《软组织肿瘤》PPT课件.ppt

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1、成人软组织肉瘤化疗成人软组织肉瘤化疗ContentslOverviewlDrugslTreatmentneoadjuvant chemotherapyadjuvant chemotherapyAdvanced or metastatic diseases chmeotherapytargeted therapyContentslOverviewlDrugslTreatmentneoadjuvant chemotherapyadjuvant chemotherapytargeted therapylSarcomas constitute a heterogeneous group of rare

2、 solid tumors oflmesenchymal cell origin with distinct clinical and pathological featuresl成人软组织肉瘤（成人软组织肉瘤（Softtissuesarcomas，STSs），包），包括一组发病相对较少，组织学多样的恶性肿瘤。括一组发病相对较少，组织学多样的恶性肿瘤。l起源中胚层和外胚层。起源中胚层和外胚层。l占成人恶性肿瘤的占成人恶性肿瘤的1%和儿童恶性肿瘤的和儿童恶性肿瘤的5%。l尚无特别有效的治疗方法，需多学科联合。尚无特别有效的治疗方法，需多学科联合。Categories lSarcomasofsof

3、ttissues(includingfat,muscle,nerveandnervesheath,bloodvessels,andotherconnectivetissues)lSarcomasofbone.The anatomic site of the primary diseaselExtremities(60%)l the trunk(19%)l retroperitoneum(15%)lhead and neck(9%)RiskfactorslAge.Softtissuesarcomascanoccuratanyage,butoverallaremorecommoninolderad

4、ults.Theaverageageatdiagnosisis57years.Certaintypesofsarcomasaremorecommoninchildren,however.lChemicalexposure.Beingexposedtocertainchemicals,suchasvinylchlorideanddioxin,canincreasetheriskofsofttissuesarcomas.lRadiationexposure.Previousradiationtreatmentforothercancerscanincreasetheriskofsofttissue

5、sarcomas.SignsandsymptomslanewlumporalumpthatisgrowinganywhereinthebodymayormaynotcausepainmayincludeabdominalswellingoralumpintheabdomenlnausealvomitinglheartburnlabdominalpainlbloodinvomitorstoolAdult soft tissue sarcoma diagnosedlIncisionalbiopsy:The removal of part of a lump or a sample of tissu

6、e.lCorebiopsy:The removal of tissue using a wide needle.lExcisionalbiopsy:The removal of an entire lump or area of tissue that doesnt look normal.core needle biopsyPathologyandstaginglthetypeofsofttissuesarcomalthestageofthecancer(howfarthecancerhasprogressed)lthegradeofthetumour(howabnormalthecance

7、rcellslookandbehave)lPleomorphic sarcoma also known as malignant fibrous histiocytoma(MFH)l GISTslLiposarcomal leiomyosarcomal synovial sarcomal malignant peripheral nerve sheath tumorsIncidenceofSoftTissueSarcomaSubtypes(1978-2001)SitesofMetastasisGadd M,et al,Ann Surg,1993ContentslOverviewlDrugslT

8、reatmentneoadjuvant chemotherapyadjuvant chemotherapytargeted therapyChemotherapylSingleAgentsDoxorubicinIfosfamideDacarbazineGemcitabinePaclitaxelDocetaxelChemotherapyPemetrexedTemozlomideIrinotecanTopotecanPelyatedliposmaldoxorubicinTrabectedinDoxorubicinlThesingleagentresponserates(RR)areintheran

9、geof20to30%lsurvivalintherangeof7.7-12monthslThebestresponseratesareseenwithdosagesintherangeof75mg/m2to90mg/m2DoxorubicinlEpirubicinisalesscardiotoxicanalogofdoxorubicin,whichfailedtodemonstrateanybenefitascomparedtodoxorubicinlliposomaldoxorubicincanbeusedinpatientswheredoxorubiciniscontraindicate

10、d,buttheresponseratesofthisdrugasasingleagentarelowerthantheconventionaldoxorubicin.Ifosfamideladose-responserelationshipandhigherdosescanbeusedasitlackscardiotoxicitylmonotherapywithanidenticaldose(9g/m2),givenoverthreedays,byeithercontinuousinfusionorthree-hourinfusionsdailyDacarbazinelincombinati

11、onwithdoxorubicinandifosfamide(MAID)lgivenasashortinfusionof1.2g/m2over20minuteswiththeavailabilityofeffectiveantiemetics.TemozolamidelTemozolamide,theoralequivalentofdacarbazine,appearstohavethesameactivityagainstleiomyosarcomaaswell.Trabectedin(Ecteinascidin-743,ET743,Yondelis)lThistetrahydroisoqu

12、insolinemoleculewasderivedoriginallyfromatunicate,orseasquirt,Ecteinascidia turbinate(foundintheCarribbeanandMediterraneanwaters)lApooledanalysisof183patientsfromthethreesinglearmphaseIIstudiesl1.5mg/m2administeredasa24-hourinfusiononceeverythreeweekslInthisanalysisthoughtheORRwasonly7.7%,therateoft

13、umorcontrol(i.e.,ORRplusminorresponsesplusdiseasestabilization)was51%.ContentslOverviewlDrugslTreatmentneoadjuvant chemotherapyadjuvant chemotherapyAdvanced or metastatic diseases chmeotherapytargeted therapyTreatmentlsurgerySurgeryisthemostcommontreatmentformanysofttissuesarcomas.Dependingonthesize

14、andlocationofthesarcoma,allorpartofthetumourmayberemoved.Ifthewholetumourisremoved,awidemarginofhealthytissuearounditisalsoremoved.Inmanycases,limb-sparingsurgerycanbedoneforasofttissuesarcomathatoccursinanarmorlegandamputationcanbeavoided.However,insomecases,softtissuesarcomainalimbmayrequirethelim

15、btobeamputated.lradiationtherapyRadiationtherapymaybeusedbeforeoraftersurgeryor,lesscommonly,insteadofsurgery.lchemotherapyIfthesofttissuesarcomahasspreadtootherpartsofthebody,chemotherapymaybeusedtocontrolthecancerandrelievesymptoms.Chemotherapyissometimesusedbeforesurgerytoshrinkatumouroraftersurg

16、erytohelpreducethechanceofthecancerrecurring.软组织肉瘤软组织肉瘤:传统治疗传统治疗l局限期肉瘤:扩大范围的手术为标准治疗l对于高度或中度复发风险或者切缘阳性的软组织肉瘤而言，通常需行术后放疗1三维适形放疗,近距离放疗,或调强放疗1.Clark MA,et al.N Engl J Med.2005;353:701-711.2.Wunder JS,et al.Lancet Oncol.2007;8:513-524.但是仍有50%的软组织肉瘤患者会出现远处转移2 Surgical ManagementlMainstay of treatment for

17、all STS of the extremity is wide local excision(+/-)XRTAdjuvant/neoadjuvantRole of neoadjuvant chemotherapylWiden bloc resection 1-2 cm margins in all directions Limiting factors:neurovascular juxtapositionBony juxtapositionRadical Surgical MarginAmputation新辅助化疗新辅助化疗l134例患者，单纯手术组与新辅助化疗例患者，单纯手术组与新辅助化

18、疗+手术，每组手术，每组67例。例。l成人高危成人高危STSs（肿瘤（肿瘤or=8cm，不论分级如何；或分级为，不论分级如何；或分级为II/III，但肿瘤但肿瘤5cm，以及深部肿瘤，以及深部肿瘤Role of Adjuvant ChemotherapylSarcoma meta-analysis collaboration,lancet,1997 1568 patients from 14 studies Median follow-up 9.4 years 10-yr.DFS improved from 45 to 55%(p=0.0001)Local 10-yr.DFS improved

19、from 75 to 81%(p=0.016)OS only improved from 50 to 54%(p=0.12)lData does not support routine use of adjuvant chemotherapy outside a clinical trialAdjuvantChemotherapyTrialsMeta-Analysis#2MetastaticdiseaseschemotherapyAnEORTCSTBSGstudylA total of 2,185 patients with advanced soft tissue sarcomas who

20、had been treated in seven clinical trialsResultsResultsMetastaicSoft-Tissue Sarcomas chemotherapyMetastaicSoft-Tissue Sarcomas chemotherapyDose-intensivechemotherapywithgrowthfactororautologousbonemarroworstem-celltransplantsupportinfirst-linetreatmentofadvancedormetastaticadultsofttissuesarcoma:acl

21、inicalpracticeguidelinelDose-intensive chemotherapy with growth factor support is not recommended in the first-line treatment of patients with inoperable locally advanced or metastatic soft tissue sarcoma.lThe data are insufficient to support the use of high-dose chemotherapy with autologous bone ma

22、rrow or stem-cell transplantation as first-line treatment in this group of patients.lEligible patients should be encouraged to enter clinical trials assessing novel approaches or compounds.CombinationRegimensbeyondIfosfamideandAdriamycinFixed-doserategemcitabineplusdocetaxelasfirst-linetherapyformet

23、astaticuterineleiomyosarcoma:aGynecologicOncologyGroupphaseIItriallForty-twowomenenrolled,with39evaluableforresponsel900mg/m2over90minutes,d1andd8;docetaxel100mg/m2onday8,lWithgranulocytegrowthfactorsupportdaynineofa21-daycycle.ResponselORR15of42patients(35.8%overall;CR4.8%,PR31%,90%CI23.5to49.6%),l

24、11(26.2%)SDlmedianprogression-freesurvival(PFS)4.4months(range0.4to37.2+months)lMedianoverallsurvival16+months(range:0.441.3months)Fixed-doserategemcitabineplusdocetaxelassecond-linetherapyformetastaticuterineleiomyosarcoma:aGynecologicOncologyGroupphaseIIstudylForty-onewomenenrolled,with48evaluable

25、forresponseunresectableuterineleiomyosarcomaprogressingafterpriorcytotoxictherapylgemcitabine900mg/m2,d1andd890minutes,ldocetaxel100mg/m2d8,21-daycyclelwithgranulocytegrowthfactorCR 6.3%(3/48),PR 20.8%(10/48)ORR 27%(95%confidence interval 15.3%41.8%).An additional 50%(24/48)SD,clinical benefit rate

26、of 77%.Median PFS for all 48 patients was 6.7+months(range 0.7 27+months)Adverse eventslThepredominanttoxicitywasmyelosuppressionlleukopeniagrade3(14.5%),grade4(8.3%)lthrombocytopeniagrade3(29%),grade4(10.4%)lneutropeniagrade3(12.5%),grade4(8.3%)lanemiagrade3(20.8%),grade4(4.2%).RandomizedPhaseIIStu

27、dyofGemcitabineandDocetaxelComparedWithGemcitabineAloneinPatientsWithMetastaticSoftTissueSarcomas:ResultsofSarcomaAllianceforResearchThroughCollaborationStudy002lFixeddoserate10mg/m2/10mininfusingemcitabineat1200mg/m2d1andd8ingemcitabinearmlGem-Docarm,gemcitabnedose900mg/m2fixeddoserateinfusion90min

28、,d1andd8;docetaxel100mg/m2d160minlRepeatevery21daysInvestigationalNewDrugs(targetedtherapy)lMammalian target of rapamycin(mTOR)inhibitorsmTOR inhibitors in clinical developmentThree rapamycin analogs:CCI-779(temsirolimus),RAD001(everolimus),and AP23573(deforolimus)lInsulin like growth factor 1 recep

29、tor(IGF-IR)inhibitorslOthersAngiogenesis and STSslAngiogenesisplaysanimportantroleinthegrowthanddisseminationofSTSsltheVEGF/VEGFRpathwayplaysthemostimportantrolelHighVEGFexpressionisanindependentpoorprognosticfactorforincreasedriskofmetastasesanddecreasedoverallsurvivalCompassionateuseofbevacizumab(

30、Avastin)inchildrenandyoungadultswithrefractoryorrecurrentsolidtumors Bevacizumab was administered at 510 mg/kgbody weight intravenously every 23 weeks,Most patients received chemotherapy in addition to bevacizumabOthers苹果酸舒尼替尼苹果酸舒尼替尼索坦索坦：药物结构：药物结构l小分子吲哚酮类化合物小分子吲哚酮类化合物l分子式：分子式：C22H27FN4O2C4H6O5l分子量：分

31、子量：532.6lATP位点竞争性抑制剂位点竞争性抑制剂抑制磷酸化和激活阻断信号传导NHONHFNHONOHCOOHHOOCHSutent Product Monograph舒尼替尼主要作用靶点舒尼替尼主要作用靶点*对于GIST而言尤其重要；*对于GIST/乳腺癌和小细胞肺癌而言尤其重要舒尼替尼同时具有抗肿瘤血管生成与舒尼替尼同时具有抗肿瘤血管生成与抗肿瘤细胞增殖双重效应抗肿瘤细胞增殖双重效应Sandrine F,et al.Nature,2007舒尼替尼治疗腺泡软组织肉瘤舒尼替尼治疗腺泡软组织肉瘤S.Stacchiotti,et al.Annal of Oncology,2011 Feb舒尼

32、替尼治疗非舒尼替尼治疗非GIST软组织肉瘤软组织肉瘤晚期/转移性非GIST软组织肉瘤,既往可接受1-2个化疗方案失败，ECOG PS 0-2(N=53)持续治疗直持续治疗直至疾病进展至疾病进展舒尼替尼舒尼替尼37.5 mg,每天持续口服lII期临床：多中心、前瞻性舒尼替尼持续期临床：多中心、前瞻性舒尼替尼持续37.5mg口服口服ArmA:血管结缔组织肿瘤血管结缔组织肿瘤(n=18)平滑肌肉瘤平滑肌肉瘤,脊索瘤脊索瘤,血管肉瘤血管肉瘤,孤立的纤维瘤孤立的纤维瘤,硬纤维瘤硬纤维瘤,内膜肉内膜肉瘤瘤ArmB:高分化多形性肉瘤高分化多形性肉瘤(n=21)恶性纤维组织细胞瘤恶性纤维组织细胞瘤,未分型肉瘤

33、未分型肉瘤,未分化肉瘤未分化肉瘤,滑膜肉瘤滑膜肉瘤,脂肪肉脂肪肉瘤瘤,粗纤维增生性小圆细胞肿瘤粗纤维增生性小圆细胞肿瘤,脂肪肉瘤脂肪肉瘤,腺泡软组织肉瘤腺泡软组织肉瘤ArmC:脊索瘤脊索瘤(n=9)J George,et al.JCO 2009,Vol 27II期临床：舒尼替尼治疗期临床：舒尼替尼治疗STS疗效疗效lII期临床提示舒尼替尼对STS具有抗肿瘤活性l根据肿瘤代谢评价疗效PR 48%,SD 52%J George,et al.JCO 2009,Vol 27Conclusionsl Sarcomas are a rare,heterogeneous group of diseases.

34、l Existing challenges need to be overcome.l Progress is being made.ContlThedataforneoadjuvantchemotherapyisrobustifregionalhyperthermiaisaddedtothecombinationofetoposide,ifosfamide,andadriamycinlAdjuvantchemotherapywithsingleagentadriamycinshouldbeconsideredifhigh-riskprognosticfeaturesarepresentlme

35、tastaticSTSsordevelopingmetastaticdiseaseafteratreatment-freeintervalwillrequireamultidisciplinarydiscussionandchemotherapywithasingleagentadriamycinorcombinationtherapyofifosfamideandadriamycinlNovel therapeutic approaches are needed.ParticipationinclinicaltrialsofnewertargetedtherapieslikemTORinhibitors,IGF-1Rblockers,andVEGFinhibitorsshouldbeencouraged.ThedataforthesenewerdrugsappearpromisingCont