Relationship Between Sorafenib-associated Hand-food Skin Reaction And Efficacy In Treatment Of Advanced Hepatocellular Carcinoma

Background and ObjectiveNexavar is a type of oral multikinase inhibitor recently on the market to treat hepatocellular carcinoma (HCC). It mainly targets multiple kinase transduction pathways to inhibit the growth, differentiation and proliferation of tumor cells and the generation of tumor vessels, thus slowing down the tumor progression and showing better therapeutic effects on HCC than previous treatment methods. In1998NCCN Guideline has appointed Nexavar as a first line drug to treat late stage HCC; EMEA in Europe, FDA in USA and SFDA in China have also approved Nexavar to treat HCCs that are not suitable for surgical removal or have undergone distant metastasis.Up till the present time, AFP, CA-125, CA-199, CEA, liver function and CT/MR are still main indicators evaluating the effects of HCC treatments. However, objective assessment based on these indicators cannot be performed until1-2months after the treatment, thus they cannot provide prompt, direct clinical information and are of limited use.As with traditional chemotherapy agents, various adverse reactions also occur when Nexavar is used to treat tumor, such as hand-foot skin reactions (), diarrhea, high blood pressure, gastrointestinal reactions, hair loss. rash, fatigue, hypersomnia, drowsiness, edema, constipation and bleeding; yet with the advantages including unique multi-target inhibition and minimal damages to normal tissues, Nexavar exhibits good tolerance and safety. Among drug related adverse reactions, the most common, specific and severe one is, which shows a series of symptoms that affect the skins in hand and/or foot, mostly in the palms of the two hands, finger joints, foot parts subject to frequent pressure and friction, and between fingers or toes. is mainly manifested by the following symptoms:numbness, tingling, increased sensitivity, burning sensation, erythema, swelling, hardening or callus, vesication, drieness and/or chaps, desquamation and/or peeling of skins frequently pressed. Grade1-2is of mild or moderate degree; no special treatments are needed and the patients can usually tolerate the symptoms. Yet of grade3or higher causes discomfort to the patient and affects their daily lives; based on clinical symptoms if the drug is stopped or the dose is reduced and proper treatment, the symptoms can be substantially alleviated and there will be no irreversible damages.Some previous studys has shown that:occurrence of is related to the antiangiogenic function of Nexavar; when the doses are increased or other antiangiogenic drugs are used along with Nexavar, the occurrence of HFSR increases or the degree is aggravated, mostly within2-4weeks after taking the medicine. Therefore, it remains a question whether can be of potential significance predicting the antitumor activity of the drugs, whether it is correlated with the treatment effect, and whether it can be used as a new evaluation indicator in addition to the aforementioned ones. In order to address this question, we performed an analysis on51middle-, late stage HCC patients who received Nexavar treatment.MethodsWe retrospectively analyzed the incidence of hand-foot skin reactions () of51patients with advanced HCC who treated by sorafenib combined with Transcatheter Arterial Chemoembolization (TACE), and graded the according to NCI CTCAE3.0version, the grade0、grade1-2、grade3defined as group A、 B、C in study. Re-examinated CT every6-8weeks in all patients, assessed of tumor lesions, under the revised Response Evaluation Criteria in Solid Tumors (mRICIST). SPSS software(version18.0)was used for the statistical analysis.χ2-test was carried out to explore the differences of tumor response and patients features among the groups, mPFS、mOS and Survival curves adopted Kaplan-Meier method, the differences in terms of PFS、OS were explored by the Log-rank test, the COX proportional hazards regression model was applied to analyze the baseline factors affecting PFS, A P-value<0.05(bilateral) was considered to indicate statistical significance.comparing tumor Objective response rate (ORR)、disease control rate(DCR)、median progression free survival (mPFS) and median overall survival (mOS) in the different severity group. The COX proportional hazard model was applied for univariate analysis and multivariate analysis, screen the factors affecting PFS.ResultsFifty-one HCC patients treated with sorafenib combined with TACE were included in this study:Until Nov15th,2011, among51patients,28(54.9%) died,17(33.3%) survived,6(11.8%) lost to visit,40(78.4%) patients progressed,13/51(25.4%) patients showed no, whereas38/51(74.6%) patients showed of different degrees, among which there were27cases of grade1-2and11cases of grade3.1. among the patients, No patients got CR, in group grade0,1case assessed at PR,4case at SD,8case at PD, in group grade1-2,8case at PR,11case at SD,8case at PD, in group grade3,6case at PR,4case at SD,1case at PD.2. among the three groups,the ORR were7.7%、29.6%、54.5%, there was a significant difference (P=0.043), group grade0vs grade3,P=0.012, group grade0vs grade1-3,(P=0.046), there were significant differences;group grade0vs gradel-2(P=0.120)、group grade1-2vs grade3,P=0.149,there were no any significant difference. 3. A significant difference was also observed in terms of DCR (P<0.05),The DCR were38.5%,70.4%and90.9%in the grade0,1-2and3groups,there was a significant difference (P=0.021), group grade0vs grade3,P=0.008, group grade0vs grade1-3,(P=0.012), there were significant differences;group grade0vs grade1-2(P=0.054)、group grade1-2vs grade3,P=0.177, there were no any significant differences.4. The three groups’ mPFS were2.8months (95%CI:1.6-4.0)、4.5months (95%CI:1.3-7.7) and12.8months (95%CI:3.7-21.9), the difference had statistical significance (P<0.05), group grade0vs grade1-2, P=0.019,(Relative risk)RR:2.591(95%CI:1.172-5.747), P=0.019, grade0vs grade3,P<0.001, RR:7.278(95%CI:2.466-21.480), P<0.001, grade1-2vs grade3,P=0.054;5. The mOS of three groups were8.5months (95%CI:5.9-11.1)、13.0months (95%CI:10.1-15.9) and25.4months, P<0.05. there were statistically significant differences between the any two groups.6.Ten variables, such as age、ECOG score、Child-pugh score、BCLC stage、AFP、 extrahepatic metastasis、vascular invasion the maximum diameter、HBV-DNA、 group, were introduced to the model.the univariate analysis shows that age (P=0.064)、BCLC stage (P=0.058)、extrahepatic metastasis (P=0.066)、group (P<0.01) have statistical significance, P<0.10as the test standard.and then pull the four factors into the COX model for multivariate analysis of PFS. in detail, age (P=0.029) and group were choosed, maintained statistical significance.Conclusions1. HFSR is the most common adverse reactions of targeted drug--sorafenib, although HFSR does not appear to directly decrease survival, severe HFSR will bring patients physiological and psychological burden, impact quality of life, interrupt sorafenib therapy, lead to sorafenib dose modification or interruption, potentially limiting the antitumor effect.2. HFSR should be closely monitored in HCC patients treated with sorafenib in relation to its potential role as a surrogate marker of efficacy;3. It has yet to be demonstrated whether the efficacy increasing with the severity of HFSR or not.