Effects of Sorafenib on Intra-Tumoral Interstitial Fluid Pressure and Circulating Biomarkers in Patients with Refractory Sarcomas (NCI Protocol 6948) 英文参考文献.docVIP

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Effects of Sorafenib on Intra-Tumoral Interstitial Fluid Pressure and Circulating Biomarkers in Patients with Refractory Sarcomas (NCI Protocol 6948) 英文参考文献.doc

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Effects of Sorafenib on Intra-Tumoral Interstitial Fluid Pressure and Circulating Biomarkers in Patients with Refractory Sarcomas (NCI Protocol 6948) 英文参考文献

EffectsofSorafenibonIntra-TumoralInterstitialFluid PressureandCirculatingBiomarkersinPatientswith RefractorySarcomas(NCIProtocol6948) ChandrajitP.Raut1,4*.,YvesBoucher2,4.,DanG.Duda2,4.,JeffreyA.Morgan3,4,RichardQuek3,4¤a MarekAncukiewicz2,4,JohannaLahdenranta2,4,J.PaulEder3,4¤b,GeorgeD.Demetri3,4,RakeshK. Jain2,4 , 1DepartmentofSurgery,BrighamandWomen’sHospitalandDana-FarberCancerInstitute,HarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica, 2DepartmentofRadiationOncology,MassachusettsGeneralHospital,Boston,Massachusetts,UnitedStatesofAmerica,3DepartmentofMedicalOncology,Brighamand Women’s Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America, 4Harvard Medical School, Boston, Massachusetts,UnitedStatesofAmerica Abstract Purpose:Sorafenibisamulti-targetedtyrosinekinaseinhibitorwiththerapeuticefficacyinseveralmalignancies.Sorafenib may exert its anti-neoplastic effect in part by altering vascular permeability and reducing intra-tumoral interstitial hypertension.AscorrelativesciencewithaphaseIIstudyinpatientswithadvancedsoft-tissuesarcomas(STS),weevaluated theimpactofthisagentonintra-tumorinterstitialfluidpressure(IFP),serumcirculatingbiomarkers,andvasculardensity. PatientsandMethods:PatientswithadvancedSTSwithmeasurablediseaseandatleastonesuperficiallesionamenableto biopsyreceivedsorafenib400mgtwicedaily.IntratumoralIFPandplasmaandcirculatingcellbiomarkersweremeasured before and after 1–2 months of sorafenib administration. Results were analyzed in the context of the primary clinical endpointoftime-to-progression(TTP). Results:In15patientsaccrued,themedianTTPwas45days(range14–228).Intra-tumoralIFPmeasurementsobtainedin6 patientsatbaselineshowedadirectcorrelationwithtumorsize.Twopatientswithstablediseaseattwomonthshadpost- sorafenibIFPevaluationsanddemonstratedadeclineinIFPandvasculardensity.Sorafenibsignificantlyincreasedplasma VEGF,PlGF,andSDF1aanddecreasedsVEGFR-2levels.IncreasedplasmaSDF1aa