| BackgroudPrimary hepatocellular carcinoma is one of the most common human malignancies, its global incidence is increasing every year, and has more than626,000per year, become one of the five most highest incidence rate of malignancies, and nearly600,000deaths per year, ranking the third of cancer-related deaths. Liver cancer have a high incidence in China, the current number of cases in our country is about55%of the total cases in the world, ranked the second of the cancer-related deaths. Thus, we can see that liver cancer is a serious threaten to the health of our countries and the development of the national economy.The major cause of liver cancer in our country is hepatitis, such as hepatitis B, hepatitis C,aflatoxin, alcoholic cirrhosis and so on are also the major cause of liver cancer. PHC can be divided into three kinds by histological type, they are hepatocellular carcinoma, intrahepatic cholangiocarcinoma, mixed hepatocellular carcinoma. The commonest kind of liver cancer in our country is hepatocellular carcinoma, it takes about90%of all the liver cancer incidence. Now, the main treatments for liver cancer including surgical treatment (such as tumor resection and liver transplantation) and none surgical treatment (such as arterial chemoembolization, radiofrequency ablation, biological therapy and molecular targeted therapy, etc). However, due to the disease characteristics of liver cancer, early stage liver cancer patient often have no symptoms, so the majority of liver cancer patients always diagnosed with advanced disease, and lost the chance of surgical resection. Now, transcatheter arterial chemoembolization has become the preferred treatment method of liver cancer patients for whom with advanced primary hepatocellular carcinoma or those who reject to surgical resection. However, its efficacy, recurrence rate, long-term survival rate are still unsatisfactory, and after TACE it’s observed the phenomenon of immune function decline in the patients, this phenomenon is thought more likely to lead to tumor recurrence and metastasis. So, how can we enhance the efficacy of TACE and improve the quality of life, reduce the recurrence of liver cancer patients and repressor their distant metastasis have become an urgent problem in clinical.With the rapid development of tumor immunology and deepening research of clinical immunotherapy, immunotherapy has become a new method of cancer treatment after surgery, radiotherapy, chemotherapy, molecular targeted therapy. CIK cells are cytokine-induced killer cells, they are new type of immune cells. They are collected from the peripheral blood mononuclear cells, induced by varieties of cytokines in vitro, and produced classes of CD3+and CD56+double-positive cytotoxic killer cells after co-culture. After CIK cells transfusion, they can produce anti-tumor effects through varieties of pathways. Dendritic cells are the most powerful antigen-presenting cells in our body, they can intake, processing and presenting antigen, pass the information of antigens to the T lymphocyte, and then triggering a series of body-specific immune response. Under the condition of co-culture CIK cells with DC cells, the IL-2, IFN-γ secretion in the cell supernatant are higher than in the simple CIK cells under the same condition; at the same time the co-culture of DC-CIK cells have been significantly noticed of higher enhanced of proliferation, more number of effector cells and higher cytotoxicity on tumor cells than mere proliferation of CIK cells. As a representative of adoptive immunotherapy, DC-CIK cell therapy become an important method of liver cancer treatment. DC-CIK cells have the characteristics of high value-added activity, high killing efficiency of tumor cells and low toxicity, etc. By adjusting and improving the immunity of the body, further remove the residual disease in vivo at the same time, and reach the purpose of inhibit and kill the tumor cells. Therefore, DC-CIK cell immunotherapy is currently considered the preferred adoptive immunotherapy.In this study, a retrospective analysis is discussed of68cases previous liver cancer patients after TACE in Nanfang Hospital, we grouped the patients into two groups according to whether they were treated combined with cell immunotherapy; and we take clinical data collection, follow-up, statistical analysis at the same time. We aim to evaluate the clinical efficacy, quality of life, safety of DC-CIK therapy, change of AFP level and liver function of the primary liver cancer patients who were treated combined with DC-CIK cell immunotherapy after TACE in our hospital, and then we may provide more evidence for further clinical application of DC-CIK cell immunotherapy.ObjectiveTo explore the clinical efficacy,safety and others of dendritic cells-cytokine-induced killer cells immunotherapy combined with TACE therapy in primary hepatocellular carcinoma.Methods 1. We collected68cases of patients who were diagnosed with advanced primary hepatocellular carcinoma between April2010to April2013in Nanfang Hospital, and all the patients were treated with TACE.2. According to whether combined with DC-CIK cells immunotherapy, the patients were divided into two groups:the combination therapy group (30cases who were treated with TACE combined with DC-CIK cells therapy) and control group (38cases who were only treated with TACE).3. Analysis the change of progression-free survival, overall survival, quality of life improvement, AFP level, liver function (ALT, AST, Tbil) and the safety of DC-CIK cells therapy between two groups after treatment.4. In this retrospective study, we use SPSS16.0statistical software for statistical analysis, the count data were compared using chi-square test, and we calculate the patients’progression-free survival and overall survival by using the Kaplan-Meier method. While cox regression model of risk proportion univariate and multivariate analysis were used to screen prognostic factors of progression-free survival and overall survival. P value of <0.05was considered statistically significant.Result1. Progression-free survival:compare the30cases of combination group to the38cases of control group, the median progression-free survival is16months (95%CI,7.9-24months) in the combination group and7months (95%CI,5.2～8.8months) in the control group, there have significant difference between the two groups when compare with PFS (P=0.033). Cox regression model of risk proportion multivariate analysis show that whether combined with DC-CIK cells immunotherapy (P=0.016),BCLC stage (P=0.006) are two independent prognostic factors of PFS. 2.Overall survival:until the end of follow-up time, the combination group had11patients died among the total of30cases, and there had19patients died among the control group, the median overall survival is24months (95%CI,16.3～31.7months) in the combination group and13months (95%CI,3.0～22.9months) in the control group. The1-year survival rate comparison of the two groups is80%versus75.2%.Analysis showed that there had not significant difference between the two groups (P=0.089). Cox regression model of risk proportion multivariate analysis show that BCLC stage (P=0.011) is the independent prognostic factor of OS.3. Evaluation of quality of lifeDuring the30patients in the combination group, there are10patients (33.3%) got improvement in the quality of life, and18cases did not change. But in the control group, there are4patients (10.5%) got improvement in the quality of life, and26cases did not change. The improvement in quality of life between the two groups have significant difference (P=0.034).4. Evaluation of AFP levelIn the TACE treatment group, there have18patients with positive AFP level (AFP≥400μg/L),16patients (88.8%) got improvement after treatment and2patients got worsen. In the combination group, there have10patients with positive AFP level, all of them got improvement after treatment, the improve rate reach100%. However, no significant difference is noticed between the two groups (P=0.274).5. Evaluation of liver function①Evaluation of Alanine aminotransferase (ALT):during30patients in the combination group, there have only3patients got worsen after treatment, accounting for10%; however, in the control group, there have20patients got worsen in ALT during38patients, accounting for52.6%. There have significant difference between the two groups (P=0.000).②Evaluation of Aspartate aminotransferase (AST):during30patients in the combination group, there have only6patients got worsen after treatment, accounting for20%; however, in the control group, there have24patients got worsen in AST during38patients, accounting for63.2%. There have significant difference between the two groups (P=0.000).③Evaluation of Total bilirubin (Tbil):during30patients in the combination group, there have only5patients got worsen after treatment, accounting for16.7%, and in the control group, there have11patients got worsen in Tbil during38patients, accounting for28.9%. There have no significant difference between the two groups (P=0.236). However, the patients got worsen of Tbil in the combination group is significantly less than in the TACE treatment group (16.7%versus28.9%). DC-CIK cells immunotherapy do not increase patient’s liver dysfunction, and may improve the patient’s liver function after TACE treatment.6. Evaluation of safety of DC-CIK cells therapyIn the combination group there are only three cases/times (3.19%) presented with fever after DC-CIK cell therapy, and these patients’temperature did not exceed38.5℃; only one patient (1.06%) had mild allergic reactions. After simple physical cooling, anti-allergy and other symptomatic treatment, all the patients returned to normal, and no anymore uncomfortable occurred. In the long term follow-up after the DC-CIK cells therapy, we didn’t find liver function damage, renal function damage and autoimmune diseases occurred in all the patients.Conclusion1. Compared to TACE alone, DC-CIK cell immunotherapy combine with TACE can helps to improve the patients’ progression-free survival, but there was no significant difference in overall survival. In addition, combination therapy can improve the quality of life in patients with advanced hepatocellular carcinoma 2. DC-CIK cells immunotherapy can help to reduce the patient’s AFP level; and compared to TACE alone, instead of aggravate the injury in patient’s liver function, combination therapy may help to make some improvement.3. DC-CIK cells therapy is safe, reliable, repeatable, and does not have significant side effects. |
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