A Prospective Study Of Evaluating The Efficacy And Safety Of Sorafenib Plus Best Supportive Care In Patients With: Advanced Intrahepatic Cholangiocarcinoma

A prospective study of evaluating the efficacy and safety of sorafenib plus bestsupportive care in patients with advanced intrahepatic cholangiocarcinomaCholangiocarcinoma are the tumors deriving from the intrahepatic or extrahepaticbiliary epithelium. According to anatomical site, bounded to the secondary branches of thebile duct, cholangiocarcinoma is divided into intrahepatic cholangiocarcinoma (ICC) andextrahepatic cholangiocarcinoma (ECC). ICC incidence accountes for5%～10%of theliver cancer[9], ranking second in primary liver cancers[1,2], about3%in the digestivesystem cancer[1]。In recent years, the incidence in NorthAmerica, Europe,Australia andAsia is rising[2,3,4]。Because of the difficulty of early diagnosis,highly malignant and poortreatment,the prognosis for most patients is poor.Now in most experts’opinion, radicalresection is the most effective treatment to cure cholangiocarcinoma,but the recurrence rateis high and only about10%of patients are suitable for surgery when they have beendiagnosed with cholangiocarcinoma. Reports indicate that the5-year survival rate ofpatients with bile duct carcinoma after curative resection is less than30%[5-7],so thechemotherapy has become the only choice,which are mostly based on5-Fu or gemcitabine.Sorafenib is a multi-kinase inhibitor, on the one hand it blocks the tumor cellproliferation by targeting the RAF kinase in the RAF/MEK/ERK signaling pathway, onthe other hand it plays a important role in antiangiogenic effection by targetinganti-vascular endothelial growth factor receptor-2/-3(VEGFR-2/-3) and platelet-derivedgrowth factor receptor β (PDGFR-β), Flt3and C-kit receptor[8],and has been successfullyapplied to the treatment of renal cell carcinoma, hepatocellular carcinoma, etc. In vitrosorafenib alone or in combination can induce tumor cell growth inhibition and apoptosis.In recent years, scholars have done a lot of research and try to explore an entry point of thesorafenib treatment from cholangiocarcinoma molecular mechanism. The two followingfindings provide the sorafenib’effection in intrahepatic cholangiocarcinoma treatment astrong theoretical support. Alexander, etc[38]found that the EGI-1and TFK-1incholangiocarcinoma cells are in a dose-dependent relationship with sorafenib, through thispathway it can inhibit cholangiocarcinoma cells growth,and cell proliferation inhibition ison the performance of inhibiting the cell cycle (G1/G0phase).They also observed thatsorafenib can activate the MAPK pathway (the critical signal pathway of regulating the cell growth, transformation and apoptosis). Another vitro and vivo experimental in humanICC cells on sorafenib[39]showed that, the sorafenib-treated ICC cells have both expresseda dose-dependent inhibition in (mitogen-activated protein kinase kinase) MEK pathway,MAPK (mitogen-activated protein kinase) pathway, and IL-6-induced STAT3(signaltransducer and activator of transcription3) pathway. In vivo experiments, the growth ofsubcutaneous tumors in immunodeficient mice could be both inhibited significantly whenthey were given oral sorafenib of10mg/kg,30mg/kg, and100mg/kg.In conclusion, such studies have shown that sorafenib is a relatively active drugs forintrahepatic cholangiocarcinoma. It can simultaneously inhibit tumor angiogenesis (VEGFand PDGF signaling pathway) and tumor cell growth (Raf kinase and STAT3signalingpathway). These researches have provided a reliable theoretical basis for treatingintrahepatic cholangiocarcinoma by sorafenib monotherapy or combination therapy withother drugs. The purpose of this study is to observe the efficacy and safety of advancedintrahepatic cholangiocarcinoma by sorafenib.Objective:To evaluate the efficacy and safety of sorafenib plus best supportive care inpatients with advanced intrahepatic cholangiocarcinoma.Methods:45patients with advanced intrahepatic cholangiocarcinoma,eligible for theinclusive and exclusive criteria,will be enrolled and given the sorafenib(Nexavar, Bayer),400mg,bid. Patients should continue taking the drugs until they meet any one of thefollowing stopping criterias, such as tumor progression, or drug intolerance, or poorcompliance or withdrawing informed consents. Observed indicators:main indicator(12weeks disease control rate); secondary indicators(time to progression, TTP; progressionfree survival, PFS; overall survival, OS; duration of treatment, DOT;toxicity). Follow-up intreatment period:1to3months visit once every3weeks, visit window:±3days; onceevery6weeks after3months, visit window:±7days. Content: ECOG performance status,laboratory tests (complete blood count, liver and kidney function tests, coagulationchecking), tumor assessment (CT/MRI once every6weeks, imaging methods should beconsistent), sorafenib medication informations, toxicity and adverse events. The adverseevents should be recorded within30days after the sorafenib treatment. Survival follow-up:follow up the whole lifetime, once every three months (telephone available), recording thepatients’ survival informations. Statistical analysis: analyse the clinical follow-up datas andoutcomes. Results: Forty-five cases were analyzed and compared retrospectively fromSeptember2012to March2014,whose pathological diagnosis were intrahepaticcholangiocarcinoma in eastern hepatobiliary surgery hospital. Throughout the wholeclinical trial, toxicity of all patiences would be closely monitored and assessmented,nograde4case(NCI CTCAE4.02) and drug-related death.11grade3cases(24.4%),andrelieved after changing the dose(400mg,qd). The most common adverse reactions wererash, followed by diarrhea,and the third is hand-foot syndrome.The12weeks DCR is35.5%(16/45), and there was no CR case to March12,2014as the endpoint of thestudy,while1PR case and15SD cases.3cases (6.6%) were lost,24PD cases (53.3%)confirmed by radiography and2cases (4.4%) dropped out of the research because of theintolerance, expulsion rate11.1%.The median TTP was86days(range:39-213),95%CI(83.02，88.98),so was the PFS,and the median OS129days(range:68-398)，95%CI(117.77，140.23). The median DOT was86days(range:9-213),95%CI (83.92，88.08).Surgical type taken before enrollment has a significant impact on PFS and OS.In R0recurrence group the median PFS was126days, while palliative biopsy group was81day(P=0.035). The median OS in R0recurrence group was148days, while palliative biopsygroup was87days (P=0.002).Conclusion: Based on our findings,the12weeks DCR was no significant differencefrom that of5-Fu or gemcitabine chemotherapy,but the TTP and OS is not ideal,only86days and129days, respectively. By comparison with previous historical data, our clinicaltrial indicated that sorafenib hadn’t significantly improved the survival time, and expandi-g the sample size should be essential.While the toxicity was no significant difference frothat of sorafenib in HCC and advanced biliary tract cancer (including gallbladder cancer,extrahepatic bile duct), therefore, sorafenib in patients with advanced cholangiocarcinomawas well tolerated.