According to the statistics of China Liver Transplant Registry (CLTR), nearly 50% of the patients undergoing liver transplantation in China are patients with hepatocellular carcinoma, and about 50% of them are patients with advanced hepatocellular carcinoma exceeding the Milan criteria, so the high recurrence rate of the tumor after transplantation is still a serious problem affecting the long-term survival of patients. Sorafenib has shown some efficacy in the treatment of advanced hepatocellular carcinoma, and this study aims to investigate the role of sorafenib in the prevention and treatment of tumor recurrence after liver transplantation in hepatocellular carcinoma patients exceeding the Milan criteria. DATA AND METHODS I. GENERAL DATA A total of 96 cases of liver transplantation were completed in the Department of Hepatobiliary Surgery of our hospital from March 2008 to June 2010, of which 30 patients with primary hepatocellular carcinoma exceeding the Milan criteria had hepatocellular carcinoma in their postoperative pathology. These 30 patients were randomly assigned into the experimental group (taking sorafenib) and the control group (taking capecitabine), 15 cases in each group. In the experimental group, there were 12 males and 3 females, aged 52.3±7.7 years (40-64 years); in the control group, there were 13 males and 2 females, aged (49.2±8.9) years (31-64 years). The differences between the two groups in terms of age and gender were not statistically significant. II.Surgical data There were 2 patients in each of the test group and control group who had recurrence of hepatocellular carcinoma after resection, and the rest were all first-onset patients. All patients routinely underwent preoperative whole-body nuclear bone scan and lung CT scan to exclude extrahepatic metastasis of the tumor. All donors and recipients were compatible or compatible with each other in terms of blood group. Whole liver grafts were harvested by rapid combined hepatic and renal dissection with UW fluid for perfusion and cold preservation. The surgical approach was classical in situ liver transplantation, and the principle of tumor-free operation was followed during the operation, and the following measures were taken to avoid tumor dissemination and reduce postoperative recurrence: (1) gentle operation, avoiding excessive squeezing of the tumor and repeated moving of the liver, and tumors protruding from the surface of the liver should be covered with gauze; (2) if the tumor is adherent to the diaphragm, the abdominal wall, or the greater omentum of the surrounding area, the adherent local tissues need to be resected at the same time during surgery; (3) if the cancer is close to the first hepatic hilar, at least the tumor will be removed by the first hepatic hilar. cancer is close to the first hepatic portal, at least 2 cm of portal vein trunk should be resected or the portal vein trunk should be ligated in advance; (4) 5-FU 1g should be slowly infused through peripheral vein during the operation, and 20mg of epirubicin should be infused into the vein during the liver-free period if there is a thrombosis in the portal vein; (5) lymph nodes next to the common hepatic artery and lymph nodes within the hepatic-duodenal ligament should be cleared at the same time when the hepatic artery is free; (6) lymph nodes inside the hepatic-duodenal ligament; (6) Fully rinse the abdominal cavity with 2000 ml of warm sterile distilled water during the hepatic-free period and before abdominal closure, respectively. Postoperative follow-up and treatment A triple immunosuppressive regimen of tacrolimus, merti-mescaline and prednisone acetate was used after surgery. Tacrolimus dosage was adjusted according to blood concentration and liver function results, and the trough concentration was kept at the level of 8-10 ng/ml in 1~3 months, 5-8 ng/ml in 3~12 months, 5 ng/ml in 12~24 months, and it could be lower than 5 ng/ml after 24 months. mortimecrolimus ester was usually taken at the dose of 1g/d until 6 months after operation, when the leukocytes below 3 x 1012/L can be reduced to 0.5g/d or discontinued. Prednisone acetate was discontinued in all patients within 1 month. A regimen of hepatitis B immunoglobulin + lamivudine/entecavir was used to prevent post-transplant HBV reinfection. Experimental group: Oral sorafenib 400 mg bid was started 1 month after surgery, and could be changed to 200 mg bid if intolerable side effects occurred, or continued after 2 weeks of discontinuation of sorafenib until symptoms resolved. Control group: start taking capecitabine 1500 mg bid orally from 1 month after surgery, take 14 days and then rest for 2 weeks, no serious side effects can start the next course of treatment. Discontinuation criteria: the drug can be discontinued if there is no recurrence 18 months after the operation, and if there is a recurrence in the course of treatment, the original dose will be maintained until the patient is no longer suitable to continue taking the drug. If serious adverse reactions occur, the dosage will be reduced or discontinued. Routine outpatient follow-up programs include routine blood tests, liver and kidney functions, tacrolimus blood concentration, and hepatitis B surface antibody titer. In addition, serum AFP was rechecked monthly, and lung CT and abdominal CT enhancement scans were rechecked every 2 to 3 months. All patients were followed up until patient’s death or cut-off date (June 30, 2011). Statistical methods: The mean +/- standard deviation was used to describe all the measurement data, x2 test was used to compare the rates between two groups, and the survival time was plotted as a Kaplan-Meier curve, and the log-rank test was used to compare the survival times, with P<0.05 being considered as a significant difference. The statistical software was SPSS 11.5 (SPSS Inc). RESULTS All patients had no perioperative deaths and received standardized postoperative follow-up for 6-34 months. Twenty-one patients (8 in the experimental group and 13 in the control group) developed recurrence of hepatocellular carcinoma within 1 year after surgery, and 9 of them died within 1 year after surgery (1 in the experimental group and 8 in the control group), and the difference between the 1-year recurrence rate and the 1-year survival rate of the experimental group and the control group was statistically significant. By June 30, 2011, a total of 23 patients had recurrence (9 cases in the experimental group and 14 cases in the control group), of which 15 died (3 cases in the experimental group and 12 cases in the control group), and there were 8 cases of tumor-bearing survivors (6 cases in the experimental group and 2 cases in the control group). The sites of first tumor recurrence in patients were lung metastasis (14 cases), abdominal implantation metastasis (7 cases), abdominal lymph node metastasis (1 case) and transplanted liver metastasis (1 case). On the basis of continuing oral sorafenib/capecitabine, the patients all received local treatment for recurrent tumors, and the whole group of cases received gamma knife treatment for lung metastases in 24 cases; resection of abdominal metastases in 4 cases, and gamma knife treatment in 6 cases; and ablation of liver metastases in 2 cases, and gamma knife treatment in 2 cases, respectively. The survival curves of the two groups of patients were plotted by Kaplan-Meier method, and the survival curves of the two groups of patients were compared with the log-rank test, and the calculated χ2 value=7.154, P=0.007, which indicated that the survival time of the experimental group and the control group was different, and the difference between the two groups was statistically significant, and the experimental group's survival time was longer, and the therapeutic efficacy was better than that of the control group. The majority of the common toxic side effects of the patients were graded as I~II degree, and the symptoms could be relieved after symptomatic treatment, so it was not necessary to reduce the drug. In the experimental group, there were 3 cases of Grade III hand-foot syndrome, 2 cases were improved after reducing sorafenib to 200 mg bid and symptomatic treatment, and 1 case discontinued sorafenib until the toxic reaction was relieved to Grade I. After 3 weeks, sorafenib 200 mg bid was continued to be given orally, and there was no recurrence of Grade III hand-foot syndrome. The chances of diarrhea and hand-foot syndrome were higher in the experimental group than in the control group, and the difference was statistically significant (P < 0.05). The chances of occurrence of rash and hypertension were also higher than that of the control group, but the difference between the two groups was not statistically significant (P > 0.05). The chances of complications such as fatigue and weakness, digestive reactions such as nausea and anorexia, granulocytopenia, and alopecia were close to each other in the two groups, and the difference was not statistically significant (P > 0.05) (Table 2). Discussion At present, there are many patients with advanced hepatocellular carcinoma beyond the Milan criteria in China who have lost the opportunity of surgical resection at the time of diagnosis, and their lives can only be prolonged by liver transplantation, but tumor recurrence is still the most important cause of postoperative long-term death in such patients. In fact, liver transplantation has minimized the tumor load in such patients, and if effective anti-tumor drugs can be applied prophylactically after liver transplantation, tumor recurrence can theoretically be prevented or delayed. Ideal antitumor agents become important measures that may improve the prognosis of patients with ultramilan standard hepatocellular carcinoma. Sorafenib, an oral multikinase inhibitor, as a small molecule multi-target targeted therapeutic agent, inhibits tumor cell proliferation by inhibiting the RAS/RAF/MEK/ERK signaling pathway on the one hand, and on the other hand, it inhibits vascular endothelial growth factor (VEGF-2), platelet-derived growth factor (PDGF) receptor, and other tyrosine kinases that are associated with tumor neoangiogenesis and tumor tyrosine kinase receptor activity related to tumor neoangiogenesis and tumor development, thereby blocking tumor neoangiogenesis and inhibiting tumor growth (1,2,3). Theoretically, sorafenib has inhibitory effects on a variety of tumors including renal cancer, hepatocellular carcinoma, non-small cell lung cancer, and melanoma (4,5,6). The international multicenter, randomized controlled phase III clinical trial (SHARP trial) proved that the median overall survival (OS) of advanced hepatocellular carcinoma patients in the sorafenib group versus the placebo group was 10.7 months versus 7.9 months, and the median time to progression of the disease (TTP) was 5.5 months versus 2.8 months, with statistically significant differences between the groups, which demonstrated that sorafenib could prolong the survival of patients with advanced hepatocellular carcinoma (6,7,8). The results of phase III randomized controlled clinical trials of sorafenib in advanced hepatocellular carcinoma in Korea, China, and Taiwan also demonstrated that sorafenib was effective in prolonging the survival of patients with advanced hepatocellular carcinoma in the Asian-Pacific population (9). These trials have demonstrated that sorafenib can be effective in the treatment of unresectable advanced hepatocellular carcinoma. The aim of this study is to investigate whether sorafenib can also play a better role in the prevention and treatment of liver cancer recurrence after liver transplantation. Preliminary results showed that the 1-year tumor recurrence rate of patients in the experimental group using sorafenib was 53.3%, which was significantly lower than that of patients in the control group using capecitabine (86.6%), while the 1-year survival rate of the experimental group was 93.3%, which was significantly higher than that of the control group (46.6%), and the difference between the two groups was statistically significant (P < 0.05). Since our previous study found that the time of tumor recurrence after liver transplantation was mainly concentrated in 6-14 months, and recurrence cases after 18 months were rare, generally the absence of recurrence at 2 years after surgery can be considered as a clinically cured case (10). Because this study is still continuing the follow-up process, it is possible that new recurrence cases may appear in both experimental and control groups with the prolongation of time, but the available results at least suggest that the prophylactic application of sorafenib after liver transplantation in patients with hepatocellular carcinoma with ultra-Milanese criteria may have reduced or delayed the process of recurrence of hepatocellular carcinoma in the patients. Also statistically calculated, the mean survival of patients in the sorafenib group was 24.6 ± 1.7 months (7-28 months), and in the control group it was 16.4 ± 2.7 months (5-34 months). Plotting the survival curves of the two groups by the Kaplan-Meier method also showed that the patients in the experimental group survived longer than those in the control group, and the difference between the results of the two groups was statistically significant. Therefore, according to this study, it can be made a preliminary inference that the application of sorafenib after liver transplantation can prolong the survival time and improve the prognosis of patients with ultramilan standard hepatocellular carcinoma, and the therapeutic effect is better than that of patients using capecitabine. The sites of tumor recurrence in both groups of patients were consistent with the results of previous studies in our center, mainly lung metastasis, abdominal implantation and abdominal lymph node metastasis (10). We believe that early detection of recurrent foci on the basis of prophylactic application of antitumor drugs, together with necessary local therapy, such as gamma knife therapy, surgical resection of metastatic foci, or ablation therapy, is beneficial and necessary for controlling tumor progression. However, patients with postoperative pathology suggesting the presence of abdominal lymph node metastasis (+) and hepatic vein branch cancer embolism tend to have early tumor recurrence and have a poorer prognosis, and such patients should be more aggressively treated with sorafenib at an early stage. The main adverse reactions in the experimental group were diarrhea and hand-foot syndrome, which could be alleviated by reducing the dosage of sorafenib. The incidence of serious adverse reactions (degree III) is not high, if necessary, stop the drug for a period of time, after the toxicity is relieved and then take it again at half the dosage (400mg/d), serious toxic side effects usually do not occur again. To summarize the preliminary results of this study suggest that prophylactic application of sorafenib after liver transplantation can improve the prognosis and prolong the survival of patients with ultra-Milan standard hepatocellular carcinoma, and the toxicity and side effects of sorafenib can be tolerated, and the prospect of its application is worthy of further study.