乳腺癌的化疗进展ppt课件

1 乳腺癌的化疗进展 2 乳腺癌化疗的历史回顾 70年代 CMF80年代 蒽环类 anthracyclines 90年代 紫杉类 taxanes 21世纪 化疗 生物靶向治疗常规 剂量密集 3 TX方案与AC方案比较 docetaxel capecitabine TX ADM CTX AC 目的 无蒽环类方案与含蒽环类方案比较 3期单中心随机试验 LeeKS etal BreastCancerResTreat 2007 4 TX方案与AC方案比较 209例腋窝淋巴结阳性 II III期BC行4周期TXorAC TX与AC比 增加了pCR 21 10 P 0 024 RR 84 65 P 0 003 TX恶心 呕吐少 但口腔炎 腹泻 肌肉痛 皮肤及指甲改变比AC明显 DFS无差别 P 0 932 pCR者复发少 P 0 025 hazardratio 0 189 95 CI 0 044 0 815 LeeKS etal BreastCancerResTreat 2007 5 PhaseIIItrialcomparingACwithTC doxorubicinandcyclophosphamide AC docetaxelandcyclophosphamide TC 1016例AC n 510 TC n 506 every3weeks 完成化疗后给予放疗 受体阳性者给予tamoxifen JonesSE etal JClinOncol 2006 24 34 5381 5387 6 PhaseIIItrialcomparingACwithTC 结果 TC的5年DFS明显高于AC 86 v80 P 0 015 ORR TC AC90 87 P 0 13 肌肉痛 关节痛 水肿 粒细胞减少在TC组多见 恶心 呕吐 充血性心衰在AC组多见 JonesSE etal JClinOncol 2006 24 34 5381 5387 7 AphaseIItrialofdocetaxelassecond linechemotherapyinpatientswithMBC docetaxel100mg m 2 every3weeksRR 35 MS 12MMTTP 4Mdocetaxel是治疗MBC的有效2线药物 特别是对anthracycline耐药的病人 BaurM etal JCancerResClinOncol 2007 8 Nab paclitaxel ABI 007 Abraxane 是将paclitaxel包裹在白蛋白里 HendersonIC etal ExpertRevAnticancerTher 2007 7 7 919 943 Nab paclitaxelforbreastcancer anewformulationwithanimprovedsafetyprofileandgreaterefficacy 9 Nab paclitaxelforbreastcancer anewformulationwithanimprovedsafetyprofileandgreaterefficacy 随机II期临床试验提示每周一次nab paclitaxel比每3周一次nab paclitaxel或docetaxel更有效 更安全 nab paclitaxel的优势在于安全性提高 可以增加剂量 且进入肿瘤细胞内的药物比例更高 HendersonIC etal ExpertRevAnticancerTher 2007 7 7 919 943 10 Thetrastuzumabandvinorelbineortaxanestudy 此为一项前瞻性 多中心 随机对照研究 方法 HER2过度表达的MBC 未进行过化疗的病人随机分为trastuzumab vinorelbine每周一次 trastuzumab taxane每周一次 结论 vinorelbine trastuzumab和taxane trastuzumab一线治疗HER2阳性的MBC疗效无差异 BursteinHJ etal Cancer 2007 11 Aphase IIItrialofdoxorubicinanddocetaxelversusdoxorubicinandpaclitaxelinmetastaticbreastcancer resultsoftheERASME3study MBC患者随机分为AD组或AP组 每3周一次 AD 4 docetaxel 4AP 4 paclitaxel 4 CassierPA etal BreastCancerResTreat 2007 12 Aphase IIItrialofdoxorubicinanddocetaxelversusdoxorubicinandpaclitaxelinmetastaticbreastcancer resultsoftheERASME3study 结果 RR 39 6 forADand41 8 forAP medianPFS和medianOS 8 7M和21 4M AD 8 0M和27 3M AP p 0 977and0 081 AD的血液学毒性比AP重 p 0 0000 3 4度疲劳AD重 p 0 03 而神经病变在AP组多见 p 0 03 CassierPA etal BreastCancerResTreat 2007 13 Aphase IIItrialofdoxorubicinanddocetaxelversusdoxorubicinandpaclitaxelinmetastaticbreastcancer resultsoftheERASME3study 结论 AD与AP在生活质量和有效率无差别 但在副作用方面有差别 CassierPA etal BreastCancerResTreat 2007 14 Evidence baseduseoftaxanesintheadjuvantsettingofbreastcancer AreviewofrandomizedphaseIIItrials 6个大型临床试验 验证taxanes在乳腺癌辅助治疗中的作用 各种不同的以anthracycline为主的方案作为对照组 有充分证据支持常规使用taxanes治疗乳腺癌是有益的 包括激素受体阳性和Her 2阳性的病人 Est vezLG etal CancerTreatRev 2007 15 Combiningchemotherapyandlow molecular weightheparinforthetreatmentofadvancedbreastcancer 凝血激活在肿瘤进展中起作用 低分子肝素可影响肿瘤生长 显示低分子肝素可影响化疗疗效 Enoxaparin 0 5or1 0mg kg 每天一次 Docetaxel35 45mg m 2 每周一次 PR 36 SD 36 SeeholzerN etal BloodCoagulFibrinolysis 2007 18 5 415 423 16 Vinorelbine docetaxelcombinationtreatmentofmetastaticbreastcancer aphaseIstudy 方法 DOC 60or70mg m2 day1NVB 20to25mg m2fori v onday1 60mg m2onday8orday15fororal every3weeks BonneterreJ etal CancerChemotherPharmacol 2007 60 3 365 373 17 AphaseIIclinicaltrialofZD1839 Iressatrademark incombinationwithdocetaxelasfirst linetreatmentinpatientswithadvancedbreastcancer gefitinib250mg oncedailydocetaxel75mg m 2 every3weeks untiltumorprogression toxicityorotherreasonsfordiscontinuation DennisonSK etal InvestNewDrugs 2007 18 AphaseIIclinicaltrialofZD1839 Iressatrademark incombinationwithdocetaxelasfirst linetreatmentinpatientswithadvancedbreastcancer 33例 中位治疗周期为5周期 临床受益率为51 5 CR 1 PR 12 SD 4 ORR 39 4 DennisonSK etal InvestNewDrugs 2007 19 AphaseIIclinicaltrialofZD1839 Iressatrademark incombinationwithdocetaxelasfirst linetreatmentinpatientswithadvancedbreastcancer CONCLUSION ThecombinationofgefitinibanddocetaxelisanactiveregimeninpatientswithpreviouslyuntreatedMBC DennisonSK etal InvestNewDrugs 2007 20 MulticenterphaseIItrialofneoadjuvanttherapywithtrastuzumab docetaxel andcarboplatinforhumanepidermalgrowthfactorreceptor 2 overexpressingstageIIorIIIbreastcancer resultsoftheGETN A 1trial 方法 HER 2 阳性患者 trastuzumab4mg kg day1 followedby2mg kgweekly docetaxel75mg m2 every3weeks carboplatin areaundercurve 6 forsixcycles CoudertBP etal JClinOncol 2007 25 19 2678 2684 21 MulticenterphaseIItrialofneoadjuvanttherapywithtrastuzumab docetaxel andcarboplatinforhumanepidermalgrowthfactorreceptor 2 overexpressingstageIIorIIIbreastcancer resultsoftheGETN A 1trial RESULTS Sixty sevenpatients HER 2 positive completedsixcyclesoftherapy CRandPR 95 85 and10 Grade3 4neutropeniaandfebrileneutropeniawere2 Nosymptomaticcardiacdysfunctionoccurred CoudertBP etal JClinOncol 2007 25 19 2678 2684 22 MulticenterphaseIItrialofneoadjuvanttherapywithtrastuzumab docetaxel andcarboplatinforhumanepidermalgrowthfactorreceptor 2 overexpressingstageIIorIIIbreastcancer resultsoftheGETN A 1trial CONCLUSION TrastuzumabplusdocetaxelandcarboplatinachievedagoodpCRrateandfavorabletolerabilityinstageIIorIIIHER 2 positivebreastcancer CoudertBP etal JClinOncol 2007 25 19 2678 2684 23 Pathologiccompleteresponsewithsixcomparedwiththreecyclesofneoadjuvantepirubicinplusdocetaxelandgranulocytecolony stimulatingfactorinoperablebreastcancer resultsofABCSG 14 epirubicin75mg m2docetaxel75mg m2onday1granulocytecolony stimulatingfactorondays3through10 ED Gevery21days threeorsixcycles StegerGG etal JClinOncol 2007 25 15 2012 2018 24 Pathologiccompleteresponsewithsixcomparedwiththreecyclesofneoadjuvantepirubicinplusdocetaxelandgranulocytecolony stimulatingfactorinoperablebreastcancer resultsofABCSG 14 SixcyclesofED G comparedwiththreecycles resultedinasignificantlyhigherpCRrate 18 6 v7 7 P 0045 ahigherpercentageofpatientswithnegativeaxillarystatus 56 6 v42 8 P 02 Ratesofadverseeventsweresimilar andnopatientsdiedontreatment StegerGG etal JClinOncol 2007 25 15 2012 2018 25 PhaseIIstudyofneoadjuvantdocetaxel vinorelbinefollowedbysurgeryandadjuvantdoxorubicin cyclophosphamideinwomenwithstageII IIIbreastcancer beforesurgerywith6cyclesofdocetaxel60mg m2andvinorelbine45mg m2 repeatedevery2weekswithgranulocytecolony stimulatingfactorandquinoloneprophylaxis LimentaniSA etal ClinBreastCancer 2006 6 6 511 517 26 PhaseIIstudyofneoadjuvantdocetaxel vinorelbinefollowedbysurgeryandadjuvantdoxorubicin cyclophosphamideinwomenwithstageII IIIbreastcancer RESULTS 59patients RR 98 CR 63 Grade3 4neutropenia 95 neutropenicfever 22 mucositis 5 andpulmonarytoxicity 5 LimentaniSA etal ClinBreastCancer 2006 6 6 511 517 27 Dosageofcapecitabineandcyclophosphamidecombinationtherapyinpatientswithmetastaticbreastcancer oralcapecitabine628to829mg m2twicedaily bid oralcyclophosphamide33to50mg m2bid ondays1to14acycleevery21days OhnoS etal AnticancerRes 2007 27 2 1009 1013 28 Dosageofcapecitabineandcyclophosphamidecombinationtherapyinpatientswithmetastaticbreastcancer CONCLUSION Thecapecitabine cyclophosphamidecombinationregimeniswelltoleratedandactiveinMBC andisbeingevaluatedinaphaseIIstudyinanthracycline pretreatedMBC OhnoS etal AnticancerRes 2007 27 2 1009 1013 29 PhaseI IItrialofadjuvantdose densedocetaxel epirubicin cyclophosphamide TEC instageIIandIIIbreastcancer docetaxel T 75mg m 2 epirubicin E 75mg m 2 cohort1 n 3 or100mg m 2 cohort2 n 12 cyclophosphamide C 500mg m 2 day1 withpegfilgrastim6mgsubcutaneouslyonday2 every2weeksforsixcycles Burdette RadouxS etal BreastJ 2007 13 3 274 280 30 PhaseI IItrialofadjuvantdose densedocetaxel epirubicin cyclophosphamide TEC instageIIandIIIbreastcancer 结论 剂量密度TEC化疗是可行的 与TAC等剂量时 docetaxel75mg m 2 epirubicin75mg m 2 cyclophosphamide600mg m 2 毒性反应中等 Burdette RadouxS etal BreastJ 2007 13 3 274 280 31 GemcitabinePlusDoxorubicinasFirst LineTreatmentinAdvancedorMetastaticBreastCancer MBC APhaseIIStudy gemcitabine1250mg m2IVondays1 8doxorubicin60mg m2IVonday1every21days for6cycles ElSerafiMM etal JEgyptNatlCancInst 2006 18 3 209 215 32 GemcitabinePlusDoxorubicinasFirst LineTreatmentinAdvancedorMetastaticBreastCancer MBC APhaseIIStudy RESULTS CR 17 1 PR40 SD 22 9 ORR 57 1 MTTP 7monthsTheoverallsurvivalat1and2yearswas74 2 and34 2 ElSerafiMM etal JEgyptNatlCancInst 2006 18 3 209 215 33 Gemcitabineinthemanagementofmetastaticbreastcancer asystematicreview 共83个试验 包括4个III期随机临床试验 全部III期临床试验均为一线用药 结果 其中2个III期试验证明含gemcitabine方案治疗MBC疗效高 副作用小 而另外2个III期试验却认为没有临床受益 而副作用大 结论 Gemcitabine taxane一线或二线治疗MBC疗效显著 DentS etal BreastCancerResTreat 2007 34 LowdoseGemcitabinepluscisplatininaweekly basedregimenassalvagetherapyforrelapsedbreastcanceraftertaxane anthracycline containingregimens gemcitabine G initialdose750mg m 2 or600mg m 2 ifthepatienthadreceivedmorethantwopreviousCTlines pluscisplatin P initialdose30mg m 2 or20mg m 2 incaseof 3priorCTlines ondays1and8ofa21 daycycle Treatmentwaspostponedtoday15ifitcouldnotbegivenonday8 withoutdosereduction Iftreatmentcouldnotbegivenonday15 a20 dosereductionwasallowedandtreatmentgiventhenextweek S nchez EscribanoMorcuendeR etal ClinTranslOncol 2007 9 7 459 464 35 LowdoseGemcitabinepluscisplatininaweekly basedregimenassalvagetherapyforrelapsedbreastcanceraftertaxane anthracycline containingregimens Allhadprioranthracyclinesandtaxanes Otheragentsusedincluded5 FU eniluracil MTX RPR109881A trastuzumab cisplatin VP16 vinorelbine capecitabineandirinotecan 72 7 hadreceivedradiotherapy68 1 hormonaltherapy S nchez EscribanoMorcuendeR etal ClinTranslOncol 2007 9 7 459 464 36 LowdoseGemcitabinepluscisplatininaweekly basedregimenassalvagetherapyforrelapsedbreastcanceraftertaxane anthracycline containingregimens Results PR 9 1 SD 36 4 ClinicalBenefitRate PR SD 45 5 MTTP 4monthsMediansurvival 8monthsToxicitiesgrade 3wereneutropenia35 andthrombocytopenia15 S nchez EscribanoMorcuendeR etal ClinTranslOncol 2007 9 7 459 464 37 LowdoseGemcitabinepluscisplatininaweekly basedregimenassalvagetherapyforrelapsedbreastcanceraftertaxane anthracycline containingregimens 结论 曾进行过多次化疗的 PS较好的MBC 每周一次的cisplatin gemcitabine是安全有效的挽救治疗方案 S nchez EscribanoMorcuendeR etal ClinTranslOncol 2007 9 7 459 464 38 Dose findingstudyofcapecitabineincombinationwithweeklypaclitaxelforpatientswithanthracycline pretreatedmetastaticbreastcancer CONCLUSION capecitabine1 000mg m 2 twicedaily days1 14 paclitaxel60mg m 2 week paclitaxel剂量大于60mg m 2 week是不合适的 因出现严重的皮肤毒性 SusnjarS etal JBUON 2007 12 2 189 196 39 AphaseIIstudyoftrastuzumabandcapecitabineforpatientswithHER2 overexpressingmetastaticbreastcancer JapanBreastCancerResearchNetwork JBCRN 00Trial 59例病人由6个中心提供 进行trastuzumab capecitabine治疗乳腺癌的研究 86 接受过化疗 CMF 7 1 anthracyclines 28 6 taxanes 25 0 或两种方案化疗 25 0 YamamotoD etal CancerChemotherPharmacol 2007 40 AphaseIIstudyoftrastuzumabandcapecitabineforpatientswithHER2 overexpressingmetastaticbreastcancer JapanBreastCancerResearchNetwork JBCRN 00Trial RR 65 0 trastuzumab capecitabine作为MBC的一线治疗 有效者62 5 在HER2 3的患者中 二线或三线治疗者也有许多有效 trastuzumab capecitabine作为一线治疗比作为二 三线治疗有更长的TTP和OS YamamotoD etal CancerChemotherPharmacol 2007 41 PhaseIIstudyofcapecitabineplustrastuzumabinhumanepidermalgrowthfactorreceptor2overexpressingmetastaticbreastcancerpretreatedwithanthracyclinesortaxanes 27例HER 2 过度表达的MBC 曾用anthracyclinesand ortaxanes治疗 给予口服capecitabine1 250mg m 2 bid 1 14天 trastuzumab4mg kg 第1天 以后每周2mg kg RR 45 CR 15 PR 30 SD 33 MOS 28M MPFS 6 7M SchallerG etal JClinOncol 2007 25 22 3246 50 42 Vinorelbineandcisplatinformetastaticbreastcancer asalvageregimeninpatientsprogressingafterdocetaxelandanthracyclinetreatment Cisplatin 75mg m2onday1VNR 25mg m2ondays1 8every3weeks CR 5 6 PR 41 6 OR 47 2 neutropeniagrade 47 Thrombocytopeniagrade3 4 11 Therewerenotreatment relateddeaths VassilomanolakisM etal CancerInvest 2003 21 4 497 504 43 Vinorelbineandcisplatinformetastaticbreastcancer asalvageregimeninpatientsprogressingafterdocetaxelandanthracyclinetreatment 结论 DDP VNR耐受好 且对anthracyclines和docetaxel耐药的病人有效 VassilomanolakisM etal CancerInvest 2003 21 4 497 504 44 TrastuzumabplusvinorelbineortaxanechemotherapyforHER2 overexpressingmetastaticbreastcancer Thetrastuzumabandvinorelbineortaxanestudy trastuzumabwithweeklyvinorelbinetherapyorweeklytaxanetherapy paclitaxelordocetaxelattheinvestigator schoice BursteinHJ etal Cancer 2007 45 TrastuzumabplusvinorelbineortaxanechemotherapyforHER2 overexpressingmetastaticbreastcancer Thetrastuzumabandvinorelbineortaxanestudy RESULTS RR vinorelbine trastuzumab51 taxane trastuzumab40 P 0 37 MTTP vinorelbine8 5months taxane6 0months P 0 09 BursteinHJ etal Cancer 2007 46 Docetaxel ifosfamidecombinationinpatientswithadvancedbreastcancerfailingprioranthracycline basedregimens resultsofaphaseI IIstudy docetaxel70 100mg m 2 over1honday1followedbyifosfamide5 6g m 2 dividedoverdays1 2 2 5 3 0g m 2 dayover1h every21days KosmasC etal JChemother 2007 19 3 322 331 47 Docetaxel ifosfamidecombinationinpatientswithadvancedbreastcancerfailingprioranthracycline basedregimens resultsofaphaseI IIstudy RR 56 medianTTP6 5MmedianOS13MGrade3 4toxicitiesincluded neutropeniain72 ofpatients with60 developinggrade4neutropenia or 7days andin10 ofthesefebrileneutropenia Othertoxicitiesincludedperipheralneuropathygrade2onlyin10 grade2myalgiasin8 grade3diarrheain8 skin nailtoxicityin14 KosmasC etal JChemother 2007 19 3 322 331 48 Docetaxel ifosfamidecombinationinpatientswithHER2 non overexpressingadvancedbreastcancerfailingprioranthracyclines RR 58 medianTTP6MmedianOS12M KosmasC etal InvestNewDrugs 2007 25 5 463 470 49 Arandomized double blind phaseIIstudyoftwodosesofpemetrexedasfirst linechemotherapyforadvancedbreastcancer 新诊断的MBC病人 pemetrexed600mg m 2 P600arm or900mg m 2 P900arm ofonday1 21天一个周期 结果 P600 47patients 和P900 45patients 组RR分别为17 0 和15 6 每组的SD约50 Llombart CussacA etal ClinCancerRes 2007 13 12 3652 3659 50 Pemetrexedinpatientswithlocallyadvancedormetastaticbreastcancerwhohadreceivedpreviousanthracyclineandtaxanetreatment phaseIIstudy Pemetrexed500mg m2wasadministeredasa10 minuteintravenousinfusiononday1 every21days RESULTS ORR 9 Llombart CussacA etal ClinBreastCancer 2006Dec 7 5 380 385 51 Gemcitabineplusdocetaxeladministeredeveryotherweekasfirst linetreatmentofmetastaticbreastcancer preliminaryresultsfromaphaseIItrial docetaxel65mg m 2 followedbygemcitabine2 500mg m 2 bothonday1ofa14 daycycle ORR 66 SD 22 Grade3 4neutropenia 46 Pelegr A etal SeminOncol 2004 31 2Suppl5 20 24 52 Weeklypaclitaxelinwomenwithheavilypretreatedmetastaticbreastcancer aretrospectiveanalysisofcasestreatedattheChangGungMemorialHospital Paclitaxel80mg m2 每周一次 连用3周 4周为一个周期 ORR 21 7 无CR SD 43 5 LuCH etal ChangGungMedJ 2007 30 1 33 40 53 Epothilones mechanismofactionandbiologicactivity Epothilones是一种新的抗癌药 临床前研究提示 epothilones与微管结合 但又与paclitaxel的作用机理不同 故对耐paclitaxel的实体瘤仍有效 GoodinS etal JClinOncol 2004 22 10 2015 2025 54 Targetingthemicrotubulesinbreastcancerbeyondtaxanes theepothilones epothilones及其类似物是一类新的微管稳定剂 其与微管蛋白结合致细胞凋亡而死亡 此类化合物有patupilone ixabepilone BMS 310705 ZK EPO和KOS 862等 此类药不易出现多种耐药机制 MRP 1和P gp溢出泵 微管蛋白过表达 微管蛋白突变 CortesJ etal Oncologist 2007 12 3 271 80 55 ixabepilone BMS 247550 Ixabepilone 40mg m 2 asa3 hourinfusionevery3weeks ORR 18 3 12 41 5 Grade3 4外周神经病变 14 疲劳 13 肌肉痛 8 口腔炎 6 PerezEA etal JClinOncol 2007 25 23 3407 3414 USAThomasE etal JClinOncol 2007 25 23 3399 3406 USARoch H etal JClinOncol 2007 25 23 3415 3420 France 56 AphaseIIstudyofepirubicin cisplatinandcapecitabineasneoadjuvantchemotherapyinlocallyadvancedorinflammatorybreastcancer epirubicin60mg m 2 day1 capecitabine1000mg m 2 bid days1 14 cisplatin60mg m 2 day1 every3 weeks ORR 74 CR 13 VillmanK etal EurJCancer 2007 43 7 1153 1160 57 Clinicalefficacyofcapecitabineasfirst linechemotherapyinmetastaticbreastcancer Howlowcanyougo 63例 capecitabine1000mg m 2 twicedaily days1 14 every21days RR 29 TTP 4 5M 11 TTPof 1y YapYS etal Breast 2007 16 4 420 424 58 PhaseI IIstudyofcapecitabineandvinorelbineinpretreatedpatientswithmetastaticbreastcancer Capecitabine 1000mg m 2 Bid d1 14 停1周 再重复 6周为一个周期 Vinorelbine25mg m 2 或30mg m 2 days1 8 22 29 ORR 55 WeltA etal AnnOncol 2005 16 1 64 69 59 Pilotstudyofprimarysystemicchemotherapywithdocetaxel DOC epirubicin EPI andcapecitabine Xeloda inpatientswithadvancedbreastcancer XLD 2 400or3 000mg day d1 14DOC 60or70mg m2 d8EPI 50or60mg m2 d8 every3weeks RR 77 8 TagayaN etal GanToKagakuRyoho 2006 33 1 39 42 60 Dose denseadjuvantchemotherapyinnode positivebreastcancer docetaxelfollowedbyepirubicin cyclophosphamide T EC orthereversesequence EC T every2weeks versusdocetaxel epirubicinandcyclophosphamide TEC every3weeks AEROB03randomizedphaseIIstudy docetaxel75mg m2 epirubicin75mg m2cyclophosphamide C 500mg m2 TEC x6 every3weeks E100mg m2 C600mg m2x4 thenT100mg m2x4 EC T or T EC every2weeks PiedboisP etal AnnOncol 2007 18 1 52 7 61 Dose denseadjuvantchemotherapyinnode positivebreastcancer docetaxelfollowedbyepirubicin cyclophosphamide T EC orthereversesequence EC T every2weeks versusdocetaxel epirubicinandcyclophosphamide TEC every3weeks AEROB03randomizedphaseIIstudy CONCLUSIONS Dose denseregimensyieldmorefrequentandseverenonhematologicaltoxiceffectsthanstandarddoseTECregimen PiedboisP etal AnnOncol 2007 18 1 52 7 62 Gemcitabine oxaliplatincombinationinheavilypretreatedmetastaticbreastcancer apilotstudyon43patients gemcitabine1 000or2 000mg m 2 of D1D2orD1D8schedule respectively oxaliplatin100mg m 2 overallresponserateof7 5 and11demonstratedstabledisease grades3and4neutropenia thrombocytopenia andanemiain42 19 and14 CarubaT etal BreastJ 2007 13 2 165 171 63 Gemcitabineandoxaliplatininpatientswithmetastaticbreastcancerresistanttoorpretreatedwithbothanthracyclin