=1.68 (95% CI:1.20,2.36), P< 0.0001], tumor size [OR=1.73 (95%CI:1.29,2.31), P=0.003] and microvascular invasion [OR=1.91(95%CI:1.12,3.24),P=0.017].Conclusions:Residual tumor is related to increased preoperative serum AFP level, large tumor size and the presence of microvascular invasion. Patients at the high risk of developing residual tumor need to be closerly followed up and would be candidates for multimodality therapy to supplement surgery.Part three:The Significance of Aurora Kinase B,VEGF and MKP-1 Expression for Residual Tumor after Resection of Hepatocellular CarcinomaObjective:To explore the expression of Aurora kinase B,vascular endothelial growth factor (VEGF) and mitogen-activated protein kinase phosphatase-1 (MKP-1) in HCC for assessing whether these markers could be the predictive factors for residual tumor after resection.Methods:We reviewed the case of HCC patients who underwent radical resection between 2004 and 2006. Hepatic artery angiography was performed within 2 months after operation and followed by post-Lipiodol computed tomographic (CT) scan 4 weeks later to monitor residual tumor. Recurrence within the first 3-month postoperative period was defined as residual tumor. Patients were divided into 2 groups:recurrence and recurrence free within the first 3 months after surgery. A case-controlled study including 28 patients with residual tumor and 28 patients without residual tumor was conducted. Immunohistochemical analysis of Aurora kinase B,VEGF and MKP-1 expression were perfprmed on paraffin-embedded tissues derived from these 56 HCC patients. The correlation between Aurora kinase B,VEGF,MKP-1 expression and residual tumor were investigated. Results:Immunohistochemical analysis showed that the MKP-1 expression levels were decreased in 14 (25%) of 56 HCC patients. Decreased MKP-1 expression was significantly more in patients with residual tumor than in those without residual tumor (11 patients vs.3 patients;χ2=6.0954, P=0.014). The expression of Aurora kinase B and VEGF showed no difference between two groups. Decreased MKP-1 expression was an independent factor for residual tumor at conditional logistic model multivariately analysis [OR=10.48 (95%CI:1.03,106.31), P=0.047].Conclusions:The MKP-1 expression was significantly associated with the development of residual tumor. The abnormal expression of MKP-1 may play a role in the pathogenesis and progression of HCC. It may be a prognostic biomarker for HCC.