臺(tái)灣藥師a工作模式索拉菲尼在肝細(xì)胞癌中的進(jìn)展

1SorafenibinAdvancedHepatocellularCarcinoma報(bào)告地點(diǎn)：萬(wàn)芳醫(yī)院報(bào)告時(shí)間：2009/11/6報(bào)告者：和信醫(yī)院李建勳藥師指導(dǎo)藥師：2FiveA’sAssess：了解臨床的需求（ClinicalProblem）Ask：發(fā)現(xiàn)問(wèn)題的所在（Question）Acquire：找尋最好的資料（BestEvidence）Appraise：分析資料（Validity,Importance）Apply：應(yīng)用在病人身上（Patient）3ClinicalSituationMr.Chengisa60yearoldmalepatient.HewasdiagnosedashepatitisBandCvirusinfectionrelatedhepatocellularcarcinoma(HCC)on2003.Hehasreceivedradiotherapyduring2003/1/24~3/6,transarterialchemoembolization(TACE)during2006/3/4~2007/12/4,computertomography-guidedradiofrequencyablation(RFA)on2008/8/5.In2009April,abdominalsonographyshowedthatHCCprogresstoretroperitoneallymphnodes,whichissuspectedextrahepaticseedingtumorbetweenabdominalwallandrightlobeliver.Atthattime,thelabdatashowedelevatedalpha-fetoprotein(AFP)93.46ng/mL.Atthattime,thedoctorconsideredsorafenib400mgPOBIDforthispatient.Issorafenibeffectiveforthispatient?4FiveA’sAssess：了解臨床的需求（ClinicalProblem）Ask：發(fā)現(xiàn)問(wèn)題的所在（Question）Acquire：找尋最好的資料（BestEvidence）Appraise：分析資料（Validity,Importance）Apply：應(yīng)用在病人身上（Patient）5臨床問(wèn)題的種類背景問(wèn)題（BackgroundQuestions）：對(duì)疾病的基本認(rèn)識(shí)5W1H：Who,Where,What,When,How,Why疾病的某一面向前景問(wèn)題（ForegroundQuestions）：對(duì)病人的特定問(wèn)題處理某疾病病人的特定問(wèn)題每個(gè)病人有不同的特性：年齡、性別、伴隨疾病與疾病嚴(yán)重程度等6Epidemiology肝癌是全球排名第五位的癌癥，每年約有五十萬(wàn)至一百萬(wàn)的新病例。肝癌更是死亡率第三位的癌癥，全球每年約有六十萬(wàn)人死於肝癌。全球肝癌的盛行率有地理分佈的差異，低盛行區(qū)如北美和中美洲等，其盛行率約每10萬(wàn)人口3-4人；而亞太地區(qū)屬於肝癌高盛行區(qū)，盛行率高達(dá)每10萬(wàn)人口30-40人。西元2000年全球肝癌患者，亞洲地區(qū)高達(dá)44萬(wàn)人，而北美地區(qū)只有1萬(wàn)2仟人，全球肝癌患者約75%集中於亞洲地區(qū)。肝癌為臺(tái)灣10大癌癥發(fā)生率的第二位，每10萬(wàn)人口發(fā)生率男性約26人、女性約8人，男女比例約3:1。林志陵,高嘉宏.肝癌的流行病學(xué).中華癌醫(yī)會(huì)誌.2008;24(5):277-2817RiskFactorsLivercirrhosisHepatitisBVirusHepatitisCVirusAlcoholCigarettesmokingBetelnutAfaltoxinObesityFattyliverNon-alcoholsteatohepatitis(NASH)DiabetesHereditarytyrosinemiaHepaticporphyriaGenetichemochromatosisα1antitrypsindeficiency林志陵,高嘉宏.肝癌的流行病學(xué).中華癌醫(yī)會(huì)誌.2008;24(5):277-2818ClinicalFeaturesCommonSymptomsAbdominalpainWeightlossWeaknessFullnessandanorexiaAbdominalSwellingJaundiceVomitingCommonPhysicalSignHepatomegalyHepaticbruitAscitesSplenomegalyJaundiceWastingFeverDeVitaVT,etal.Devita,Hellman&Rosenberg’sCancer:Principles&PracticeofOncology,8thEdition9DiagnosisRadiologyX-raySonographyComputedtomography(CT)Magneticresonanceimaging(MRI)BiopsyAlpha-fetoprotein(AFP)SerologyDeVitaVT,etal.Devita,Hellman&Rosenberg’sCancer:Principles&PracticeofOncology,8thEdition10TreatmentOptionSurgeryPartialhepatectomyLivertransplantationLocalAblativeTherapyCryosurgeryMicrowaveablationEthanolinjectionAceticacidinjectionRadiofrequecyablation(RFA)RegionalTherapy(hepaticarterytranscathetertreatments)TransarterialchemotherapyTransarterialembolization(TAE)Transarterialchemoembolization(TACE)Transarterialradiotherapy90Ymicrospheres131IlipiodolConformalexternal-beamradiationtherapySystemicTherapyDeVitaVT,etal.Devita,Hellman&Rosenberg’sCancer:Principles&PracticeofOncology,8thEdition11StagingSysteminHCC除了腫瘤侵犯程度外，需考慮肝臟存留機(jī)能病理報(bào)告取得不易，臨床分期應(yīng)用廣泛依應(yīng)用目的區(qū)分預(yù)後的預(yù)測(cè)與治療方法的選擇12StagingSystemPrognosisTNMOkudaCLIP(CanceroftheLiverItalianProgram)JIS(JapaneseIntegratedScore)TreatmentBCLC(BarcelonaClinicLiverCancer)13StagingSystem–TNM盧勝男,顏毅豪,林芷蕓等.肝細(xì)胞癌之臨床分期.中華癌醫(yī)會(huì)誌.2008;24(5):295-30314StagingSystem–Okuda15StagingSystem–CLIPCLIP:CanceroftheLiverItalianProgram16StagingSystem–JISJIS:JapaneseIntegratedScore17StagingSystem–BCLCBCLC:BarcelonaClinicLiverCancerBruixJandShermanM.Hepatology2005;42(5):1208-123618TreatmentGuideline–JSHKudoM.Oncology2007;72(supp1):2-15JSH:JapanSocietyofHepatology;TAI:transcatheterarterialinfusionchemotherapy，也稱作hepaticarterialinfusion(HAI)19臨床問(wèn)題的種類背景問(wèn)題（BackgroundQuestions）：對(duì)疾病的基本認(rèn)識(shí)5W1H：Who,Where,What,When,How,Why疾病的某一面向前景問(wèn)題（ForegroundQuestions）：對(duì)病人的特定問(wèn)題處理某疾病病人的特定問(wèn)題每個(gè)病人有不同的特性：年齡、性別、伴隨疾病與疾病嚴(yán)重程度等20P.I.C.O.One-sentencedQuestion（請(qǐng)用一句話表達(dá)你的問(wèn)題）AstoadvancedHCCpatient,cansorafenibimprovesurvival?PatientorProblem（描述病患、疾病或病徵的型態(tài)）HepatocellularcarcinomaInterventionorInvestigation（包括治療、檢驗(yàn)、或預(yù)後因子）SorafenibComparison（通常用於比較目前的治療或診斷）PlaceboOutcome（對(duì)病患有意義的臨床結(jié)果）SurvivalTypeofQuestion■Therapy□Diagnosis□Prognosis□Harm□Others___________TypeofStudyDesign■Meta-analysis■RCT□CohortStudies□CaseControlStudies□CaseSeries□CaseReports21Fiv織eA’sAss怖ess：了解臨謹(jǐn)床的需求庸（Cli票nic病al叢Pro限ble豪m(xù)）Ask：發(fā)現(xiàn)問(wèn)股題的所在噸（Ques吃tion）Acqu伶ire：找尋最鍋好的資料掏（Bes霞tE抹vid踩enc漏e）Appr斬aise：分析資含料（Vali絨dity然,Im晚port化ance）App盲ly：應(yīng)用在盞病人身上傘（Pati樣ent）2223搜尋策略：□Systems□Summary□Synopses□Synthesis□Studies關(guān)鍵字PrimaryorMeSHTerm同義字1同義字2PHepatocellularcarcinomaORORANDISorafenibORORANDCPlaceboORORANDOSurvivalORORAND搜尋結(jié)果174articles:limittoclinicaltrials(byreviewer)1.LlovetJM,RicciS,MazzaferroV,etal.NEnglJMed2008;359(4):378-90(PhaseIIITrial)2.ChengAL,KangYK,ChenZ,etal.LancetOncol2009;10(1):25-34(PhaseIIITrial)3.Abou-AlfaGK,SchwartL,RicciS,etal.JClinOncol2006;24:4293-4300(PhaseIITrial)4.StumbergD,ClarkJW,AwadaA,etal.TheOncologist2007;12:426-437(PhaseITrial)5.FuruseJ,IshiiH,NakachiK,etal.CancerSci2008;99:159-165(PhaseITrial)6.WornsMA,WeinmannA,PfingstK,etal.JClinGastroenterol2009;43:489-495(Smallsamplesize,regardlessofliverfunction,andnegativeresults)7.11articlesshowstheefficacyofcombinationwithothersystemicchemotherapy資料來(lái)源：□UpToDate□CochraneLibrary□ACPJP■Pubmed□___關(guān)鍵性結(jié)論24Fiv海eA’sAsse霞ss：了解蹦臨床的扎需求（Clin顯ical餡Pro壘blem）Ask：發(fā)現(xiàn)問(wèn)逼題的所在街（Ques帝tion）Acqu躁ire：找尋從最好的奶資料（Best依Evi警denc獸e）Appr穩(wěn)aise：分析鍋資料（Vali洽dity銅,Im曉port劉ance）Appl虛y：應(yīng)用抵在病人耀身上（Pati陰ent）25Sor輸afe錦nib陪in員Ad牛van息ced閘He鄉(xiāng)豐pat洞oce售llu言lar濕Ca拿rci右nom威aNEn兩glJ穩(wěn)Med硬200捏8;3禽59:住378-富90Llo賤vet樣JM常,R盤icc蛾iS直,M處azz謙afe睜rro舍V,慨Hi鴉lga納rd儲(chǔ)P,擇Gan治eE糊,e丟ta攀l.26Stud叢yDe乒signStud牙yDe龜sign經(jīng):Ra奧ndom嗎ized毀,do這uble瘦-bli撞nded煉,pl磚aceb亦o-co頸ntro嶼lled策tri怒alStud呆yPl止ace:諒121省cen幟ters井in為21c鍛ount證ries律in跪Euro動(dòng)pe,互Nort蛋hAm攀eric涼a,S哀outh不Ame剪rica膊,an角dAu蒙stra跡liaInte強(qiáng)rven俘tion蘿:so紀(jì)rafe脫nib節(jié)400m嗓gBI戴Dor煤pla名ceboIncl問(wèn)usio探nCr釣iter幸ia:Adva惹nced爽HCC腸,co養(yǎng)nfir輝med銹byp桐atho副logi嬌cal朽anal按ysisECO租Gp胳erf醫(yī)orm撲anc俘es炸tat求us電of芒2o龍rl韻essChil迷d-Pu尿ghl李iver姿fun稿ctio毀ncl沸ass可AAdeq瓜uatehem蜜ato著log晴ica或l(演PLT黨,H細(xì)b),踐he開pat褲ic膽(Al據(jù)b,財(cái)Bil姐-T,勺GO散T,必GPT洽),角and偷re周nal激fu你nct誰(shuí)ion去(s隱Cr)Exc愉lus楊ion頭Cr久ite值ria半:Pre去vio吩u(píng)sl奪yr殿ece哥ive努dm國(guó)ole夏cul企arl暮yt燦arg侵ete融dt恰her姐apy挪or種sy趨ste哥mic展tr顧eat臭men猛t27Outc暈ome潔Asse袋ssme示ntThe功Pr封ima穗ry著Out悼com星eOver滴all季Surv攀ivalTime受to雖Symp隊(duì)toma抖tic杠Prog醒ress都ion:態(tài)FHS艷I8↓4詳,EC嫂OGp論rogr竹ess獵to4貓,or揮dea事thThe馬Se蹦con聚dar情yO堆utc光omeTime認(rèn)to薄Radi程olog宋ical肚Pro趟gres禍sion宜:by惕REC咽ISTThe在Di鏟sea羨se-鎮(zhèn)con設(shè)tro歲lR預(yù)ate命:C艇R+P培R+S某DSafe鴉tyFHS愉I8澇Que獲sti知onn浴air形e：用以評(píng)估HCC病人癥狀狗的嚴(yán)重程礎(chǔ)度CR:導(dǎo)co洲mpl詢ete供re翁spo辭nse龜;P觸R:犬par繩tia件lr妹esp憂ons閘e;賞SD:真st效abl豎ed燒ise恐ase28902南Pati歉ents絡(luò)wer炎esc憲reen注ed300累we低re鞋exc柱lud載ed244繪ha歸dp猛rot律oco營(yíng)le岡xcl魯usi蜻on帳cri倍ter省ia24附w星ith腔dre漂wc扯ons六ent15尼h笛a(bǔ)d歸an波adv設(shè)ers摧ee埋ven鄭t11哭die仁d6變wer菊el桶ost秧to拔fo番llo蛙e-u飄p602寺un誼der羽wen輕tr么and薯omi挨zat肚ion299鍬were征ass例igne顯dto特rec伯eive沃sor送afen棄ib(酷inte記ntio逢n-to鬼-tre咐atp限opul付atio桂n)303使were派ass牌igne針dto吵rec誼eive伐pla守cebo裕(in盈tent譜ion-宜to-t蕉reat是pop察ulat跟ion)1ha蜘dan羅adv全erse寨eve勤nt1h傳ad財(cái)ap矮rot贏oco船lv戒iol奶ati售on1ha狀da畝prot竊ocol右vio吧lati脫on297全rece盈ived饅sor翅afen圖ib(精safe崇typ按opul朗atio長(zhǎng)n)302灑rece凳ived飲pla撒cebo筍(sa暫fety螞pop績(jī)ulat唯ion)226份Disc溫onti般nued椒sor勢(shì)feni鴿b86銷ha迷da鑰na確dve抽rse外ev埋ent61罰had跑radi搞olog晌ica魄ndsymp潮toma嶼tic攏prog充ress涼ion28其with罵drew逃con五sent3資die疊d1樸had冠EC貢OG惹sco烏re比of殃447蛙had蒜othe轟rre蓄ason242俊Di撓sco歌nti纖nue灰dp勵(lì)lac糕ebo90霞ha稀da眉na因dve塔rse裳ev既ent62懂had沃radi裕olog壓ica萄ndsymp職toma椒tic偷prog腫ress戲ion25管wi廚thd烤rew抽co伙nse披nt7領(lǐng)die源d6絨had雙EC訂OG燒sco旨re安of找452答ha合do慌the裁rr烈eas遇on71頭inc諷lud續(xù)ed齡in壩the游on熄goi刊ng缸stu乎dy60蒸inc負(fù)lud滾ed品in貌the扮on插goi袋ng濤stu痕dyEnro筋llme債nt&拐Out件comeLlov脾etJ善M,e錘tal畝.New嗚En設(shè)gl既JM蘭ed2008劑;35陪9:3臺(tái)78-9居029Dem雕ogr枯aph賀ic信&B治ase暑lin社eP電rof協(xié)ileVariableSorafenib(N=299)Placebo(N=303)Sorafenib(N=299)Placebo(N=303)Age–yr64.9±11.266.3±10.2Lung67(22)58(19)Sex–no(%)Macroscopicvascularinvasion,extrahepaticspread,orbothMale260(87)264(87)Absent90(30)91(30)Female39(13)39(13)Present209(70)212(70)Region–no(%)Child-Pughclass–no(%)EuropeandAustralia263(88)263(87)A284(95)297(98)NorthAmerica27(9)29(10)B14(5)6(2)CentralandSouthAmerica9(3)11(4)BiochemicalanalysisCauseofdisease–no(%)Albumin–g/dLHepatitisConly87(29)82(27)Median3.94.0Alcoholonly79(26)80(26)Range2.7-5.32.5-5.1HepatitisBonly56(19)55(18)Totalbilirubin–mg/dLUnknown49(16)56(19)Median0.70.7Other28(9)29(10)Range0.1-16.40.2-6.1ECOGperformancestatus–no(%)Alpha-fetoprotein–ng/mLo161(54)164(54)Median44.399.01114(38)117(39)Range0-208x1040-5x105224(8)22(7)Previoustherapy–no(%)BCLCstage–no(%)Surgicalresection57(19)62(20)B(intermediate)54(18)51(17)LocoregionaltherapyC(advanced)244(82)252(83)transarterialchemoembolization86(29)90(30)Macroscopicvascularinvasion–no(%)108(36)123(41)percutaneousethanolinjection28(9)20(7)Extrahepaticspread–no(%)159(53)150(50)radiofrequencyablation17(6)12(4)Lymphnodes89(30)65(21)radiotherapy13(4)15(5)30Val葛idi賄ty可信度本篇研究邀病人分配太是否隨機(jī)碎？是隨機(jī)分配翅是否對(duì)研傷究人員保叮密？是本篇研姜究隨機(jī)備分配後民的病人饒是否都逆被納入缺分析？是在接受治符療當(dāng)中，請(qǐng)病人與醫(yī)史療人員是或否雙盲？是除了要比辜較的治療綠外，兩組旋病人是否塊都被同等糊對(duì)待？是一開始分羽配的兩組架條件是否忍相同？是31Sum俗mar因yo敲fE叮ffi絕cac兼yM五e(cuò)as己ure適men旦tOutcomeSorafenib(N=299)Placebo(N=303)Hazardratio(95%CI)PvalueOverallsurvival(mo)0.69(0.55-0.87)<0.001Median10.77.995%CI9.4–13.36.8–9.11-yrsurvivalrate(%)44330.009Timetosymptomaticprogression(mo)1.08(0.88-1.31)0.77Median4.14.995%CI3.5-4.84.2-6.3Timetoradiologicprogression(mo)0.58(0.45–0.74)<0.001Median5.52.895%CI4.1-6.92.7-3.9Levelofresponse(%)Complete00NAPartial210.05Stabledisease71670.17Disease-controlrate(%)43320.002Llo拼vet幟JM誘,e乒ta脅l.New嘗Engl掃JM創(chuàng)ed2008般;35淘9:3獄78-9暗032Llov層etJ嶼M,e鮮tal咱.New箏Engl咱JM妄ed2008篇;35拿9:3泥78-9泉033副作用1.最重要的副作用：

Grade3/4

Hand-footSkinReactionControleventrateExperimentaleventrateRelativeriskincreaseAbsoluteriskincreaseNumberneededtoharmCEREERRRI=(EER-CER)/CERARI=EER-CERNNH=1/ARI0/302=0%8/297=2.693602%2.693602%37ARI:以sorafenib治療100人，會(huì)增加約3人三/四級(jí)手足癥候群的機(jī)會(huì)。NNH:每治療37位病人，會(huì)有1人會(huì)發(fā)生三/四級(jí)手足癥候群。NNT墾(Num插ber真Need似to擴(kuò)Trea忌t)o陪rNN用H(N停umbe州rNe度edt踐oHa殖rm):在一段實(shí)描驗(yàn)期間內(nèi)袋，使一位禾病人達(dá)到頌實(shí)驗(yàn)組治屠療之有益某結(jié)果（或賀不良反應(yīng)修）所需治燙療的病人棗數(shù)目。34副作用1.最重要的副作用：

Grade3/4

diarrheaControleventrateExperimentaleventrateRelativeriskIncreaseAbsoluteriskincreaseNumberneededtoharmCEREERRRI=(EER-CER)/CERARI=EER-CERNNH=1/ARI2/302=0.662251%8/297=2.693602%3.0632632.028649%49ARI:以sorafenib治療100人，會(huì)增加2人三/四級(jí)腹瀉的機(jī)會(huì)。NNH:每治療49位病人，會(huì)有1人會(huì)發(fā)生三/四級(jí)腹瀉。NNT倡(Num紹ber度Need逐to匹Trea忽t)o膨rNN氏H(N羊umbe舟rNe允edt計(jì)oHa蔥rm):在一段實(shí)撐驗(yàn)期間內(nèi)蝴，使一位備病人達(dá)到樣實(shí)驗(yàn)組治技療之有益秤結(jié)果（或饞不良反應(yīng)拾）所需治竿療的病人經(jīng)數(shù)目。35Effi笨cacy蘭and很Saf司ety飲ofS之oraf讓enib淡in悶Pati歲ents剪in挑The轉(zhuǎn)Asia好-Pac鼠ific汁Reg境ion砌With泊Adv卸ance舊dHe候pato壁cell搬ular構(gòu)Car機(jī)cino檢ma:爺APh笑ase紫III甩Rand判omiz理ed,咐Doub每le-b饑lind置,Pl屋aceb賞o-Co而ntro溉lled撤Tri解alLan數(shù)cet對(duì)On堡col喂20痛09;蝦10嗽:2縮慧5-3閱4Che耐ng擦AL,罪Ka戚ng括YK,貫Ch次en但ZD,貼Ts且ao鴨CJ,才Qi匆nS兆K,歐et菊al.36271陳Pa習(xí)tie淹nts飄we裝re晃scr瞎een英ed45富Not脅rand橋omiz盟ed3液had而ana咳dver謝see出vent4拆wi黨thd數(shù)rew1惱lo濁st倦to南fol斷l(xiāng)ow踐-up37p坐roto己col熄excl萬(wàn)usio穴ncr績(jī)iter川ia226嚇unde惱rwen抱tra燭ndom蟻izat盟ion150特we嗽re申ass英ign軋ed謎to滲rec毀eiv遲es拘ora群fen指ib僑(in絡(luò)ten牲tio謎n-t余o-t偷rea螺tp壺opu左lat扒ion新)76抽wer取ea蘭ssi演gne斧dt腫or愚ece善ive資pl滑ace悠bo提(in關(guān)ten蔑tio雷n-t欠o-t專rea竿tp肚opu養(yǎng)lat食ion餡)1ex際clud栗edd陣uet誰(shuí)oad志vers津eev桿ent1h右ad稈ap倡rot掩oco谷lv轉(zhuǎn)iol抗ati四on149挽rece瞧ived瞞sor講afen勺ib(予safe舒typ褲opul醉atio暑n)75廟rec酒eiv痛ed歇pla慌ceb距o(悅saf籌ety焦po艘pul株ati軟on)129閘Disc袋onti杏nued冊(cè)sor遷feni嶄b69南ha帆dd肆ise瞧ase地pr挽ogr掩ess綁on22膏had繪adve亮rse祖even屠ts23紫wi澆thd我rew梨co故nse脊nt12豬died2控l套o(hù)st勉to售fo音llo針w-u門p1階non哪-com周plia機(jī)ntt地otr仆eatm鐘ent72戰(zhàn)Dis求con簽tin買ued粉pl盞ace鳥bo48幣had羞dise磨ase布prog精ress獅ion7南had尊ad冒ver作se釋eve郊nts11卡wi財(cái)thd牲rew艘co倘nse艙nt2d批ied3l付ost逝tof號(hào)ollo優(yōu)w-up1p愛roto協(xié)col廚viol接atio販n20征inc圍lud神ed醬in斥the穗on殃goi頭ng撐stu橫dy3in平clud遷edi桌nth剛eon船goin綠gst怠udyEnro枝llme困nt&航Out貸comeChen啞gAL寨,et湖al.Lanc蜻etO檢ncol200榴9;蚊10:貴25系-3437Dem依ogr勉aph哭ic墓&B山ase減lin沫eP獸ofi芳le38Vali左dity可信度本篇研云究病人丑分配是移否隨機(jī)熟？是隨機(jī)分配倉(cāng)是否對(duì)研條究人員保座密？是本篇研究約隨機(jī)分配摸後的病人病是否都被晉納入分析聾？是在接受顧治療當(dāng)胡中，病從人與醫(yī)雖療人員桃是否雙昨盲？是除了要比輕較的治療悼外，兩組鍋病人是否伐都被同等耀對(duì)待？是一開始分菠配的兩組伶條件是否匠相同？是39Sum飯mar美yo侍fE花ffi拍cac買yM貧eas衣ure兵men粒tOutcomeSorafenib(N=299)Placebo(N=303)Hazardratio(95%CI)PvalueOverallsurvival(mo)0.69(0.55-0.87)<0.001Median1077.995%CI9.4–13.36.8–9.11-yrsurvivalrate(%)44330.009Timetosymptomaticprogression(mo)1.08(0.88-1.31)0.77Median4.14.995%CI3.5-4.84.2-6.3Timetoradiologicprogression(mo)0.58(0.45–0.74)<0.001Median5.52.895%CI4.1-6.92.7-3.9Levelofresponse(%)Complete00NAPartial210.05Stabledisease71670.17Disease-controlrate(%)43320.00240Sum塞mar摔yo哥fE延ffi滅cac壘yM醒eas皇ure唯men點(diǎn)tOutcomeSorafenib(N=150)Placebo(N=76)Hazardratio(95%CI)PvalueOverallsurvival(mo)0.68(0.50-0.93)0.014Median6.54.295%CI5.56-7.563.75-5.466-mosurvivalrate(%)53.336.7NDATimetosymptomaticprogression(mo)0.90(0.67-1.22)0.50Median3.53.495%CI2.80-4.242.40-4.08Timetoprogression(mo)(byRECISTcriteria)0.57(0.42-0.79)0.005Median2.81.495%CI2.63-3.581.35-1.55Levelofresponse(%)Complete00Partial5(3.3)1(1.3)Stabledisease81(54.0)21(27.6)Disease-controlrate(%;95%CI)53(35.3;27.7-43.6)12(15.8;8.4-26.0)0.00194142副作用1.最重要的副作用：

Grade3/4

Hand-footSkinReactionControleventrateExperimentaleventrateRelativeriskincreaseAbsoluteriskincreaseNumberneededtoharmCEREERRRI=(EER-CER)/CERARI=EER-CERNNH=1/ARI0%16/149=0.10738210.7%9.3125ARI:以sorafenib治療100人，會(huì)增加約11人三/四級(jí)手足癥候群的機(jī)會(huì)。NNH:每治療9個(gè)病人，會(huì)有1人會(huì)發(fā)生三/四級(jí)手足癥候群。NNT香(N看umb巨er桿Nee指dt結(jié)oT陳rea縮慧t)依or熄NNH甜(N鉤umb護(hù)er漫Nee馬dt紡oH訂arm鳴):在一段買實(shí)驗(yàn)期通間內(nèi)，胖使一位雄病人達(dá)魄到實(shí)驗(yàn)相組治療乏之有益舌結(jié)果（流或不良悄反應(yīng)）損所需治吼療的病單人數(shù)目扣。43副作用1.最重要的副作用：

Grade3/4

diarrheaControleventrateExperimentaleventrateRelativeriskIncreaseAbsoluteriskincreaseNumberneededtoharmCEREERRRI=(EER-CER)/CERARI=EER-CERNNH=1/ARI0%9/146=0.0616436.143%24.83ARI:以sorafenib治療100人，會(huì)增加6人三/四級(jí)腹瀉的機(jī)會(huì)。NNH:每治療24.83位病人，會(huì)有1人會(huì)發(fā)生三/四級(jí)腹瀉。NNT柱(Num創(chuàng)ber指Need繪to摘Trea芝t)o繞rNN坑H(N電umbe蛋rNe針edt畝oHa窗rm):在一段聚實(shí)驗(yàn)期痛間內(nèi)，你使一位桐病人達(dá)短到實(shí)驗(yàn)日組治療稅之有益慢結(jié)果（絞或不良葡反應(yīng)）絕所需治鏈療的病機(jī)人數(shù)目盆。44Com賞par沒(méi)iso糾nB需etw招een肉2宜RCT綱SSHARPTrialChengAL.RegionofStudyEurope.AmericanAsia-PacificHCV/Alcohol/HBV-relatedHCC(%)28%/26%/18%8%/?/73%ECOGPS:0/1/2(%)54%/38%/7.6%26%/68%/5%Extrahepaticspread(%)51.3%68.6%ClinicalOutcomeSorafenibPlaceboSorafenibPlaceboOverallSurvival(mo)10.77.96.54.2SurvivalRate(%)44(1yr)33(1yr)53(6mo)37(6mo)TimeToProgression(mo)4.14.93.53.4TimeToRadiologicProgression5.52.82.81.4DiseaseControlRate(%)43325312HHRofGradeIII/VHSR379HHRofGradeIII/VDiarrhea4924Com躬men戚tb測(cè)yC由hen比gA筍L.需et藍(lán)al:甩Mo等re搏adv丟anc僵ed籍dis候eas扎e(串ext朋rah亮epa惰tic脈sp鳳rea避d,越num宋ber觸of嬸tu魄mor淘,E尋COG卡PS姿,a屑lph廊a-f節(jié)ero陶pro程tei棕n(肌AFP喬)l陸eve域l)45Sora非feni爬bin堆HCC萍Tre機(jī)atme猴nt46Five抽A’sAsse天ss：了解儉臨床的愿需求（Clin呼ical踩Pro再blem）Ask：發(fā)現(xiàn)問(wèn)餡題的所在康（Que箭sti氣on）Acqu懷ire：找尋最欣好的資料偷（Bes邀tE蓮vid金enc活e）App拒rai嘗se：分析企資料（Val及idi棉ty,瘋Im掘por菊tan燦ce）Appl喘y：應(yīng)用疏在病人夠身上（Pat躬ien史t）47Pra爛cti饅cab確ili素ty目前Sor全afe離nib璃(N折exa哥var?)在本院旦為臨採(cǎi)芒品項(xiàng)，丟健保給恩付規(guī)範(fàn)富如下：1.晚期腎捧細(xì)胞癌痕且已接圈受int牌erf莊ero英n-a坦lph櫻a(bǔ)或int典erl挑euk辜in-用2治療失敗塞，或不適米合以上兩銳種藥物治瓜療之病患濟(jì)。2.無(wú)效後則語(yǔ)不給付tems福irol沸imus及其他杯酪胺酸慶激酶阻巧斷劑（tyro客sine亭kin足ase凝inhi廢bito媽r,T哄KI）3.需經(jīng)事逆前審查揚(yáng)核準(zhǔn)後易使用，灣每次申囑請(qǐng)之療膊程以3個(gè)月為限鼠，送審時(shí)雖需檢送影煉像資料，含每3個(gè)月評(píng)估腦一次(98粗/10酸/1)。病人需自賓費(fèi)購(gòu)買，鍬自費(fèi)價(jià)為琴一錠1387元，一死天5547元。研究結(jié)化論應(yīng)用辱在此病丸人時(shí)無(wú)暮已知可勉能的限慣制：根拼據(jù)病歷車所記載更資料，Chi愛ld-影Pug特hA場(chǎng)-B(未知腹水伶與腦病變雞程度)，BCLC臟Sta冷geC箏(ad差vanc漂eds折tage躬)，亞洲人云種，HBV/給HCV-立rela臺(tái)ted淋HCC，大致血符合臨邀床試驗(yàn)純收案條纏件。依據(jù)鄭安理柜教授等附人之亞橫太地區(qū)泊大型第荒三期臨縫床試驗(yàn)雜的結(jié)果招，我們渠預(yù)期此回病人透純過(guò)治療寇存活時(shí)捕間可延便長(zhǎng)2.3個(gè)月，但招發(fā)生Grad抱e3/趙4的手足癥期候群、腹野瀉的NNH分別為9和24。48Clin類ical安Eff扭ecti客vene勤ss&丸Saf略ety3/27~4/24~5/1~5/8~5/15~5/22~5/29~6/5~6/12~6/26~7/3~7/17~8/14~Sorafenib2#BIDSorafenib3#QDAFP93.46104.774.3749.7443.0437.9446.0348.3856.51100.9126.6148.1242.25/1：wate架ryd蓮iarr安hea烈6~7欣time搜son逗day債1,扁musc余l(xiāng)es寺oren浸ess,稍art臂hrit塌is,章ches歷twa服llp逢ain令afte游rco央ugh,貝los瓣sof伐app狂etit鍵e,h句and-陵foot脈ski榮nre毫acti廣on5/8：hand美-foo誦tsk骨inr掀eact沉ion的&Gr垃2-3搶bul粉lae原atb補(bǔ)ilat畜eral油fee提t(yī)5/1扣5：hand尺-foo才tsk郵inr蘇eact血ion超&Gr蘋2-3濟(jì)bul箏lae欠atb倘ilat呈eral盟fee珠t,s侍kin削rash極at結(jié)face嗓and膠leg5/22：Gr扎2h視and援-fo射ot賊ski山nr品eac裳tio賄n,屬ski宇nr該ash罵at希fa吃ce蠢and垮le里g↓5/2易9：Gr娃2h綢and財(cái)-fo春ot盲ski忍nr葡eac紙tio糾n,齊ski景nr錢ash腥at眼fa軌ce遍and仍le嫩g↓,教ho蒼tf非las宋h,塌hyp梳ert溜ens皆ion6/5：Gr2睬han鋪d-fo已ots垂kin壞reac買tion武,sk插inr教ash律atf店ace昏and俊leg↓手,ho粘tfl風(fēng)ash,腰hyp晉erte臟nsio溪n,g愉ener曉alm妻alai丘se,49Tha竊nk忍You誦Fo賽rY易o(hù)ur四Li誦ste皂nin蠶g50Refe魔renc安e教科書DeVi澆taV暫T,e跑tal儀.De贈(zèng)vita術(shù),He折llma筋n&簽Rose劇nber烏g's避Canc每er:旁Prin群cipl外es&探Pra嘗ctic齊eof聽Onc驚olog扣y,8秋thE得diti獻(xiàn)on臨床準(zhǔn)則AASL江DPr萌acti塌ceG波uide故line負(fù):Br辟uix污Jan頁(yè)dSh嗓erma汗nM.矮Man堅(jiān)agem靠ent意ofh材epat嗓ocel籌lula塑rca躬rcin貪oma.贊Hep武atol尊ogy高2005探;42級(jí)(5):債120慮8-12球36JSH狗Gu狼ide披lin怖e:踢Kud蚊oM掌,O宏kun童oue兇T,置an雨dC常lin君ica甘lP突rac缺tic屑eM鋒anu禮al旬of淹HCC送Ex劑per蠢tP栗ane甘l.封Man雪age指men掏to角fh港epa藥toc磚ell語(yǔ)ula敞rc禮arc順ino宵ma扒in儲(chǔ)Jap頭an:型co炕nse鎖nsu麥s-b潤(rùn)ase納dc出lin駱ica累lp缸rac漸tic勢(shì)em那anu般al遵pro免pos苦ed稿by灣the垂Ja侵pan四So更c(diǎn)ie弄ty座of戀Hep串a(chǎn)to持log危y.肝Onc士olo濾gy春200怪7;溫72(憂sup饑p1)拘:2發(fā)-15英文期間刊Llo隸vet辯JM濕,R錯(cuò)icc灣iS緩,M缺azz狼afe池rro砌V,蜘Hi臟lga晴rd哥P,罵Gan穿eE碎,e量ta刊l.Sor思afe蚊nib跑in永Ad代van正ced棍He楊pat錄oce偉llu遵lar鳥Ca幅rci伙nom覆a.NEn汽glJ霸Med貨200菠8;3耐59:強(qiáng)378-拆90Chen仆gAL或,Ka貿(mào)ngY都K,C廁hen雄ZD,護(hù)Tsao挨CJ,境Qin順SK,株etal.麻Ef安fic符acy駕an飼dS矮afe亭ty礙of令Sor抽afe璃nib至in吊Pa礦tie豈nts賭in洽Th置eA鴉sia魯-Pa排cif扶ic蘿Reg結(jié)ion悄Wi鉆th刺Adv至anc公ed海Hep衰ato符cel押lul墳ar嬸Car辰cin和oma士:A斧Ph總ase駛II因IR剝and刮omi港zed旗,D井oub游le-巡壽bli佳nd,儲(chǔ)Pl尤ace約bo-互Con烈tro劣lle刊dT紫ria能l.Lanc治etO筐ncol笛200崗9;1甲0:2諸5-34中文期沙刊林志陵,高嘉宏.肝癌的動(dòng)流行病非學(xué).中華癌盒醫(yī)會(huì)誌.2困008勵(lì);2共4(5蚊):屋277叢-28極1盧勝男,顏毅豪,林芷蕓尿等.肝細(xì)胞覽癌之臨勻床分期.中華癌圖醫(yī)會(huì)誌.20摟08;昨24(5播):2妻95-3娃0351Sora圖feni激bin蝴Adv虹ance靠dHe肺pato醋cell里ular貞Car火cino蘇maNE邁ngl符J割Med稅20唉08;穴35番9:芽378譽(yù)-90Llov敘etJ尚M,R賠icci卡S,乏Mazz仍afer暑roV配,Hi柴lgar驚dP,我Gan炕eE,堆et閱al.52Eff熱ica輸cy餡and呀Sa邊f(xié)et殖yo勻fS喇ora賞fen灣ib想in膠Pat片ien醒ts碼in受The碎As廊ia-捆Pac閣ifi哲cR股egi置on吧Wit面hA芹dva促nce誰(shuí)dH控epa嗓toc畜ell罰ula戀rC伶arc曠ino承ma:最A(yù)月Pha顯se斯III蔥Ra蔥ndo去miz羊ed,胳Do蠻ubl釋e-b鉤lin校d,字Pla趨ceb礦o-C順ont創(chuàng)rol且led歡Tr介ialLan蛾cet喘On矮col銳20跑09;鏡10鳥:2哥5-3科4Chen帆gAL帝,Ka摧ngY張K,C蠢hen裝ZD,貫Tsao拜CJ,村Qin騙SK,柏et仆al.535455565758Out鳴lin外e5St桌eps閣inE柳BM(榮5As)Ass拉essAskBac三kgr咽oun傲do篇rf怖ore雷gro邪und事qu作est袖ion炊,P校ICOAcqu膽ireLeve燒lof沈evi覽denc嬌e,S稿e(cuò)arc暢hing選ski稿llsAppr霸aiseVali煌dity油,im某port由ance孟,an班dpr細(xì)acti爹cabi溜lityApp壤ly59Wha歪t(yī)i交sE破vid池enc眨e-b表ase我dM陷edi咬cin放e?Evid糠ence帖-bas貞edm服edic和ine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ClinicalExpertiseBestresearchevidenceEBM60臨床問(wèn)綿題的種薯類背景問(wèn)題數(shù)（Back刺grou漏ndQ層uest誤ions）：對(duì)疾伴病的基本次認(rèn)識(shí)5W1H：Who吐,W診her貴e,盟Wha妙t,玩Whe狐n,豪How勒,W括hy疾病的陷某一面謹(jǐn)向前景問(wèn)題鉛（For脫egr呆oun譽(yù)dQ認(rèn)ues凍tio鵝ns）：對(duì)疾志病的基本玻認(rèn)識(shí)處理某開疾病病點(diǎn)人的特東定問(wèn)題每個(gè)病煉人有不劃同的特跌性：年差齡、性鉆別、伴短隨疾病磁與疾病短嚴(yán)重程緞度等61Ask烤Qu學(xué)est點(diǎn)ion查sBack鑰grou址ndQ滔uest數(shù)ionHow手does些HBV遮inf歸ecti珍onp早rogr梅ess慨toH枕CC？How洪coul榴dwe敗dia蘭gnos瘦eHC股C？How水coul裁dwe消det絲式ermi傭net舒hes愈tage植of拋HCC？When假sho達(dá)uld濫wec胸onsi敘der截live側(cè)rtr悉ansp殿lant繁atio銳n？For銷egr桶oun保dQ傘ues案tio歇nIsu策ltra葬soun蘿dmo區(qū)rea淘ccur柄ate紙than冠com走pute某dto全mogr轉(zhuǎn)aphy？Iss驢oraf者enib帳mor免eef辜fect博ive癢than能dox慎orub她icin因-bas快edc些hemo植ther矮apy？62形成臨床績(jī)問(wèn)題常遇建到的困難不知道要惜如何開始先問(wèn)背景怨問(wèn)題，對(duì)盞疾病的基限本認(rèn)識(shí)問(wèn)題很廁多，時(shí)妄間很少考慮問(wèn)瓶題的優(yōu)橋先順序問(wèn)不到想盼要的結(jié)果問(wèn)題結(jié)僅構(gòu)的不淺清楚，鳳使用PICO模式產(chǎn)第生前景椅問(wèn)題63形成前趙景問(wèn)題-P娘ICOCom切pon壟ent跡so衛(wèi)fC絕lin唐ica揭lQ撓ues惜tio堡nsPat唐ien芒t/Prob榨lemInt響erv責(zé)ent本ionComp薯aris薄onOut舊com還e病人特幸性病人疾病過(guò)去病史…檢查藥物治療外科治療………觀察、安刑慰劑另一種由藥物另一種沖手術(shù)住院天數(shù)生活品質(zhì)死亡率64搜尋實(shí)證蜓常見的障槳礙資源太多地，不知道險(xiǎn)從何下手不知道怎根麼定義關(guān)捕鍵字PIC襯O，plu緒s同義字，MeS撕HT劣erm塌s不熟悉驗(yàn)搜尋方粒式只找到（票看到）片陽(yáng)面現(xiàn)象，訂而非貼近加事實(shí)。65Leve當(dāng)lso昂fEv瓶iden管ce66如何下惕手？實(shí)證醫(yī)學(xué)殊資源金字匹塔Systems連結(jié)個(gè)別病歷的臨床知識(shí)與支援決策系統(tǒng)越上層資訊精粹簡(jiǎn)單的關(guān)鍵字省時(shí)搜尋與評(píng)讀由下層累積越下層文獻(xiàn)雜多完整的關(guān)鍵字費(fèi)時(shí)搜尋與評(píng)讀注重檢索技巧資訊新穎Summaries整合証據(jù)提供特定臨床問(wèn)題之概述與建議UpToDateDynaMedBMJClinicalEvidenceFirstConsultACPPIERSynopses對(duì)單篇研究或回顧性文獻(xiàn)作摘要與評(píng)述ACPJournalClub,Evidece-BasedMedicine(PubMed,OvidMedline)Syntheses特定臨床問(wèn)題的系統(tǒng)性評(píng)論文獻(xiàn)CochraneDatabaseofSystematicReviewsDatabaseofAbstractsofReviewsofEffects(PubMed,OvidMedline):SystematicReviewsStudies原始文獻(xiàn)(PubMed,OvidMedline,CINAHL,EMBASECochraneCENTRAL,GooglescholarCEPS中文電子期刊,中文期刊篇目索引)67Sum盛mar效ies型資料庫(kù)低特性比較資料庫(kù)證據(jù)標(biāo)示特色限制更新UpToDate[疾病/藥物]70,000Level:1-2Grade:A-C查詢?nèi)菀缀苌贅?biāo)示證據(jù)等級(jí)書目未直接連到PubMed季DynaMed[疾病/藥物]3,000Level:1-3Grade:A-C查詢?nèi)菀祝崭旅宽?yè)首詳細(xì)註明新近更新日BMJClinicalEvidence[疾病]2,500Typeofevidence:1-6Grade:High,Medium,Low評(píng)論過(guò)程透明列出ClinicalQuestion表格呈現(xiàn)療效強(qiáng)調(diào)盡可能說(shuō)明Harm有提供excludedreference未提供etiology,diagnosis,cost更新速度慢採(cǎi)用英式英文年FirstConsult[疾病]800Grade:A-C提供test或therapy順序證據(jù)來(lái)源未逐項(xiàng)列明月ACPPIER[疾病]400Level:1-3Grade:A-C呈現(xiàn)推薦、理由、證據(jù)每頁(yè)首註明新近更新主題數(shù)很少月68資訊檢索-關(guān)鍵字選用MeS感Ht包erm（並避免臨雙引號(hào)、永切截字元棕）COX-忠2se險(xiǎn)lect澇ive村inhi蹦bito軌r>>肯COX盆-2i昂nhib扮itor列舉同家義字Con泛ven答tio膚nal類>>勻co魄nve后nti彩ona燥lO克Rt立rad理iti車ona圈l避免使懂用縮寫CVD嗎>>c寫ardi燃o(jì)vas訓(xùn)cula阻rdi隔seas蛙es使用明孝確詞彙Car石dio天vas揮cul異ar高ris亞k>柏>c巷ard犧iov榴asc奧ula瞞rd貸ise羞ase督sA豎N