ࡱ> FHABG#Y( L/ 0|DTimes New Romantt4 0DMonotype Corsivat4 0B DWingdingsorsivat4 00DSymbolgsorsivat4 0@DArialgsorsivat4 0" B). @n?" dd@  @@`` @S)tzK]\mld-:P4 X9\|@jxz{|}$7228MLUD M  6 0e0e     A@  A5% 8c8c     ?1 d0u0@Ty2 NP'p<'pA)BCD|E||s " 0e@        @ABC DEEFGHIJK5%LMNOPQRSTUWYZ[ \]^_ `abN E5%  N E5%  N F   5%    !"?N@ABC DEFFGHIJK5%LMNOPQRSTUWYZ[ \]^_ `ab f3333f33@QKS ʚ;q8ʚ;g4JdJd 0nppp@ <4!d!d@w 0t<4dddd@w 0t <4BdBd@x 0tv0___PPT10 pp6___PPT9zefgQ[bd~? $O =@7Recent advances in the drug treatment of brain tumours $863333"/   Helen Gogas, M.D. Ass. Professor in Medical Oncology 1st Department of Medicine Athens University Medical School GREECE R7I7$I e:Relative distribution of primary brain tumors by histology;;(33:  Glioblastoma 23% Astrocytoma 11% Ependymoma 2% Oligodendroglioma 4% Medulloblastoma 2% Meningioma 25%                      BRelative distribution of primary brain tumors by histology (cont.)CC(33B p Pituitary tumors 7% Craniopharyngioma 1% Nerve sheath 8% Lymphoma 3% Other 14% qq.  E f8 Chemotherapeutic agents commonly used for brain tumors 99(338  Nitrosoureas Carmustine (BCNU) Lomustine (CCNU) Procarbazine Platinum analogs Cisplatin Carboplatin Etoposide TMZ PCV regimen (procarbazine, lomustine (CCNU), vincristine) Cytarabine (ara-C) Methotrexate %- -m% mf                                          g Glioblastoma (33  D Most frequent primary malignant brain tumor in adults Median survival < one year from the time of diagnosis even in most favorable situation most patients die within 2 years Standard therapy surgical resection followed by radiotherapy adjuvant carmustine was commonly prescribed in USdZ!Z_&    dQ Meta-analysis(f3   12 randomized trial 3004 patients Survival benefit chemotherapy+radiotherapy vs radiotherapy (p<0.001) 5% increase in survival at two years (20% vs 5%) chemotherpynitrosourea Lancet 2002x  t7    C     r[Temozolomide (TMZ)*(f3(f3   0P  ~b *(f3(f3   0P  Stupp et al JCO 2002*(f3(f3   0P  d EORTC/NCIC 33   0P  ~ *(f3(f3   0P  Eligibility criteria33 d Newly diagnosed and histologically proven glioblastoma multiforme Age 18-70 years (inclusive) WHO PS2 6 weeks (42 days) since biopsy or resection Adequate bone marrow, hepatic and renal function No other severe underlying disease Written informed consent Stratification factors: Age Resection vs biopsy PS 0/1 vs 2 InstitutionJ$PPhKt+      $  *   August 2000-March 200233  573 patients 85 institutions 15 countries 286 patients radiotherapy 287 patients radiotherapy + temozolomide.  Overall survival - OS33$   33 Relapse free survival (RFS)(33  Hematologic side effects(33   No hematologic side effects(f3&     approval: Temodal capsules are indicated for the treatment of patients with: - newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment - malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy. rC33C                      FDA approval: TEMODAR (temozolomide) Capsules are indicated for the treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment. TEMODAR Capsules are indicated for the treatment of adult patients with refractory anaplastic astrocytoma, ie, patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine. PPPPPP 3333                           8MGMT Gene silencing and benefit from TMZ in glioblastoma99(33",   Companion translational study 206 assessable cases Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (HR: 0.45) Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with TMZ and radiotherapy; their median survival was 21.7 months, as compared with 15.3 months, those who were assigned to only radiotherapy (p=0.007)&ZH\   b    @MGMT Gene silencing and benefit from TMZ in glioblastoma (cont.)AA(33.,    OIn the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups - The MGMT gene is located on chromosome 10q26 and encodes a DNA-repair protein that removes alkyl groups from the O6 position of guanine, an important site of DNA alkylation s9H   '    =Chemotherapy for Brain Metastases: Concerns and Controversies>>$33=  Blood-brain barrier Pathogenesis of brain metastases Lack of effective chemotherapy agents Extensive prior treatment Concurrent systemic disease Measurement of response/efficacy  Ability to Cross BBB33 #TMZ for brain metastases: Rationale$$(33# & Crosses the blood-brain barrier - Mean CSF: plasma: 40% at equilibrium - Use in micrometastatic disease - Use in prevention strategies In vitro and in vivo activity in a variety of tumors Demonstrates a favorable toxicity profile - Does not accumulate after repeat dosing!ZuZaZ0Z%qa,.Z   .TMZ alone for newly diagnosed brain metastases//(33. {Siena ASCO 2003 RR% NSCLC 24 n=21 Breast 19 n=21 Melanoma 40 n=21||{  Treated 63 patients TMZ regimen: 150mg/m2/d, days 1-7 and 15-21 q 28 days, up to 1 year With TMZ alone, 24% response in NSCLC brain mets and 19% in breast cancer0( y.    EORTC Results33  .Medical Treatment of melanoma brain metastases//(33. Third most common cause of brain metastases after lung and breast cancer Incidence 10-40% in clinical trials; morein autopsy studies (75%) Once brain metastases develops, it is directly related to morbidity and death in 95% of patients:a.n  x  Chemotherapy 33   Traditional chemotherapy agents for melanoma are ineffective in brain metastases - DTIC (dacarbazine): does not penetrate the CNS - Converted to MTIC (poor CNS penetration)DRdRd.^   L /Chemotherapy agents with promise in CNS disease00(33/  Fotemustine [cerebral response rate 9/36 (25%)] TMZ [cerebral response rate 3/8 (37%) 8/117 (7%)] Jaquillat et al, Cancer 1990 Bafaloukos et al, JCO 2002 Agarwala et al JCO 2004 XZAZZQZ $|            `M Thank you  `f3  /        0` ` ̙33` 333MMM` ff3333f` f` f` 3>?" dd@,|?" dd@   " @ ` n?" dd@   @@``PR    @ ` ` p>>L0 (    6 P  T      + +  0   Z                 C   0h ``  X*  0  `   Z*  0± `   Z*B  s *޽h ? ̙y___PPT10Y+D=' = @B + ,  0 VN0 (     0x P3  a X*   0y  3 a Z* d  c $ ?sn  a  0 a @) a Z                 C   6 P   X*   6    Z* H  0޽hˮ ? ̙3380___PPT10.0˖ @d(  d d 0 P3  a X*  d 0   3  Z*  d 6 P   X*  d 6l    Z* H d 0޽hˮ ? ̙3380___PPT10. 0L0 0$(  r  S yb  r  S D   H  0޽h ? ̙33y___PPT10Y+D=' = @B +  0L0 4$(  4r 4 S 8   r 4 S j`  H 4 0޽h ? ̙___PPT10i.Ү`Z+D=' = @B +  0L0  0(  x  c $j   x  c $ j`9 j H  0޽h ? ̙___PPT10i.Ү`Z+D=' = @B +  0L0 80(  8x 8 c $ {   x 8 c $!  H 8 0޽h ? ̙___PPT10i.Ү`Z+D=' = @B +  0L0 <0(  <x < c $7   x < c $9,  H < 0޽h ? ̙___PPT10i.Ү`Z+D=' = @B +  0L0 $(  r  S o   r  S pj  H  0޽h ? ̙___PPT10i.@Z9+D=' = @B +  0L0 (  ~  s *N   ~  s *O    <RG "   0s /JD<4___PPT9 Oral alkylating agent Antitumor activity as a single agent in the treatment of recurrent glioma Approved conventional schedule is 150-200mg/m2 for 5 days every 28-day cycle 75mg/m2 daily for up to seven weeks is safethis level of exposure to TMZ depletes the DNA-repair enzyme O6 methylguanine-DNA methytransferase (MGMT) CZZ%$?*   :  u   <      H  0޽h ? ̙33y___PPT10Y+D=' = @B +  0L0 ((  (~ ( s *hV   ~ ( s *    ( <hG "  ( 0K jD<4___PPT9  A pilot phase II trial demonstrated the feasibiligy of the concomitent administration of TMZ followed by up to six cycles of adjuvant TMZ, and suggested that this treatment had promising clinical activity2 year survival rate, 31 percent. J Clin Oncol 2002^ZZ$t)           H ( 0޽h ? ̙33y___PPT10Y+D=' = @B +  0L0  p (  ~  s *KW  K ~  s *K K   <KG "   0k H  0޽h ? ̙33y___PPT10Y+D=' = @B +   0L0 0(  0~ 0 s *$K K  0 <'KG "  0 0@*K "j=D<4___PPT9 2^ Randomized phase III trial in newly diagnosed diagnosed glioblastoma multiforme NEJM 2005NUZ ZU b/          r 0 S X-KP  K H 0 0޽h ? ̙33y___PPT10Y+D=' = @B +\   0L0 k c `  (  ~  s *xK9   K ~  s *yK; K   <D;KG "   0rK jD<4___PPT9 q R 0 Z   RB  s *D+>RB  s *DN7    0K)  aRadiotherapy only 2    0@Kb J h  TMZ 75mg/m2 every day X 6 weeks2 2      <0BK 7Radiotherapy with concomitant and adjuvant temozolomide887 X   0PK# n  TMZ 200mg/m2 every day X 5 days repeat every 28 days; for 6 cycles& ..6F :E 3   <K_M  CFocal radiotherapy (30X2 Gy, 60Gy) Tumour volume with 2-3 cm marginDDH     H  0޽h ? ̙33y___PPT10Y+D=' = @B +  0L0  $(  r  S pKP  K r  S K K H  0޽h ? ̙___PPT10i.㒦+D=' = @B +  0L0  (  x  c $KP  K x  c $ |B8CDE F8 @`S" gh:B ?@ 3 jJgh @ 6$J U100"0   A |B8CDE F8 @`S" :B B@ 3 jJX  C B CDETF\mNN d dzz!!((177@GGPPVV__ffoou)u)>>KKKaammmmww  %%!2!2(;(;1H1H7Q7Q@]@]GgGgPgPgV}V}_}_}nnuu " "8888!D!D(D(D1N1N7Z7Z@ZIcIcOyOyXX__hhnww~!!**00999 9 @@II__hJhJnJnJwWwW~W~W``vvv  !00HHXXggw11==GGSSSSS]]]]iiiirrrrr  )2299BBHHXXaaggw$w$..::CCCCYYffffoo ))2299BBQQXX``ggppvv**777VVllllxx 0 0__hh#u#u))299AAH H Q# Q# W9 W9 ie ie pe pe yq yq { {             < <    +,@S" .   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Progression-free survival (%)  @` 0 <?o   m6.9  @` 0 <0 ?"` o  m5.0  @` 0 <1?   %Median progression-free survival (mo)&&%  @` 0 <:?o"  n26.5  @` 0 <ދ ?"`"o  n10.4  @` 0 <,b?"  x At 24 months  @` 0 <?o)" n39.4  @` 0 <ŋ ?"`)o" n20.9  @` 0 <ϋ?)" x At 18 months  @` 0 <`?o0) n61.1  @` 0 <o ?"`0o) n50.6  @` 0 <x?0) x At 12 months  @`  0 <؁?o70 n86.3  @`  0 <؊ ?"`7o0 n84.2  @`  0 <?70 x At 6 months  @`  0 <?o> n14.6  @`  0 <?o> n12.1  @` 0 <h?> Median overall survival (mo)  @` 0 <N?oR Radiotherapy + TMZ (n=287)  @` 0 <<?Ro Radiotherapy (n=286)  @` 0 <T?R tVariable    @``B ,0 0o ?RRZB -0 s *1 ?ZB .0 s *1 ?>>ZB /0 s *1 ?00ZB 00 s *1 ?))ZB 10 s *1 ?""ZB 20 s *1 ?  ZB 30 s *1 ?  ZB 40 s *1 ?  ZB 50 s *1 ?  ZB 60 s *1 ?ZB 70 s *1 ?xxZB 80 s *1 ?qq`B 90 0o ?jj`B :0 0o ?RjZB ;0 s *1 ?RjZB <0 s *1 ?oRoj`B =0 0o ?RjZB G0 s *1 ?77H 0 0޽h ? ̙___PPT10i.`e+D=' = @B +A   0L0 @@ FK K@(   ~   s *4}M   ^   6?J (^   6?J (   vBC%DE F% @`C"? &'1    vBC%DE F% @`C"? 1    vBC%DE F% @`"6 ? 1    vBC%DE F% @`C"? @A1    vBC%DE F% @`C"? 1    vBC%DE F% @`C"? 1 ZB   3 jJC"? 1    |BC9DE F9 @`S" ?L :B   3 jJ?L :B  @ 3 jJL M    <*C"?l =  S0"0     |BC%DE F% @`S" L g :B   3 jJL g    6 l   S6"0     |BC%DE F% @`"6 ?L g ZB   3 jJC"?L g    6l \  T12"0  ZB   3 jJC"?L g    6il #   T18"0  ZB   3 jJC"?L h i g    6`wl z   T24"0  ZB   3 jJC"?L . / g    6Zl K   T30"0  ZB   3 jJC"?L g    6$`l   T36"0  ZB   3 jJC"?L g  !  6|el J  T42"0   "  6Ha   S0"0   #  |B6CDE F6 @`S" L M :B $ @ 3 jJL M  %  6an P  T10"0   &  |B6CDE F6 @`S"   :B ' @ 3 jJ   (  6a P  T20"0   )  |B6CDE F6 @`S"   :B * @ 3 jJ   +  6a6 P  T30"0   ,  |B6CDE F6 @`S" ~  :B - @ 3 jJx y  .  6ЏaPM  T40"0   /  |B6CDE F6 @`S" :B 0 @ 3 jJ 1  6yaP T50"0   2  |B6CDE F6 @`S" EF:B 3 @ 3 jJEF 4  6[ahP T60"0   5  |B6CDE F6 @`S" :B 6 @ 3 jJ 7  6uaPx T70"0   8  |B6CDE F6 @`S" :B 9 @ 3 jJ  :  6Sa0P T80"0   ;  |B6CDE F6 @`S" ww:B < @ 3 jJqr =  6HaPG T90"0   >  |B6CDE F6 @`S" :B ? @ 3 jJ @  6XMa U100"0   A  |B6CDE F6 @`S" ??:B B @ 3 jJ??  C  Z B CDEF:??!!++ C C&L&L5L>L>LDXDXSaSa\m\mkvkvrr  7\\  9 ^ ^ mmv||      ,,,,55 5 5AAJJ$J$J*V*VQwQw`w`woo~~,,;B B QQYYhw!w!!****66666???KKKTTTT&`&`=i=iSuSu[u[ubbjjqyy       ((..==FU+U+[+d4d4j4j4{@{@@@@@IIIIIUUjjsss  !0 0 99? ? H>H>WhWh]~]~lluu{{33ii((II<<   @S" @6 7 (  D  BCDEF:oo!!!++77 L L&X&X/v/v55DMMSS\\bbkkrrzz  > > F \\tzz    ,,,,JJJJVVVbbbbbwwww""(1199HHWW^^mvv||       *9!9!W!W!f*f*o6o6u6u66KKKKTT``iiuuuu$$,,33JJQ Q YYhhq+q+w4w4@@@@IIUUU^^jjss&&..55= = D L L SS[ [ b b j)j)q>q>y>JJSSSSS____hhtttt  ((..77=]=]FFLLUU[[ddj(j(s(s({={=}}>>SS33<<^^  ''0091 91 ?= ?= NS NS ] ] f f l l { { P P     @S" ZZN0  E  68Ea3 0  TTMZ/RT0    F  64?aC"? I  TRT"0 33   G  <,a7K S%"0   LB J  c $DffH   0޽h ? y___PPT10Y+D=' = @B +&,   0L0 5+-+0 @T*(  ~  s *:b   ^  6?``^  6?``G q >  # #"." >?q >   <H;  ?#" `  E  m7  @`  <1  ?#" `  E  e0   @`  <ȫ  ?#" `q sE  gOther   @`   <c   ?#" `   f<1   @`   <,s   ?#" `  e0   @`   <D   ?#" `s>  ^  @`   </   ?#" `qs hAnemia   @`   <   ?#" `    e4   @`  <@n   ?#" `   e0   @`  <   ?#" `qs  { Neutropenia      @`  <*   ?#" `   TMZ/RT n=284 %    @`  <   ?#" ` E >  e3   @`  <$C   ?#" `E  >  e0   @`  <x{   ?#" `qE s>  rThrombocytopenia   @`  <   ?#" `   m2  @`  <<   ?#" `  e0   @`  <Z   ?#" `qs z Leukopenia      @`  <R  ?"O  n RT n=286 %     @`  <k ?"O  n Grade 3/4      @`  <?  ?#" `qO \  @`tB  6o ?"qOtB  6o ?"q> s> tB  6o ?"qqtB  6o ?"  tB  6o ?"qqtB  6o ?"  tB   6o ?"qq tB ! 6o ?"   tB " 6o ?">  > tB # 6o ?" > > tB $ 6o ?"  tB % 6o ?"qE q> tB & 6o ?" E > tB ' 6o ?"O tB ( 6o ?"qqtB ) 6o ?"s> > tB * 6o ?"  tB + 6o ?"q qE tB , 6o ?"  E |B - TDԔ?}I z BV  .# #"&B  / BD ?"`B V  j11"8Z    0 BX ?"`B   r14"8Z   1 B ?"`B  i4"8Z    2 BԱ ?"`B i5"8Z    3 B߱ ?"`B i1"8Z   `B 4 0o ?B`B 5 0o ?BV V `B 6 0o ?BB`B 7 0o ?`B 8 0o ?BB `B 9 0o ?BB`B : 0o ?`B ; 0o ? `B < 0o ?B B `B = 0o ?  `B > 0o ?B BV `B ? 0o ? V  @ 63 6 Adjuvant TMZ n=223 % 60(0B  H  0޽h ? y___PPT10Y+D=' = @B +f,   0L0 u+m+P @C+(  ~  s * :   ^  6?``^  6?``|  j  B #"."  T?j    <F  ?#" ` f   m3  @`  < F  ?#" ` f  m2  @`  <l*  ?#" ` f 6  l Infections     @`   <dF  ?#" `  m8  @`   <8  ?#" `   m6  @`   <  ?#" `6  ^  @`   <D  ?#" ` 6 iFatigue   @`   <  ?#" ` f  m1  @`  <Դ  ?#" `  f  m1  @`  <p  ?#" ` 6f  qNausea/vomiting   @`  <a  ?#" ` c TMZ/RT n=284 %.    @`  <Я  ?#" `   m1  @`  <گ  ?#" `  m1  @`  <  ?#" `  6  iVision    @`  <t  ?#" `  m1  @`  <d  ?#" `   m1  @`  <K  ?#" ` 6 xErythema     @`  <@K ?" c  ~ RT n=286 %.    @`  <K ?" jc  Grade. 3/4       @`  <(K  ?#" ` j  \  @`tB  6o ?" j jtB  6o ?"  6 tB  6o ?" j tB  6o ?"jctB  6o ?"  tB  6o ?"tB   6o ?"  f tB ! 6o ?"f tB " 6o ?" tB # 6o ?"  tB $ 6o ?"ctB % 6o ?"   tB & 6o ?"  tB ' 6o ?" jjtB ( 6o ?"  tB ) 6o ?"6 tB * 6o ?"tB + 6o ?" f  tB , 6o ?"f  |B - TDԔ?" "- z   .# #"&",t"dg  / B(K ?"`s   f<1    0 B40 ?"`G s  e5    1 B70 ?"`% G  e2    2 B80 ?"`%  e2    3 BlO0 ?"` f10   `B 4 0o ?`B 5 0o ?  `B 6 0o ?`B 7 0o ?% `B 8 0o ?`B 9 0o ?s  `B : 0o ?% `B ; 0o ?% G `B < 0o ?G s `B = 0o ?s  `B > 0o ?% G `B ? 0o ?G s  @ 6S0\Sw Adjuvant TMZ n=223 %40( B  H  0޽h ? y___PPT10Y+D=' = @B +   0L0 p  $i(  $~ $ HH0 8c?C"?! R The addition of TMZ to radiotherapy early in the course of glioblastoma provides a statistically significant and clinically meaningful survival benefit Chemotherapy induced toxic effects were manageable Whether the addition of chemotherapy increases the risk of radiotherapy induced cognitive deficits cannot be assessed at this time ,S0 n(S6;     $^ $ 6?``^ $ 6?`` $ 68v0 , y Conclusion * (33$33   H $ 0޽h ? y___PPT10Y+D=' = @B +'  0L0 & <(  <~ < s *a a H < 0޽h ? 33___PPT10i.py+D=' = @B +  0L0  H(  Hr H S }0 ) 0 H H 0޽h ? ̙___PPT10i.S+D=' = @B +  0L0  L$(  Lr L S (0P  0 r L S 0 0 H L 0޽h ? ̙___PPT10i.)+D=' = @B +  0L0  P0(  Px P c $̟0P  0 x P c $0 0 H P 0޽h ? ̙___PPT10i.)+D=' = @B +  0L0  T$(  Tr T S 0P  0 r T S 0 0 H T 0޽h ? ̙___PPT10i.0W+D=' = @B +%  0L0 $ $0 1X#(  Xr X S 0  0 " ' X #"2&DDDDDDD' (X <0? X  @` 'X <\0?n  s Trastuzumab     @` &X <d0?Jn  X  @` %X <0?'J jTMZ   @` $X <$0?  o Cytokines     @` #X <0?n  s Vinorelbine     @` "X <0?J n  X  @` !X <hj ?' J q Topotecan     @`  X <h ?M   q Doxorubicin     @` X <?n M   iVCR  @` X <?JM n  X  @` X < ?'M J  mOH-Urea  @` X <"? M  xCyclophosphamide  @` X <T?n M  s Carboplatin     @` X <4?J n M  X  @` X <>?' JM  iPCZ  @` X <9?  r Irinotecan     @` X <LQ?n   q Cisplatin     @` X <[?Jn  yAra-C"   @` X <hd?'J  jCCNU  @` X <m?n s Gemcitabine     @` X <v?n n kVM-26  @` X <?Jnn  iMTX  @` X <?'nJ jBCNU  @` X <?(n oTaxanes  @` X <?n (n kVP-16  @` X <ܥ?J(n n q Dacarbazine     @`  X <?'(Jn jACNU  @`  X <D?( xNo Penetration  @`  X < ?n ( nPoor  @`  X <@?Jn ( nGood  @`  X <l?'J( t Very Good      @``B )X 0o ?'ZB *X s *1 ?'((ZB +X s *1 ?'nnZB ,X s *1 ?'ZB -X s *1 ?'  ZB .X s *1 ?'M M ZB /X s *1 ?'  ZB 0X s *1 ?'`B 1X 0o ?'`B 2X 0o ?''ZB 3X s *1 ?JJZB 4X s *1 ?n n ZB 5X s *1 ?`B 6X 0o ?H X 0޽h ? ̙___PPT10i.G+D=' = @B +  0L0 p h$(  hr h S P   r h S P  H h 0޽h ? ̙___PPT10i.P!+D=' = @B +^  0L0 ]U  l(  lr l S P     l s *D S" '   r  l S p     l <D ?"6@ NNN?N k ASCO 2003    H l 0޽h ? ̙___PPT10i.<6+D=' = @B + 0L0   k (    c $4,   GEORTC study chemotherapy vs chemotherapy plus WBRT for brain metastasesHH$33.  ,   < ?"6@ NNN?NZuz  hDesign    < ?"6@ NNN?Nz2 VSCLC BM Extracranial tumor No previous therapy for BM No prior teniposide Age<76 yearsW WH   +     '  H) ?"6@ NNN?N"=? L qR A N D O M I Z E  g  H3 ?"6@ NNN?NP  %Teniposide 120mg/m2 Days 1,3,5 q 3 wk8& "