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PRINCIPIILEPRINCIPIILE TRATAMENTULUITRATAMENTULUISPECIFIC SISTEMIC INSPECIFIC SISTEMIC IN
ONCOLOGIEONCOLOGIE
PROF. UNIV. DR. FLORINEL BADULESCU
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DEFINITIIDEFINITII
TRATAMENT SISTEMIC TRATAMENT SPECIFIC
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METODE DE TRATAMENTMETODE DE TRATAMENT
SPECIFIC SISTEMICSPECIFIC SISTEMIC
CHIMIOTERAPIA ANTINEOPLAZICA TERAPIA TINTITA MOLECULAR HORMONOTERAPIA IMUNOTERAPIA
INHIBITORII DE OSTEOCLASTE
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SCOPURILE TRATAMENTULUISCOPURILE TRATAMENTULUI
SISTEMIC SPECIFICSISTEMIC SPECIFIC
1. Curativ
2. Neoadjuvant
3. Adjuvant
4. Paleativ
5. Inducie6. Intreinere
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APRECIEREA RASPUNSULUI LAAPRECIEREA RASPUNSULUI LA
TRATAMENT IN ONCOLOGIETRATAMENT IN ONCOLOGIE
- LEZIUNE MASURABILA- LEZIUNE NEMASURABILA- LEZIUNE TINTA- LEZIUNE NON-TINTA- METODE OBIECTIVE DE EVALUARE A RASPUNSULUI LA
TRATAMENT
- INTERVAL RECOMANDAT PENTRU EVALUAREA RASPUNSULUILA TRATAMENT
SISTEMUL RECIST RESPONSE EVALUATION CRITERIA INSOLID TUMORS
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APRECIEREA RASPUNSUUI AAPRECIEREA RASPUNSUUI A!RA!A"EN! IN #NC##$IE!RA!A"EN! IN #NC##$IE
% remisiune !"m#$e%& 'RC( - %um"r )is#re !"m#$e%* nu mie+is% ni!i un semn ,ii.i$* !$ini! su #r!$ini!* !re s %es%e#reen% %um"rii m$i/ne in "r/nism0
- remisiune #r1i$& 'RP( )iminure !u #es%e 234 sumei
)ime%re$"r m+ime %u%ur"r $eiuni$"r msur.i$e0- ."$ e,"$u%i, su #r"/resi ."$ii 'BE su PB( !res%ere !u
#es%e 534 sumei )ime%re$"r m+ime %u%ur"r $eiuni$"rmsur.i$e* si 6 su #ri%i un"r n"i $eiuni
- ."$ s%.i$i% 'BS( - !"ns%n% sumei )ime%re$"r m+ime %u%ur"r $eiuni$"r msur.i$e* su ,ri.i$i%%e !u m+im 234in s!)ere su !u m+im 534 in !res%ere
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S!A&IIREA S!A!USUUI 'E PER(#R"ANS!A&IIREA S!A!USUUI 'E PER(#R"AN)*)*A PACIEN!UUI NE#PA+ICA PACIEN!UUI NE#PA+IC
S%%usu$ )e #er7"rmn1& 8rn"7s9:S%%usu$ )e #er7"rmn1& ECOG
IK 100 = ECOG 0, pe deplin !"i#, !p$il % de%&%'(e !"i#i""ip(ei)$'ln#i(e &( (e%"(i!"ie
IK *0 + 0 = ECOG 1, (e%"(i!"ie !"i#i""il'( &i-i!e in"en%e d( !p$ilde%&%'(e &( e&'(" !"i#i""i &i-i!e .-.le
IK /0 + 0 = ECOG , !p$il de ."'in2(i3i(e d( in!p$il de de%&%!"i#i""i !(e p(e%.p.n e&'(" %.%"in."4 N. %" in p" )i ).l" de 506"i)p.l in !(e e%"e "(e-
IK 70 + 50 = ECOG 8, !p$il n.)i de ."'in2(i3i(e li)i"", %" in p" %.
%!.n )i ).l" de 506 din "i)p.l in !(e e%"e "(e-IK 0 + 80 = ECOG 74 di%$ili""e !')ple"4 n. %e p'"e in2(i3i %in2.(4 %""i)p.l in p" %. %!.n
IK S.$ 0 = ECOG 5, de!e%
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PRINCIPIILE CHIMIOTERAPIEIPRINCIPIILE CHIMIOTERAPIEIANTINEOPLAZICEANTINEOPLAZICE
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CICLUL CELULARCICLUL CELULAR
G1+ &- ini9il:, de !(e%"e(eS + &- de %in"e-:G+ &- p(e)i"'"i!:M + &- de )i"'-:
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MITOZAMITOZA
P('&-
An&-
Me"&-
Tel'&-
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DIAGRAMA FAZELORDIAGRAMA FAZELORCICLULUI CELULARCICLULUI CELULAR
G1 GMS
Ti)p
ADN
!
7!
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C(e%"e(e ".)'(l: depinde de;+ "i)p.l !i!l.l.i !el.l(
+ &(!9i de !(e%"e(e ".)'(l: + &(!9i de pie(de(e !el.l(:
Re-.l"".l !e%"'( +++? "i)p.l de d.$l(e ".)'(l:
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CRESTERECRESTEREE;PONENE;PONEN V3e+#'3*?@26%D(
Ti)p
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DIAGRAMA CINETICII TUMORALEDIAGRAMA CINETICII TUMORALE
C')p("i)en".l C')p("i)en".l!el.lel'( di#i-i$ile !el.lel'( nedi#i-i$ile
Cel.le %"e) Cel.le %"e)".)'(le d'()nde
Cel.le !. p'"en9il Cel.le in!p$ile$i'l'2i! li)i"" de di#i-i.ne
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RELARELA
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EFECTUL DUP= PRIMAEFECTUL DUP= PRIMAADMINISTRARE A UNUI CITOSTATICADMINISTRARE A UNUI CITOSTATIC
ANTITUMORALANTITUMORAL
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DIAGRAMA EFECTELOR TERAPIEIDIAGRAMA EFECTELOR TERAPIEICITOSTATICE ASUPRA CELULELORCITOSTATICE ASUPRA CELULELOR
NORMALE SI TUMORALENORMALE SI TUMORALE
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DIAGRAMA EFECTELOR TERAPIEI CITOSTATICEDIAGRAMA EFECTELOR TERAPIEI CITOSTATICEASUPRA CELULELOR NORMALE I TUMORALE NASUPRA CELULELOR NORMALE I TUMORALE N
CAZUL ADMINISTR=RII CICLURILOR DE TRATAMENTCAZUL ADMINISTR=RII CICLURILOR DE TRATAMENT
LA INTERVALE MAILA INTERVALE MAI MICIMICI DECT CELE OPTIMEDECT CELE OPTIME
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DIAGRAMA EFECTELOR TERAPIEI CITOSTATICEDIAGRAMA EFECTELOR TERAPIEI CITOSTATICEASUPRA CELULELOR NORMALE SI TUMORALE NASUPRA CELULELOR NORMALE SI TUMORALE NCAZUL ADMINISTR=RII CICLURILOR DE TRATAMENTCAZUL ADMINISTR=RII CICLURILOR DE TRATAMENT
LA INTERVALE MAILA INTERVALE MAI MARIMARI DECT CELE OPTIME DECT CELE OPTIME
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FACTORII FARMACOCINETICI CAREFACTORII FARMACOCINETICI CAREINFLUENINFLUEN
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CICLUL CELULAR - FAZE* DURAT= SICICLUL CELULAR - FAZE* DURAT= SILOCURILE DE ACLOCURILE DE AC
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TIMPUL NECESAR DUBL=RII VOLUMULUITIMPUL NECESAR DUBL=RII VOLUMULUIUNOR TUMORI MALIGNE UMANEUNOR TUMORI MALIGNE UMANE
CLASIFICAREA CITOSTATICELORCLASIFICAREA CITOSTATICELOR
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CLASIFICAREA CITOSTATICELORCLASIFICAREA CITOSTATICELOR
0 AGEN
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MECANISME DE ACIUNEMECANISME DE ACIUNE
A/en1ii $!i$n1i + l!il(e !i-il'( n.!lei!i i ADN+.l.i = nl'!.i(e "')il'( de id('2en
!')p.il'( '(2ni!i !. (di!li l!il .n i'n in"e()edi( de e"ilen)'ni.(.p".(i le ADN+.l.i i le2:".(i n!(.!i"e n"(e !ele !"ene le eli.l.iin"e(&e(nd !. (epli!(e ADN+.l.i i !. "(n%!(ip9i !e%".i n ARN4
A/en1i n%imi!r"%u.u$i - $!$"ii )e Vin!+ !')p.I di)e(i!i !(e %e &ie-: de .n %i".% %pe!i&i! de l ni#el.l ".$.line
$l'!nd p'li)e(i-(e di)e(il'( de ".$.lin:, )e!ni%) p(in !(e e%"e %"'p":&'()(e )i!('".$.lil'(4
- %+ni; + ind.!e(e e&i!!e p'li)e(i-:(ii ".$.linei i ini$i9i dep'li)e(i-:(ii )i!('".$.lil'
&.% )i"'"i! n'()l4
An%ime%."$i1i+ nl'2i %"(.!".(li i )e"$'li9il'( n'()li, !:('( !"i#i""e e%"e de"e()in": p(in%.$%"i".9i .n.i )e"$'li" n'()l !(e, &i-i'l'2i!, e%"e n!'(p'(" n"(+' )'le!.l!eie, de"e()innd, %"&el &.n!9i'n(e n'()l: !e%"ei4
MECANISME DE ACTIUNEMECANISME DE ACTIUNE
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MECANISME DE ACTIUNEMECANISME DE ACTIUNE
C"m#$e+e )e #$%in&+ %e le2: de -'".l din p'-i9i l (e%".l.i de 2.nin: din ADN l ' le2(e
n!(.!i": n in"e(i'(.l ln9.l.i de ADN ini$i9i (epli!:(ii !el.l(e4
A/en1i !re in%er!1i"ne& !u %"#"i"mer;+ e#i#")"7i$"%"+ine
+ ini$: p'li)e(i-(e ".$.linei, p(in le2(e de .n %i".% l !e%"ei4 +n$"/i i !m#%"%e!inu$ui+ "'p'"e!n.l &'()e-: ' le2:".(: !'#len": !. "'p'i-')e(- I, n )')en".l!li#:(ii ADN+.l.i, )piedi!nd (e&!e(e d.$l.l.i eli i (epli!(e !e%".i4
- n%i.i"%i!e n%ine"#$i!e+ d''(.$i!in de"e()in: l"e(:(i le ADN+.l.i p(in p('!e%e de in"e(!l(e, p(in!el(e i'nil'( )e"li!i de &ie( i !.p(. %. p(in 2ene((e (di!lil'( li$e(i
ini$: "'p'i-')e(- II, pe()i9nd (eli-(e (.p".(ii d.$l. !"en(e de"e()in"ede !e%": en-i):, )piedi!nd (e"(e p'(9i.nil'( de%p(in%e4
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An2i'%""in+ e%"e ' p('"ein: n".(l: !(e ini$: !(e"e(e ".)'(l: p(in $l'!(e &'():(ii de n'i #%e de %n2e i &'%" iden"i&i!" ! .n &(2)en" in"e(n l pl%)in'2en.l.i4An"i!'(p.l )'n'!l'nl HER ne.
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MECANISME DE ACMECANISME DE AC
+ )'le!.le de l %.p(&9 !el.lei i )'di&i!"'(i i %e)nl.l.i i)pli!9i in"e(!9i.nile in"e(!el.l(e i le !el.lel'( !. )"(i!e
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PRINCIPIIE $ENERAE AEPRINCIPIIE $ENERAE AEC,I"I#!ERAPIEI AN!INE#PA+ICEC,I"I#!ERAPIEI AN!INE#PA+ICE
1. !i%"s%%i!e$e ,"r 7i )minis%r%e in )"e$e m+ime %"$er%e050 s"!ieri$e mi mu$%"r !i%"s%%i!e n%ine"#$i!e se ,"r )minis%r #e
)ur% mi mu$%"r i$e #en%ru re$i un !"n%!% !% mi #re$un/i% !u!e$u$e$e %um"r$e0
20 %r%men%u$ !i%"s%%i! n%ine"#$i! %re.uie sK 7ie n)e$un/%* #en%ru 7isi/uri )e ".1inere ,in)e!Krii0
0 sun% )e #re7er% %r%men%e$e !re 7"$"ses! me)i!men%e !u me!nisme)e !1iune )i7eri%e #en%ru #re&n%m#in #ri1i reis%en1ei0
J0 se ,"r $e/e %r%men%e* )e #re7erin1K* in%ermi%en%e0?0 #"$i!imi"%er#i es%e su#eri"rK m"n"!imi"%er#iei0
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PRINCIPIIEPRINCIPIIEP#IC,I"I#!ERAPIEIP#IC,I"I#!ERAPIEI
1. -ecare edicaent utili/at in co0inaie tre0uie a ai0ainur e-ciena aia
2. edicaentele adinitrate co0inat tre0uie a ai0aecanie dierite de aciune.
3. toicitatea edicaentelor adinitrate co0inat tre0uie a
-e dierita4. tre0uie adinitrate edicaentele care nu deterina
re/itena ncruciata a celulelor tuorale7
**
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(AC!#RII CARE IN(UEN(AC!#RII CARE IN(UEN))EA+EA+**NE$A!I8 RE+U!A!EENE$A!I8 RE+U!A!EE
!RA!A"EN!UUI C,I"I#!ERAPIC!RA!A"EN!UUI C,I"I#!ERAPIC
1. locali/arile 9eciale ale tuorii
2. dieniunile aei tuorale
3. ti9ul :itoloic al tuorii4. eni0ilitatea ca/uta a tuorii la co0inaia de citotatice utili/ate
5. a9ariia re/itenei la citotatice
6. ritul lent de 9rolierare tuorala
C#N!RAIN'ICAC#N!RAIN'ICA))IIE !RA!A"EN!UUIIIE !RA!A"EN!UUI
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C#N!RAIN'ICAC#N!RAIN'ICA))IIE !RA!A"EN!UUIIIE !RA!A"EN!UUIC,I"I#!ERAPICC,I"I#!ERAPIC
0 C"n%rin)i!1ii .s"$u%e
14 $'li ne'pl-i!e n %"di.l "e()inl44 d)ini%"((e l 2(#ide484 $'ln#i den."(i9i, !e!"i!i, !')"'i, %. !. &.n!9ie e)"'l'2i!: dep(i)":474 $'ln#i !. ne'pl-ii de)'n%"("e !.($ile p(in in"e(#en9ie !i(.(2i!l: !. in"en9ie de(di!li""e %. (di'"e(pie !.("i#:4
.0 C"n%rin)i!1ii re$%i,e14 n %i".9ii n !(e $'l ne'pl-i!: e%"e %'!i": !. 2(de %e#e(e de in%.&i!ien9: (enl:,
ep"i!: %. !(di!:44 %'!ie(e !. !'2.l'p"ii, in&e!9ii %e#e(e %. ".l$.(:(i p%ii!e484 !i)i'(e-i%"en9 ".)'(ii474 n !- de %'!ie(e !. $'l ne'pl-i!: .n'( &e!9i.ni !(e p'" &i 2(#"e ded)ini%"((e !i"'%""i!el'(454 !'pii !. #(%" )i )i!: de 8 l.ni4
/4 pe(%'ne #(%"ni!e de$ili""e44 p!ien9i ne!''pe(n9i4
REZISTENTA LA CITOSTATICEREZISTENTA LA CITOSTATICE
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REZISTENTA LA CITOSTATICEREZISTENTA LA CITOSTATICE
Re-i%"en9 )edi!)en"'%: ).l"ipl: !l%i!:Gen MDRG !(e de"e()in: (e-i%"en9 ).l"ipl: )edi!)en"'%: !l%i!:
e%"e i)pli!": n %in"e- .nei 2li!'p('"eine
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REZISTENTA LA CITOSTATICEREZISTENTA LA CITOSTATICE
Reis%en1 $e/%& )e re#rre ADN-u$ui Hi )e )e%"+i7iere m"$e!u$r&5 me!nisme enim%i!e;
+ in"e(#en9i O?-$!i$/unin ADN-%rns7erei, en-i): !(e (e ('l n(ep((e le-i.nil'( ADN+.l.i i !(e !'n&e(: (e-i%"en9 &9: de2en9ii l!iln9i
+ in"e(#en9i /$u%%i"n-S %rns7erei, !(e e%"e i)pli!": n %in"e-p(e!.(%'(il'( ADN+.l.i i n p('!e%ele de de"'i&ie(e !el.l(: 4
PRINCIPALELE MODIFIC=RI IMPLICATE NPRINCIPALELE MODIFIC=RI IMPLICATE N
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PRINCIPALELE MODIFIC=RI IMPLICATE NPRINCIPALELE MODIFIC=RI IMPLICATE NAPARIAPARI
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PRINCIPIILEPRINCIPIILEHORMONOTERAPIEI INHORMONOTERAPIEI IN
ONCOLOGIEONCOLOGIE
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TIPURI DE HORMONOTERAPIETIPURI DE HORMONOTERAPIE
0 Ter#i "rm"n$& .$%i,&.0 Ter#i "rm"n$& )i%i,&
Pr"/es%%i,e$eEs%r"/eniiAn)r"/enii
!0 Ter#i "rm"n$& !"m#e%i%i,&An%ies%r"/enii
)0 Ter#i "rm"n$& ini.i%i,&ini.i%"ri )e r"m%&An$"/ii )e L-R
TIPURI DE HORMONOTERAPIETIPURI DE HORMONOTERAPIE
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TIPURI DE HORMONOTERAPIETIPURI DE HORMONOTERAPIE
414 E%"('2eni; Die%i$s%i$.es%r"$* C$"r"%rinisen* Es%r)urin* Dienes%r"$* F"s7es%r"$* -Es%r)i"$44 An"ie%"('2eni; Tm"+i7en* T"remi7en* C$"mi7en* Dr"$"7i+en* I)"+i7en* R"$"+i7en* Tri"+i7en*Zin)"+i7en484 P('2e%""i#e; Me)r"+i#r"/es%er"n !e%%* Me/es%r"$ !e%%* Ges%er"n"n !e%%*i)r"+i#r"/es%er"n !#r"%* N"re%is%er"n* E%in")i"$474 An"ip('2e%""i#e; Mi7e#ris%"n* On#ris%"n454 And('2eni; Tes%"s%er"n #r"#i"n%* F$u"+imes%er"n* Dr"s%n"$"$4/4 An"ind('2eni; Ci#r"%er"n !e%%* F$u%mi)* Bi!$u%mi)* Ni$u%mi)
44 Ini$i"'(i de (')"-:;Amin"/$u%e%imi)&* Piri)"/$u%e%imi)&* -i)r"+in)r"s%en)i"n&'F"rmes%n(* E+emes%n* Ans%r""$* Le%r""$* Lir""$* F)r""$* V"r""$4*4 Anl'2i i '()'nil'( de eli$e((e i 2'nd'"('&inel'( ; G"sere$in* Leu#r"$i)*Tri#%"re$in* Leu#r"re$in* Busere$in* N7re$in44 An"2'ni"i i '()'nil'( de eli$e((e i 2'nd'"('&inel'( ; Ce%r"re$i+* An%i)*A$in B* De%ire$i+4104 Anl'2i i '()'n.l.i ini$i"'( l !(e"e(ii
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NEOPLAZII MALIGNE CARE BENEFICIAZANEOPLAZII MALIGNE CARE BENEFICIAZADE HORMONOTERAPIEIDE HORMONOTERAPIEI
0 CANCERUL GLANDEI MAMARE
50 CANCERUL PROSTATEI
20 CANCERUL ENDOMETRULUI
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PRINCIPIILE TERAPIEIPRINCIPIILE TERAPIEITINTITE MOLECULARTINTITE MOLECULAR
IN ONCOLOGIEIN ONCOLOGIE
I)p'("nI)p'("n99 (el9iei(el9iei T.)'(T.)'(::G-d: n $'l ne'pl-i!:G-d: n $'l ne'pl-i!:
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I)p'("np 99 (el9iei9 T.)'(:G-d: n $'l ne'pl-i!:p)li2n:)li2n:
tumor in std incipienttumor in std incipient
Creterea n volum a tumoriii cu dezvoltareaCreterea n volum a tumoriii cu dezvoltarea
vaselor sanguine i limfaticevaselor sanguine i limfatice
ductductlimfaticlimfatic
Invazia celulelor tumoraleInvazia celulelor tumoralen vasele sanguine i limfaticen vasele sanguine i limfatice
Celule tumoraleCelule tumorale
MetastaMetastaze ggl limfaticeze ggl limfatice
Ggl limfaticGgl limfatichepatocithepatocit
Metastaza incipMetastaza incip
Celula tumoral ader de pereteleCelula tumoral ader de peretele
vasului sanguin, invadeaz ivasului sanguin, invadeaz i
metastazeaz la distanmetastazeaz la distan
TERAPIE TINTITA MOLECULARTERAPIE TINTITA MOLECULAR
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TERAPIE TINTITA MOLECULARTERAPIE TINTITA MOLECULAR
O !(!"e(i%"i!: i)p'("n": &en'"ip.l.i )li2n e%"e (ep(e-en"": O !(!"e(i%"i!: i)p'("n": &en'"ip.l.i )li2n e%"e (ep(e-en"":
!p!i""e !el.lei ne'pl-i!e de %e ).l"ipli! n )nie(:!p!i""e !el.lei ne'pl-i!e de %e ).l"ipli! n )nie(:."'n'):."'n'):
n ne'pl-iile )li2ne .)ne %e !"i#e-: %.%.n" de(e2l"en ne'pl-iile )li2ne .)ne %e !"i#e-: %.%.n" de(e2l"e
!')p'nen"e #(i"e le !:il'( de %e)nli-(e $i'l'2i!:, de p('li&e(!')p'nen"e #(i"e le !:il'( de %e)nli-(e $i'l'2i!:, de p('li&e(i%. %.p(#ie9.i(ei%. %.p(#ie9.i(e
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Se)nli-(e EGF+RTK
ATPATP
2($%'%
R%+GTP R&1
MEK
MAPK
.n&'% !"i#"i'n
m"$e!u$e mi!
)is#"ni.i$e
An%i!"r#i )is#"ni.i$i
C.) !9i'ne-: !e%"e d('2.(C.) !9i'ne-: !e%"e d('2.(I i$i" ii d "i l l l l
Cum !1i"ne& !es%e )r"/uriCum !1i"ne& !es%e )r"/uriQQ
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Ini$i"'(Ini$i"'(ii de "ip.l )'le!.lelii de "ip.l )'le!.lel')i!i)i!i
in"e%! i $l'!e-: ' "(ep": !en !le "(n%)i"e(ii %e)nl.l.i
D"'(i": di&e(en9ei %"(.!".(ii@in-i!e p'"e &i p'%i$il:%ele!"i#i""e
T'i!i""e e%"e n p(i).l (nd&()!'l'2i!: !'(el": !.$l'!(e !:ii de "(n%)i"e(e
M'di&i!(e )'le!.lei ( p."e(ed.!e %ele!"i#i""e, de"e()innd.n e&e!" )i p.9in %pe!i&i! !.) &i $l'!(e )i ).l" de ' @in-:
P'" &i %in"e"i-9i pen"(. !9i'n
)p'"(i# .n.i n"i2en %pe!i&i!
S.n" e&i!ien9i n.)i d!: e%"e p(e-en"!el n"i2en i n.)i d!: !el n"i2en!'n"(i$.ie l e&e!".l $i'l'2i!
n p(e-en" p'"e !9i'n n.)i lni#el.l %.p(&e9ei !el.l(e %. l ni#el.lp('"einei %e!(e""e l %.p(&9!el.l(:
S.n" )'le!.le )(i i, n !-.l n !(e
n. %.n" !')ple" .)ni-9i p'"de"e()in n&ilie
P'" de"e()in i .n e&e!" i).n'l'2i!%'!i" le2:(ii di(e!"e
An%iAn%i!"r#ii!"r#ii
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An"iAn"i!'(pi!'(pi Ce "ipCe "ip
An"i!'(pii p'" de"e()in ADCC
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C.) !9i'ne-:9n"i!'(piin"i!'(pii
Se le2: l 9in"ele%pe!i&i!e (e!ep"'(i,li2n-i
M'le!.le )(i !e p'"$l'! p('"einein"e(!9i.ni le p('"einel'( e424 di)e(i-(e
E&e!" p'"en"il i).n'l'2i!
Se le2: l %i".%.(i%pe!i&i!e le @in-el'(
P( #e !"i#i""e
%.pe(i'(: n !-.l)."9iil'(
A!"i#i""e !(e (:)ne
%e d"'(e"e "ip.l.iQild %. !9i.nii &9: d' l": 9in":
Cum !1i"ne&Cum !1i"ne&)'le!.le)'le!.lele )i!ile )i!iQQ
MM l ll l l i i il i i i "" 9i9iiill
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MM'le!.le'le!.lele )i!i ile )i!i i).")."9i9iiilele
P'" )'le!.lele )i!i %: !9i'ne-e d'( n !-.l ei%"en9ei .nei )."9 P(e ei%" ' !'(el9ie p."e(ni!: !. (:%p.n%.(i %.pe(i'(e n
!-.l p(e-en9ei .nei )."9ii l ni#el.l %i".%.l.i de &i(e l ATPn p(e-en" e%"e p('$$il &p".l !: n. "'"e (:%p.n%.(ile %e %'!i
!. !e%"e )."9ii B'l %"$ili-": i )eli'((e %i)p"')"'l'2iei %e !'n%"" n
!-.l (e!ep"'(il'( Qild "Jpe S.n" i)pli!9i i l9i &!"'(i
Gene !e !'n&e(: (e-i%"en9: )."9ii Al"e 9in"e
SS l "i i"l "i i" " d : " l $" d : " l $
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SSele!"i#i"ele!"i#i""e (ed.%: e%"e .n l.!(. $.n"e (ed.%: e%"e .n l.!(. $.n
Bl'!(e p'"en9il: )i ).l" de ' !le ( p."e &i
$ene&i!: P(in iden"i&i!(e l'".(il'( de p!ien9i %en%i$ili l )'n'
ini$i"'(i, .n din !9i.ni # &i pe(!ep.": ! d')inn": P'"en"il pen"(. "'i!i""e !(e%!.":
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84 $l'!(e !:ii %e)nl.l.i de "(n%d.!9ie84 $l'!(e !:ii %e)nl.l.i de "(n%d.!9iei i$i" i i :ii d li i$i" i i :ii d l
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+ ini$i"'(i i !:ii de %e)nl (%+ ini$i"'(i i !:ii de %e)nl (%+ ini$i"'(i i !:ii (p)J!inei+ ini$i"'(i i !:ii (p)J!inei
+ ini$i"'(i i &(ne%il"(n%&e(-ei < l'n&(ni$, "ipi&(ni$,+ ini$i"'(i i &(ne%il"(n%&e(-ei < l'n&(ni$, "ipi&(ni$,
"e)%i('li).%, e#e('li).%>"e)%i('li).%, e#e('li).%>
74 (e2l(e !i!l.l.i !el.l(74 (e2l(e !i!l.l.i !el.l(+ ini$i"'(i !d@ < &l#'pi(id'l>+ ini$i"'(i !d@ < &l#'pi(id'l>
+ )'d.l"'(i i !i!l.l.i !el.l( !. e&e!"e ).l"iple pe p.n!"ele de+ )'d.l"'(i i !i!l.l.i !el.l( !. e&e!"e ).l"iple pe p.n!"ele de
!'n"('l GS!'n"('l GS+ !"i#"'(i i !')ple.l.i E+!d@+ !"i#"'(i i !')ple.l.i E+!d@
+ ini$i"'(i p('"e%')i!i < $'("e-')i$ el!de>+ ini$i"'(i p('"e%')i!i < $'("e-')i$ el!de>+ ini$i"'(i i i%"'n!e"il-ei+ ini$i"'(i i i%"'n!e"il-ei
54 Ind.!e(e p'p"'-ei54 Ind.!e(e p'p"'-ei" TRAILRI"! TRAILRI
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+ "! TRAILRI+ "! TRAILRI+ %"("e2ii n"i%en% B!l++ %"("e2ii n"i%en% B!l+
+ %"("e2ii de !9i.ne %.p( p58 ONI 015+ %"("e2ii de !9i.ne %.p( p58 ONI 015
/4 n"in2i'2ene-:/4 n"in2i'2ene-:+ ini$i"'(i i !el.lei end'"elile < "lid')id, n2i'%""in, end'%""+ ini$i"'(i i !el.lei end'"elile < "lid')id, n2i'%""in, end'%""
TNP+70>TNP+70>+ ini$i"'(i i EGF < $e#!i-.)$ A#%"in %.ni"ini$ S."en">+ ini$i"'(i i EGF < $e#!i-.)$ A#%"in %.ni"ini$ S."en">
+ ini$i"'(i i (e!ep"'(.l.i pen"(. EGF EGFR1, PDGFR, !+@i" + ini$i"'(i i (e!ep"'(.l.i pen"(. EGF EGFR1, PDGFR, !+@i" < %'(&eni$ Ne#(>< %'(&eni$ Ne#(>
+ ini$i"'(i i R&+ ini$i"'(i i R&+ ini$i"'(i i "i('-in + @in-el'(+ ini$i"'(i i "i('-in + @in-el'(
P('d.i !')e(!iliP('d.i !')e(!ili
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An"i!'(pi Ri".i)$ 9in": CD0 n
li)&')ele !. !el.le B T(%".-.)$ + 9in": E($B
n !n!e(.l ))( Ce".i)$ 9in": E($B1 n
!n!e(.l !'l'(e!"l i n!n!e(.l din %&e( !p + 2" Be#!i-.)$ %e le2: de
EGF )piedi!nd &i(e!e%".i l (e!ep"'(.l
EGF
M'le!.le Mi!i I)"ini$ 9in": B!(+A$l nCML i !+@i" n GIST
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E%"eE%"e"'i!i""'i!i""e"edi&e(di&e(i":i":
T'"e p('d.%ele )edi!)en"'%e p(e-in": .n p'"en9i"'i!
Din p.n!" de #ede(e &()!'l'2i! n. ei%": di&e(en9:n"(e "'i!i""e de"e()in": de )'le!.lele )i!i i !e
de"e()in": de n"i!'(pi An"i!'(pii p'" ind.!e n&ilie )'le!.lele )i!i p'" de"e()in e&e!"e n'n+
&()!'l'2i!e
F!"'(i nF!"'(i n'n+!lini!'n+!lini!i pen"(.i pen"(.n"in"i!'(pi!'(pi
F!"'(i nF!"'(i n'n+!lini!'n+!lini!i pen"(.i pen"(. l l l i i
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n"in"i!'(pi!'(pi
P('!e% de de%!'pe(i(e (pid
S.n" di&i!il i %!.)pi de p('d.%
E%"e &'("e di&i!il: in"('d.!e(e
2ene(i!el'( Ad)ini%"((e I ne!e%i"
epe(ien9:
I)).n'2eni!i""e p'"en9il:
n )'d !.(en" p'" !!e% n.)i9in"e e"e(ne
P('!e% de de%!'pe(i(e ndel.n2" !9i.ne de %pe!i&i!i""e p'"e &i'$9in.": p(in in2ine(ie !i)i!:
Rel"i# %i)pl. i ie&"in de '$9in."
M'dli""e .'(: de d)ini"((e '$in.i" !le '(l:
C')plin9 p'"e &i p('$le)"i!: P'" !!e% n.)i 9in"e in"(!el.l(
)'le!.le)'le!.lele )i!ile )i!i
C(e din "e(piile n'i )'le!.l(e p'" &i !elC(e din "e(piile n'i )'le!.l(e p'" &i !el
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C(e din "e(piile n'i )'le!.l(e p'" &i !elC(e din "e(piile n'i )'le!.l(e p'" &i !el)i $ine !')$in"e !. !elell"e "e(pii)i $ine !')$in"e !. !elell"e "e(pii
%pe!i&i!e%pe!i&i!e S".diile !. (e-.l""e p'-i"i#e %.n" pn: n
p(e-en" (ele#n"e n .() %'!ie(iip'li!i)i'"e(piei !. n"i!'(pii
E&e!".l !el )i i)p'("n" e%"e de n.
n"2'ni- e&e!".l !el'(ll"e "(")en"e S.n" i)p'("n"e "" "ip.l de !i)i'"e(pie, "ip.l
$'lii p(e!.) i )e!ni%).l de !9i.ne l)'le!.lel'( )i!i
M'le!.lele )i!i i n"i!'(pii %e p'" %'!i n%i2.(n9: , p."nd #e e&e!"e di"i#e i, p'%i$ili %ine(2i!e
P'"P'" n"in"i!'(pii l.!( )p(e.n: !. !'(pii l.!( )p(e.n: !. )'le!.le)'le!.lelele
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P'"P'" n"in"i!'(pii l.!( )p(e.n: !. !'(pii l.!( )p(e.n: !. )'le!.le)'le!.lelele)i!i)i!i
M'd.(i de !9i.ne !')ple" di&e(i"eCi( i n !-.l !el.ii l'" de
p!ien9i, (:%p.n%.l p'"e &i di&e(i"
Se e%"i)e-: e&e!"e di"i#eE&e!"ele %Jne(2i!e n. . &'%" n!:'$%e(#"e
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