A prospective study on transcatheter arterial chemoembolization combined with sorafenib and sequential microwave ablation versus transcatheter arterial chemoembolization combined with sorafenib in the treatment of hepatocellular carcinoma with tumor diameter over 5 cm / 中华消化外科杂志

ABSTRACT

Objective:To investigate the efficacy and safety of transcatheter arterial chemoembolization (TACE) combined with sorafenib and sequential microwave ablation (MWA) versus TACE combined with sorafenib in the treatment of hepatocellular carcinoma (HCC) with tumor diameter over 5 cm, and to analyze risk factors affecting the prognosis of patients.Methods:The prospective cohort study was conducted. The clinicopathological data of 61 HCC patients with tumor diameter over 5 cm who were admitted to two medical centers (30 in the Laiyang Central Hospital of Yantai City Affiliated to Weifang Medical College and 31 in the Qingdao Central Hospital Affiliated to Qingdao University) between July 2012 and November 2013 were collected. Patients who were treated with TACE combined with sorafenib and sequential MWA were allocated into observation group, and patients who were treated with TACE combined with sorafenib were allocated into control group. Observation indicators (1) treatment, complications and adverse drug reactions; (2) short-term efficacies; (3) follow-up and survival situations; (4) analysis of prognostic factors. Follow-up was performed by inpatient, outpatient examinations or telephone interview once a month within the first 6 months after treatment and once every 3 months thereafter up to November 2018. The follow-up included laboratory indicators, tumor markers, abdominal enhanced computed tomography or magnetic resonance imaging examinations. The survival of patients and disease progression were fully documented. Measurement data with normal distribution were expressed as Mean± SD, and comparison between groups was performed by the t test. Measurement data with skewed distribution were described as M (range), and comparison between groups was performed using the Wilcoxon rank sum test. Count data were expressed as absolute numbers or percentages, and comparison between groups was performed using the chi-square test or pearson-corrected chi-square test. Ranked data were analyzed using the Wilcoxon rank sum test. The Kaplan-Meier method was used to calculate survival rates and draw survival curves. The Log-rank test was used for survival analysis. Comparison of survival rates between time points was performed using the Bonferroni method to adjust the test level. Univariate and multivariate analyses were performed using the multiple COX proportional hazard model. Results:A total of 61 HCC patients were selected for eligibility, including 36 males and 25 females, aged (58±8)years, with a range from 43 to 73 years. Of the 61 patients, 31 were in the observation group and 30 in the control group. (1) Treatment, complications and adverse drug reactions ① treatment information. The treatment times of TACE, treatment times of MWA, time from the first TACE to the first sorafenib medication, and duration of sorafenib medication in the observation group were 1 time (range, 1-5 times), 2 times (range, 1-4 times), 5 days (range, 5-9 days), 24 months (range, 6-72 months), respectively. The above indicators of patients in the control group were 3 times (range, 1-5 times), 0, 6 days (range, 5-9 days), and 16 months (range, 6-60 months). There were significant differences in the treatment times of TACE, treatment times of MWA, and duration of sorafenib medication between the two groups ( Z=4.701, -7.213, -2.614, P<0.05). There was no significant difference in the time from the first TACE to the first sorafenib medication between the two groups ( Z=0.573, P>0.05). ② Complications there was no TACE related complications in the two groups. There were 3 patients with MWA related complications in the observation group, including 2 cases of minor hemorrhage under the liver capsule and 1 case of pleural effusion, and they were relieved after conservative treatment. ③ Adverse reactions to sorafenib after 2 months of sorafenib medication, patients in the observation group and control group had at least one kind of sorafenib related stage Ⅰ-Ⅲ adverse reaction, without stage Ⅳ adverse reaction. The numbers of cases with hand-foot skin reaction, rash, pruritus, loss of skin pigmentation, diarrhea, decreased appetite, nausea and vomiting, pain in the liver area, fever, fatigue, liver dysfunction, bone marrow suppression were 8, 3, 4, 3, 10, 18, 20, 20, 20, 15, 3, 2 in the observation group, and 9, 3, 3, 2, 13, 19, 23, 12, 21, 12, 6, 2 in the control group, respectively, showing no significant difference in the above indices between the two groups ( χ2=0.133, 0.000, 0.000, 0.000, 0.796, 0.177, 1.082, 3.674, 0.208, 0.435, 0.601, 0.000, P>0.05). Patients with adverse reactions to sorafenib were relieved by symptomatic treatment, reducing the dose of sorafenib or intermittent drug withdrawal. (2) Short-term efficacies the level of alpha fetoprotein was 16 μg/L (range, 3-538 μg/L) in the observation group and 292 μg/L (range, 9-642 μg/L) in the control group after one month of treatment, showing a significant difference between the two groups ( Z=3.744, P<0.05). After 3 months of treatment, cases with tumor complete remission, cases with tumor partial remission, cases with stable disease, cases with progressive disease, objective response rate, and disease control rate in the observation group were 14, 11, 6, 0, 80.6%(25/31) , 100.0%(31/31), respectively. The above indicators in the control group were 2, 13, 12, 3, 50.0%(15/30), 90.0%(27/30). There was a significant difference in the objective response rate between the two groups ( χ2=6.343, P<0.05), but no significant difference in the disease control rate between the two groups ( χ2= 1.473, P>0.05). (3) Follow-up and survival situations 61 HCC patients were followed up for 9.0-75.0 months, with a median follow-up time of 22.0 months. During the follow-up, 28 patients in the observation group had progressive disease, including 8 cases of local tumor progression, 4 of portal vein tumor thrombi, 11 of intrahepatic metastasis, and 5 of pulmonary metastasis. Thirty patients in the control group had progressive disease, including 13 cases of local tumor progression, 6 of portal vein tumor thrombi, 6 of intrahepatic metastasis, and 5 of pulmonary metastasis. Among the 61 patients, 28 patients in the observation group and 29 patients in the control group died. The median overall survival time and median progression-free survival time of the observation group was 28.0 months and 18.0 months, versus 19.5 months and 11.5 months of the control group, showing significant differences between the two groups ( χ2=8.021, 10.506, P<0.05). The 1-, 3-, 5-year overall survival rates of the observation group were 97%, 37% and 20%, respectively, versus 83%, 13% and 7% of the control group, showing significant differences in the above indicators between the two groups ( Z=23.635, 4.623, 3.139, P<0.0167). The 1-, 2-, 3-year progression-free survival rates of the observation group were 77%, 40%, and 27%, respectively, versus 43%, 13%, and 7% of the control group, showing significant differences in the above indicators between the two groups ( Z=9.965, 4.900, 3.684, P<0.0167). (4) Analysis of prognostic factors results of univariate analysis showed that treatment method, maximum tumor diameter, Barcelona clinical liver cancer (BCLC) stage, liver cirrhosis, hepatitis B virus(HBV) infection, and Child-Pugh classification were related factors for overall survival time [ hazard ratio ( HR)=0.483, 6.196, 12.646, 5.049, 2.950, 4.791, 95% confidence interval ( CI) 0.284-0.823, 3.198-12.003, 5.031-31.785, 2.586-9.858, 1.366-6.369, 2.507-9.155, P<0.05] and progression-free survival time ( HR=0.427, 5.804, 7.032, 5.405, 2.925, 4.410, 95% CI 0.248-0.735, 3.043-11.070, 3.071-16.101, 2.685-10.881, 1.364-6.270, 2.331-8.342, P<0.05). Results of multivariate analysis showed that treatment method, maximum tumor diameter, BCLC stage, liver cirrhosis, and HBV infection were independent influencing factors for overall survival time ( HR=0.183, 5.886, 17.544, 4.702, 3.801, 95% CI 0.090-0.370, 2.648-13.083, 5.740-53.622, 1.928-11.470, 1.368-10.562, P<0.05) and progression-free survival time ( HR=0.201, 3.850, 3.843, 3.598, 3.726, 95% CI 0.098-0.411, 1.761-8.414, 1.526-9.682, 1.444-8.963, 1.396-9.947, P<0.05). Conclusions:Compared with TACE combined with sorafenib, TACE combined with sorafenib and sequential MWA is safe and effective in the treatment of HCC with tumor diameter over 5 cm. The treatment method, maximum tumor diameter, BCLC stage, liver cirrhosis, and HBV infection are independent influencing factors for overall survival time and progression-free survival time of patients.