The aim of this study is to explore the efficacy and safety of the combination treatment of dendritic cells and cytokine-induced killers (DC-CIK) and sorafenib in patients with advanced hepatocellular carcinoma (HCC).DC-CIK combined with sorafenib could improve the tumor response rate and prolong overall survival of advanced HCC without increasing the incidence of adverse events.
71 patients with pathologically diagnosed hepatocellular carcinoma (HCC) without abnormalities in blood routine tests, cardiopulmonary function, liver, kidney and coagulation functions. All patients did not receive pre- operative anti-tumor treatments. Patient with ECOG performance status score of 0-2 and did not have other organ dysfunction.
All patients divided into two groups, 35 patients in the observation group and 36 in the control group. In the observation group (DC-CIK), there were 26 males and 9 females. Twenty-nine males and 7 females were enrolled in the control group.
DC-CIK cell preparation
Anticoagulated peripheral blood (100 mL) was collected from the patients. Mononuclear cells were isolated by Ficoll density gradient centrifugation and washed with 0.9% saline thrice. The cells were incubated for 2 hours at 37°C, under 5% CO2, 95% relative humidity using RPMI-1640 culture medium. Then the cell suspension was isolated and seeded in another culture flask. Interleukin-4 (IL-4) and granulocyte- macrophage colony-stimulating factor were added to the culture flasks of adherent cells immediately; tumor necrosis factor-alpha (TNF-α) was added on the 5th day. Interferon-gamma (IFN-γ) was added to the culture flasks of suspension cells immediately; IL-1, IL-2, and anti-CD3 mAb were added on the 2nd day. Culture medium was changed regularly. DC and CIK cells were co-cultured at a ratio of 1:10 on the 7th day using RPMI-1640 culture medium containing IL-2.
On the 12th day, DC and CIK cells were collected, washed, sub bagged, mixed with 5% human serum albumin, and intravenously administered for two or three transfusions.
Oral administration of sorafenib was performed at a dose of 400 mg, bid. One treatment cycle included four-week administration. CT/MRI and sorafenib follow-up were performed every 4 weeks. Sorafenib was discontinued when patients experienced intolerable adverse events or disease progression. Supportive treatments were performed during the sorafenib administration, as needed.
50-60 mL of blood were harvested for monocyte extraction. The collected cells were cultured in the laboratory for cell transfusion. DCs were transfused on the
Liver function comparison
Liver function in each patient was evaluated according to levels of ALT (alanine aminotransferase) and TBIL (total bilirubin). After treatment, ALT and TBIL levels were elevated in the control group, whereas no significant differences were found in the observation group. Lower levels of ALT and TBIL were found in the observation group (DC-CIK) compared with the control group, indicating that DC-CIK combined with sorafenib could effectively improve liver function.
Tumor marker comparison
AFP is considered as a tumor marker for hepatocellular carcinoma (HCC). Oral administration of sorafenib did not markedly decrease AFP level. However, DC-CIK combined with sorafenib significantly downregulated AFP level in the observation group. Comparison of therapeutic efficacy
Six-month follow-up data indicated that the efficacy rate was 16.7% and 51.4% in the control group and observation group, respectively. Clinical benefit rate (CBR) was 41.9% and 88.6% in the control group and the observation group, respectively.
Kaplan-Meier methods with log rank test were used to analyze the overall survival in the two groups. The data showed that the median survival time of the control group and observation group was 13.8 months and 18.6 months, respectively (follow-up duration >24 months).
The main adverse events in this study were hand-foot skin reaction, diarrhea, vomiting, hypertension, fatigue, myelosuppression, and gastrointestinal bleeding. Uncommon adverse events included hair loss and hepatic encephalopathy. No statistical difference in the incidence of adverse events was registered between the control group and observation group.
DC-CIK combined with sorafenib could improve the tumor response rate and prolong overall survival in advanced HCC patients without increasing the incidence of adverse events. HCC patients achieve a better stable disease condition and over- all survival with DC-CIK combined with sorafenib.