| Background And Aims: A large number of studies have tried to combine sorafenib with TACE for patients with unresectable hepatocellular carcinoma(HCC). However, there have been still absence of proofs, we hoped to summarize the pratice in our center and prove the efficacy of combiantion therapy in unresectable HCC. 1) We firstly conducted this systematic review and meta-analysis to evaluate the safety and efficacy of combination therapy of sorafenib and TACE in the management of unresectable HCC; 2) then we investaiged the suitability of Response Evaluation Criteria in Solid Tumors(RECIST), European Association for the Study of the Liver(EASL) criteria, and modified RECIST(m RECIST), to select a more suitable criterion for combiantion treatment of TACE and sorafenib; 3) find a assessment criterion based on Alpha-fetoprotein(AFP) response to predict patients’ survival; 3) according to sorafenib-related adverse events to assess the response of patients with hepatocellular carcinoma to treatment with sorafenib combined with transarterial chemoembolization. Methods: 1. MEDLINE, Psyc INFO, Scopus, EMBASE, and the Cochrane Library were searched from January 1990 to October 2013 and these databases were searched for appropriate studies combining TACE and sorafenib in treatment of HCC. Two authors independently reviewed the databases and extracted the data and disagreements were resolved by discussion. Effective value and safety were analyzed. Effective value included disease control rate(DCR), time to progression(TTP) and overall survival(OS). 2. A total of 114 consecutive patients with hepatocellular carcinoma receiving combination therapy were retrospectively enrolled. The therapy response at different time points was assessed using RECIST, EASL, and m RECIST. Cox regression analysis and Kaplan-Meier curves were used to assess overall survival(OS) in the responders and nonresponders. 3. 118 HCC patients with baseline AFP levels >20ng/ml treated with combination therapy were enrolled from May 2008 to July 2012. A receiver operating characteristic curve was used to generate a cutoff point for AFP changes for predicting survival. The AFP response was defined as an AFP decrease rate [ΔAFP(%)] greater than the cutoff point. The ΔAFP(%) was defined as the percentage of changes between the baseline and the nadir values within 2 months after therapy. 4. All patients with unresectable HCC who received TACE plus sorafenib therapy at our department between January 2010 and June 2014 were considered. Sorafenib-related adverse events were recorded. Prognostic values were expressed by hazard ratios(HRs) with 95% confidence intervals(CIs). Results: 1. 17 papers were included. In the 10 noncomparative studies, DCR ranged from 18.4 to 91.2%. Median TTP ranged from 7.1 to 9.0 months, and median OS ranged from 12 to 27 months. In the 7 comparative studies, the hazard ratio(HR) for TTP was found to be 0.76(95% CI 0.66-0.89; P<0.001) with low heterogeneity among studies(P = 0.243; I(2) = 25.5%). However, the HR for OS was found to be 0.81(95% CI 0.65-1.01; P = 0.061) with low heterogeneity among studies(P = 0.259; I(2) = 25.4%). The common toxicities included fatigue, diarrhea, nausea, hand foot skin reaction(HFSR), hematological events, hepatotoxicity, alopecia, hepatotoxicity, hypertension and rash/desquamation. AEs are generally manageable with dose reductions. 2. The response rates obtained using EASL(50.6%) and m RECIST(51.6%) were greater than that obtained using RECIST(16.5%) at the third follow-up(median, 94 days; range, 89-102 days) after therapy. The agreement was strong between the m RECIST and EASL results(k = 0.9) but weak between m RECIST and RECIST(k = 0.3). The EASL and m RECIST responses significantly correlated with survival. Risk reductions of 52% and 50% were observed for EASL and m RECIST responders, respectively, compared with nonresponders. However, no significant association between the treatment response and survival was observed using RECIST. The earliest time to evaluate the response to combination therapy is 3 months(median, 94 days) after therapy. 3. The median follow-up time was 8.8 months(range 1.2-66.9). A level of 46% was chosen as the threshold value for ΔAFP(sensitivity = 53.7%, specificity = 83.3%). The median overall survival was significantly longer in the AFP response group than in the AFP non-response group(12.8 vs. 6.4 months, P = 0.001). Multivariate analysis showed that ECOG ≥ 1(HR = 1.95; 95% CI 1.24-3.1, P = 0.004) and AFP nonresponse(HR = 1.71; 95% CI 1.15-2.55, P = 0.009) were associated with increased risk of death. 4. Overall, 160 HCC patients were included. Hand-foot-skin reaction(HFSR)(85.6%) and alopecia(85.6%) were the most common adverse events. HFSR(69.3%) was the most common grade 2-3 adverse event. As the type and grade of sorafenib-related adverse events were not restricted, the overall survival was statistically better for patients with adverse events and those without(P=0.005). The overall survival was significantly better in patients with grade 2-3 adverse events than those with grade 0-1 adverse events(P=0.032). Patients with grade 2-3 HSFR had significantly better overall survival than those with grade 0-1 HSFR(HR=0.465, 95%CI: 0.311-0.694, P<0.001). CONCLUSIONS: 1. Combination therapy may bring benefits for unresectable HCC patients in terms of TTP but not OS. 2. Radiologic response according to EASL and m RECIST in 3 months after combination treatment of TACE and sorafenib correlated with survival better. 3. A level of 46% was chosen as the threshold value for ΔAFP as AFP response could predict survival more accurately. 4. Sorafenib related hand-foot-skin reaction could predict better outcome of patients with intermediate-advanced stage HCC after combination therapy. |
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