tiepiah`yh xapakthpii:tik!!n iipoiontoi
Transcription
tiepiah`yh xapakthpii:tik!!n iipoiontoi
/:,/:,YETI-E.4250-J3/2 (24a) EMHNIKH l1HMOKPATIA ynOyprEIO yrEIAl: & KOINONIKHl: M/\H/\ErrYHl: E0NIKOr oprANlrMor Cl>APMAKON MWOYEiwv 284, 155 62 XoAapyo~ www.eofgr 11/vofl 1110lKflT1KWV YnflP£OlWV EAtyxou npOTOVTWV A0HNA,17-6-2010 AP. npOT.:41473 nArlPoq>opiE~: TflAtcpmvo:21 (}·6507200 ErKYKAIOr - AnOCl>ArH 0EMA: KoeoplolJO~ nEpiAfltpfl~ XapoKTflPIOTIKWV TOU npO"OVTO~ Kal <POMo OOflYlwV v,a TO XP~OTrl q>OPIJOKEUTIKWV npoTovTWV nou nEplEXoUV opaoTIKo OUOTOTIKO GEMCITABINE HYDROCHLORIDE "EXOVTE~ unotpfl: a) TI~ OIOTO~EI~ Tfl~ KOIV~~ YnoupYIK~~ Anoq>aofl<; l1yr3 (0) 83657/2005 "nEpl EvaPIJOVIOfl~ Tfl~ EAAflvIK~~ NOlJoe£Oio~ IJE Tflv aVTioTOIXfl KOIVOTIK~ OTOV TOIJEO Tfl~ KUKAocpopia~ ........ " ......... TWV cpaPIJOKEUTlKWV npoTovTWV, nou npoopi~OVTOI v,a ovepWTTlvfl XP~Ofl", /3) Tfl rVWIJOTEUOfl TOU ETTIOTfllJOVIKOO l:UIJ/3ouAiou EYKpim:wv ap. <p-88/5-3-20 10 AnOCl>ArIZOYME 1. H nEpiAfltpfl XapaKTflPloTIKWV TOU npOiOVTO~ q>OpIJOKEUTIKWV npoTovTWV nou mplEXouV OPOOTIKO ouoTariKo GEMCITABINE HYDROCHLORIDE Opi~£TOI w~ E~~~: 2. TIEPIAH'YH XAP AKTHPII:TIK!!N IIPOIONTOI: 1. ONOMAEIA TOY <l>APMAKEYTIKOY npOIONTOE 2. nOIOTIKH KAI nOEOTIKH EYN0EEH 'Eva cplaAiolo mplEXEI uOPOXAWPIK~ YEIJOITO/3ivfl lOOOOvalJfllJE 200 mg YEIJOlTo/3ivfl<;. 'Eva CPIOAfOIO mplEXEI uopOXAWPIK~ YEIJOITO/3ivfl lOOOOVOlJfl IJE 1000 mg YElJolTa/3ivfl~. 'Eva cploAiolO mplEXEI uoPOXAWPIK~ YElJolTa/3ivflloOOuvalJfl IJE 2000 mg YElJolTa/3ivfl~ . METa TflV avaouoraofl, TO OlaAulJa nEpltXEI 38 mg/ml YEIJOITO/3iv'1~. 'EKOOXO: ria TOV nA~Pfl KaraAoyo TWV EK06xwv, /3Atm napaypacpo 6.1. 3. Cl>APMAKOTEXNIKH MOPCl>H 3. KAINIKEr nAHPOCl>OPIEr 1111YED-E.4250- J 3/2 (24a) 4.1 0EparrwTlKic;; Evo£i~EIC;; H yqJOITa~iVIl £VO£iKVUTOI yla Til 8Epamia TIl~ oupo06xou KUOH::W~ O£ OUVOuaol-'0 1-'£ TOU TOTTIKO TTPOXWPIlI-'£VOU 0I0TTAaTivll· ~ I-'ETaOTaTlKOU wpKivou H YE\JOITal3iVIl £VO£iKVUTaI yla HI 8EpaTTEia a08Evwv I-'E TOTTIKO TTPOXWPtllJtvo aOEvOKapKivwl-'a TOU TTaYKptaTO~. ~ IJETaOTaTlKO H YEI-'OITal3ivr}, OE ouvouaol-'0 I-'E 0I0TTAaTivr}, EVOEiKVUTaI yla Tr} 8Epamia TTPWTr}~ ypOIJI-'~e;, a08Evwv I-'E TOTTIKO TTpOXWPr}I-'£VO ~ I-'ETaOTOTIKO 1-'r}-I-"KpOKUnapIKO KapKivo TOU TTvEUI-'0va (NSCLC). H YEl-'olTal3ivll We; I-'Ov08Epamia I-'TTOPEi va EivOi 8Epamia EKAoy~e; yla r}AIKIWlJtvoue; a08EVEie; ~ yla HI 8EpaTTEia a08Evwv I-'E KOTOoTOoIlIKavoTr}TOe; 2 H YEI-'OITal3ivll EVOEiKVUTOI. yla~ Tr} 8EpaTTEia~a08Evwv I-'E TOTTIKO TTpOxwprlIJEVO ~~ I-'ETOOTarlKo ETTl8r}AlaKo KapKivo w08flKWV, OE ouvouaolJo I-'E Kapl3oTTAarivll, OE a08EVEie; IJE UTTOTpOTTlO~Ouoa ao8tvEI0 \.lETO OTTO OIOOTr}I-'O TouMXIOTOV 6 I-'r}vwv xwpie; UTTOTpOTT~ I-'ETO aTTO 8Epomia TTpWTr}e; ypal-'I-'~e; IJE TTAarivfl· H YEI-'OITOl3ivll EVOEiKVUTOI, OE ouvouaol-'o IJE TToKAITO~tAIl, ylo Tr} 8EpaTTEia ao8Evwv I-'E OVEYXEiPflTO, TOTTIKO UTTOTpOTTlO~OVTa ~ I-'ETOOTaTlKO KOPKivo I-'OOTOU, 01 oTToiol txouv UTTOTPOTTIOOEI I-'ETO OTTO EloaywYIK~/ETTIKOUPIK~ Xfll-'El08Epamio H apXIK~ Xfll-'El08Epomio 80 TTptml va mp1Aal-'13ovEI 8EpoTTEia I-'E OV8POKUKAlv£e;, EKTOe; EOV OVTEVOEiKVUTOI fl Xp~or} TOUe;. 4.2 L\oO'oAoyio KOI Tporroc;; xop!'JY/lO'/lC;; H YEI-'0lTol3ivfl TTptml vo ouvTayoYP0<pEfTOI I-'0VO aTTo Ylarpo EKTTOIOEUI-'tvo OTIl XP~OIl Tfle; aVTIKopKIVIK~e; Xr}I-'EI08EpaTT£iae;. KapKivo( oupoooxou KU(JT[W( ;[uvouaofJEVI] aywYrJ H OUVIOTWI-'£Vr} 06011 Y£I-'0lTal3ivfle; EivOi 1.000 mg/m2, XOPIlYOUI-'EVfl I-'E tYXUOIl OlopKElae; 30 AmTwv. H MOr} 8a TTptml vo xopr}y£iTaI KaHl Tflv 1~, 8'1 WI 15~ IllJtpa K08E 28~I-'£poU KUKAou XOp~YIlOr}e; O£ OUVOUOOI-'O I-'E OIoTTAarivr}. H OUVIOTWI-'EVr} MOfl OIorrAarivfle; EivOi 70 mg/m2 XOPIlYOUI-'£Vr} I-'£TO Tfl Y£l-'oITOl3ivr} Tr}V 1'1 r}lJtpa ~ Tr}V 2~ r}l-'tpa K08£ 28r'IIJ£POU KUKAou. AUTOe; 0 KUKAoe; TWV 4 £~OOIJOOwv Xop~Yr}or}e;, ea TTptml va mavaAal-'f3oV£TaL M£iwor} Tfle; MOr}e; O£ KOeE KUKAo ~ Karo Tfl OIOPK£lO KUKAou Xop~Yr}Ofle; I-'TTop£f va yiv£1 ovoAoyo 1-'£ TO 13081-'0 TO~IKOTrlTae; TTOU TTapouOIo~£TOI OTOV ooe£v~ KapK/VOr; rraYKp{aroc; H oUVIOTWI-'£Vfl MOfl Y£I-'0nol3ivfle; £ivOi 1.000 mg/m2, XOPllyoUI-'EVfl 1-'£ Evoo<pAEl3la tyxuofl OIOpKElae; 30 AmTwv. H MOr} aUT~ 80 TTptml va mavaAal-'l3oVETOI \.lla <popo Tllv £13001.1000 KOI twe; 7 £f3oolJoo£e; oKoAou80ul-'£Vfl OTTO 1-"0 mpiooo OIOKOTT~e;, OIOpK£lOe; 1-'10e; £f3ool-'oooe;. 01 mOIJ£VOI KUKAol 8a TTptml va o<popouv £YXUO£Ie; £13001-'00101£e; ylC 3 OIOOOXIKte; EI3001-'00£e; K08£ 4 £l3ool-'oOEe;. MEiwofl Hle; MOfle; O£ K08£ KUKAo ~ Karo Tfl OIOPK£lO KUKAou Xop~YflOfle; I-'TTop£f VO ylv£1 ovoAoya 1-'£ TO 13081-'0 TO~IKOTIlTae; TOU <pOPI-'OKOU TTOU TTOPOUOIO~ETOI OlOV a08£v~. Ma /JIKpoKurrapIKoc; KapK/Voe; TOU rrvn)jJova MovoB[parr[ia H oUVIOTWI-'£Vfl MOfl Y£IJOlTol3lvfle; £ivol 1.000 mg/m2, XOPflYOUI-'£Vr} 1-'£ £voo<pAE~la tyxuOfl OIOpKElae; 30 AmTwv. AUT~ 8a TTptTTEI va mavaAalJ~oV£TOI IJla <popo Tflv £13001-'000, mi 3 £f3001J00E~, aKoAou80ulJ£VIl aTTO IJla mplooo olaKoTT~e;, olopK£la~ 1J10e; £~oolJooae; AUTOe; 0 KUKAoe; TWV 4 £f3001-'00wv, 8a TTptml vo mavoAOlJl3ovETaL MElwOIl Tile; MOr}e; O£ K08£ KUKAo ~ Karo Tr} OlopK£la KUKAou XOp~Yr}Ofle; IJTTOpEi va yiVEI IJE 130011 TO l3a81J0 TO~IKOTIlTOe; TOU <papIJOKOU TTOU TTOPOUOIO~£TOI OTOV a08£v~. 2 /)./).YED-E.42S0-13/2 (24a) Luv6uaopEvq aywYrJ H OUVIOTWIJEV'1 060'1 YEIJOITOf3iV'1<; EIVOI 1.250 mg/m2, XOP'1YOUIJEV'1 IJE EVOOcpAtf310 tyXUO'1 OIOPKEIO<; 30 A£TITWV, XOP'1YOUIJEV'1 T'1V 1~ KOI 8~ rwtpo TOU KUKAOU xop~Y'10'1<; (21 rwtpE<;) MEiwo'1 T'1<; 060'1<; OE KoBE KUKAO ~ KOHl T'1 OIOPK£lO KUKAOU xop~Y'10'1<; yiVETOI IJE f300'1 TO ~081JO TO~IKOT'1TO<; TOU CPOplJOKOU nou napOUOIO(ETOI OTOV a08EV~. H OIonAOTIV'1 tXEI XP'1011J0nOI'18Ei OE OOOOAOYIKO OX~IJOTO IJETO~U 75-100 mg/m Ko8E 3 E~OOIJOOE<; 2 IJla <popo KapKivo( Maorou Luv6uooptvq 0ywYrJ o ouvouaolJo<; YEIJOITO~IV'1<; IJE naKAITO~tAIl OUOT~VETOi va XPIlOllJonOIEITOI IJ£ naKAlTo~tAIl (OE 060'1175 mg/m2) XOP'1yoUIJEvll Tllv 1~ IllJtpo IJE EVOOcpAt~IO tyXUO'1 OIOpKEla<; mpinou 3 wpwv o.KoAou8ouf.lE\l'1_arr6xop~Y'101l YEIJOITO~IV'1<; (IJE 060'1 1.250 mg/m2) IJE EVOO<pAt~IO tyxuorJ olopK£la<; 30 AETITWV KaTo TrJV 1~ Kal 8~ '1lJtpa Ko8E 21-~IJEPOU KUKAOU XOP~YrJorJ<;. MEiworJ TrJ<; MOrJ<; OE Ko8E KUKAO ~ KOTO TrJ OlopKEla KUKAOU XOP~YllorJ<; IJnopEf va yivEI tJE 1300rJ TO l3oBIJO TO~IKOTrJTO<; TOU cpaplJOKOU nou napouOIo(ETOI OTOV a08£v~. 01 a08£vEf<; 80 nptnEI vo txouv IJtTP'10'1 onoAuTOu apI8IJou TWV KOKKloKunopwv TOUAdXIOTOv 1.500 (x 106 /1). nplv ano TrJV tvap~rJ xop~Y'1o'1<; TrJ<; 8£pamia<; ouvouaolJou Trl<; YEIJOITOl3iv'1<; IJE nOKArTO~tArJ, KopKivo( [)OeOKWV Luv6uOOPEVT) aywYrJ H OUVIOTWIJEV'1 MOil yqJolTol3ivll<;. OE ouvouaolJo IJE Kopl3onAOTiv'1. EivOI 1,000 mg/m2. IJE EVOOcpAt1310 tYXUOIl OIOPKEIO<; 30 AETITWV, XOP'1YOUIJEVIl TrJV 1~ KOI Tllv 8~ IllJtpa Ko8E 21 r'ltJEPOU KUKAOU XOP~Y'101l<;. METa Tllv tyxuOIl TrJ<; YElJolTol3iv'1<;. rJ Kopl3onAOTivrJ XOPrJyEiTOI TrJV 1 ~ rJtJtpa OUVEXW<; KOI tJtXPI ETIiTEU~Il<; mplox~<; uno T'1V KOlJnuArJ OUYKEVTPWOEWV-XPovou (AUC) TWV 4,0 mg/ml.min, MEiwOIl T'1<; 06011<; OE Ko8E KUKAO ~ KOTel Til OIOPKEIO KUKAOU XOP~YIlOrJ<; yiVETOI tJE J3001l TO J308tJo TO~IKOTrlTa<; TOU cpaptJ0KOU nou napOUOIO(ETOI OlOV a08EV~. nOpOKOAou8non roc TO~IKOTr:rac; KOI OOOOAOyIKt<; UET0!30AtC; Myw ToE.IKomTO<; .1000AOYIKE( IJ[raf3oMr; Aoyw /.lO ol/.JOroAoYIKQ( ro[IKOTma( no TrJV oViXVEUOIl 1J'1-0ItJOTOAOYIK~<; TO~IKOTIlTO<; nptml va yivETOI mploolKO, CPUOIK~ E~tTOoll KOI tAEYXOI T'1<; VECPPIK~<; KOI IlnOTIK~<; AEIToupyia<;. MEiwOIl TIl<; 060'1<; OE Ko8E KUKAO xop~Y'1o'1<; ~ tJtoa OE Ko8E KUKAO IJnopEi va yivEI OVOAOYO tJE TO J308tJO TO~IKOT'1TO<; nou EIJ<Povi(ETal OE Ko8E 008EV~. rEVIKO, '1 8Epomio tJE YEtJ0nol3ivrJ nptml va OVooTtAAETor ~ va tJEIWVETOI, Y'O tJEi(ovo (808tJou 3 ~ 4) tJrJ-OitJOTOAOYIK~ TO~IKOTIlTO, EKTO<; TIl<; vauTia<;lttJEToU. OVOAOYO tJE Tllv Kpioll TOU 8EponovTo<; IOTPOU, H XOP~YrJOIl TWV MOEwv nptml va ovaoTOAEi tw<; OTOU 11 TO~IKOT'1TO E~aAEI<p8Ei, oUtJcpwva tJE T'1 yvwlJll TOU 8EponovTo<; IOlpOU. riO TrJ pu81J10'1 T'1<; ooooAoyio<; orr) ouvouaotJtvrJ 8Epamio tJE OIonAOT/v'1. KopJ3onAOllvrJ KOI napaKOAE/oTE va avoTpt~ETE OT'1V aVTioTOIX'1 nEpiArJ4J'1 TWV XOpaKT'1pIOlIKWV TOU npOTOVTO<;. nOKAno~tA'1. .1000AOYIKt( /Juaf3oM( Aoyw AI/JoroAoVIKQ( ro[IKororar; Evap~T) KOeE KUKAOU XOPrJYT)oT)<; rio OAE<; TI<; EVOE/~EI<;. 0 008EV~<; 80 nptml va nopaKoAou8EiTOI nplv ana TrJV XOP~YrJO'1 Ko8E ooorJ<; IJE IJtTprJOrJ TWV altJonETaAiwv KOI TWV KOKKloKunopwv. 01 a08EvE/<; nptnEI va txouv ToUAdXIOTOV 1,500 (x 106 /1), Kal anoAuTO opl8tJo 6 OlIJOmTOAiwv 100.000 (x 10 /1), nplv ana TrJV tvap~rJ TOU KUKAOU 8Epamio<;. onoAuTo apl8IJo KOKKloKunopwv Kara TT) ol(jpKEla KOeE KUKAOU XOPrJYT)oq<; 01 OOOOAOYIKt<; IJETOJ3oAt<; TrJ<; YEtJoITaJ3ivrJ<; IJtoo OE Ko8E KUKAO nptml va yivovTOI oUIJ<pwva IJE rou<; aKoAou80u<; nivoKE<;: .doaoAoYIKtt;; J.1EToJ3oAtt;; HIt;; YEJ.1O'1raJ3fVIlt;; J.1tao aTOV KUKAO 9EPOTTEiOt;; KOPKivou Tilt;; oupoo6xou KuaTEws, TOU J.lll J.lIKPOKUTTOPIKOU KOPKivou TOU TTVEUJ.l0VO KOI KOPKivou 3 fo,fo, YET1-E.42S0-J3/2 (240) TOU naYKpiaTOe.;, we; pOVOBEpanEi<:x~ OE ouvouaopivt) aywylj J.lE OlonAaTivr] ~' AnoAuToe.; aplBpot) I AplBpot) alp~nETaAiwv l % HIt) nAr'Jpt)t) ?OOt)t) TOU KOKKIOKUTTOPWV (X 10 II) • ((ONOMA npOIONTOr» . 6 (x 10 11) . . 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H DNA TToAulJEPOOIl tlfJlAov EivOi oUOIaoTIKo aviKavf'] va aq>OIptoEI Tf']V YEiJolTo~ivf'] Kal va ETTIOIOp8wOEI TOU<; aVTlypmpOIJEvoU<; KAwvou<; TOU DNA. METa If']V EVOW~OTWOIl Tf']<; YEiJOITO~ivr]<; OTO DNA, TTPOOTi8ETOI tva ETTITTMov vouKAEOliolO OTOU<; aVOTTTUOOOiJtvou<; KAwvou<; lOU DNA. METo Illv TTpo08~Kf'] aUT~, UTTOPXEI oUOIaOTIKo TTA~pf']<; avooToA~ Tf']<; TTEpOlTtpW OUV8tOEW<; DNA (KPU<pO<; IEpIJOTIOIJO<; oAuoioa<;). METO Tf']V EVOWIJOTWOf'] OTO DNA, f'] YElJolTa~ivll q>OiVETOI vo TTPOOYEI Tf']V oloolKaoio KUTTaplKou 80VOTOU, TTOU EivOi YVWOT~ w<; aTTOTTTWOf'] (apoptosis). KAIVIKO OTolXEia KopK/voe oupoo6xou KUOTEWC rE iJlO TUXOIOTTOIIlIJ£vf'] IJEAtTr] <POOfl<; III OE 405 008EVEi<; IJE TOTTIKO TTpOXWPf']iJtvo ~ iJETOOTOTlK6 KOPKivwiJo aTT6 fJETO~OTIKO ETTl8~AIO, OEV TTOpOUOIOOTr]KE KOiJio olaq>opo fJETO~U TWV 000 OIJOOWV 8EpoTTEla<;, YEiJOITO~ivr]<;/OIOTT AOTIVf']<; tvavTI iJE80TPE~OTfl/~IVfJTTAaOTivf']/ooplaIJIKivf']/0I0TTAOTivfl (MVAC), w<; TTp0<; Til iJtOfl ETTI~iwof'] (12.8 KOI 14.8 IJ~VE<; aVTioTOlxa, p=0.547), TO XPOVO tw<; Tllv UTTOTpOTT~ (7.4 KOI 7.6 IJ~VE<; aVTloTOlXO, p=O.842) KOI iJE TTOOOOTO aVTOTToKpIOf']<; (49.4 % KOI 45.7 % aVTioTOlXO, p=0512) nopoAa aUTd, Il ouvOUOOIJ£VIl aywy~ Tfl<; YEiJOITO~ivfl<; IJE oloTTAOTivfl EIXE KaAuTEpoO TTpo<piA TO~IKOTflTO<; aTT6 6TI IJE MVAC. 13 66YEn-E.4250-13/2 (24u) KapKfvo( rraVKptaTO( L£ IJIO TUXOIOTTOIIlIJEVIl 1J£A£TI1 Q)()OI1e; III O£ 126 o08£v£ie; IJ£ TOTTIKO TTPOXWPI1IJ£vo ~ IJnOOTOTlK6 KOPKivo TOU TTOYKPEOTO<;, 11 XOP~YI1011 Tile; Y£IJOITO~ivl1e; ti5£I~£ OTOTIOTIKO 0I1IJOVTIKO u4JI1AOn:pO TTOOOOT6 KAIVIK~<; OVTOTT6Kp1011e; OTT6 TI1V 5- <pAouOpOUpOKiAIl (238 % KOI 4.8 % oVTioTOIXO, p=0.0022). ETTiol1e;, OTOTIOTIKO OI1IJOVTIK~ Olj~l1ol1 TOU XP6vou we; TI1V UTTOTpOTT~ oTT6 0.9 £we; 2.3 lJ~v£e; (log-rank p < 0.0002) KOI OTOTIOTIKO OI1IJOVTlK~ OU~11011 Tr]e; 1J£011e; ml~iwol1e; oTT6 4.4 EWe; 5.7 IJ~V£e; (log-rank p < 0.0024) TTopOTl1p~8I1K£ O£ ooS£v£ie; TTOU EAol3ov SEpomio IJ£ YElJolTol3ivl1 O£ OUYKPIOI1 IJE TOUe; 008£v£i<; TTOU £Aol3ov 8Epomio IJE 5 <pAouOPOUpOKiArJ, MO /lIKpOKUTTaplKO( KapKfvo( TOU rrvEuvova LE IJIO TUXOIOTTOII1IJEVI1 IJEAtTI1 <pool1<; III OE 522 008£VEie; IJE IJI1 mI0£x6IJEVO X£lPOUPYIK~ mElJl30011, TOTTIKO TTpOXWpqlJ£vO ~ IJnOOTOTIK6 Mil MIKpoKunoplKo KopKivo TOU nVEUIJOVO, 11 XOP~YI1011 Tile; YEIJOlTol3ivl1e; OE auvouooIJ6'1J£"OIaTTAOTivl1'EOEI~E OTOTIKO 0I1IJOVTIKO 'UWI1MTEPO TTOOOOTO OVTOTT6KPI011<; oTT6 OTi IJEIJOVWIJEVI1 XOP~Yl1ol1 TI1<; 01OTTAOTivl1e; (31.0 % KOJ 12.0 % oVTioTOIXO, P < 0.00001). LTOTIOTIKO OI1IJOVTIK~ OU~11011 TOU Xpovou we; TI1V UTTOTPOTT~ oTT6 3.7 £we; 5.6 IJ~VEe; (log-rank p < 0.0012) KOI OTOTIOTIKO oI1IJOVnK~ OU~11011 TI1<; 1J£011<; ml~iwoll<; OTT6 7.6 EWe; 9.1 IJ~VEe; (log-rank p<0.004) TTopOTl1p~811KE OE 008EVEle; TTOU EAol3ov 8Epomio IJE YElJolTol3ivl1/olOTTAOTivl1 OE OUYKPIOI1IJE TOUe; 008EVEie; TTOU EAo/3ov 8Epomio IJE OIOTTAOTIVI1. LE lJlO oMI1 TUXOIOTTOIIlIJEVI1 IJEAtTI1 <pOOI1e; III OE 135 008EVEi<; IJE Mil MIKpoKuTToPIKo KopKivo TOU nVEUIJOVO oTOoiou IIIB ~ IV 11 OUVOUOOlJtVI1 8Epomio IJE YElJonol3ivl1 KOI OIOTTAoTivl1 aiEI~E OTOTIOTIKO 0l1lJOVTIKO UWI1MTEPO TTOOOOTO OVTOTTOKPIOI1<; OTTO on 11 oUVOUOOlJEVI1 oywy~ IJE OIOTTAOTivl1 KOI nOTTooiol1 (40.6 % KOI 21.2 % oVTioTOIXO, p=0.025). LTOTIOTIKO OI1IJOVTIK~ OU~11011 TOU Xpovou we; TI1V UTTOTPOTTIi OTTO 4.3 EWe; 6.9 lJ~VEe; (p=0.014) TTOpOTl1p~SI1KE OE 008EVEie; TTOU tAol3ov 8Epomio IJE YElJolTo/3ivl1/O1OTTAOTivl1 OE OUYKPIOI1 IJE TOUe; 008EVEie; TTOU EAol3ov 8Epomio IJE ETOTTooioI1/01OTTAOTivl1. KOI OTle; ouo lJEAtTE<; 11 OVEKTIKOTI1TO ~TOV TTOPOI-lOIO KOI one; 500 OlJOOEe; 8Epomioe;. KapKfvoc wof}OKWV LE IJIO TUXOIOTTOII1IJEVI1 I-lEAtTI1 <pool1e; Ilf OE 356 008£VEi<; lJE TTPOXWPl1lJEVO ETTl811AIOKo KOpKivo WOSI1KWV TTOU UTTOTPOTTiooov TOuMXIOTOV 6 lJ~VE<; I-lno TI1V OAOKA~pwol1 H)e; 8Epomioe; I-lE TTACTivl1, TUxoloTTol~8l1KOV OE 8Epomio IJE YEIJOITOl3ivl1 KOI KOP130TTAOTivI1 (GCb), r') KOP130TTAOTivI1 (Cb). LTOTIOTIKO 0I1IJOVTIK~ OU~l1ol1 TOU Xpovou we; TI1V UTTOTpOTT~ OTTO 5.8 EWe; 8.6 IJr')VE<; (log-rank p=0.0038) TToPOTI1Pr')8I1KE OE 008EVEie; TTOU EAol3ov 8Epomio I-lE GCb OE OUYKPIOI1 I-lE TOUe; 008EVEie; TTOU tAol3ov 8Epomio IJE Cb. 01 OIO<pOpEe; OTO TTOOOOTO OVTOTTOKpIOI1e; r')TOV 47.2% OTI1V 01-l000 8EpOTTEioe; lJE GCb tVOVTI 30.9 % OTI1V olJoeo 8Epomioe; IJE Cb (p=0.0016) KOI Tile; IJtOI1e; ETTll3iwol1<;, 18 IJI1VEe; (GCb) tVOVTI 17.3 (Cb) (p=0.73) TTOU wvoouoov TI1V olJoeo 8Epomioe; IJE GCb. KapKfvo( vaoTOr) LE ilia TUXOIOTTOII1IJEVI1 IJEAtTI1 cpOOI1e; III OE 529 008EVEie; IJE IJI1 mIOEXOIJ£VO XEIPOUPYIK~ ETTEIl/30011, TOTTIKO UTTOTPOTTlO<ov (I IJnOOTOTIKO KOPKivo TOU IJOOTOU, TTOU UTTOTPOTTiooov IJno oTT6 EIOOYWYIK~/ETTIKOUPIKr') XI1IJElo8Epomio, 11 XOP~YI1011 Trle; yqJolTol3ivl1e; OE OUVOUOOIJO IJE TTOKAITO~EAI1 EeEI~E OTOTIOTIKO OI1IJOVTIK~ oU~11011 TOU Xpovou we; TI1V UTTOTPOTTr') OTTO 3.98 EWe; 6.14 IJ~VEe; (log-rank p=0.0002) OE 008EVEie; TTOU tAo/3ov 8Epomio IJE YElJolTol3ivl1/TTOKAlTo~tAI1 OE OUYKPIOI1 lJE TOUe; 008EvEie; TTOU EAol3ov 8Epomio IJE TTOKAlTo~EAI1. METa OTTO 377 80VOTOUe;, 0 OUVOAIKOe; xpovoe; ETTll3iwol1e; ~TOV 18.6 IJt')VEe; EVOVTI 15.8 I-ll1vwv (log rank p=0.0489, HR 0.82) m: 008EVEie; TTOU EAo130V 8Epomio IJE YElJolTol3ivl1/TTOKAITO~EAI1 OE OUYKPIOI1 IJE TOUe; 008EVEie; TTOU EAol3ov 8EPOTTEio IJE TTOKAITO~EAI1 KOI TO OUVOAIK6 TTOOOOTO OVTOTT6KPI011<; t')TOV 41.4 % KOI 26.2 % OVT{crTOIXO (p=O.0002). H cpapIJOKOKIVI1TIKr') TI1<; YElJ01TO/3ivl1<; EXEI IJEAnI1S£i OE 353 008EVEie; OE mTo (7) IJEAtTEe; 01 121 yuvaiKEe; KOI 232 ovepE<; Efxov EUpOe; I1AIKioe; oTT6 29 EWe; 79 nwv. ATTO OUTOUe; TOUe; 008EVEie;, TTEpiTTOU 45% Eixov IJI1 lJIKpOKunopIK6 KOPKivo TOU TTVEUIJOVO KOI 35% E{XOV eloyvw08Ei I-lE KOPKivo TTOYKptoTOe;. 01 TTOPOKOTW <P0PlJOKOKIVI1T1KE<; TTOPOIJETPOI TTopOTI1Pr')8I1KOV lJE 560EIe; oTT6 500 EWe; 2592 mg/m2, 01 oTToiEe; XOPl1yr')8I1KOV lJE tyxuol1 OIOpK£lOe; OTT6 0.4 tw<; 1.2 WpEe;. J4 66YETI-E.42S0-J3/2 (24a) MtYIOHl OUYKtVTPWOr] OTO nMolJo (mITUYXOvETOI EVTO<; 5 AmTwv fJETO TO TtAO<; Tr]<; tyxuor]<;): 3,2 tw<; 45,5 fJg/mL. 01 OUVKEVTPWOEI<; Hl<; IJr]TPIK~<; tvwor]<; OTO nMolJo IJETa ono 060r] 1.000 mg/m 2 /30 AmTo EivOI UtjJr]MTEPE<; ana 5IJg/mi Via nEpinou 30 AmTo IJETO TO TtAO<; T1']<; tVXUOIl<; KOI UtjJI1MTEPE<; ana 0.4 IJg/ml Via lJio mmAtov wpo. talOVOblrj o 0YKO<; KOTOVOfJ~<; OTO KEVTPIKO OIOlJtPIOIJO ~1OV 12.4 11m2 Via YUVOiKE<; KOI 17.5 11m 2 Y'O OVOPE<; (11 fJE1O~U TWV 008EVWV fJE1013Ar]TOH1TO ~TOV 91.9 %), 0 OYKO<; KOTOVOfJ~<; OTO mplcpEplKO OIOfJtPIOfJO ~1OV 47.4 11m2. 0 OYKO<; KOTOVOfJ~<; OTO mplcpEplKO OIOfJtPIOfJO OEV mIlPEa~ETOI ana TO CPUAO TOU 008EVOU<;. H ouvowr] fJE npwTEivE<; TOU oifJOTO<; 8EWp~8IlKE nw<; Eivol OfJEAr]TtO. Xpovo<; HIJI~w~<;: Eupo<; ana 42 EW<; 94 AmTo, E~OPTWfJEVO<; ana Tllv IlAIKio KOI TO cpUAO. ria TO OUVIOTWfJEVO 8EpOnWTlK0 OX~fJO, r] ono13oA~Tr]<; VEIJOIT013ivr]<; nptnnvo'0AoKAr]pWVE101 EVTO<; 5 tw<; 11 wpwv OTTO Tr]V tvoP~11 TIl<; tyxuor]<;. H YEfJOIT013ivll OEV OUOOWPEUETOI OTOV XOPIlVEiTOI ano~ E13oofJooloiw<;. METo!3oAIOblO<; H yq.JOlTo13ivr] IJE1013oAi~ETOI 1OXtW<; ana Tr]V onofJlvaor] Tr]<; KUTlOivr]<; OTO ~nop, OlOU<; VECPPOU<;, OTO oifJo KOI OE aMou<; 10TOU<;. 0 EVOOKUnaPIO<; fJETol3oAIOfJO<; TIl<; VEfJolTol3ivr]<; nOpaVEI Tr] IJOVO-, 01- KOI TPI-CPWOCPOPIK~ YEfJOIT013ivIl (dFdCMP, dFdCDP KOI dFdCTP, oVTioTOlxa), ana TI<; onoiE<; 01 dFdCDP KOI dFdCTP 8EWPOUVTOI OpaOTlKt<;, AUToi 01 EVOOKUTTOPIOI fJET013oAiTE<; OEV txouv oVlxv£u8£i OTO nMofJo ~ OlO oupa. 0 KUPIO<; fJETol3oAITIl<; 2/0£O~u-2,2/-olcp80poouploivr] (dFDU) OEV EivOI OPOOTlKO<; KOI OVIXVEUETOI OlO nMofJo KOI OTO oupo. AnoSoM LUOTIlIJOT!K~ Ka80por] fJE EUpO<; ana 29.2 IIhr/m2 tw<; 92.2 I/hr/m2 EivOI mIlP£O~oIJEVr] OTTO TO cpuAo KO! H]V IlAIKio (11 fJETO~U TWV 008EVWV fJET013AIlTOTr]1O ~TOV 52.2 %). H Ka80pol1 OTI<; YUVOiKE<; EivOI mpinou 25 % fJlKPOTEPIl ana OUT~ OTOU<; aVOPE<;. napa H] VP~YOPIl Ka80POll, TOOO YIO TOU<; aVOPE<; 000 KOI Via TI<; YUVOiKE<;, 11 Ka8apoll EfJCPovi~ETOI va fJEIWVETOI I-IE TIlv r]AIKio. rIa TO OUVIOTWI-IEVO 8EpamUTIKO OX~fJa 1000 fJg/m2 fJE 30AETTTr] tyxuor], 11 XOfJIlMTEPIl Kd80pOll VIa TI<; VUVOiKE<; KOI aVOPE<; OEV nptml va K0810Ta onopoiTr]Tr] Til fJEiwOll Tr]<; 06011<; Tr]<; YEI-l0lTo13ivr]<;. Ano13oA~ 010 TWV oupwv: AIVOTEPO OTTO 10 % ono13dMETol w<; ofJETaI3Ar]TO cpdPfJOKO. NECPPIK~ Kd80porr 2 EW<; 7 IIhr/m2. Mia E/300fJOOO fJETC] Tr] XOP~YIlOIl, 92 % EW<; 98 % Tr]<; ooor]<; Tr]<; VEIJOIT013ivIl<; ono13aMETOI, ana TO oTToio 99 % OTO oupo uno Til fJOPCP~ dFdU KOI 1 % TIl<; 06011<; ono/3aM£TOI 010 TWV KOTTpdvwv. KIVOTlKI) TO<; dFdCTP /JETo/3oAiTr]<; aUTo<; fJTTOPEi va oVlxv£u8£i 010 nEplcpEplKO /JovoKunopo TOU OifJOTO<; KOI 01 mO/J£vE<; nArlPocpopiE<; ovOcptpovTOI OE aUTO TO Kunopo. 01 EVOOKUTTOPIK£<; OUYKEVTPWO£I<; OU~OVOVTOI KOl' ovoAoyio fJE 06oEI<; YEfJ011O/3ivr]<; TWV 35-350 mg/m2/30 AmTa, TTOU TTOPOYouv OUVKEVTPWOEI<; oT08EPWV mmtowv TWV 0.4-5 fJg/ml. LE OUYKEVTPWOEI<; YEfJOITOJ3ivr]<; OTO nMolJa UtjJr]MTEPE<; ana 5 fJg/ml, TO mimoo dFdCTP OEV nopouOIo~ouv aU~r]or], npaVfJa nou oEiXVEI OTI 0 0XIlfJOTlOfJ0<; TOU fJE1O/3oAiTIl fJnop£i va Kopw8£i OTO Kunopo aUTO. XpOVO<; r]fJl~W~<; TEAIK~<; aTTo13oA~<; : 0.7-12 WPE<; o KIVOTlKri Toe; dFdU H IJtVIOTr] OUYKtvTPWOr] nMOIJOTo<; (3-15 AETTTd fJETO TO 1tAo<; Tr]<; 30AETTTIl<; tvxuor]<; 1000 mg/m2): 28-52 fJg/ml. taIOIJWr] oUYKtvTpwoll fJETa OTTO XOP~Yr]OIl 06011<; ano~ E1300fJooloiw<;: 0.07-112 I-Ig/ml, xwpi<; EfJCPav~ ouoowPEUOll. TplcpaolK~ KOfJTTUAr] oUYKtvTPWOll<; nMOfJOTo<; OE OUVapTIlOIl fJE TOV Xpovo, fJtoo<; Xpovo<; IlfJl~w~<; TIl<; T£AIK~<; CPOOEW<; - 65 WPE<; (EUpO<; 33-84 WPE<;). LXIl/JOT10fJ0<; TIl<; dFdU OTTO TrlV fJIlTPIK~ tvwoll 91 % - 98 %. MEOO<; OVKO<; KOTOVOIJ~<; OTO KEVTPIKO OlOfJtP101J0 18 11m2 (EUpO<; 11-22 11m2). MEoo<; OYKO<; KOTOVOfJ~<; OE oT08EpoTTOIllIJEVIl KOTaOTOOIl (Vss): 150 11m2 (EUpO<; 96- 228 11m2). KOTaVOfJ~ OTOU<; 10TOU<;: EKTETOIJ£VIl. 15 t:,t:, YEn-E.4250-J3/2 (24a) MEO'1 CPOlVO~£V'1 Ko8apo'1 2.5 I/hr/m2 (EUpOS 1-4 IIhr/m2). 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