| Background&AimsSorafenib in combination with Transarterial chemoembolization (TACE) is increasinglyused in patients with unresectable hepatocellular carcinoma (HCC), its current evidence isstill controversial when compared to TACE alone. Additional, we found sorafenib relatedadverse events (AEs) linked with patients prognosis. Thus we aim to explore the followingquestions:1. the effectiveness and safety of TACE plus sorafenib versus TACE alone forunresectable HCC,2. the characteristic of sorafenib-associated AEs and the relationshipbetween drug-related AEs and survival,3.establish a points-scoring system to helpclinicians predict the prognosis of HCC.Methods1. We searched PubMed, EMBASE and the Cochrane Library for clinical trialscomparing TACE plus sorafenib with TACE alone for unresectable HCC. The studyoutcomes included overall survival (OS), time to progression (TTP), objective response and AEs.2. From January2010to December2011, we prospectively collected data from142consecutive HCC patients who received combination therapy with sorafenib andTACE. Primary items included the incidence, severity, onset and length ofsorafenib-related AEs, as well as overall survival.3. Patients who underwent sorafenib combined with TACE therapy from2009.1to2012.6in our center were candidates for this study. To eliminate confounding factors,we included patients with well-preserved liver function and measurable target lesions,these resulted in that83patients were included in the present study. Cox proportionalhazards to calculate the significant survival predictors and those were included in thefinal model.Results1. Six studies including1181patients were included. Meta-analysis of all studiessuggested that the combination therapy group had significant longer OS than TACEgroup (hazard ratio [HR]=0.64,95%confidence interval [CI]=0.43-0.97). For TTP,meta-analysis suggested that combination therapy was superior to TACE group(HR=0.74,95%CI=0.61-0.90, I2=33%). The combination therapy was alsoassociated with better response to treatment (risk ratio=1.45,95%CI=1.04-2.02).However, the sorafenib associated AEs were more frequent in the combination therapygroup.2. Common types of sorafenib-related AEs included hand-foot skin reaction (HFSR)(62%), alopecia (52%), rash (50%), diarrhea (58%), fatigue (57%) and anorexia and/ornausea (24%). These usually occurred within13-35days after sorafenib and lasted for0.7-5months. The presence of sorafenib-related AEs was an independent predictor ofoverall survival (HR:0.465,95%CI:0.261-0.829). The occurrences of HFSR, rash,alopecia, diarrhea and hoarseness were significantly associated with better survival.Additionally, the survival benefit was more significant if rash and HFSR occurredwithin4weeks of starting treatment or if the severity of these AEs was increased. 3. In the multivariate analysis, HFSR response (HR:0.305,95%CI:0.127-0.732, P=0.008)and3months image response (HR:0.149,95%CI:0.039-0.572, P=0.006) wereindependently associated with survival and were included in the final relative risk(RR), where RR=exp[-2×(14weeks image response:0of no,1if yes)+(-1)×(HFSRresponse:0if no,1if yes)]. According to the cut-off value of0.51, our patients weredivided into two groups: patient has the RR <0.51was named group1, and patient hasthe RR>0.51was named group2. The median survival time for group1wassignificantly better than group2.(21months vs.7.6months, P<0.001)Conclusions1. The combination of sorafenib and TACE is likely to improve OS, TTP and responserate to treatment when compared with TACE monotherapy. The combination group isalso associated with more sorafenib-related AEs.2. Sorafenib-related AEs generally occurred within1month after sorafenib treatment andlasted for0.7-5months. Many types of AEs, especially early and sever dermatologicside effects predicted a better survival in unresectable HCC patients.3.3months mRECIST response combined with HFSR response may improve the abilityto assess the prognostic of the new combination therapy. |
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