Advances in Cancer Treatment

がん治療のあゆみ
2015/第35回一般研究助成

35

公益財団法人 がん集学的治療研究財団

&*')!Connecting the Dots"$'%(#!
¹úi

â

þ

,

oberyNÍ8.­MR¾3øÉEúÃ;Z!k8Ù9Z]P7Ö<aè¼RòÏÇ´#%z¼¾3øÉUM<!½¹N¸PR©ÁM²AµD]LEUJH"GRÂ!òÏÿ%n¾3
øÉNeRNÙ9L7Hué`R©¸ú¶M6\+Ç´0Dú¶,UM<!¿VàPúZ`Ó;9L7\"¹°S!F­«¶;ZR®»R\êÊQY\ÿ%nÇ´R¹öN¾3øÉ©Áú¶QY
F\²AµM!¡¶ Translational Research)TR*«M6\Ç´0Dú¶MX!¾3øÉQjÂ
F\ú¶NEL¹D]!²AEY8NF\!u·SRa)Ð%*<ª`ÕBL7\"

&<a)¢nþ»Ç´é`MX!®»ú¶(<.(.-QÁÊE!+¶S}NÝ?D]
L=H®»QY\Wè´ÿ%n¾3øÉ)®»QY\´RHW!«¶¨MR¸±z<1MÑC<ÄûD]L=H*UM<²AD]!GRÂ!ÿ%nÇ´S¾æ¦M!õ$¿VàNPJ
LEUJH"; R ¯ ¥ P Steve Jobs ÷ <!/--2 Q Stanford University M Ú J H Commencement Address M!
+Stay hungry,N+Stay foolish,NÍE!M@;Zd©`)WH"E;E!<µgEH;J
HRS!!S+Connecting the Dots,M6JHNó_]\"TI!=¿RÔ`XHZFMLRú¶)Ç´*RáËS!Î&RD`p+Dots,NELÀ@CNM!C]< DNA RÓ6)$"!=½D*

QKP<[!=¿RÔ)ÿ;Rsliy*`±³M=\NRÂ¹oM6\"
NC^M!ué`R­¡ðBS!¥#DaQ®E?!þ»DIQjÂM=\MMÒºnP+<a­»,`oF\CNQ6[!CRTR TR «`Ç´0Dú¶NELoF\CNS!EQ+
»¤xMR},M6[E{M!C]`¿nQVA\CNMÇ´³<*!E!GRÂ+Dots,<À<[!¾3RÌ7M<a¥#DaQÛÆM=\ú¶QoM=\M6JH"
ú!!ué`MS/--1Q+¥#Q®E7<a­»!txjdfp5,`³E!Ü!W?R¾
3øÉ`oE!äºMS.#---À6R\²§¾3øÉMX°¨Q²m4À?`h9L)HM=!WÞ¨¾3øÉ)IDEA*QXîM=!gx'rwP§p;ZX/Þ;ZÝ7<|Z]\¾3ø
Égw'tQUMoEL=H"UH!DRW?SíùQtØ$å´D]!L?].°»°9Z
Qw^M=HN:yÿE!£U¦`¤_7!rM=\²¦<VP>JL7H"~Q!>Ç´
«MS!z\fª`Y5QEH GWAS `´7H¨µn
Y5QEH HER2qñG)¬.1--À*!{<Ú$ãª`qñÌsRG)¬.0--À*!| Stage!\f<a`Y5QEHã¬Èñ

NELR CEA mRNA Åì)¬/4--À*v&<-gQ<V!¢ç¦MXpntfvkQº7¾3øÉg
w'tNR²¦`¤_8CN<M=\±<L?VP>JL=H"~Q!¥#ÅX`´7H

qñGS!ý@[R The Cancer Genome Atlas \¼<ahqutxjdfp)TCGA*QjÂF\äJ_«M!ué`MS¯Q/-.-ß;Z¨µnqñG`ïEL:[!

­è¯ú5`hqumctMF\OPO!TCGA QÀ<\äJ_`©ôEH&[NV`ïEL=H"NC^<ü[Rb};!Ç´0Dú¶UMX<!oberyEúÃR¡;Z¬±9ZNP[!
+K.-¥R$'Ç´#Q!.--¢)¡¶SQ£²mM6JH<%*`RlEL=H<!ëRD/3
sQS4¥QÊZE!¶sS×QÊ2$Ê£!~7Sú¶cöRCD9¬ÃD]\9ZQ·I7

JK5]"¼X!(LPuH©t§=W«@^K8\!®¡RV#P.!EVK<À,H<QfÀÃ`_AKLW!Í¥ª$CS;M·7K5]:!GAKtÍ=LÄ@:C[^]9çNL4]"
FfQ!OþkOWjL,+JP-^`É4@^K;G:!¼Pztî£LÇQ±ÐØ5{àË¯WjMFPýWjPO`iÉAGyP®¡WjTLW:î@^^R!{à°æLlAK5]
×ÙxÈXsüL³u5N:akYxcPO7`IeAK5]Õ@aPeOW>7[^D!íLW
N±ê»ON]Lï:@^]PL!»Pÿ

N&Á:¸B[^]>M`õeAK5]"@K!fF8D<ATAG):aÏxP4YU*./¹Q!Zð-0J9ÛäÕP®¡ðP^º`TMVGÂÆL4\TC"<Ý,+®¡*:¿q@^TAG:!,*QÅKN:[®¡.Oi5Pá}ì:C[^N9JG'®¡&ãÚ:ß:aPGV$(MPtnL@^!fÂÆLQ3*P®¡ð`ÓS#;¶35G""I!![LQ+:.*!w!(0:-*!MMûvù:,*M%¾L!ÏxcWaÔøÏx!aÔøxcMaÔøÏxWjPcp&io:U[^!lkegq
berXnhjnf&dmr~X{rG=(\¤h4]èA5EpW_\!ÓS35GyP®¡ÞðtO¨v`TA!C[^G¥ôP@[N]7O(;N'``5K5]"½±O!gJyP®¡Þð§ÛäÒPÒ6OQÀ,tÍ!ß÷Boú·uz2QBVú·uzPöò
b=%O?|óÌ\!sU9[?ÜÑ`ÌJK5]"Zð-1J9Q!´ò?â­µ¦2PX:mñöò
M²|À,cëFf&:a¢2P8/òöò9[ç~T]?ÜÑ`35G"1?%dPwöòOQ
ç9[Ö`éAå=!<À,PO7PGV!¼±MW|%P?Ê}M?¢y!?ÉA!?]`Ì\T
CZ6!õO85éAå=]Î)L4\TC"Zð-2J.¬.,F

%

#

"

!

&

$

kÿØglw

glè

Â

Ö

ö

C

Øv^~äM<2È?Å:S@!
½F5YÁÎàÄ·^,'§:8"^LÃNTJ?"LÃ°J?H,úeøM¶®sûI0[;J"=YM",Î)*úðXZ%}·MA?1@)J4&^AÕ?H¦ã@[;JJLFH4ZS@!
SDªúð5Y¹K·OCN,úO¤p1I7L1"J12Ìð^êUS?D!
p1ËO"6úðO+'I?D!p1ìUÒZO.*(ù"CNp1ÀMN`c$^±;XZÚHNØglMÞ&?"±Ù#r^?H1DE7S?D!CN±Ù#rIO"Ôà#rNR5M#r6YL1X2#rý*^êUDÜà#rI¦ï^41?H4ZS@!CNØu^±;I»?"
[('(+ùMá+'xkÿØglw^y£?S?D!Øgl6Åf5YkâAGQ^¼*MFH"ÐM#r^1S?D!;NØglw±PO",ÍQô>Í^I?"iWGB^P?"/ß?H4ZS@!
CNu".NÁÎ¹K·^US?D!ÁÎ^¹K=\[3Oç2JL[5V?\SB_6"(úN6µîMHu^þ"?H1DE7S@!V?þ"6%sûI0FDÆOÁÎN.
^U[DêI¢1S@!SD"A\DO¬5ñ

6_adb$MÊ×@[;JMLFH4ZS@!
ÁÎ^¹K=\[ÕÑ3M41?S@!
Q+^þ"=\[¨MO%6_»zí´J©åÁÎ&N0Á^÷D¯^>?Hé8X24
1?S@!©å5YNÁÎÝ{O"xSII-q*"/''7oI0ZS@!N´JM?HFH

1[VNJÊ«?H4ZS@6"6©åOn4ÉI@NI"acknowledgement ^&?DQ+^|1
DE8;JO"¾ELh9^²FH4ZS@!

p1=\[üNDUMV"acknowledgement ^'?DQ+|^41?S@!SDÉíL3I@6"ÁÎ¹K,úeøMQ+^|=\D¹K·N®Ó5YNp1MG1HO"Ý÷ïM=YMkêNïË^ÅNB@[;JV3H4ZS@!¶O
Åf(,f8Y1Oõï¸?8O(")ïëðN¡?5<8"!ÇM(â<JNóQM³655ZS@!
=YMO,úM"DJ3('*IVþ"sûLÕÑMONÎu^þ"1DE9\PJ­FH4ZS@!;N)ïMG1HOSESFH4ZSB_6"1A\©åM<Üæ?D1J­FH4ZS@!
¥MLZS?D6"ÁÎ=\[.=NÕÑ3"

xO6òM4UIJ2<>1S@!SD;NÛÏY

?1ÕÑ3^<Ê×1DE7S?DÊ×·Nzè"jz(QOz(Nz(è"tè"$mè"
¿èLKN3#M"84NÈ?Å:S@!
eÅIv2^º]ZS@!

" & ( * # ! % $ )'5B:?)Connecting the Dots*2:3<0! &&&&&&&êÁ    Ý°}kÚ &&&&&&&&&&&&&&&cÓx°_dm"_dÁ  ­ Ê ã,±ì¯v=º7AÖrzÅÙÀÛ®î>¼#´

&& ª



Ï

ô && !

fl\9.9cdPZ69#dPZQp9$

ê && %,½Êv±hqÛ®îÜ;69> TS1+CDDP+Û®îÜ> && Ò á
Do?R\9.9c¼"%#´'¸¬yÉð(/`!S5<86,ÕÞÃ`Câ7Aöv=º7AS1+SIZMHL[}¨ß"ÕË× && ë b ó Ø &&!!
;X.6\9
çîÜ>îjC~ 7A8@>¼#´¸¬yÉð
869JK,«iÍ<.|"»|-|av=º7A±TS1+CDDP && Ð ª
B>\9.9c×çhqÛ®îÜ>¼"%#´ &&!%86,HER2è¥«ÔÍ£Ñav=º7AS1+Oxaliplatin+ &&  ¾ » í &&"!
I2L]eU%&FA7kia0
Trastuzumab'SOX+Tmab(
×çîÜ>¼#´ðS5<_6,ñ£Î2Ds>äCo²7A8@>¡60ZQTZO$ && Ë Ç ì { &&"'
Y4GmY4%&)-*"
KY]"félÌÜ>pÑ
H@<_6

&&#"
,£öµv=º7AJXKMT]×çWT1VUNP\IN]hqà && § Ä \M\9.9cb[a0gîÜ>ðpÑ
H@<!j1',+("_69,»¿vtÃ`=º7AConversion therapy>Ñä¶=u7A && ï
æ  &&#(
Cg\9\90Wh69FAc
REFW$G$x#hqîÜ·õË=14A/IB1 index
S5<869>âç¥=u7A~È,ñ!Â¢¹"¦êwÍ=º7A»¿vhqîÜ>^³¥= && ¤ Æ  ò &&$&
\M\9\90.9EFA6
uå7Ae>n©
3TV^O:Nn9=bJK

> e ÒR 8 ] Y1

/8.&"1!$,5%'4637+-*9#2!0)(÷ÉU-&% "þS¨S¤.Q+DL9aØM8`"0./3SQS;óR6/QPaNx'CbL9a!¿Ö
QVöEaIZXEí2Q]9R==_P9hÕýÒdÿ7EaÖ>+;L9aiM"nkMSHbQ3EaIZRï $*<>\-DL9aR>´éM8a!n°¥M8K=:âb¦HhÕýÒ

SBbXMRZÝE^åÕ^`:¡MÒ >D"=K·[JI=8a9SçaBN>¡4CbL9aijM8a!dMSQ»@¾c

bKK8a>"QnMSòÎúMÐ±EQ¾cbL9aRYMQnïÖRp&n>rM8a!HBMQnï"þÖQ3Eaâb¦He?hÕýÒ

R~#óNw·ód[EasEM6")Ð±d¬DI!û¾Ea6!)Ð±Q^`7Gy+2>ðàýNDL®CCbIRM"«/DL6")Ð±Q^`~#óNw·óR[d¾:xCM
8a!

# ! $ "
"þS¨Sc>ÂM¤­Q+DL9aØM8`"LQ¿Ö>1@Ea!;óR#ÂðC
S?õ(0.//S"Ýï¸Sä4.SRwp{ï¸"/.pï3)MR"þS44#
6N""
5>QÑ9M1WsQ¿@";ó#^R/2#
7,düZa!0./3SQSS76"
2..ï>D;ó
R/WsQPaNx,CbL9a!XIÏlò[çãD"0./3SQSS/0"0..ïN;óR4WsQP
aNx'CbL9a!
Ò

jNDL×Ü$hÕýÒ

N9JI§Þ

jN#í

jM8au{w|j$

j>"¶%RæQÀcGL8N8a9SczDLz9_bL9a!"þS¿ÖQVöEaBN>1@"í2U
R]9>âP9hÕýÒRIEt>S%+DL?L9a!

"þQ3EahÕý
I!×ÜNJy§Þba!¨SMSÒ

jSk|sx&n¢ÜR@-RîfN89XJL"ìEe!dNAL?

jM8aIZ"ÄRFS§Þµ§M8`"þ#DßÜNJIRôø>K_ôøRYP_F"kmq"Àcæ$`Æz"Mó"öRÔ[½DIçMÑÒ

jdÿ7Ea©¹Q8`"hÕýjS×ÜNÃÒ

´Å"nkMÊzCbL9ahÕýÒ
|ÍýÒ<^TÛÍýÒ

jdPbEaijNPJL9a!

QSÈÑ²åÕ(3DCRT)"¦He?hÕýÒ

POR^åÕ"yh$/03Q^aq_áý³£(RÒ

lhv/70Q^a¿ý%êOåÕPORáý³ÒMåÕEa[RMu0}¯RÒ(IMRT)"

j<^Tgz>8a!ZÝEP^åÕS5.'6.Gy d13*2.b¡>Y{NPa!iMáý³ÒSòQMÙEaBN>M?a[RRùAoñM"þOQftzj&ndËREaY{>8`^åÕQ@_VLëÚ>¦9!
n°¥M8K=:âb¦He?hÕýÒ

S"BèR^åÕN%êOåÕ&iR}GdÀcGLw

DL<`"%êOåÕQXVLëÚ>âP@"BèR^åÕQXVLÒ

¡>:9GMvbIijM

8a!XI"þShÕýöaEPL=>0RØNP`"QåÕEaý>19WO¿9¼
Ø·>¡4M?aIZBè^åÕQ@_VLôø>¹çEaTó>8a!Ä¨MSdÂ\iroR^RÎú=_âbhÕýÒ
ôø>ÓCbL9a

Rôø>gÁCbÌZL<`"ªÇ¡S:9[RRºPÒ

!

/)
*4)

-m~5^ hÕý(hÕýØ)

2

íXìPùD\ÒE)H#JÈëÅYQû!ñÃ©

72%':!831&0,.>
íXìPùD\ÒE)H#JÈëÅY_1LßÉP'{D\P8HIKqîâ_ID\Q&Lû6ñÃ©_²IH!v4#,Gy"4#
1Gy ;YS5#,Gy Q¿þLRÄ×_@~CH!ë[_5^
EJ@~CH= Grade 3 rØQRÄ×=ÍªD\AMRO?v5#,Gy)0=àÑë[P¥$CH!
Ê`á­WPCKWZ±L"¢¾"yÿ=.5Mü9WQQ-,,+LÊ`á­=L>K9\ÙL8\!
<@531&/"!=;
1LßíXìÉPùD\5Gy)0QÒE)H#JÈëÅYQR¯âMqîâ_@~D\!
Primary endpoint _/5RÄ×8ã´"secondary endpoint _/5=ã}&º8WMD\!
#!96?-PL\ÓÃ©Q'Î;YSÐÎ_ÆD!JÈëÅYR³_ÉXîÞÙú=<&BZOÉLWL&PÂ²6L8["äÜÇXdpho&nBZQÌÕ+3AONQ´GÕ=N9«['{
MCK9\!
+! *&'("$#)%'(&"#$-(íXìã§PKïÚ&PìMÝýB]K9\!
.(T3b'TNM E]3:(r|L8\!
/(mpjç(u=O9!
0(x(u=O9!
1(.,»rØL8\!
2(PS'ECOG(=,UHR-L8\!
3(µ;CPùD\JÈëÔÈQz=O9!
4(ô6=IH]K9\!
5(Ã©ÀPJ9KÉLß<ZFÏPY\-t=.Z]K9\!
%!#$-(äÜAUHRäÜÕÙ_´GCK;["Ã©TQÀ=·0M9ýB]\!
.(fgoai½Q£ö&OîÞ*S'/DUHRåM/(_Ë@K9\!
/(dpho&nBZQ+3A_´GCK9\!
0(,âQ¼ ;YSÛ êÕ_RD\!'/4*rØQ84_RC"óÝýWC?R¼
K¼ ê=ÖOB]K9\(

&§¹P$!<31&4?*()+
è²D\û6ñÃ©PY["5Gy)0=ÒE)H#JÈëÅYP;@\àÑë[MCK¥$B]H!CH=IK-1-5Gy"P$¡$¦$T1Q0"òÅY21_Lfcel&nMCKÁUD\!És!´^FQä)_³V\Q&LíXì/P¡k&b&_¢

w&P%CP.J"é

CP-Jð2D\AMMD\!
CT ÅY¤_U9KíXìîø_\Ó>&øæ'clinical target volume%CTV(MC"Ø CTV P
ÔÈ"QãV&Oôu,"É¬$ºªâQ®¸_¨¶`L7õP/77"GQ÷QK°P177Qk&ep_:HWQ_¤>&øæ'planning target volume%PTV(MD\!>&ÎøæR"PTV3> ^ ¨ = N 8 V R

ÑÃN62,KC"úä¯ÑÃM°'B[EÇ>]°'Ç>KDZ!PTV PNÇ>Ngjd_>úä¯åÇ>N(2,pïM#HW:è?DZ!DVH&Dose Volume Histogram']Skb`ÌNÇ>¿&û/']ß;L9W:¼¬M¨={]:!
ïÿ÷=(M¿OÅ@L9!Ùê÷ðyrNôÚMWY!5DZ!QExX=N82MWYhmf
a$l¨=>çÜJÜ¥MLGE¹Oáºÿµ©]£5CIýÎÿ]$:!
1! &%$.'#-3*(

"!

V31
V28
V24
V20

+25%
+40%
+55%
+65%

ED

V28
V24

+30%
+50%

ðí
ÕÔë
ÂÊ
³Þ

°'Ç>N./-%-,
28Gy -,
LC
24Gy -,"!0587194$/,*)zM\[E´ÿµ©NÀÄMWZKöN Grade 2 p¸N1§·OòðA>.2,ãé"àÞA>2,ãéK%B[I<Y"sõMàÞAWYTòðAN1§·>Ð9&û0'!A[XN
e$c=X+N1§·óÁNÓÛO.2,MÅâCE!QEÏNµ©'(]£5CE%JO
0-,ãéN1§·óÁ:T%B[I<Y4'"FÛKCI0-,QJO4B[ZK;E!"Ín*-#-2"o*-#/-KC1§·óÁ:NÓÛ].2,"FÛ]0-,KDZK"2-@N¶@>ù6K¢­B[
E!Ø7UtØ¶@];I22@]/úæB¾MÅâCE!*9ÕüuJO+¦NÒ·KLZÉ;È
ªO´L?KTñ /2-@ãéQ[Z!.-,NªMìq>îX[ZKwâCIñ /2@ãéNæB>Q[Z!0/ñNæBJ¶@«Ã><DZ3âJ8Z!
1" /10)2+,1ñ"6-,

öòðA1§·
Grade 2 p¸/-,öàÞ1§·Grade 2 p¸
5,03#
/2Gy%2|2ñ"6/#
4,

6#
2,

/#
2,

05Gy%1|

.--,

.0,

5,

03#
/2Gy%2|

1ñ"61,

5,

/,

Ýª.

Ç>

Madsen00#
2Gy%2|

FreemanJabbari
King

øÁvä

ó:

-.&362++MÆ;HÖ7Ë¦N«Ãi$b>)C?L?½²Ç>>6Gy)1|MâCEN>..±®
J8GEES"Ö!Ë¦O}¤CI

TL9»J8Z!¡"æB3âª>0.KLGI9Z!
# ( ' %

É;ÈMÒDZ¨=(OÐM\EGI<Y"áºN~þ&©Ç¨=F@JOL?ñC×MLGI

½í»yMÄAY©ÛuÒÝÎßºðNÇ!À

4

3Yba_`¥U¤îºðLKT¼ÈMxRZY!@7@L8W}ÂMòj8AASãâN¯]5YJ"ÑLÁå]ä@CeðOíE7L;LY=J8è¿?ZY!ba_`¥U¤îºðO×®MtLàáI2Y=J8ÍWZH6X"Ì¶NóvìÇ)dN½í»y]Ä¬JAYMOeðÞ

µÒPNÚÉ8Æ9A:Y!

fà"ã~I2G74©ÛuÒÝÎßºðO­MT|@CV4MÏ®N«8+-$,(m%æ*c&Nð{w]ØêJAYNM;WQH,m%æ)¢w&I¡ïAY=J8kÖI2X"ØêJAY
³gUw8qËM©L;HS!BZI3HlUçp¬ONÙ¦ðJÔÓ7"S@[n¾?
ZYkÖ¶T{ÅI9YàáI2Y!ãðáOiÜIOzM;6=L\ZGG2YàáI2Y8"ãâIO´¹8ÑM4MJKRFH3Y!ãñª~MVFHÕã³MÄAY©ÛuÒßºðN·¸]A=JO¨ëNÕã³½í»yvMJFHç¶8;@7TÑLeð]ÐAYf§MLYJr°@H3Y!
M"ãñª~MÃÆL>h]3CD9R@C"8^£sÑð~ÊNoéM±²@­<
RA!
"

!

)&Madsen BL, Hsi RA, Pham HT, et al : Stereotactic hypofractionated accurate radiotherapy of theprostate%SHARP&, 33.5 Gy in five fractions for localized disease : first clinical trial results. Int J Radiat Oncol Biol Phys 67%4&#)(11'))(-"*((/*&Freeman DE, King CR. Stereotactic body radiotherapy for lowrisk prostate cancer : fiveyear
outcomes. Radiat Oncol 6%1&#+"*())+&Jabbari S, Weinberg VK, Kaprealian T, et al : Stereotactic body radiotherapy as monotherapy or
postexternal beam radiotherapy boost for prostate cancer : technique, early toxicity, and PSA response. Int J Radiat Oncol Biol Phys 82%1&#**0'*+,"*()*,&King CR, Brooks JD, Gill H, et al : Longterm outcomes from a prospective trial of stereotactic
body radiotherapy for lowrisk prostate cancer. Int J Radiat Oncol Biol Phys 82%*&#0//'00*"*()*-&Koh DH, Kim JB, Kim HW, et al : Clinical Outcomes of CyberKnife Radiotherapy in Prostate Cancer Patients : Shortterm, SingleCenter Experience. Korean J Urol 55%3&#)/*')//"*(),.&Macias VA, PerezRomasanta LA : A clinical review on extreme hypofractionated stereotactic
body radiation therapy for localized prostate cancer using nonrobotic linear accelerators. Cancer Invest 32%5&#)1)')1."*(),/&Rene N, Faria S, Cury F, et al : Hypofractionated radiotherapy for favorable risk prostate cancer.
Int J Radiat Oncol Biol Phys 77%3&#0(-'0)("*()(

; ` Ï o O 5 X T

59;+15)*<04>='%&(
TS1$CDDP$<04>=(8!!"6/"7.3,:?2/-#J_j*&% .<P¿6~ò8_cAd³MpMÑJ5\;"ÄÏöÞlO·è_]ÌAFÛúTÝoX;2]@]I6\!
^]^]PVÒø#Éf_cB\ TS1K CDDP _RfAFÛúVÒøOzjv}_»AF![sáÍ¯JP"öÞF.<_(çN CDDP OÆ+)fqKïßfqNH6I¬:_¼7![®O©".<N9>\ÛúVÒøoXOcµò;¬æ@]".<ÏoOíSN½­J<\?K_*AF6!

# ! $ "
±È".<ÏoN96IöÞÛJPÄÏ_*J<\ÏoXPM=d³P¢UIMpJ5["üÂ.<7u',443&-++/C(NY\K"A;P".D".öÞåtO0Cô%lPD]E]0-#3)"/,#1)"..#,)K3/J5\,(!öÞ;aOÄÏoXJP5\VOOÛ³ÅH;¿lJ5\F

U"TÝoX_ÿTÀ^CF×4ÏoOm;UZ]I6\;"öÞF.<N96IPÂ?K
VN+\sáÍ¯PRK`L%ÈAM6O;±êJ5\!

KN".<JPÄÏÛN¿6ëÖò_I

7FU"Û³":ZØQMTÝoXOË;Ã@MéÀ;'6?K;+<M^,6J5["ÛúTÝo
XOcfòNH6I0]@]I6\!
VÒøoXJPVÒøäÒ_O5OhñWñ´N8I¡ÜÅHñ´;î@]\;"
VÒøO#µ_ÎGF`Ç;ù-@]\?KJDOcµò;¿S\Fò;5\!1JV 5FU P
VÒøO#ÇKAIcµò;Ð@]"'=O²¤N(AIRfoX;ÍTZ]I6\;".<N9
6IPDOÏoµPØQJPM6!ÙiO 5FU s%kVÒøoXOóõ_è\FUNP"Y[cµMºÇOHW9eWXOûWäÒXO¹OML;LgK»8Z]\!
na%ck|}'TS1(P"[YJH@]Fì§¶qmpxtj}¦º~òÕxÇJ5[".
<NcµM`ÇKAI-++2C3«NâB@]I6\![ÇP 5FU Or{owmhJ5\nfq%y
Ngvwiy'5FU Q¦k$¾þO4wºÇ(9YQdnwiyexbu'5FU x}Ê¾þ
O4!Ç(_GÀB\?KNY[ª1 5FU E8_¿UIºÕxµ_#

B\KKVN"Nð

AI#+B\ã>òO¨°_ýGF`ÇJ5\!
.<N9>\ TS1 RfVÒøoXO¬:_¼GFUÁPàM6;"TS1 NP 5FU Y[Vb]FºÕxµ;*@]I9["&ÔN96I TS1 KVÒøoXKORfoXOcµò;Ð@]F?K:Z-(".<N96IVDOµ;*@]I6\!@ZN"TS1 NGÀ@]I6\gvwiyNPVÒøO#Éf_ÐB?KVUÁ@]I9["@ZM\µ;*@]\.(!SF"öÞMF.
<N(B\oXKAIO ABC02 Í¯9YQ BT22 Í¯O©:Zikrwl}'CDDP(Rf£Jp¸Móõ;=Z]I9[/(0("?]SJNUÁ@]F 5FU s%kVÒøoXO1JV CDDP
_RfB\UÁ;'=µVcZJ5\!
D?J^]^]P"öÞF.<Ó_(çN"Y[*¥vÚ+P

K$ã

rMÏo÷nKAI"TS1 K CDDP N0+#/

6ý,ÊíHÃëUINFLR TS1+CDDP+HÃëUIRü!&"ò¼¨

Gy RHÃëÔÃ\CRFJÊíHÃëUIRÇ%¿Urant\¯F"WÓü!ò¼¨ksf`q\¹åFJ!ý,Q?CZÊíGÎUIRWÓ¼¨Sã%QV;ÙQÒPB"@K TS1+CDDP
CRHÃëUIRrantSÝäA±B"ÆÊR´¿ä\±UZ4ä\]M=ZDN@X"K¼¨S³¬Rý,¿UQÝJP4ä\VJXGÈSPWÓ¼¨M<Z!'UMINID000009028($#

ý,QùGZ TS1+CDDP+øHÃëÔÃQWZÊíHÃëUIRîä\>F"CDDPR¶ûúRV'Maximum tolerated dose ; MTD(NáÐRV'Recommended dose ; RD(\¤$GZ!
"!

çÏ4ý,'OAý"ý"ý3"/*A(Q[F"ÄSõ4AFJ[JÕX\ùÖNFJ!&ËNÏË\=1"2QÀG!
&! %"#$

1(ìLSì\D×:M<ZDNA1E[L=Zý,'ý"ý3"/*A(ÕX/©ö%QðÛ%Q1\°>A¸JÞRØ²Srlq5RÕX"TJSô×ý,NÞþE[JÕXV(Z4NGZ
2(ý,ÅY=Qü59QL Stage""#"$;RçÏ4ý,NÞþE[JÕX/)çÏ@4¢Íß°ý,QùGZHÃëUINFLR TS1+CDDP+HÃëUIRü!&"ò
¼¨*N¡+MÂ»GZJU)çÏ@4¢Íß°ý,NÞþE[JÕX*VNGZ
3(ý,QùGZí¿U'HÃëUI"UIPO(AÂ»E[L=P=ÕX
4(BA CT TJS MRI QL"©6ñNpthê' \10cm-10cm RÔÃPQUZDNA4M<ZN
HÃë¿UA7þFL=ZÕX
5((Zí28.-R CT"MRI":ë§µ)R%½TM>4?EA1E[L=ZÕX
'÷$4?ES<àNFP=(
6((Z¾R2YA20·×80·NMRÕX
7(Performances Status'ECOG(A0"
1R=H[@M<ZÕX8(£­èÅA4M<ZÕX
9((Zí7.-RWÓ§µe%cQWY"Ú¦\MJGÕX
u5¥ â$3"
500&mm3 ×v®# â$2"000&mm3 ×w¥Ñ8â$100"
000&mm3 ×x¥ÜïV$9#0g&dL ×y^qjmt$3#
0g&dL ×zóipqit$ªÌ!PFRØ²2#0mg&dL ªÌ!<YRØ²3#0mg&dL { GOT'AST($ªÌ!PFRØ²100U&L ªÌ!<YRØ²150U&L | GPT'ALT($ªÌ!PFRØ²100U&L ªÌ!<YRØ²150U&L }¥æ_r^dgt$»éË×«ÿ~_r^dgt_p^otb$60mL&min ×//24¾"0QWZ_r^dgt_p^otb\Â÷FJØ²S"IRÿ\R=Z!
Â÷ÿAP=Ø²S"R CockcroftGault á$Á\R=Lá$ÿ\ºÉGZ!
á$Á.øÈ'kg(-'140,2Y(&72-¥æ_r^dgtÿ'mg&dL(

< Y ³ L K 7 S O

7ÀØKÊ£L>UJÿUWBíX-#
52,@V!
.-+ùQÞ/5%*1º+t#KÎøÔF"OÂõJDéGIVvË½<I8ÅP..+·=Ò;UK6¾JTVþu<ÿUWE8VÅP

&! %"#$.+ÕHØK|JR?ØK|JIH8òbrfp'n<¤$F7VÅP
/+h^gf\r"qnhZmr_m]j"hncfcrX§I?E8VÅP
0+Õ"7V8L3Õ<ïK?E8VÅP
1+ýØKÜÅXF@VÅP2+ýØK»4*þ±Ø»4:TMB0<2*t#Kv±Ø»4+XF@VÅP3+Ã}KýØóSXF@VÅP
4+»!I£7Å*Î1ß"Ó1ß"1ß"ð>R"brfp'n1MIü'0IH+XF@VÅP
5+»!IÙÐÈ<7VÅP
6+»!IE5[on`'<7VÅP.-+(2$¸&î:TM(ÍK+ØNBLuª<7V"NBL¯X<@VÅP..+AKä"y©<=­XsßJµ«@VKJ1öûG.ì@VÅP!

"=OÂè!à­LÛÁ1+½Ñ¢ëJç@V}:¶ÝL;G?EK TS1,CDDP,:¶Ý
L;Kè!à­GþF¢9!*UMINID -----4140+}:¶ÝL;L1/%X.b'eG?"úGodkrXÔ.J´@!TS1 L day1).1"day29)1/J5-mg(m/(%KúGNX.%/K¡úGX¢9!CDDP L day1G day29 Jt|KINF/±t///
É;=EÚA#úGX¢9%1-mg(m*Level
0+&2-mg(m*Level
1+&3-mg(m*Level
2+!S1 L day1

)14"day29)1/J.%/K¡úGX¢9!:¶ÝL.%."º2%"..#5Gy"/5*áÝN 2-#
1Gy+KæÄ¶X¢9!
CDDP KúGNL Level 1 ;U¨?"IN×"Ø*Doselimiting toxicity ; DLT+K-Å£XQ
CE Leve l KâX¢9!

oinKÅPÖL0)3PG?"þzoinFùQ>WB0PKF®Ç<.C?B±÷FoinKw¢X.ì@V!DLT <0PîJ.PQ)PUWI;CBÊ£L"²oin
Jw¢@V!DLT <0PîJ.)/P)PUWBÊ£L0Pñ~@V!DLT <£3PîJ/PNF)
PUWBÊ£L"²oinJw¢@V!DLT <0PîJ0P7V8L3PîJ0PtÉ)PUWBÊ£L"AKoinX MTD G.ì?"ÏBIùQXî¬@V!=­J:=V DLT KôX/0J"âN
eadl'nX/1J´@!
RD LãG?E MTD K.oin|KING@V!Level 2 F MTD Jê?I;CBÊ£J:8EL"
âNXî¬? Level 2 X RD G@V!Level 1 < MTD KÌX@B?BÊ£JL"Level 0 FKåûØX
Æ@V!
¦¹úG%;UãG?E/)1º@V!x°L;R¼J¥³ÛÁX«¢@V!ÛÁö{<I8Ê£Lx°L;X«¢

9¿L;JD8ELô?I8!

8

f\bª~±«D;BG TS1'CDDP'ª~±«G!#"yq

2" 69-(*.

8# DLT &50)&Grade 3 G£skr*&,UFjI Grade 4 G¢okr J?Hskr+&Grade 4 Go¥r,&Grade 3 UG¦oXb%­wDGW_el7E3[´"ch¡aH8&-&®azFMO*/¬G\b±«Gv`Q)dUZg>:PQE8E@?u.&©¯\bª~±«G®azFMPixGum7)-QY5?u

8$ 4:)'(+!,"#$*&,'!+%,'

()

(#+²

|GTRSFVt<P)$*#+²

9NF+²^%um.²&<P+²#+²

120D¤<P)#.²|GTRSFVt<P*²#.²|GTRSFVt<P+²U#.²

120D¤<P# $ " !
*()- .p{C³²H)*²DE@?!Level 1 CH+²)²C DLT QK??K"+²^
Qt4L DLT QK="Level 2 FVt;?!Level 2 CH+²)²C DLT QK"+²^FMPv¨]Qt4L DLT QKE6@?!UMO"Level 2 CH MTD F>="CDDP G RD H.(mg#m*
Fn;"!yq7°;?!®azFA3B§-".F}<!
8% 1/73

; _  ï O 5 X S

9'! &#"%$&%

ÎO²¤^Ù7¢§^ÜëKA\g¶Î£óJ5\±Ð|Wô|M96IP§ºâ©ïåOçê¶;ã?]I9["ÄÐ|M96IV§ºâ©ïåOïs;}À?]I6\!æð­JP"ouÌkµK¨Øìµ^}À@Iqvä¡¹ïåOdace^i@F!ÑMÄÐ|JP·ªÅÃOl¶q;UI¦ëJ5["éMÈ

A\>K;?]I6\1(!

ÄÐ|M9=\ TS1 ÂJO}Á"½JP¼î.0#+*',/&/+("TTP.#
2fJ5["`d%b.5\6P/OmÒ¶9YQÛmÒ¶PKVMØÞÎ;É<"ßrËL¦ÎOÒ¶5\6P
é}CNÒ¶PÔUZ]B2("6 feasibility ;}À?]\!RF"zJ?]FyÓÄx|^{T·ªßÖÄÐ|M9=\ TS1)CDDP OÁ"½JP¼î.+#+*',0&0+("TTP/#
3fJ5["ÏdaceOç¶;?]F3(!?ZM"TS1 K CDDP P6B]Vä¡¹O¾wê^çA\>K;
ã?]I9[.(4("qvä¡¹ïåM96IP?ZL\ç¶;}À?]\>K:Z"ædaceM
ê@F!
æð­Á!½JP Level 1 9YQ Level 2 JD]E],ñBHO DLT ^ÔUF!Level 1 M9=\
Grade 3 j°Oçt®K@I"mÒ¶JP×¬'..#.*("Ç¬',1#
2*("Ý
'..#.*("«Ú¬',1#2*("ØÕ¶Ç¬',1#
2*(^ÔU"ÛmÒ¶JPpí',1#
2*("ÄÐw¸'..#.*("Ón',1#
2*(^ÔUF!Level 2 M96IP"mÒ¶P×¬'..#.*("Ý',1#2*("
«Ú¬',1#
2*(^ÔUF;"ÛmÒ¶PÔUL:GF!6B]O Level M96IVçt®P¥àMµrÖJ5GF!RF"CDDP Oçt®K@I<ÆZ]\|èØ¶g³$òÍW´~Ö¯tMH6IVµrÖJ5GF!j°Y["CDDP O RD ;1+mg&m-KÊ?]IVædaceP
6 feasibility Kh»¶^çA\rÖ¶;6K8Z]\!
! $ # "·ªrÖÄÐ|M¿A\ TS1K CDDP Oáêqvä¡¹ïåM9=\ CDDP O MTD 9YQ RD ;^sX\oD;BG TS1(CDDP(oG!&"mf

10c;"=G RD MJ@Bl~amfC4L"mfFUi<LC4L!h|FA5BH:
KELdw6C4L6"QOPRH}vY^F<LsuD;BtD;BG
SM[<LY|64L!
#
e`GT_M9Z5>?7"

"E9kWM5>?7I;>gVj{6Nr\ne`jG]bpG%Fyqz;x8I<!
$!

+'Miyakawa S, Ishihara S, Horiguchi A, et al : Biliary tract cancer treatment : 5,584 results from the
Biliary Tract Cancer Statistics Registry from 1998 to 2004 in Japan. J Hepatobiliary Pancreat Surg
16$+)1",**3#,'Matsuda S, Takahashi T, Fukuda J, et al : Phase I study of neoadjuvant chemotherapy with S1plus biweekly cisplatin for advanced gastric cancer patients with lymph node metastasis : KOGC
04. Radiat Oncol 9$3",*+.#-'Nakata E, Fukushima M, Takai Y, et al : S1, an oral fluoropyrimidine, enhances radiation responseof DLD1&FU human colon cancer xenografts resistant to 5FU. Oncol Rep 16$.0/)1+",**0#.'Valle JW, Wasan H, Johnson P, et al : Gemcitabine alone or in combination with cisplatin in patientswith advanced or metastatic cholangiocarcinomas or other biliary tract tumors : a multicentre randomized phase " studyThe UK ABC01 Study. Br J Cancer 101$0,+)0,1",**3#/'Okusaka T, Nakachi K, Fukutomi A, et al : Gemcitabine alone or in combination with cisplatin inpatients with biliary tract cancer : a comparative multicentre study in Japan. Br J Cancer 103$.03).1.",*+*#
0'Higuchi R, Ota T, Araida T, et al : Prognostic relevance of ductal margins in operative resection ofbile duct cancer. Surgery 148$1)+.",*+*#
1'Furuse J, Okusaka T, Boku N, et al : S1 monotherapy as firstline treatment in patients with advanced biliary tract cancer : a multicenter phase " study. Cancer Chemother Pharmacol 62$2.3)//",**2#
2'Kim YJ, Im SA, Kim HG, et al : A phase " trial of S1 and cisplatin in patients with metastatic or
relapsed biliary tract cancer. Ann Oncol 19$33)+*-",**2#
3'Hsieh CH, Hou ML, Chiang MH, et al : Head and neck irradiation modulates pharmacokinetics of 5
fluorouracil and cisplatin. J Transl Med 11$,-+",*+-#

9 [ ¾ g J 4 S O

11HKE1)M#(Q3%C#( S1".+/-*,05?L!H9G
INOJ&<O82)6>#($'&D!AB:@4FP=;7domI*+& æÍC;pJÿEQFS+lÁK"ó±HÝ>ÏÔITVâJÀ9&v?W!<XITV"wgMJð9­7FHWAP"âY^¡9PDChFHW<F9L«=XD5W,'-'!@J\G1÷8UFS+lIõ?WÆcJw
gM´J¾g¢|Kß=XD7V"]¢H¾gMKUB==XD5H5!µYXYXK"Ê~¾g^(E"òïs+lJH5FS+lpÁIõ>D"S1+Paclitaxel&PTX'äV#F¥6/_&iv%ip'H`gMJ¾g¢|
ZÐ?Wó¹ç2ù"ì»Z¦CD5W!ÂaBx©[K,:âñe"E½)Bx©[K¤Äo¢|"ÏÔl¢|"jêà"êâñE4W!µ^(J..X9?EI,k=X"$åFHCD5W!

$ ! % #pÁêôJ0:âñeK0)kvE4V"þºeJª5ÄE4W!-+,,:.IKpJnÁÞ
HULIºOÁÞK7T@.."+++ÚIJNV"îyJq-ZAGCD5W.'!pØû¼I"7T@2+)9}íÒæÍC;FØû=X"@Jó;K,:k6JâY^¡I?:H5!æÍC;pJÿEQFS+
l&FS<Ã"F¥èÓ²NØRFÛ²NØbà'ÁK"F%"FDQT"FÛ!f"#J°HGó±
HÝ>ÏÔZ'>"âJÀ9&v>D"w

gMJð9­7FHW<F95"E4W,'!]gi`J

populationbased study-'R Takahara U/'JITWF"@JâñÿtüK1(2ÅE4V"Performance status 9^¡Ir?W<F9L«=XD5W!
Ishigami U0'K"mJFS<ÃIõ>D S1+PTX iv%ip gMI?W phase 3%" study Z¹¦>"
R¾gM9]PE4W<FZL«>D7V"µn¸Â3jÎ¾Z¦CD5W!pipI75DK"
Takahara U/'9"8½¾gk¨JFS+lÁ&òïs+l]V'Iõ?W S1+PTX iv%ip gMJ¾g¢|Z9?WAPJù"ì»Z¦5"àFÛMJ?uàR0¾gJh£H feasibility ZL«>D7V"¬¡JÙ*9ö=XD5W!
¬~YXYXK"Ê~¾g^(E"Ö®F¥Q>;KFÇ&d\e_ÇHG'IDØû=XAòïs+lJH5FS+lpÁIõ>D"S1+PTX iv%ip gMJ¾g¢|FjêàZÐ?WAP
Jó¹ç2ù"ì»Z}#Ü¦>A!
('")*
0¾gJ informed consent ZÌZE9>A¡I"}íÒæÍC;ËÙ¦pEÖ®F¥®
IDFS+l99=XA³R"æÍz;pEFÇ¼IFS<Ã99=XA³I"F¥6^a$ahfý`f$b&d$cf$b(Ti F¥`!'ZFK@vI(>D"PTX F¥6/_h$bZ¶á?

W!
õÑJéúHULIÍÈKAI¿?T6I"×ÉàpJëÕQ>;K²N)Øû94UX"òïIs+l9W5<FZ CT"PET"F¥6·ITV9>4AÊ~¾g^(JpFS+lÁZõÑF>A!
*ãn{ø

{ §¯

12

Zh7}

J,BU S1+PTX iv'ip ydK+Áú=-!&Â©

3 1.)+%02#'&$-(*,&"#$/*$äISMJ»e4JêÕó Gì/@VU
0*ç·Z²¢¨·JEZhMÌQZðPA=Lüâ»eìuó<ì/@VU
1*!ydXÎ>E9I9"PA=L<0s§jiF8T"Æy¾­JlS;IÍKí³QÑ
?IpÃßXHOE9I9
2*ÖÆyÉ3*PS)ECOG \|*<.(/KÉ
4*Êt()µñ$$ï$N:*KK<cÄ@VE9UÉ)8!/2B{@*tO¦ò%1"
3..'mm1{á"/0"...'mm1jiu¯1ò%0"...'mm1{áv¦å#z%6#.g'dL {áw¦ÛRò%/.."...'mm1{áx'kmnkr%0#.mg'dL {-_¹ó J,BU« ÓXÎ>E9UÉL1#.mg'dL {y AST :RM ALT 0%/3.U'L {z^oZeir%ÁúÔ0á¬{
5*¥®ùË<KIÞ}
6*fÂ©KS©ÉGIU?GXfîRT]ØJE=|<>SVE9UÉ
7*0.º{á6.ºjiKôJÉFfÂ©K=|X>UKJÐ\IQ/{<8U%!#$/*v%{K)×)mrjû{Kmrjû""N"¡h"L"ñh"µIH*7}É
0*ªP%<øÚKF8U"ZðQüâ»eìuóÉ
1*S1 NDLj^md]cnK9q£É)¸éK6W]Ø¼Ý*
2*lS;Iý"ÞXpBUÞ})16#.,{áKPIXHOUÉIH*
3*Ñ?I)DyXTtGBU*èÇNDL"CK~XpBUÉ
4*Ñ?I)DyXTtGBU*´^Þ)3g"3_¹"ÈóNNDLNþ~Þ"_rfp&n<¶AI;EU"ïV""±`IH*XpBUÉ
5*+zK)ÞãKDOKgoh&aXTtGBU*Zð2xÉ
6*¤TaAo¦XtBUÜéÿÒ¦XHOUÉ
7*w)/B2{áNDLðrb*K8UÉ/.*°õënFÆy1NDLÆyXtBUGÀWVUõëàXpBUÉ//*8ÅJ=Å<óKÑ[XpBUÉ/0*GXNDLÏCX:RMGæKKó)|À*K8UÙó
/1*CK*"Â©÷F)\.*¿<fÂ©K,ßGAEV5øGQ/ADÉ/2*ln`f`r"l\if[r"qnlYmrX½sAE9UÞ}Æy¾­0/BX/_&bGA"S1LÔz)6.mg'm0*X/2B@YA"5BnBU!PTX L-/"6BmJ3.mg'm0
X¥ök9q"0.mg'm0XZ²@9qBU!

/ S1"PTX iv!ip 4786%56

; ` ß  N 6 W R"MàDX8M"ßÖ½.-i_-b%dKC"S1 O

13

ë

'4,mg&m.(_-0ifzC"3i£D[!PTX OG-"4iM1,mg&m._°,]".,mg&m._{Åf]D[!-èN£
N½"]Ö"Ã"£"LÙë_ìåCIb%d_±@D[!

_¢ò¶¥O"+wF¡txLYPMÔØ0N¢ò¶¥üÎtxJNók_cI$Æ
CI7[!
ät

ÇO-l*A"yÞWtþzYJtÇOÂç¨¿'>{ CT MX[9¿"{#${Å3ùÑ("õú§¿'{#é»"O~Ïé»"/ïS("q8("8*A¡KCG!
_¶¥NclhjcaeO"½êNAK>ÕéCG!~Yu_D[©ãN-l*A_.1+"
hkgb%jßNF\_01+K:UCG÷É"×%|w_UCGifjJ?n*,#,1"o*,#."Z¦¡.l"Ó¡-lKD[ø´Jsõ¤%_¤T[K".0KLZ"vX$ï¤_ÄCI/,KCG!_¶¥OG!<Ú¸KCI"Á\Fô"bFô|!"áÜ\F"¢F"®ËuyI©"V¦F"^¦wFô$ðÜ|"^¦F

"^¦Fôf"^FF©uy"^FI©"¼Fô

!"iwF"+wFKNBØ0§`Ú¸_ÆHI7[!
#$.,-.l-.³XZZ¦_ÖC".,-1l-³QJ//NZ¦_CG!l¥25'0.)35(Ð"î(-5"©Cqx.2¤"¹o;N/ï(tO«í!Æ/ïvm-5"/ïm¨--"/ïm/"{næ..J6HG!ç¨¯LK/4#
1'..)-,1(mm"ßÖÝ CA19)9 308'-).141,(IU/L J6HG!
»ÒÚ¸NQ.¡KLHI7[!¶¥²O.,-2l[MÊUJ6[!
"!

6YW[çM:7I"{næV({#_D[ãO"FN¢òWdNKCI"{#M"{R"ûvý"|S"8ÿúEv_kT"

N±@;ÌgLGT½O­TIvJ6[!©

M:7IOFN*A¡LKO2)3èKÊB\I7[.(0(!@NX8LãJO"DJM=ö·({#VBo{²1_kTI:Z"B>N÷É"þJÝMDJMp}âM6[!^\^\O"r6X
Z=ö«í!Æ©ã50MDCIüÎ{ÅªµÎ-(3(_ajC"FN1/+NãJrð~Yu;
þJB\G@K_ÊCG!8CN0,+;{YuHe'{næUC>O{#V{Å3ùÑþ((
J6HG!rð~YuxsM*A¬5_pCGK@]"{YuãO-lrfN{#é»;È>"N±@¡VhÞNØÆ;S>"ßÖ½-l*AOSJ6HG@K_

ÊCI<G!@NX8L{Yu©Nß)-_7D[GTM"{nævM:7ILß¿
_àCG S1+PTX iv&ip _ajCG!{ÅfTÝNP7 PTX N{Åf]MXZ"{Y

1(

uNu'_&¾D[@K"S1+PTX °,]MX[¹o;V4Ò(Yu_&¾D[@K_WM
S1+PTX iv&ip }

MD[BØ0§`G!<Ú¸_ÆHG!

»ÒQJ_J_ß_ÆHG-5Nß)-O"ß±@¡LKO-,m³',#
4).-#
4("9¿
O03+"{Å3ùÑþzY45+J6HG!ßÖ½-lrfN{#é»O.2+MD=E"2
M conversion surgery ;ØÆB\G!FN*A¡LKO-4#
2m³K­TIÀJ6HG4(!@\Y
N)-O"Ishigami Y1(N{nævMDD[ S1+PTX iv&ip *A34+"9¿12+"{#

N phase ! study M:?["-lºñ2.+"{#ÑþzY42+"ÍßWv/ï15+M£ÛD[²KÄ9Y\[!
{Yu©O"=ö/ïm©N1+5("=ö«í!Æ©N0,+_2TI:Z-("©Nlîøßb/yJÍAT S1)PTX iv&ip (õKÌÃæÒ!Ç¡

14

w-u¤¼X.."+++¹HATH.("ËÈzßbKI6îøßbu¤L9QB/".++ûJãÓAT=HHI
S"ú

@èI6u¤¼H8RUT!÷´}£(JQS"îøßb/yu¤JéØÝI»ì®²G5T£(Ü½îºª':Úh@"£(É|w:eÙ@"¥.©¬J conversion surgery :WUT=HJQS"¾Ê|wKeÙ:|Î?UT!
! $ # "«l£("ÛG"ËÈzgqßbKI6îøßb/yu¤JÍ@F"S1)PTX iv&ip ð$(õKËÃæÒ!Ç¡XDF6T!áo£(L"Æ·ir(õ:kÝJîøJãÓ@I6:"ÞÂI£(õ:I6/yîøßb/yu¤K´}£(õKmëKCPJ¨%IHIS7TG5V7!"÷kJ{E6F"Ä¸c(µÀX6"óÞ$nG5T/yu¤NK PTX ¿K$IRM
Jîêà#Kó¦KçXÔTCPJ"?RJÑ}ý)­¡X7"ÛG5T!
'&÷JÌÑIT>fX¢SO@C:Y§rÝ£(ÖKxpaJ³QS*µ@°<OA!
(

%

ï
,(Satoi S, Yanagimoto H, Yamamoto T, et al : A clinical role of staging laparoscopy in patients withradiographically defined locally advanced pancreatic cancer. Hepatogastroenterology. 2014 in press.
-(Thomassen I, Lemmens VE, Nienhuijs SW, et al : Incidence, prognosis, and possible treatment
strategies of peritoneal carcinomatosis of pancreatic origin : a populationbased study. Pancreas
42%2-*0"-+,.
.(¹åÏâ '¾+ä¯Ñ¶töâ±ôíò(. Matsuda A, Matsuda T, Shibata A, et al : Cancer

Incidence and Incidence Rates in Japan in 2008 : A Study of 25 Populationbased Cancer Registries for the Monitoring of Cancer Incidence in Japan'MCIJ(Project. Japanese Journal of ClinicalOncology 44%33*.41"2013/(Takahara N, Isayama H, Nakai Y, et al : Pancreatic cancer with malignant ascites. Pancreas 44%.3+*.30"-+,0#0(Ishigami H, Kitayama J, Kaisaki S, et al : Phase II study of weekly intravenous and intraperitoneal
paclitaxel combined with S1 for advanced gastric cancer with peritoneal metastasis. Ann Oncol
21%12*2+"-+,+#
1(Takahara N, Isayama H, Nakai Y, et al : Intravenous and Intraperitoneal Paclitaxel with S1 for
Refractory Pancreatic Cancer with Malignant Ascites : an Interim Analysis J Gastrointest Cancer
45%.+2*.,,"-+,/#
2(&d,ñ"ÿ÷Ðü"÷×~"Ë : Å½îøßbX!AT/yu¤JÍAT S1)^[_]Z\`Áù$îêð$(õvÕ/ 71%00*1,"-+,0.

3(&d,ñ"ÿ÷Ðü"÷×~"Ë : Å½îøßb/y£(J9;T conversion surgery Kþs)­nj-+,0 in press.
4(Satoi S, Yamamoto H, Toyokawa H, et al : Selective Use of staging laparoscopy based on Carbohydrate Antigen 199 level and tumor size in patients with radiographically defined potentially orborderline resectable pancreatic cancer. Pancreas 40%/-1*/.-"-+,,#

@ d º P S : \ W

153598.@(%1!>1$1,0)='+7; TS1#CDDP AD-/B6:EC*?&"!<42,Þº.

&% J¦4Q3'ð2sRïEÃäy>¼ãP@)CRT*c¡"ñ9'"è¹£c»·"DVTñ9èRM
;N=°F`!Ð³6¬O T4a"CY0"P0 c )EJ3'ð2sS5T@ïË!RT T1Gy'day x 1/)¡3/
Gy*!8MyP@T TS1+CDDP O:`!Level 0 : TS1 60 mg'm1, day 0,03¨ÿK!Level 1 : TS1 80 mg'm1,
day 114. Level 2 : TS1 80 mg'm1 c day 114, day2235. CDDP T60mg'm1 c Level 0, 1 : day 1"Level 2 : day 1,
day 22 RÝE&ÿK!Level 1 OTMR×%Ø%DLT Â¤HG"Level 2 O2TS DLT @Â¤EJJY"ÕÉMR%RD
c level 1 PEJ!åTRsåûÃ D2 @·­"0TRA¯4åc)YJ@:ìüRºHEJ!¤¶"ñ"è¹£c

ëõ

O:`!

# ! $ "
1//7*"sTåÖO1/FR¸C@í;O:_"åÖO626"///Ô@sO¸CEN;`0*!(D$±$õ±cX!eieOÖS5/-Ss@-ÜEN>_"IS¯TôØO0//"///Ôõ17#0
Ô"ÇØO0//"///Ôõ02#/ÔO:`!sT(DÔ@WE[F;O:`@"*(D±&R>C`sR]`*UöÚ¸COTôÇPZRùx©R:`!DBOTÒó$¢Ò@-òEN>_"tPÃSÓ;@KEN;`ZSP«=^aN;`!
ºPÙà@©ÌEN;`sSõOZ"®ýÓ­sSJ¦T4QO:`!vþ^TsSJ¦c'
ü7SO¢"E"4*ÜìOT/&8/#
2-"0&42#
7-"1&33#
2-"2&3/#
3-O:`@"3
T7#
4-PYNùBJ¦@µZ4QO:`P=°EN;`1*!VJ2sSJ¦Tø@ðABQ
`RMaN4QPQ_"3NæÎü¿X@3(7cm O4*ÜìO@26#/-"7(01cm O1/#
2-"01
cm c÷=`P/-O:LJ2*!$LR"Roviello ^T´-O@3(7cm SÍ¯T50-"7cm pÌSÍ¯T71-P"¿XhfjP´-PSc=°EN;`3*!
s@dgfkmfoñ2.R]`P9Ñòý T2 pÌSáÈ{+sRïF`2ÄüQºP?@Tú¾Ã+Ã¦ TS1 R]`<ÆyP@O:`!E?EÌS]<R3s[¿X@7cm pÌSð2sSð57@êF` Stage @ÓdKÊTOT"ú¾Ã+Ã¦ TS1 R]`<ÆyP@R]L
NZJ^Da`wT¥úDa`!pä]_"J¦4QQ3s[¿X@7cm pÌSð2sSºPÙàc©ÌDH`½_æW@­baN;`!
sSºHT R0 ¾Ã)3çSåáÈ*còÙEQ;¥_4{+O:`JY"~@±OTð2s@d[3s@dRïENZßüRð¾Ã@¹W^aNAJ!Furukawa ^T3sRïE"sc½_qXFUNSécáÈF`²Ì65&éåûÃ[[î15áÈPZéc¯8áÈF` Appleby ¾
Ã+ð#EÀqSnolâÛc·­E"Stage #SÊTRTð¾ÃSIMØT)Y^aQ;@"
Stage !SÊTS4*ÜìO@34-P Historical control P0ENIrRQªO:LJP"3sRïF`ÅP@SI§Øc=°EN;`4*!E?E}ðÏÁRz=[î15Zc¯8áÈF`JY"[uYS-Ü@G2/-R)Y^aJ!
.ðt5 |

5©!6©4©V4Kcá) TS1.CDDP \r CRT W7;(".Ó³

16[O#§KGW`>UÆPW¾²¨V4IQX#á)Vß[UwcfÑ½KcGSRáµÆPuW´

SUcUç?WáµW¡­U0ófeELÿBÖÄHdQ@b7+#k¸W@Aa^o¸S»?adQ=c"[OVâ=ÕwR<cÚáµW_åwcX#Úá¿\êB"JOï¿UTVXÑ
½RCU=ï¿<c"NW@#á)W_åwcX compliance W@Aa^¸B5RCc"%æYLù½ÆPBgV4KcVâ=UymtzR<c TS1V CDDP f\rIOymtzWá)_åwcSIQW|*ÿfJKcÓ³B#ÃÕ%æLU6©4©S5©f4ìSIQÑ
½HdO*JCOG 0210+"Fujitani aXqvhsw'izprhzoR<cÕwûuX84/#MST1.44
K#4K"3uX37/S`ÀIQ=c8+"[OGW®fÜFQ#,Úá.áµ_åwc¨-S,TS1+
CDDP fr=Oá)wc.Úá.áµ_åwc¨-fSKc7!.zèÓ³B JCOG 0501SIQ
×ÑHdQ=c"Vê|Þ#XÝvIQ@b#®WPWB5Odc"
b#^ÁRXºÛ¸SS^V radiosensitizer SIQW¸f5IQ#aØ(wcVwc
f+\¿eMOzèÓ³B`ÀHdQ=c"Ajani aX5FU(LV(CDDP05FU+45Gy radiation Ñ½µV
ÃÕ%æf½=#Clinical response 93/#Pathological CR 41$
4/#Pathological PR 35$
3/S¾=o¸ÿf`ÀIQ=c9+"P[baØ(wcX¦äþ¶fmÐIOÕwSIQ¾=o¸ÿfÖIQ=c"
IfRWwcVÎrKcnËSIQQrHdQ=c TS1 BoKcjtvlxVaØ(0£ÌrBÖHdQ=c:+"[O CDDP V^aØ(0£ÌrB9adQ=c"È&aX%æYLù½V
4IQ TS1+low dose CDDP VaØ(éØf\rKcGSV`b#TðVx¹UÕw!$BEadOG
SB`ÀIQ=c21+"[Oá)wcSIQ S1+CDDP fr=OzèÓ³WXt=*,·*pCR+uX JCOG 0210Ó³RX3/*2(61+8+R<cWV4IQ#S1+CDDP VaØ(f?OzèÓ³W pCR
uX24*5(3:+)25*2(8+/R<c21+22+"GWqVV4KcaØ(wcW pCR rate XTðV¾
D#¦äwcSIQW¸B5Hdc"P[b TS1+CDDP+Radiation \rwcfyV@=Q^zèR±CKc~

X<cS»?adc"}îWM«`bpµYxSHdc5©(6©4©f4ìSIQ#aØ(wcfÑ½KczèÓ
³f¬IO"ymtzf]aWá) TS1+CDDP \raØ(wcnkmu'xfr=#yV@Fcá)aØ(wcW|*ÿSo¸ÿVP=Q±CKcGSSIO""!

>ê|X}WKZQWñ°fhOK^WSIQ=c"2+FÒ¥"±VQ#*+ô©[{WR©W=LdA+BëlHdQ=c"3+H©[{VQ#4©[OX5©"U@#H©[{B4©Wï¿#FÒ¥^IDX CT R2<IOÛWÇ6ªB9cm }îR<c"4+A~)W/±Å_Z¼¥±ÅVQZg?BUD#APZ¼¥±ÅÔWZg'òÊdøRWBgÊ
dfJ]U="
5+ÃÕ%æ*R0+LS»?adc"
6+A~)W/ø8R#õD÷ãB2cm }#ßGÐ;YW÷ãfJ]U="
7+A~ÔWK}B31É}î#86ÉihR<c"8+Performance Status*ECOG+&0#1"
9+wc%aØ(wcWBjD#V4IQ%WÚáwcWBj=":+WÙX-AaWlaAUà¯_;W:lU¤ÍBU="21+Ùs1*Âü#ö#N##úUT+V¾BUíBUD#ÕwÏÔWzè±ÅB}WâfhOIQ=c{O¯¢ý&5#
111(mm4 }îAP23#
111(mm4 ih

; ] · = M 5 U R

17t¥ëÓ%-"+++'mm. {ËuÇþÓ%,++"+++'mm. {Ëvjl`rhs%4#+g'dL {Ëw AST(GOT)$ALT(GPT)%,++IU'L {xáhophs%-#+mg'dL {y_q^egs_o^nsd%1+mL'min {Ë,,)¿%J¤Ù»;ûH5Y!
,-)*³ñBÜK³÷7M¿%JÚ,;§[ZE¢"¹*Ï:W&ÅKVYô};õWZG6Y!
,.)$¦¬µKË$#KªòM2ê\ùSJ6!
9:*³NÁÜ(¸Û·=*ØÆM?Èè!'"à³I@G@E!
"!.3&)8-2;:,)(¸Û=)M·=N Level 0"1 HN-3ø"Level 2 HN.0øIAY!
-)TS1N"å!-×K«[Cî?ZEÃó6>\í$5Î¢M,ø-¤ó6AY!
.)Level 0 HN day 1 VX TS1 1+ mg'm- \,/øAä@G¤ó6¢,/ø1AY!
/)Level 1 HN day 1 VX TS1 3+ mg'm- \,/øAä@G¤ó6¢,/ø1AY!
0)Level 2 HN TS1 3+ mg'm- \ day 1 VX,/øAä@G¤ó6¢,¾1"DM¢ day 22:W,/øAä@G¤ó6AY!
1)CDDP N1+mg'm- \ Level 0"1 HN day 1"Level 2 HN day 1"day 22KÖ+÷ó6AY!
2)(¸ÛÉ¸N-#+Gy'day"-+(/¾)M%É¸I@"áÛ>/+Gy IAY!É¸N"0øAäÉ¸@-ø²AYdacm&pH/¾X'A(Ñ,)!
3)­çæ8> maximum tolerated dose(MTD)N(¸Û=)¯:W Level 0"1 HN-3ø"Level
2HN.0øHM4´ÊKVXýéAY!
4)(¸Û=)ëK8>ÔöÕ%Dose Limiting Toxicity(DLT"îN¢Â);ü

@EÌ«KN(¸Û=)\ë²AY!
,+)º9"©.\ÞÍðì£;I@G6Y>I:W"ß£;õWZEÌ«M/¾{¨M confirmationNÿÐHNJ6!
#!('610.
¼ÁNî¼Á($KVY~ÝïÁT@<N3/ã~ØÆ)IAY!(¸Û=)½<¢VX/¾\.ÄKÁÜ"\§7!¼ÁN(¸Û=)½<¢VX/-ø\.z(01ø{÷N7)K±§AYTMIA

Y!DZQHK¼Á;§8J6Ì«KN"irfb&p·=ë²I@"{¢M·=N°MýéK|LY!
$!.+7/&);:~ØÆÁKVX R0 ØÆ;õWZEÌ«"9VP"R1 ØÆHT CY1 {KN®;J6Ì«KN"À
:7Y¡X~ØÆ¢1¾{÷(¼Áø\+øI@GÁ¢/-øQH)K TS1 M¤ó6\¯AY!TS
1 M-3øAäó6I,/øM1\.zK"Á¢0,ú(3b&d%/3¾)ó6AY!
%!5!4,*,)Level 1 VX³\¯@"MTD ;Òî?ZYQH 1 Level BFâ>\§7!
-)ôó6> Level K96G.@\ñBAY!.@ë,@T DLT ;ü

@J=ZO"¶M8>qkp

0q!«q/q^lJ©@R£ TS1)CDDP ÇÏ CRT K¬5&#¥w

18

J/×UµØ@R"/×¯-×C<J DLT :¾z?BJL·_ÏÕ\Y[J6G/×UµØ@
R"K/×¯.×]F DLT :¾z?B#AKÏÕL MTD UfDBGÀ®?E§ÕL
A=F¯@R"/(DLT K²oL]bK±QG@R"!Grade 4 K½upyO?;L}¯py#uÁy:»NPSB
!/3*]K¾¼O?;Lj¡U¿8}¯py:»NPSB
!Grade 3 ]KÂu`¸:»NPSB'ÑÅ#vªjU;(!TS1 K¶Îº&re¶Îº:.&/ËÊF6DB'Level 0#1 FL¶Îº:-,ºËÊ#Level 2 FL-4ºËÊ(!É¢Ô{12º]¹J²NPSB´anUÊB>I7
0(ÏÕ recommended dose'RD(Lx¨G?E MTD K 1 Level bKÏÕG@R:#g Level FKÆÏIHU¦³JÀ®?E RD Us²@R=GG@R"
1(Level 1 JE.&2'//+(]K×J DLT :»NPSBJL#Level 0 KÏÕJE@R"

2(Level 2 J97EO MTD J­?I7L#Level 2 U RD$¶ÎXVWZ%[G?E#AS]
K§ÕU~TI7""!(!'$#¬"¥wFs²?B RD UÏ7EÖwU~8"ÐÄcÌU¤h³°|Ò'Grade 3(G?
B"Í²µØ×L/,×'¬5¥wJE RD JµØ>SBiUkM(G?B"'! &($"#%%&

mJÓ?B¬"¥wKtdUÈ@R"¬"¥wJ2×K×:µØ>SB"µØ×K characteristics UÃ-J@"

7 K p ½ A 3 F C

19

9$ 6!5.,(7>&*'0=) characteristics"/;4#
±

y
¥À
V&n ( n{'\q¼$performance statusg§b®Q
~®
®
X®
¡_c
c-c
.c
c
tub
por
S^tHO4`·&+.ª'°
T4a
MNLR
N0
N1
NX
U[R
M0
Stage
!B
"A

-¿
-¿
00#
/
&.2(1+'
*$0¿
*¿
0¿
*¿
,¿
.¿
,¿
.¿
0¿
,¿
-¿
+¿
0¿
+¿
/¿

/4)'!*1034"%$#-,34
Level 1 =B DLT Bvi:?6<;7"Level 2 =-¿A DLT 7vi:;;D&¬,'"RD J level 1>:;!
9% :<+283!Dose Limiting Toxicity )1º}¿
Level 1&-¿'*¿

Level 2&-¿'*¿-2)P~A§¤E:8B]J¨5kah|7£DGI;m*¿*¿

Grade 3 P~A«eT7£DGI;m&»­"f]Jz8'*¿+¿

TS1 Ar¹¢ %dY¹¢ 7,%-¶µ=3<;m*¿,¿³sp½j/0¢P @DGI;
uwW`xJµ;9?4m*¿+¿

Grade 4 A¦eah|E:8Bkah|"e{©h|7£DGI;m(&2.+
0¿@ D2 MNLZJ¨5Sw7ol9I;!+¿@ ClavienDindo ¯¾ grade 2 A´m­
J£D;7²@p¸:;!

/i!i.iReG?N TS1)CDDP ¦° CRT H5&#~p

20

'

%

"~pHn[ level 1'TS1%day 1KM TS1 3+mg&m-P,/¢c´>Bjs¯r,/¢cg¬"
CDDP I1+mg&m- P day 1#Level 2 CI day 1 G«¡¯"¨I 2.0Gy&day#-+^'/(H¥a%³/+Gy(P RD Dm>@"W`¨²rG}u>@Hv¦JlC#Q
F~p²k<Y£Dt9LO@"! $ # "
qw#!~pPkC6N"(&,(Eisenhauer EA, Therasse P, Bogaerts J, et al : New response evaluation criteria in solid tumours :revised RECIST guideline'version 1.1(Eur J Cancer 45%--3#-++4$-(VS­%RebH®rT|*§³]GKNo*¢ªWf_Z`\y 30%2++#,442$.(x|z±#d{hS%ReG:=NW`²©PE8¤X?N;*UHDpHGA
7B*$Wf_Z15%,04#,44-$/(Roviello F, Marrelli D, et al : Prospective study of peritoneal recurrence after curative surgery for
gastric cancer. Br J Surg 90%,,,.#-++.$
0(Furukawa H, Hiratsuka M, Iwanaga T, et al : Extended surgeryleft upper abdominal exenteration plus Applebys methodfor type 4 gastric carcinoma. Ann Surg Oncol 4%209#,442$
1(Fisher B, Saffer E, Rudock C, et al : Effect of local or systemic treatment prior to primary tumor
removal on the production and response to a serum growthstimulating factor in mice. Cancer Res
49%-++-#,434$2(Fujitani. K, Sasako. M, Iwasaki. Y, et al : A phase ! study of preoperative chemotherapy'CX(withS1 and cisplatin followed by gastrectomy for clinically resectable type 4 and large type 3 gastriccancer : JCOG 0210. . J Clin Oncol 25%/1+4#-++2$3(Ajani JA, Mansfield PF, Janjan N, et al : Multiinstitutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma. J Clin Oncol 22%-22/#-++/$
4(Nakata E, Fukushima M, Takai Y, et al : S1, an oral fluoropyrimidine, enhances radiation responseof DLD1&FU human colon cancer xenografts resistant to 5FU. Oncol Rep 16%/10#-++1$,+(Saikawa Y, Kubota T, Kumagai K, et al : Phase ! study of chemoradiotherapy with S1 and lowdose cisplatin for inoperable advanced gastric cancer. Int J Radiat Oncol Biol Phys 71'1(%,2.#-++3$,,(Takahashi T, Saikawa Y, Takaishi H, et al : Phase I study of neoadjuvant chemoradiotherapy consisting of S1 and cisplatin for patients with resectable advanced gastric cancer'KOGC01(. Anticancer Res 31%.+24#-+,,$

< e Ö d R 6 ] Y

21

HER2 <12.860+,7()%4$'S1#Oxaliplatin#Trastuzumab!SOX#Tmab"
9;=:&5!3>/-*Å("c,&% HER2 bóªæhdþèMBK"S1+Oxaliplatin+Trastuzumab K`dOdÐÃB"FRùó:^TZ¾ó
REdÃ8#"ûgãÓ»d¶BG!þèS"ü*?FLdZDa/-Éê42ÉTS"PS <-XGS.L HER 2ë@½d=ZaöàG?XGSÈ@Røªæh!S1 S"80120mg&day d day1 R[;_ day15 R)XL.;/
µ¿4^Da!Oxaliplatin S.0-mg&m/ d"Trastuzumab Sß4^ÕP5mg&kg d"/WÄS3mg&kg d7Eb
[ day1 P0-õ'Da!/.;d.m%qMBK"&Ñ­ÞR7Eb;P¢5DaXL4^d³`MD!Primary endpoint
Sú¾¦Æ"\*2jæhòS42hMBG!A_PHñº±P^` HER2 bóªR¾\üÏd¹6\*L6a!/-.2>3¸/1;^`

Î"/-.2>..¸0-;½Ì"/2h<2jAbK7a!QÓ»S HER2 bóªP:7K[tyôËSCisplatin ;_ Oxaliplatin Vo}w?;"Oxaliplatin RÒ/`fS.--mg&m &0ÜM.0-mg&m &0ÜR7EbL6a;"//

M78UGJRlzilgqtd¹6DaP6G`ÝaO¯dÔIK7aMÂ9a!

# ! $ "HER2 bóRîÃ#È@<e§ØdþèMBKB¤¹6dÃIGÇÊ²7##ûgãÓ»'ToGA Ó»(.(R·"Trastuzumab'w

qvr~"{%st!$ Tmab(SªP:7KßZKU¾R£=AbGJÏD.ÖdXL6`"/-..>0¸PªP:?a/dÙ8"@R·dÚ?K/-.1>P,AbGªÖdjfx

f'/-.1>2¸, #1A(/(P:7KS"HER2 bóªP:7K

S}u|p´ÁªË'Capecitabine XGSõ'5FU(M CDDP P Tmab dK`DaÖd<ðáAbK7a!XG"Ç:LK`¥dOP S1+CDDP'0ÜRp(d`7G#"ûÓ»L6a
HERBIS1 Ó»0("A_P S1+CDDP'2ÜRp(P Tmab dK`BG WJOG7212G Ó»1(L[eÀO·<8_b"S1+CDDP P Tmab dK`DaÖd[7+3RÖd¾<8_ba@M<×AbG!
7EbRpP[©Xba CDDP Sª¥dOP:?a key drug L6a<"IÍ`MBKïé
¡\í#k1ON<6`"WMeNRìÆNRGZP$¬<d]®O>Ab"§ØR QOL dýQ
a¼MOIK7a!@RGZ7Cty´Lïé¡\å«9óRâO><<GaL6ahkn

t'LOHP(VR%=¨9<¹6AbK7a!QPP:7KÃcbG GSOX Ó»2(P:7KS"

÷HIKÛLÃcbG REAL2 Ó»3(M7_P LOHP R CDDP PþDaCió<¹çAb"/-.2>
0¸P LOHP R)ÖYöàG?OîÃ#È@ª*R¾?#¾°T`O#`f<ä=AbG!@bP^` S1+Oxaliplatin'SOX(dOS S1+CDDP dOR!ÿMO`8a@MMOIG<"HER2 bóªæhLR SOX dORESTHOAbK7O7!

,<eº±ZVF å«:HER2NæTùH_ SOX,Tmab =LPBUû!ó»¨

22/)('$&%"!.HER2 NæéÐ:3Þ¯´5ÔRaùÕRGP"SOX+Tmab =LPBaº¯G"KUïæ@\WH¬æU7a¯>!
Primary endpoint%ñ¬°(Response Rate%RR)

Secondary endpoints%Fôç÷(Progression free survival%PFS)"ïç÷(Overall survival%OS)"
ïæ(H¼ÕU5Ô9)$$))=JP"þ¸%¦*RGP"Tmab U¾P¬Jö¹TN=P¦*H_!
#!,+*0"!&#$%
3)ðÚ%TíQ<_ERB1F`P=_éÐ:3YLV´5UÔR!S@"Û-ê°;A]Ö4cm /TÈU!Ü;B<_Û-ê°;aKH_!

4)øUBbÇTùH_¾P[ZPPB"AÃìPB"AÃìPB"@\WmrntPBU=
I`U[S=!LMG"S1 ý·T\_Ì«@ÏPBaÉDL´5QÌ«@ÏPBµÊ¾P0\^´510YQUB8v¥a"?P=_[UVRH_!lpijè·=LRV:!
5)RECISTversion1.1 TOCÒSCR[NÖUö#38>aHH_!
6)©5òYLV&òT@=P HER2 ×5ª(IHC 3,"YLV IHC 2,AN ISH*FISH B[GCV DISH B+Næ)B1Z]`P=_ÔR!
7)(T0U2SB42¶Ö97¶EDUÔR!
8)ECOG Performance status(PS)B2YLV3UÔR!
9)ÔÙaHH_!åÝ£¢U&aHFS=!
:)T¿HÅMõ(±ã""à)3B?½F`P=_ÔR!(T360/U¦³ÿTPU
HXPaDLHÔR!
w4¤ä/5"
222'mm5x®!ä/3"
722'mm5y¤Ñ6ä/32-326'mm5z AST.322IU'l{ ALT.322IU'l| T.Bil.3#
7mg'dl} Cr.3#
4mg'dl~fsciktfqcpth/82ml'min1Âöÿ<_=V CockcroftGault Uâ#À;)(Tî4:0/TÜdg&[GCV MUGA heota¯=²Á¡ËO(LVEF%Left
Ejection Fraction)B720ÖQ<_!
32)(Tî4:0/U34I,Ü'áQ"QÓ%TGüRS_
33)£­ëÆ3!
34)(T0\^5u¥ÖUç÷BúF`_ÔR!
35)ÄCßA]U<ÎT\_+B.]`P=_ÔR!

ØÍ§BS=ÔR!

Ventricular: Z · J L 5 R O

23"!&#$%,(S1"LOHP"Tmab LóDG5VËN'°ÓLï+0Æ³Ê(!
-(ý,5V6MýÑ>F6V#ØL5VÇØ!k%fh%LýÑY8?VæØ!
.(÷ØLÝËYB?VËN'%ÿ.3*xÍ(!
/(HBs ª¦GØLËN!
0(xLS7JÒ¹YB?V"5V6MÏãK5VËN!
!7E¤ØÒ*ßLO!j\pd`Jaufs%q*#L*Ù>!ªÒËAY'FH?VÒË!Ò«±LO:5V!MÈÍÀäJÒà6:Ë
!ÒñÖÍ"2Ø«±L¡Ü:þPTWV
!aufs%q*¿/J­¤v'N$½Á¤v),3+mmHg ;Mé¤v),++mmHg"CD>­¤vG5V:"A.J7KSEF¿/KH=WF6V»MîH?V(
1(ÀøJ®1ËL5VËN'ºØ$~;M$Þ{Ë"Ò*ß"Õ*ß"*ß"aufs%q*KLöü)JI(!
2(wÚ¶§¯ú'$ðz"Ã¹õKSV(L5VËN!
3(|Q>;MÉëP9TL÷ØLÂ¤L5VËN!
4(I',û/xÍNCM×E5(L5VËN!

,+(#ÌY&7ÀòLyÎ;Mç*ßL5VËN!
,,(÷ØÀ-:ZYB?VËN'?):0!=<LÀ-:ZB?V!CD>"":ùL)3M
÷ØÀ-:ZHM>J6(!
,-(lqbfbu"l^if\uNCMtql[pu_p]nL£áíJóD:'FJËN!
,.(des\g²L£áíJßÔóDY¼<F6VËN!
,/(åô}:9µ¥L³K*îôH¬8VËN!
"!'(%#$&·JrcouYÖ,K¸?!-,û'.¾(Y,a%dH>F"msfa%q·JLè´ÄL6@W9
Kô?VNGóDY

U4?!

'! &($"#%

S1 M"â(@ÛK®XAFxL(,K¸? S1 LÅÄóDLGì=WCóDL'3+mg&

day",++mg&day",-+mg&day(YóD?V!day 1 LCÐ¨9T day 15 LêÐ¨NG,ûÐ¨(¢©óD>"BL¨2ûA?V!

'ê#C

HER2;ÊoKÞCV SOX*Tmab &8?*Lá!Ø¬

24+! S1#(%*,-

Ýý2Î

/8@

/õ8@

/#
03m0./#
03m0'/#
3m0.0
/#
3m m¾

2.mg
3.mg
4.mg

6.mg
/..mg
/0.mg

Tmab M¸ï6­K 6mg&kg(Ýµ)X"03m

M 4mg&kg(Ýµ)X"LOHP M/1.mg&m0

XDWEW day 1 KìéÍ/åCV!
ë"Éí¤IBG NK1 ³7ÝE¤"5HT3 ³7ÝE¤"æ§8$Äù°]`i[aðXÎêK&8CV!
#!=;4>8&3.*)"1(29ToGA ¬L}<T"Capecitabine*CDDP(XP)*Tmab ?*?*K;?Võ+Ã subset L×
¡M42#
2-HDL73-CI wM27-H8V@I"HERBIS1 ¬K;?V S1*CDDP(1´,h\ej)*Tmab &8?*;SN WJOG7212G ¬K;?V S1*CDDP(3´,h\ej)*Tmab &8?
*L×¡=46-(73-CI$32+6.-)"41#
4-(73-CI$26+56-)H8V@IXòP:"SOX*Tmab&8?*LGâ×¡X3.-"ß×¡X43-H8VIyèCV!5nÆ· α,.#/LRIH)ø
<LèHþzCVI>((ÚÞ=yÒ)"¶A/+k=.#
7m¾KJVû:£ºú±ÈM5/CH8V!
DLFQ"!ëCX>BG3ü½CÈX53CIBF!
¬

MîD

$0ö

"çÏ

$0ö

L2ö

IB"ý0K¯C¢ô/.«Ñ=¨{CVÜ«Ñó¬H8V!
+" &$')"!#$=Y~50ÿrà¦p|à

¼xô|x?*^j_%Ó9=Y^j_%B»¬ÅÂ#lã=Y^j_%äuÿr©¢=Y^j_%

4%?*#

¼xô|

¢==Y^j_%äuÿrÍv=Ív=Y^j_%Ív=Ù¡ÿr

¼xô|

²Fô|

ÌdfZjbp|àq¿=äuÿr

¼xô|

²Fô|

¼xô|

$!/0'6:5,+¬M0./3ö402õSUªAW"0./3ö//1.õ¥"03C=îDAWG9V!
%!<7-+"ÇKónBF½CK;9G"HE ÔÁ"HER2 ÔÁXDWEW9ÖÀ'L®?}"PFÐ
¹ü+K;9GM²FôL HER2 heterogeneity =®?}KOCsXDWEWñCV!PF HER
3"PTEN L÷X1tÔÁKGþzB"Ë HER2 hcgX®?ªÕKÛèB®?}ILXþ

> k Ñ W V 8 b ^25

Gf!EdUØ^ûê<cYú²=dJgKg DNA j)ÞF"PCR <cYulqxr'qmt
j½9 PIK3CA exon9"20V"ÃKF<cY FcÙQ"V0Ì!¯RÑW»UO9PaJgKg
³4Gf!
'

%

MZåÐµW LOHP j£_sU#Gf Tmab DSVO»ò"úòj³4Gfá`PVÐµ
Q8f!MÐµU<9P SOX+Tmab DSWJ>@ßÑWQ8f XP+Tmab WJR5-3V»$ú
ò>7dgfCR>ÒÁEggX"HER2 òç[5R"HER2 Uòç[U<9Pa Key Drug Q8fvzöÅV CDDP =d LOHP ZVr~x>ù%=RTe"NV;ÑW>BTUTfTSÔZ
åU¨\Gl|qxWäE@T9!
]L"LOHP V¾8æ<SXW REAL2 ÐµV±jÙAP"/1.mg(m0(1ÛQ8f>"G,SOX
ÐµU<9PW/..mg(m0(1ÛjËSXRFPÔÎEgLL`"ÔÄVZåÊSU8LNPW"/..mg(m0(1ÛQËGfCR>:M¤

ce/ôÊSéH5*RFPïãEgP<e"SOX WJU<AfLOHP VSXRFP/..mg(m0(1ÛR/1.mg(m0(1ÛV9Hg>/÷=W±]>ÞP<dH"LOHP/1.mg(m0(1ÛVAWZåÐµQ<Egf[?REgP9f!CVL`"MÐµQW LOHP /1.mg(m0(1ÛjÂSFL!CgUce SOX WJU<Af LOHP VÏ/SXV§]>=UTfQ8h:!
EdUCñ´©RFPûê¯EVÑW»"Ø^8V HER2
]L HER3"PTEN V>·$²õ HER2 heterogeneity >ÑW»U¨\G¬"$PIK3CA exon9"20V"ÃKF<cY FcÙQ"V0Ì!¯RÑW»UO9PaJgKg³4GfCRRFP<e"ÑW»jPþGf{ln'o'¹Gj'ÈGfP,Q8f!
! $ # "HER2 Uò¤ç[Wú"V0.-R!@T@"ZåÐµVð½W&ÎøQWÀ9Q!Îøª5Q½:CR>ÝTQ8f!MÐµW!@VÉÎøV«YVaR"·Æ]Qà*U1\>TEgP9f!{ln'o'´©aDIP½9"°FP&Tf$!ýÐµQÚidH"plylU+¥Egfc:T±j6?ÞFL9R¼;P9f!EdUML=d¤WJVëLTm}wtjüÞQ?fc:¿¸Ra2YjÿAP9?L9!
)(

M´©V¦jDV9LM?´©âójDÍ9LM?]FLºÇ(Jî>kÜ.ÑW´©Ç

(V¢®ÖVI&Uì×íFèB]G!
*&/*Bang YJ, Van Cutsem E, Feyereislova A, et al : Trastuzumab in combination with chemotherapy
versus chemotherapy alone for treatment of HER2positive advanced gastric or gastrooesophageal junction cancer)ToGA*: a phase 3, openlabel, randomised controlled trial. Lancet 376%465,
75"0./..
0*:M¤

%¤ÑWplyl $2? ­¶Þ?¡ÓÕ"0./2#

1*Kurokawa Y, Sugimoto N, Miwa H, et al : Phase ! study of trastuzumab in combination with S1plus cisplatin in HER2positive gastric cancer)HERBIS1*. Br J Cancer. 110)3*%//41,46"0./2#
2*Miura Y, Takano T, Sukawa Y, et al. : A phase ! trial of 5weekly S1 plus cisplatin)CDDP*combination with trastuzumab)Tmab*for HER2positive advanced gastric or esophagogastric junction

26

HER2kXGL<\5> SOX(Tmab fjmg=]"[SM&EGJ'cancer : WJOG7212G&TSPACE'study. J Clin Oncol 33$2015&suppl 3%abstr 126'".'Yamada Y, Higuchi K, Nishikawa K, et al. Phase ! study comparing oxaliplatin plus S1 with cisplatin plus S1 in chemotherapynaïve patients with advanced gastric cancer. Ann Oncol $2014
Oct 14. [Epub ahead of print]/'Cunningham D, Starling N, Rao S, et al : Capecitabine and oxaliplatin for advanced esophagogastriccancer. Ann Oncol . 2015 Jan ; 26&1'$+-+)1"0'bhGLKJ$UiZVec;WN#Pd=GL=`I:@ECDABa_Y^H?4Rj2673
Q=lFTO<829!,*+."http : //www.jgca.jp/pdf/Oxaliplatin201503.pdf

; d ã  Q 5 \ X

27;F<>:A$,8<(D9+6?&*')(=%#2/02."-13!4E5@C(7BXS

´,"Ú

=,,".Ú

É,,,",·=,,,,+& L$Éêa;d¢êP9>`"!@"%>ª_QrO^SPFQNªTQ³c~^:PA"M0O
#T[QuvcCØC`á!uv$ôvcí>`3-ÓþQ!+"©&Èg÷Ôwa;d2-c?üNA"vÛ6Q;dç"l{kUse"IQlQcFÑA"ãÛÂQ>ñ"ößy>ñ"sÈ_"¶
Qrc2"./ïÂPFÑAG!WGFQZÿ+¡T×"ÖZ)"

fP¬VC³cjAG!º$à¾PQâOMd)þ;;dç"l{kUse"IcJA"Â2ï¤XP>ñ"ößy>ñ"sÈ_"¶±P
P¿øAG!;dçQ}R[Z)O^SP fQ;P¥;5IG!º$Éê&Èa;d¢êP96
LR":©]_ý"%>ª_ý;òÀA&ÈAL\=GZ"$D:©:^Q#T[Qh*;äÐ@aG!

$ ! % #
'ÄÉ;&Y;ËQ8*ìQ7Ha;dQÞxRÒ[É="7H3-ÓþQÉê;Þx
Q4c3Z`!uMÆ;dãQ&sP]_Éêa;dQ+<©¤RAnPGAL6`GZ"ÍÂ)a;dN±P+<`Éê*;®;C`NÇ8^a`!%R?aWM"É&Èa;d¢êQùà¾cHB";d$DQâOM¨Pd););dç*N67WëOýcA"3;Ì¶¿øû'l{kwse(cC`ácäAG !FALFQá;"e^Q%>_cNA"P/(Ã!@NO_"+¡Qç'QOL(cI@E`_*;5`NÇ8^a`!A:A";dçcC`&È;dQI!@cHÿQ[M7C`áRÎYN@aL6`!WGQhur|nM5`ig|oz|jPJ6L[[uv;ió@aL6O60(!UP";dçNÌ¶¿øcc7&È;d¢êP?C`T[Qhur|n[µZLøO="RCT Mä@aGióãR<Ö
AO61(!ðIL"&È;dP?C`NTvRî;É6P[::b^D|bQ¼¯o
M5`!
F?M%R"¹EQ)É&Èg÷Ôwa;dP?C`:©#T[Q\*à¾*Q§9NO`r&pcV`GZ"/½/;do|p& IRB Qú]cVL")&Èa;dcC`ÉêP
9>`Zÿ+¡T×Q£Ù¼¯*'UMIN000009768(cèÝAG!
('")*
z¼¯RRÝ1 IRB P96L°cVLèÝAG6Å<£Ù¼¯M5`!ôvcÝÈ

KQ"

PS02"^3-Óþc5B«óNAG!"æ¢"Ì¥2æ¢"#¸æ¢"û!cC``N"-#k
WGR-#û!cÊqAL6`ûRöAG!põUcVLûPA!/-.0^.»:^/-.1^0»
WMP"ÏãL²mté4ãcí>G0-N8%vcí>G0-Q¹2-;PAG!ûP
Â"ôãÛWMQ©¤cv&nyf|'T1(NA"2ïÂ'T2("./ïÂ'T3(M(.Qjc
ÈIG!Zÿ+¡T×R Barthel index c6G!;dçRËÕ$D§óP§K<"Q}{R~,/½/;do|p& Á­¦X
,,U ztuzq&mx|,,,U å,,,,U ù¼¯Üo|p&±=ÄÖ¯$A^ÄRçF[ù$4þ.S%

28

RöF[Î<PEI4)!z5y§~ûR4.~ÏSæÊ«Í"{ BMI-1/kg'm1@M5y§~ûR1.~ÏSæÊ«Í!´¢äðRT"Üæó`xo&kxg*Ý.(TANITA BC118, jmj
ÁÃ"õ)P CT ÝS1È;S-.]3<I!àÄOT,Û¸»¢8]ÕíSüÐOÌEI,Û¸»´¢8ºÙ(ASM index)]·ËE"ý/×S¨ÑÅ!ÄS ASM index S+¡ë2SD ~]fverm_PÔêEI5)!CT RX[´¢Säð-.T"é2³îwqvS¢1ÞS²¥]äðEÕí
S1ÐOÌEI´¢ºÙ(LSMI"cm1'm1)]äðEI6)!âÝRT SYNAPSE VINCENT version
3(FUJIFILM Medical System, Japan)]3<I!4)T4Òè)((Mini Nutrition al Assessment%MNA!)]3<I!Õæ")T"áã shuttle walking test S6(ISWD, m)"}9(5BÇ"kg)]ðòRäðEI!7½¬S53RM<NT"¼ªô>@YS:Þ¶ýÙ":Þ7']ÝEI!nts&j&S&R?C[çS;[©ðRT Wilcoxons signedrank ©ð]3<I!
ÜåÝRT KaplanMeier .QYUR Logrank ©ð]3<I!ø¥iplab_T JMP version 01#/(SAS Institute, USA)]3<I!

+! $0)-"*,'.#/%(&!

"/¼ª@YúY\I¦T"~S4ò"ùò"QYUR7ÃòÚR*;D\[!~G\H\S¦]ñ¿F[!
!&#%$"
Ä#£](0R¿F!!=SìëT65(6/,78)µO;Z"A^|

ÂT240(47#2.)"fve

rm_T270(53#3.)"*ï4+VIT*ï4S?G\+(MNA ))]230(45#6.)RÿWI!
A^|ÂSÔê]ÉCI240S MNA )°2S=K"gcu&mxd°29(2y§S¤®ßÆÒ)S÷O*Ó¾8S«ÍQE+P÷>I-T13<(57#5.)"_hgsxl°2:(4ÒèSÀ­))S÷O*À*Tï4JP¹=+P÷>I-T0/<(17#5.)O;LI!VIØð¤®ßÆ

: W  ë J 6 Q N

29

ÏìK-02,*14.kcal%ÍF6S"Y_cZ$¤ºêK--0*01+F6CB!g­Jo9R"ð°
Ò:WFKêI:Wek:ÎORUB:"ÔRJµìKwÇIP}wÇIPÀ;<©?E

8RA"¼<JekvKjé®¾JemVÎ?E7H7>G:äR9GHCB!Þ~JèKÁ
-4rÍÞØ¾jéuqÐu§£qFÊ²·V="uq{yIÊNF6T!

,! $'+&!&#%$"
ÉñJ Barthel index ×nK¸ï-,,È&àÈ'F6CB!`$[bXdHRLIësJ½¹³]$\G¯½{ÑVÖ.I@!¨Ý½¥"LSMI"ISWD"fíKÌÐ¿JÄiðGÕ?EÅ
ÃF6S"¸EJåKmuëÜßKÛ¶ëJs9R2¢xgËuÇIçhI

©?B!-.¢

x&T3 aXd^'MFI"îªÇIh|J6TÙm&minimal clinically important difference'K ISWD
&0,m g­'ID7EK.3â&1.#
5+'IÎORU"fí&2#,kg g­'ID7EK-/â&-/#
,+'IÎ
ORUB!
MB(:WvI8=T¡ã)VÉñ9Rèp®¾GHT&Barthel Index5,ÈglGHT'M
FJ´»zx&disabilityfree survival'GÆ|@TG":WekJ»"HRLIÚÑí¬t&ISWD:.5,m áà'K7AUP¡ãVæ-ÐxÂ¦@TV?B&±.'!Þ~JèK Multinational
Association of Supportive Care in Cancer, 2014, Miami, HRLI 2015, Copenhagen FÓÖ?"Bestposter award V«?"Ìuq{yIÊNF6T!
," ()%*-#

30

4´Âî4V{´FÖ;Siè#j.pì!Gtï

7" *-4)@>!=2;B6.'015?')/D(%$&!(%#$'&"«ä6®3Q®áF3É:BO6ìhsÄ"¢hëÄ"EQIF4V5f0òFA0BrÈU@?!>Go"ÀÛ®G4Vck²GÔ¢4>GG¢hëÄDf0òUØûFÑØ9="ÆÔ~GlÞDF9QFv44S8DU°:?$Ã+%!#

G-ªHÙ.s Cachexia conference,2015,

Paris Cïö)àC/S!

7# *-4)@>'C93,:8!C9+A<')/D(%$&

"
#

!

CH"K<4Âî4V{´GÀÛG®ãCF&-y44Vck²D[aZ`^WU(;S¬U°:">GoðQG2Dþí2Hß6">G8D4¯0~ÝF*dF-p¾×DES8D
FAE4S¬U°:?!
#_b\XY]G¹áEmÍH"&âÊEj.¨é'U·7"&âæEiè'U:E4Q4V¯0U·7?4´H">1CE04´DñJ"¸$4Þ6"¢hëÄ4Ú6"ìhf0òU¤C5SD01¬C/S!j.pìGtïFA0BH"Âî4V{´F27SËµ¾Dô-j.
ÎGºÒ/FA0BG

U0"4VÀÛÐGÜuCj.F;S{´gD4V¯0Gú£,Ö¥UÏLT=S8D4»-Dÿ:? $Ç§"¿Q"÷×j.wq"å"*(),"7ýçÝ%!K?"ièpìGtïFA0BH"&Âó¼
Õzè1G}¦"î4VU(;S4´F27SnÓæø5þÄU,0?Á

'$UMIN000012845%U³©ÝC/R"Ö½{´FÖ;SâÅE%õþÄÌàDÁÕ

zè1e­G?MGÆz+±pìFA0BGrÈ4ÂÝC/S$§#Q"ë#|wq"ù§"*(),%!
8GP1Eó'üwáEpì!Hê¶ENxE'¡Uô-D:E0?M"ò,ÖoH6"K?

< e Ü z S 7 ^ Y

31

9ZJ?NQ>"!zî]Â#a¸×("gn!z"gn£Â"qhl&umQPN"rRá×ìwbUt%dÛL!êKM"Ë}ãS<eSuÂãd¾`FJ?NQ>"Ò;zd0"D"Âã
S\=d¶¾D"¡ãOHS2S'SàdÆ÷D"<ÌSz´ÐS*R\9=>ÊºN=bO
È:M8b!XI*à+O*l~kxsf+dpFbj%ó%ß¡TXøR58!<e"9@<e"N<ed§[I4S%æS4"í¢¨³ß¡"j%`Ï%Sß¡"R·¤ö"j%$/Z"HIV'AIDS QPS{%ß¡\àS½OQb!êKMi»¬NÝCcIOdeT"ðw"5sQj%ß
¡WStR_a"C`R9=Qz´ÐÄ<ª8Ccb!C`R"<eR¡DM\ò*b=3?b
AO+<ÞyDI'dZSRëuN7bOÝCccU"*j%ß¡O­R'=bË}ã+<.:3?
b<ÌSâ+6Rv$IWSI«[?dÕZÚ<ª8Ccb!ASAOT"ÌLS¸ÇçlSûÕ¯^od%D"vgortmi}wQPk¥Ú¯ãSüIQÀtdÕY"?
PdAEM?

Sl&i~IQ

kz|spgS%R\ÊºFbAO<ìwbOÈ:M8b!
! $ # "

ÍÁT"/-.2QRT1DIMi<ely&pgwjfO~²DQ<`"*Ë}"ÉXñÑfS<eR7Fb,ªv$IOSPr%Ø¼+Q`VR*Ë}"ÉXñÑfS<eR7Fb,ªv$I
OS5×(­J}n{:!-Ø¼+dá×D"i»¬;`K`cI»¬)S¹õd"[M^>q
BN7b!
(
.)9ÿ

hGµùc]%_&/2QFÌkzWS®

%Å'Hô #/-.2#/)Kimura M, Naito T, Kenmotsu H, et al : Prognostic impact of cancer cachexia in patients with advanced nonsmall cell lung cancer Support Care Cancer 23(6)%.366,.4-5"/-.2#0)Baldwin C, Spiro A, Ahern R, et al : Oral nutritional interventions in malnourished patients withcancer : a systematic review and metaanalysis J Natl Cancer Inst 104(5)%04.,052"/-./#
1)Grande AJ, Silva V, Riera R, et al : Exercise for cancer cachexia in adults Cochrane Database Syst
Rev 11%CD-.-5-1"/-.1#
2)Fearon K, Strasser F, Anker SD et al : Definition and classification of cancer cachexia : an international consensus Lancet Oncol 12(5)%156,162"/-..#
3)Tanimoto Y, Watanabe M, Sun W, et al : Association between muscle mass and disability in performing instrumental activities of daily living(IADL)in communitydwelling elderly in Japan Arch
Gerontol Geriatr 54(2)%e230e233, /-./#
4)Prado CM, Lieffers JR, McCargar LJ, et al : Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts : a population
based study Lancet Oncol 9(7)%3/6,302"/--5#'&i»¬RBx8IJ=59QBÖdÙaXDIÃÓ>e#<eéCÜz»¬Ó>S¦±ãsRýäþD÷@XF!iï&°d©RASQ¥N5úåR_béC»¬S©Vd¿[bAO<ìwX
DI!ÍÁTC`R»¬dTDCGÎèmYd<&N=b_9E|DMÔaXF!

úÆ

32

*R2E`htikpy`v WT1rqmoxgmyk|eSðN

86B95":!$&.'(+0<?
WT1 -,)*/%)024>1@=#A73;!A&% $îYMúÆ

ëÁ.

*R2D"Uê=|eN8`htikpy'GEM(R WT1 @Ø×^cU=RDI>dx

gmy|e'WT1 xgmy(c`vE`k|ec"GEM 7HÝ|ORE`uylt6"(ðÚ·cÆ9"`
vÝ|SðÀR<A`oþcWE`ðµ§c¯DI!àWÉmT0Lÿ/Ë!2òT"HLAA.02 : 01"*"WITé½ÑN

24 : 02"WITHS{ßcpE`"iÝ|S©ìúÆ"?þúÆ*!ÒïeR]_ A ­'GEM+WT1 xgmy(WIT B ­'GEM(UuyltRZA^aI!¾cñn05/R HLA ³ÐcÞÙD"70
>BCaI!ã"cúZM primary endpoint cZIðÀ\k"²RL9MÍ½¿Vs<N8`!úÆ*R2E`Uê=Ý|Sa>8_"s<ñüSæ#%RBcåzDIIZ underpower Ú·OQ`>"hÚ·NF^a`²T>dk|ecY>dæ=Ý|cNE`óN5?QÇ´cIE[SOÅ;^a`!

# ! $ "
ø8e\÷IQÝ|eSúb>8`R[b^F"*TiJJÝþ>dSLN"0@SñT

=$îS>OQ^Q9úÆSõ4NN¶Ca` !ÄR"?\Ë`ñR]_&ùõ4>Y}QB
0(

O[8_"#ª=Ý|S>>ÎJQñ[09!úÆ

*R2E`çySUê=Ý|eThtikp

y'GEM(7H|eN8`>"«L FOLFRINOX \ GEM+nabPTX S0Ô`v|eSpvþ>dÌCa"HSÝ|e>aDLL8`!D=D"9FaSÝ|e[HSÝ|GþR]_>T»<
CaM9`!BS]:Qºõc±E`IZ"¡/SÝ|eOÖv£í>5?@Q`Ý|eSN>g
Wa`!HS0L>)>dk|e*N"HSðN>¦,RúdN?M9`!
%T1///L|y"PäÂ¹N8` WT1 cU=OE`>dk|eSðNRá_'dN?I!
WT1 T¸%ïÛûäNñS¹

OQ`>dxý@ØODMD<CaI>"HS½S%SSµ§=^"WT1 @ØSÜ.ÊNº>*cY0@S>dNKZ^a">d%¬ÓfS)ö+úO_xýc"HDMÂesn&ijÖvc)¨E`QP"WT1 @ØT)>d@Ø*=ÖvcpE`BO>j^=RQKI1(,3(!ÄR"WT1 Tÿ1IRTbKM9`ÂäkSU=OQ`èwQ>dÂ¹
S0LN"WT1 @Ø×^R2E`ÂäkcrEE`BON¨~R>dcÃ°N?`Mþ>8`
BOc%TdÌDI1(!Ba^c rationale ODM WT1 cU=ODI>dk|eSðNRLQ>`

Q=µ§cÆ9"1//3L|È"u%QzþäcpE`ßc2òODM WT1 rqmocv9I>

dSk|e'WT1 xgmy|e(ðÚ·cÞÙD"HSpÀþcdÌDI1(4(!Ò«T"æ=>
dÝ|S0LODM WT1 xgmy|ec¡/SÝ|O'XËbG"($(ôÀc¢3E`ÚXcÆ
KM?I!HS0L> GEM `v WT1 xgmy|eN8`!BS`v|eSÞÙMþcWEV@"$îYMúÆ

*c2òR6!(Ú·c%TÞÙDI5(!{&þRD"àQÝ|GþT GEM

R]`¡9SGþN8KI!WT1 xgmyqySÝ|GþTCt]}SS[OSXN8KI!20Oï¤lQÚ·N8KI>"Ý|½R WT1 rqmoR2E`:®kO'DTH(cKZIñT"DTH SQ=KIñR2DMp~Qÿ/¢S;ÀcKZI'0Lÿ/Ë,DTH 8_36-"
DTH QD6#
6-(!Ý|½SÏÝ=âéÞÙc1'0T©ìúÆ"0T?þ(KZ"HS.5Õ5]\-X ¼¥$kewvf&I< ^ ³ D N 8 W T

33¤Vï×âKLGF!
7JO"ØÃ.$Ñ¦LáSFOº¤«%LáJÚ¦³DI<L9ÇG]åÈM"*»ó³D
6KAIA9Y\[ GEM ³DM WT1 k_dl]3AB[|:xD6] GEM éþ³DK'B[hlcg|æ#àFÅ±]µ°A"Ñ¦LáMåB[73AD6MX[×âyï¥]úB[KKVM":xó¥4QMoÝÕ],}B[?K<7N=óJ8[!
&UMIN IDUMIN-----2/15'
10$34"!-,('&)
7±~A"

Ohlcg|(<æ#àFÅ±ã°ÙüKAIµ°AF!¨ÿN6°Ù<7±M®

°ÙNEBÌ©quJÆ!@\FÉMµ°@\F!hlcg|Oe$balb$MI¬Ä|6]A9I¦9"¶].#.M/HN³DMD\E\/>F!/îÖv¯O"¡%ß&Lû0"Lä)0'"-&ÀÑ¦"ôsÕ"«%Õ'"ôsN?8"HLA &HLAA,02 : 01"HLAA,24 : 02
èA"C¶]?B[Ê§O7,02 : 01KAInGF'"°ÙKAF&Ò.'!

*" ('$#!%#!10.%2*+/
¶XZÁ;MI±®~Nür]ýF!ÀÑ¦SFOôsÕNØÃ.$Lá"SFOº¤«%Lá¶J"Ú¦³DI<L=&º¤«%JO"«%ò¤N³D<L9'"HLAA,02 : 01SFO,24 :029C\;]?A""H/-­pÉ46­p{"Karnofsky Performance Status&KPS'5-%.--+"¹2L
á$]?B[VN]ÛçAF!Ûç»KÃ»]+."/MD\E\´B!
-" +,&).'ØÃ.$Ñ¦Lá&UICC Stage!SFO"'VA=O«%LáJ8[/'(L·n9>&æ3&')M:>[Î¼ÕLJ8[?K<ÞËóMÐê"VA=O9½NL9À<ýY\I9[&í.'0'HLAA ª&tõ¯'< A,24 : 02SFO A,02 : 01J8[
1'ìÔÏRNôs<L92'ìù÷pÉN1Ó"Ó"Í#w]!UL9
3'*.¿³DG#LáMåB[³DI<L9*/º¤«%G#LáMåB[º¤5Â|D6°¦GJO"DN¬¸ø@;Y3mpÉN8³D
<8Z";H«%!¤N³DI<L94'öJ²N"H</-­pÉ46­p{J8[5'Karnofsky Performance Status&KPS'<"5&3-,'%.--+J8[,Kð`lfj$i.¹2SFO¢z¾ë°¦J PS <ñ{AI9[<"ÜB\P KPS5-+pÉKL[ÇGM£[

+ÑBµRHF\f}hlv| WT1ywmpdmªSü¥o34

7*ÂÍ9ë@¡kN;\/.*1Å!S4F@¹INA\®é//*êB¶Sºk@ðzR~àD]M<\nÄ¼/ 1"...(l !/0"...(l  ?L ÎP¼ /"3..(l !
Äúq /.."...(l !
x~evN7#.:(dL !
 AST)GOT*(ALT)GPT*%ÉôOQES"Ò% /..IU(LÉôO;[S"Ò% /3.IU(Lv v%ÉôOQES"Ò% 0mg(dlÉôO;[S"Ò% 1mg(dlÄ3d`mr+/#3mg(dl UJT Ccr,23ml(min/0*ÞÈÙ R³EM",?ZS{öRY\^@_Z]M<\
Q/%âS<G]?^JFXS!?%4ÆRY\u*L;[ ¦¢8ùsNu*L@¸R;["üURÕoXEBTW@©hD]J ?%4ÆXEBT×*N<µS*LE?Q<"ÒT"(ò1°µRóEQ<¤@õÇ@;\&! %"#$/*¬]1Sñy@_)^á1"3ibSá1ñy@_*^F\!JE"!rbµ"jbµT´UQ<!
0*g&P$g&S¡k1@;\$íePSø1!u'oq'Sg&^·F\M1!
1*5)uUJT5)þ#^Ò|EM>[ÞÈÙ @ÔcN;\!
2*P[X!SjnapØ)µ1SRHF\÷UTùB*UJT"0ØSÃEUQ=+Y^ìCM<\!
3*l;þUJT²æ1l^F\!
4*go' wQ¬]1S¯:þ)ba j1±TùB*^F\!
5*ñ`QÒ|þ)ñXS=KÄ1'w>"­w>"1?ÅbS'¾ÐÖ"-w>"­w>"R° "R}Ö"go' wQ\fuQP*^F\!
6*Ó.À2þÌ¿"Ó.A$1å®^Ò|F\!
7*ñXSØ£vþ)'pÁCØ^ùB*S¸@;\!
/.*HSG"Û@ÞÈ^>RçÜF\SRwVZOpLEJ®é!

"!'(%#$&|ã¿)A ¿*NT"f}hlv)GEM&/"...mg(m0 7Q"day1"8"15"28dî¹*O WT1dm)WT1 ywmp1mg(body rbY"day1"15*^YEJ!Hýã¿)B ¿*NT"GEM)/"...mg(m0 7Q"day1"8"15"28dî¹*^YEJ!û"WT1 dmRHF\wkzT<M<Q<!WT1 dmT"WT1 ywmpO`itoN;\ Montanide ISA VG51 STERILE)Seppic è*OSc{i6ØN;\!WT1 dmSê2zN;\ HLAclass I ÏD1ywm

pS`|sÚm^t1RäF!HLAA-02 : 01^F\®éRT np126 ywmp^"HLAA-02%.0^F\®éRT mp234 ywmp^"HLAA-02 : 01 O8-24 : 02 é^F\®éRT np126ywmp^´W WT1 dm^H]I]YEJ!
ÞÈãT"/*u#S+Ñ"0*ñþQ§ßÿSo4"1*®éSPÝ·"<G]?R¨ZF\
UN«xCZ]Jã^ÃEEJ!
Ëã^»TEM<Q<@"u#+ÑRY[ÞÈã^ïOQKJ®éRÊ["|ã¿)8¿*
SVQZGHýã¿)9¿*NX"ËãOEM WT1 dm^ GEM OS|UJTKaNSY
^½EJ!

< _ ¿ M O 8 W S

35

7$ HLA 154' WT1-,*+

HLAA ´tskm@

`vo¸&Q!ñHLAA*+-$+,np,-1

RMFPNAPYL

HLAA -/$+-

mp-.0

CYTWNQMNL

WT1 !÷Mµ;Ì×
7z{r^FþB[*%!@.4B
Ä0°BP,$Øé±!5¾÷0°BP"?ã}Øé&PFS'"àØé"E½Ð'Ø
±"A÷xniz{fûJ8[!â¤³På CT ^¨çH9I¯9"¿MßK¿M©Nô÷
&0|£BRJ1Æ="~©3Æ='NÁºAF!E½ÐO0NP(E½ÐóHªÉ v4.0"<ªD JCOG )&NCICTCAE v4.0'^H9F!
&!A+0<@."WT1 ?*<A+,>#
WT1 ­¨!÷A

üO0KAI",'WT1 tskmNëB[ï+3(&DTH'"-'>

Í¢ðO WT1 !÷µ;Ì×dy%7µ;Ù".'WT1 tskmNëB[ IgG Ù^0B[!?
\Y~N"4Õ¥KAI<¿M:OE¬×NB[qabu%c%ì¶ÙUGôB[!
'!D7<-:(C;=E89;)52"<SäOSùR9²-++2Ol%iXZ"óÑSO,ÜËPN:>[-++,$;Y-++/$OØé&ðî'P2#
3|£",$Øé±P-1)J8[!ëÎ¿M&6'O,$Øé±^-0)K¦ÚUZ"7H¿M&5'^pg%m*+#
10KáôB[K"5O,$Øé±P/+#1)K¡·@\[!ùR^.$"ùRÅK©OòÛ^,#0$"5K6O2>*^,$,"Type I error ,+)&Læ'J3+)O¤ÈNKB[K"Ù-IÏPÖP,2,PKM[!ÃOÙËPO'Ø^®JA"
ÇÚB.ÏPÖ^,20P"±¡,0+PKÝôAF!
3/$!=E16-+,,$0£;Y-+,0$2£RJN"à4ºÝð2ºÝJC,1+PO«8ÂN HLA hez%n{f¤³<¯]\"4,P<¼§NùR@\"D\E\O¿MQy{jwN2>Y\F&Ô-'!HLA ¤³J
Ë@\FÂP/+Pöú&C-0)'8GF!DOê"èM1ÒÓ¯VíÿÞÏMLO±7ÏOFT"¼§ùRN»YM;GFÂ<-0Pöú&C,0)'8GF!ùR4,Pð"¿M¹ßN,PCHOý
ø<8Z"¿MPP5//P"6/0P"±¡34PJ8GF!-+,0$4£>RJNõÈ@\FÂ%
9²Ê^#J=F31PNH9I"ÄMÂ%^//NÀB!LKUÄM1P"UICCTNM 6

O stage !J8GF&524)"621)'!

3# 6/48.!HLAscreening"%)2:09(&Û´\çRìH^cqehnvAO WT1poilubivIRFSTÖ136/# ),.*!-'+0(%$&";GEM-WT1ubivAO<
GEM ð*

ØVÜ02

54V

54V

"YÅ.W+õô,

77#
1¾

76#
1¾

)48.88*)54.88*38V$27V

36V$29V:1.211/

41V

43V

91/

22V

8V

81/03

3V

5V

24V

25V

41V

3:V

ÐÛ´)Stage!*

8V:Vþ|Ý)Stage"*

45V

44V

Î®½1

3V

2V

\&?+\]?X,36V)2V*

34V)2V*\ë8?

29V)2V*

31V

)

*.W5z

ÝB%óÝ$ÒÝ
Karnofsky Performance Status

HLAA ¼)}ÿÀ¢*HLAA002 : 01'X04
0

HLAA 24 : 02'=

05<)UICCTNM @U*«1æ?y )*½1V

02%3126.:¨HVNRØVD·Ñ)È0£*`-NCJØV
03%BaÝ[ødvkt&r=SV[¬ lsm&fR\^ PS ùV
04%A024 : 02`X"05%A002 : 01`VQ?

"!('*0ÃªÆRÇÁd&gÜSõôT";7d&g)5z%2.31d&g*"<

29d&g*N"%¥ü;T´KM?Q?B";

B<4d&g)5z%2.

\]ZéDÇÁF_J¡±N>KJ!

#!/%)+Q

OZ grade 3 xÚSLÄÙ`-YJB"1Ø¶NTQ

N»`-YQ?¡±N>KJ!ÊQ

ZST"²õ¬ÕØ[§Ô4¬ÕØQPS§)Ý"Z$Z!QPS×)Ý"I_Rñ'ãØ
N>KJ!WT1 ubivÆRX)ÝOGM"grade 1(2 S#N?y7>3)1à"³¦*`-YJ!
$!-.,&
GÃªSÍßMûT4.S¥N>KJB"J9ØVÜRïGQAKJ!Ãª¤èSê$ÝOÍßöS6`°wåÝ;{RK@UD"3125.:¨RõÞ`´?"IS¦2.SöOQKJ!~EN"âÓ=/Û´\çRìH^9ÏÆRSäîÂB.CG"GÃªSìÙØV)(RÉ.È[ PS S²VQP*Rcqehnvð*ÆR`ýOH^EOB¬KMCJEOZ>KM"ö®ZÍßTúíGM?J!¹®SÍß¤èNJ9ØVÜRïH^EOTº,O2òF_"3126.8¨HNØV"Y`ÌPGJ!­¿Tj&hSËÍOØV÷á`´KM?^!Ê;µJRL?M under.
power ÃªOQ^B"3127.+R endpoint RL?M¯:NC^©¸WN>^!

; f Þ  R 6 ^ Y

"

37

!

%S".õvf%È¢<ªXHSðÁÒh¢<ªRùeEüQ"GEM Q WT1 kte{Db£R)e GEM IaNm¢BLsDU="sG"9øÛ½eÌbCÚ
/²\¼°NBLãÚBH!underpower Û½RH[æsÉQK7LZ¹£SQ definitive Pº
eßD@NSM<P7;"øÃN£SsNR¨)eûÔQ,B"GEM N WT1 kt
R{ÞR proofofconcept ;ÎÁßAcb@Ne¬FDb!
rù'Qì-ù';HBP:JH!Â|ù'S6JH\RR"HLA ·RvT¡"t!R®@%È]Ê{ùYQ_aVM<P:JHm&p;C:JH!WT1 ktS HLA+class I Å?)R}|
tweæ*zNDb\RM"GR}|twQÊJDb HLA UÙ·eDbùMP>cTÃed[P7!

Û½MS0çR}|twe/P#ñpBH!cýGR&M HLAA 02 : 01S0.,Q"-

HLAA 24 : 02S1.,Qd[`cb@N:`"Â|R3.,;ÓëSQT¡)eHD@N;8PAc"-ÎRº\VWGRlbM6JH!
{ÞR5)Q¨B"WT1 ktXQi8´ónwj;5Qd[`cH;"GRBRÜüS"GEM ¨"XHSâ¥Ê{ùQ_b\RM6JH!GEM IaÞ¶NRm¢M"WT1 ktQ_b´ónwjeõ>Tï¿uWRPÑSP="WT1 kt{;"CÕ{£
R_8Qí_P

Üüe;AFb@NSP7NÇ9`cb!

Ä PD1 ÄDPORtiuk~hv7

ÄDe7H;fRÃ);")Í#è]o÷Ô)gªPOMµeßAc"GRh]»ú;®@Q%fM7b2*!"tiuk~hv
7ÄDMÃed[P7è¡R^L\`:QPaKK6b!GR/KQ"Ô"æNBL5z¯Rè¡b$òed[P7@N;±?`cb2*!Ä PD1 ÄDNÄ PDL1 ÄDRæP×­ôS"effector NPbè¡b$ò5z¯;AÖDb@Ne3QQ"@c`5z¯;h¿Db PD1 Nè¡>R PDL1 R9À×M+Cb5z¯R()'{&j(*eÄDM7z¯)Ôö)j&5z¯$CTL*RÔö

Db@NQ_JL"T×eÒ¤)Db@NM6b!Oÿ·¢ª)æNBL$ò)¢¦ª*SkQ"è¡b$ò T z¯;B76":M"tiuk~hv7ÄDRÞÃ;B7R/KM6b!@R_8PÔR$ò;B7è¡QEDb;f

R1NBL"effector NPbÔeè¡bQXE]Db)'gkq(R³*@

N;qM6b!GRR/K;"}|twkte©Z;fktM6b!ÆQ"CpGODNPORÊ*goyv]"ä2]xRÄ;fÕQ_bè¡~Q_a+CbbÖ)RgoyvÃQ_JL"Toll éDPORzr&dáéDeBHà4¸R¤))'hlxn(*e{Db@NM"_a³PÄè¡e]Db1\6b!NBL"¢<ªQE
Db;fMÓµKAcL7b GMCSF h¿¢ªÔkt)GVAX Pancreas*Nå`Listeria goyv)CRS207*R{kt;6b!«ÞR%È¢<ªùQXAc"
Äè¡;]AcHº"+A¬§RNÃ;ßÐAcH3*!GEM e©ZÄ;fÕQ_b immunogenic function QK7L"7=K:}Ë;6b!GEM S"ê!ÔýM WT1 POR;fÄ¾N HLAclassI zÙRyÊDRh¿e=%BLê!ÔQ_b;fÄ¾Qßfe;³Db×]"Myeloidderived suppressor cells POR()ÔRM0QI"ºSQÄ¾^S CTL R];³)'gkq(R³*;¬FAcb4*/.*!GEM N WT1kt{G!9Û½M}ËBH"ÞQ_aè

¡î÷ed[ÏÞS.õeé>H/RRïè¡bQS"T z¯"^Q WT1 ^S CTL R$
òeC=d[H1*!GEM RÝKØÔÃQ_bbÖ)goyv×Q WT1 kte{
Db@NMÄè¡×R9#9þÃ)'gkq(R³*;"@RùRøÃQÃQ[7HNßÐAcH!B:BP;`"{Þeé>H5Q@R_8P×eqEB\d[bd>M«Ø²~KµAV\g^`dkÆÒ WT1febcj[bkrzËnÔÉLÕ¥yÄ

38

MJ7!vLhkagrÕ¥X¼?GÁDÇL]keiX¦Ku¯?"GEM I WT1 j[bkLÆÒKSVÂm¾¡×ËnLÀ·LÂ­XÓu?"Õ¥¾³ÌIËn¾³ÌIL|Ö­X»O
V<IKSUÊÔXSUÏJÔÉNÄ¿>BVºXÁTWVI¶AV!
! $ # "
ÊHM"´LrzÔÉK%ËnZ[_i&X

rAV8Yfebcj[bkÔÉXÆÒ?DÔÉLÎp­XÅsAVÍ¾Hhkagr¸!±Õ¥X?D!Õ¥¾ÅsÍX}Q¢tMÈLÐ½H6V!Ø²~XM@RIAVÃ­8YLÔtLw°KM¨DJÔÉLyÄ8R
TWG7V8"CL-F88YËnÔÉH6V!Êt8"8YËnÔÉX}RD£z¾8YÔLÄ¿KH9V<IX¶AV!K"ÊÕ¥LlX=Óu7DE9"¤®X=q7D
E9P?D)o¹É¬

8Y£z¾Ô¹*L|LxÑK©:{ª?§;PA!

' & ( %-(Stathis A, Moore MJ. Advanced pancreatic carcinoma : current treatment and future challenges.
Nat Rev Clin Oncol 7$-2/+-3.".,-,#.(Sugiyama H. WT1'Wilms tumor gene 1($biology and cancer immunotherapy. Jpn J Clin Oncol
40$/33+43".,-,#/(Oji Y, Nakamori S, Fujikawa M, et al : Overexpression of the Wilms tumor gene WT1 in pancreatic ductal adenocarcinoma. Cancer Sci 95$14/+3".,,0#0(Nishida S, Hosen N, Shirakata T, et al : AML1ETO rapidly induces acute myeloblastic leukemia
in cooperation with the Wilms tumor gene, WT1. Blood 107$//,/+-.".,,2#
1(Oka Y, Tsuboi A, Taguchi T, et al : Induction of WT1'Wilms tumor gene(+specific cytotoxic T
lymphocytes by WT1 peptide vaccine and the resultant cancer regression. Proc Natl Acad Sci USA
101$-/441+5,".,,0#2(Nishida S, Koido S, Takeda Y, et al : Wilms Tumor Gene'WT1(Peptidebased Cancer Vaccine
Combined With Gemcitabine for Patients With Advanced Pancreatic Cancer. J Immunother 37$-,1+-0".,-0#3(Sharma P, Allison JP : The future of immune checkpoint therapy. Science 348$12+2-".,-1#
4(Le DT, WangGillam A, Picozzi V, et al : Safety and survival with GVAX pancreas prime and Listeria Monocytogenesexpressing mesothelin'CRS207(boost vaccines for metastatic pancreaticcancer. J Clin Oncol 33$-/.1+//".,-1#
5(Zitvogel L, Apetoh L, Ghiringhelli F, et al : Immunological aspects of cancer chemotherapy. Nat Rev
Immunol 8$15+3/".,,4#-,(Takahara A, Koido S, Ito M, et al : Gemcitabine enhances Wilms tumor gene WT1 expression andsensitizes human pancreatic cancer cells with WT1specific Tcellmediated antitumor immune
response. Cancer Immunol Immunother 60$-.45+53".,--#

9 [ ± 1 I 4 S O

39?@31A.&>%( Conversion therapy 7'
8DG<&2%(,)*-"+"64!/0IE7
9=:JC&#$( MIB1 index 'FH;&2%(5B2,,(% z#ù«ôç±1IËûHTV¸0JÐ¼÷òE4CAÞãéu9Ð¼{òFGW¿49©>X"z1

ÿF Ð¼Z-5A Conversion therapy HTW+IÓ9ý¡>XD5W!vþE" Ð¼Qª ï¤óJÛ<3½
ÃI'ßFGCD5W!ÞãéuÐ¼4HÝ@W+ÓZ&çF?DÐ¼H¹Ò#¹ü»z1ÿZú-@WÞ%3½¯9YXA}"ü»z1ÿHTW¤ó/Í}JîUXA9+IÓ9îUXWNEHJ®CD5
G5!³J+Ó9îUXD5G5wF?D"ÝÂH

Ð¼IOE£±9îUXW¿4(¤ó low risk )9*>XW=FZ¬æ?D8V"®èGü»z1ÿIíðGULH+IÓHJ¤ó
.@W¿4Iìå9#F7UXW!"EJ MIB1 index Z-5AÞãpda"ØBÈHü»1ÿZ

éuHÝ@W Conversion therapy ¤ó#++Ùj]_m$`$F?DI*-ÎZÁ?"¤ó pdaIìåZ¯OA!

# ! $ "
×JÞãIéuÖF?D¥QöëI
DJ@EH
°Î

éuZñP(ì°Î

éu)

!

/)
0)

Ð¼JÞã

5øsE4V"ÞãFÉà>XA(.2*/2+I¿4H85éu) "2-*3-+I¿4EõIËFFQH.)

éuZñPW(téuHÝ?D£±Z¢PW)vIþÿE4W9"

XA6BÐ¼{ò4J(.2%/-+H~;G5!@GYBÞÛÌIÐ¼÷ò

.)
0)
1)

éuFÉà>

éuHÝ@Wôº±1

J"+IyäR¿Å6F5CA6Z&çF?AÔÊz1ÿ9´ÜFGW9"z1ÿÒHJ£±µ¹÷òE4CAéuÖ9z1ÿIÕHTV£±Ð¼¹MuE:W=F94W!=I±1diog
c$J &conversion
E4CAÞã

therapy'FÀ>XW!ÇAGz#ù«ôç±1IêÄHTV¸0JÐ¼÷ò

éu9Ð¼{òFGW¿49©>XWT6HGV"z1ÿF

version therapy HTW+IÓ9ý¡>XD5W

Ð¼Z-5A Con-

!

2)
3)

vþ"5

Ð¼97A¿4H85DQªï¤ó9Û5=F93½ÃI'ßFGCD5W!ÞãéuÐ¼4HÝ@W+ÓZ&çF?Dn$qfkZâÆH

Ð¼H¹Ò#¹ü»z1ÿZú-@WÞ%3½¯(FFCD ACHBTH AURC 9002 trial R EORTC 40983)9YXA}"ü»z1ÿHTW¤ó/Í}JîUXA9+IÓ9îUXWNEHJ®CD5G5!³J+Ó9
îUXD5G5wF?D"ÝÂH
FZ¬æ>XD8V"Þã
H+IÓHJ¤ó

Ð¼IOE£±9îUXW¿4(¤ó low risk )9Ú§@W=

éuHÝ@W Conversion therapy I®èGü»z1ÿIíðGUL

pda"ØBÈHü»1ÿZ.@W¿4Iìå9#F7UXW!
'&"I&çJ"¦!¶5erka² Ki67IóZdb\z?A MIB1 index Z-5AÞãéuHÝ@W Conversion therapy ¤ó+ÙI*-ÎZÛ­ÑEÁ?"+Z+Ù@Wj]_m$`$Z¨@W=FE"ÞãéuHÝ@W·ç±1H85DÇ?5^lhrdIáK5DJä,"ÞÞxÏ$|ø ¾z|gdWq£>/4FPHJQ$K$<6:? MIB1 index ?¢¤40h£mGa7F5<;-F!
()*!&#"'%$
Dako {?n Ki67n%)#)((&G¤.:"by¡%high power field&;STNR>,y¡Geu
68!gt>7F Ki67 ¥t

GKITO6 MIB1 index Gv}68!rBo. index G§? index <6:s¤68!l?|¨G¢7F§;@"LHM?2.B?0D~=3<B*B63@+l?|¨G¤.:_68!Ki67k@^c¦>CE`x>f98V;@kGA=.1"H.E. ;gt?wGA8V;j3k6:.8%)&!MIB1 index#+('UG

Ki67ok§"+('U]Gk§<i68%*&!

p&H.E.  >:X>|¨?wGAF
\&Ki67
[&Ki67 %b&w|¨t @o.Gz6:.F
Am J Cancer Res, Hayashi et al. *(),CEaY¤/! Conversion therapy *,71.&#$(,72-4'+3p&MIB1 index ¥§? H.E [&MIB1 index ¥§? Ki67
p]&MIB1 index Z§? H.E []&MIB1 index Z§? Ki67
Am J Cancer Res, Hayashi et al. 2015CEY¤/" MIB1 index 506%)06

= X  È L 9 Q O

41

%$#&
?VNHK"¸°¢om§dKAG"glÈ¾«­yKi°IJT conversion therapy
W{ED5/Ë¡1ËHM H.E. µÀKGo~¿W®PJ<EDDP"47ËH Ki67LÂfW{:
MIB1 index W·hAD(Training set)!@SK MIB1 index L¨Wv©BUDP validation set
IAGHglÈ¾ymW{ED¢om§d15ËWÆ:Gv©AD(¶0)!
'"!&$#%(Training set%n,47)
2,)+

0*/!1("'%$&-3.!#"

¯Ì(})

u³(0/3'bL)mK;>Uu CEA
Ís(mm)±ÍÍxª'c
ºµ¦È9T
glÈ¾[YZaCR'PR'SD'PD.Grade 1'2'3.Ã¹$½

54(24+72)
23(46-)
08#
0(5#
4+26#
4)
5#
2(0#
/+061#
5)
12#
4(4+05/)06(17-)
1#
4(0+08)30'08
22(44-)
5(1+27)
1'21'04'4
2/'17'1(ng'mL)ÈLl¦zj²¥pKRU(validation set%n,15)
2,)+

0*/!1("'%$&-3.!#"¯Ì»(')ºµ¦È9T(*'+)
mK;>Uu CEA

56(30+73)
05'0/
6'06
5#
0(/#
8+050)(ng'mL)"!

Training set K;>UkHM Pathological CR KRTo~¿W®PJ:47ËH·hW{:26Ë(53-)=|±w"10Ë(25-)=¤±wH9ED!
NC"Conversion

therapy yL£rKqÅBUeWÁS<KBUDPK"Cox L´Ë_\&^`]aWÆ:G¼ÊkW{: Conversion therapy yLÄy¸ÉKnÅBUeKF:Gv©AD(¶
1)!v©Ltj"MIB1 index |I=ÁS<KJED!

M Conversion therapy yLÄy¸ÉKnÅBU¬ÇeH9U?

42

he[w¨J:>PWTUX%V%H@FK MIB1 index K§©

C$ Conversion therapy 8+F8DG3:*4(,7A"Cox +BH0-!/1.2#.(#'-&,)+%$!DFS"£­c~¯m,1cm~¯p 1e CEA,5ng&mL
RECIST SD or PD
MIB1 index,1.£­c
MIB1 index,1.*)+%$!OS"£­c~¯m,1cm~¯p 1e CEA,5ng&mL
RECIST SD or PD
MIB1 index,1.£­c
RECIST SD or PD
MIB1 index,1.-

Hazard Ratio Exp!B"

/#
660
/#
303
0#
573
/#
452
3#
4.6

.#
753)1#
410.#567)0#
723/#
166)3#
41/.#627)1#
1.00#216)/1#
0.2

3#
4.6

/#
603
/#
25/
0#
30/
2#
133
4#
.6/

.#
.4.
.#
0.7
.#
..2
.#
/15
+.#
../
+.#
../

.#
434)3#.6/.#324)1#
742.#652)5#
053/#
347)/0#.65/#102)05#
712

2#
077
3#
144

.#
027
.#
224
.#
.65
.#
..3
.#
.0
.#
./
.#
.2

MIB1 index tlHlJ:>P KaplanMeier ¥JOP
9C(S}A'1(!MIB1 index tlLlH

P valuek'oJL logrank test S©

MF§ZJiw<='P +.#../("¨q¡¬G8DC'P +.#./(!J MIB1 index tlJ:9FL/YKw®<="<aH
IP§rI`d«¥qG8DFNye micrometastases KyK^j<}u?QC!

v(¦w ª]( ªfxig'_(11;n!oJL logrank test Sz©!

;% Conversion H*&', MIB1 index 9?6)@?6*&',<>5="KaplanMeier E#\¤"{iJ`d«¥SsRBJaG8DC®'n*3/(G MIB1 index H¨qJE9F
o@C<!MIB1 index Kt$Gw$¨qJ^jLI;DC!
>F"Conversion therapy ®J:>P`d«¥JAP|«rb¢'PR, partial response ; SD, sta-

8 U w ª H 4 N L

43

ble disease ; PD, progressive disease%Gk@ MIB1 index qH`rTx>$}-%!SD"PD ¬DI"
£1`8 MIB1 index qHy¬D4A@!K@",)(VzH

n$PR%¬G75CM£.`I MIB

1 index qHy¬D4A@!;SI MIB1 index E[_ª¡Ho\Gb­84R;ETxs=C5R!
<PG

nE<SR PR ¬$n&,0%GlAC"MIB1 index Hq8¥mG¦6RZeTj=@!Kaplan

Meier ¡GORg$jGI logrank test T¨5@%Tx>$}.%!f9;EG]|znE<SR PR ¬G75CM"MIB1

index qHy¬I¤WGd$G*V%u85i\

D4A@$P ')#))*%!

6# Conversion therapy 4A)%&+,:591>?)0' MIB1 index 2<*-3t}%¢u©
Y}%©
jGI logrank test Tv¨!

6$ PR A)%&+ MIB1 index 2</(=</)%&+7;.8!KaplanMeier @":C"{n$Grade 1, partial response ; Grade 2, stable disease ; PD, progressive disease%

Gk@ MIB1 index qH`rTx>$}/%!<PG{_G

nE<SR Grade 2 Hy¬$n&+2%

GlAC"MIB1 index Hq8¥mG¦6RZeTj=@!KaplanMeier ¡GORg$jGI logrank test T¨5@%Tx>$}0%!{_znE<SR Grade 2Hy¬G75CM"MIB

1 index qHy¬I¤WGd$G*V%u89¥m«Fi\D4A@$EMG3')#).%!
§G MIB1 index 8 conversion therapy mH¥mG¦6RZeGB5C"validation set$n&+/%T¨5C^TpA@$}1%!?Hi\"MIB1 index qIhEJC¤WG¥m«D4Q"caXG>R Conversion therapy mH¥m¥G7:R MIB1 index H¤¨~8xs<S@!

44

AB65D39EH?)$%,1./2"0"(&'* MIB1 index *GI<

9$ Conversion therapy 6E+'(-=8.7>3BC+2) MIB1 index 4@,/5

8;#F9E=@J
4;#>=@J
7C)+ logrank test -:I!

9% Grade 2 +'(- MIB1 index 4@1*A@1+'(-:?0;"KaplanMeier D#7C)+ logrank test -:I!

9&!Validation set +'(- MIB1 index 4@1*A@1+'(-<:?0;"KaplanMeier D#

: _  ß N 4 W R

&

45

'

Ï}O"?\QIN±|ÑáM85H±µzx»kM°C[ËowßÍMXZ¶{Õ©:ÀY\L5mJBH"Å low risk ~:®C[?JM´ÒB"ËßÍ^ÙC[eba~(N¾¸^RD!}rXZ"MIB1 index ³: conversion therapy

Nu

ã'Å

NÕ

Èàm

JBHÔØI4[?J:ÐY9JLGD!¨ª£M8=[®zÎM85H MIB1 index :³I
4[

ãO+ÃhÁNÅÝ:;]TH<"xÁMäg§¼: high grade L micrometastases :®BH5[qÄ§:<ËowßÍ:ÆÙL

ãI4[J7Y\[!lÌI"®zÎM85H

MIB1 index :·³I4[

UàI4Z"ËowßÍ:ÈÙI4[ãOÅÝU·<Õã^¯<ySJ7Y\[!?NX6M"¨ª£M8=[®zÎM8=[ MIB1 index NÇpOÅeba~N¾¸MÓÞF"ËowßÍ^½C[67IML[J7Y\D!QD"«ãJA\[s¬¢ PR N

ãVª£w¢«JA\[ Grade 2 M85HU"MIB1 index ³ãOÔiMÅB

VC<"ÚNÇpÍ'äNÇp(JOjL[`df&c'®äNÇp(MX[ebaÊâJ
7Y\D!
Stage "±µzM°C[ºLËowßÍN¿ÂLYPMÕ

^ÛØBDÅeba~"­F¦MËßÍ^ÙC[

Nu©MO"MIB1

index LKã^°¡JBDáUÆÙJ7Y\[!

! $ # "
"Ï}ÁÖNlÉO American Journal of Cancer Research M Publish'Prognostic value of Ki67
expression in conversion therapy for colorectal liverlimited metastases 2015%5'3($+,,/)+,--(A\QBD!ÏM@Üt^5DE;¯±L@n^5DE;QBD:_w¹ß}²Nv×M¤¥B¢>QC!
(%+(Alberts SR, Horvath WL, Sternfeld WC, et al : Oxaliplatin, fluorouracil, and leucovorin for patientswith unresectable liveronly metastases from colorectal cancer : a North Central Cancer Treatment Group phase ! study. J Clin Oncol 23'36($3,.-)3",**/#,(Van Cutsem E, Nordlinger B, Adam R, et al. Towards a panEuropean consensus on the treatmentof patients with colorectal liver metastases. Eur J Cancer 42'14($,,+,),+",**0#-(Ismaili N : Treatment of colorectal liver metastases. World J Surg Oncol 9$+/.",*++#.(Poston GJ, Adam R, Alberts S, et al : OncoSurge : a strategy for improving resectability with curative intent in metastatic colorectal cancer. J Clin Oncol 23'28($1+,/)-.",**/#/(Adam R, Delvart V, Pascal G, et al : Rescue surgery for unresectable colorectal liver metastases
downstaged by chemotherapy : a model to predict longterm survival. Ann Surg 240'4($0..)/1%discussion 0/1)2",**.#
0(Adam R, Wicherts DA, de Haas RJ, et al : Patients with initially unresectable colorectal liver metastases : is there a possibility of cure? J Clin Oncol 27'11($+2,3)-/",**3#

¼RÓ""åö#ìL£/ÓQ÷D`øÿM>SïéQHD`ÊSí

46/A1!;27"4?.<1$8#&9:-)+@=%'63$,>#&(0%*5è(¸U,"ä'

FÈ,,"ãëÖ,,-( )Q:7L/--4.+/-.1SQîÚ5/Sæº#Á1øÿQ÷BLM><ËºAaFÓc÷ÞNB"32ÂSßS¼RÓQ÷D`/0|lx~(¼RÓ¨)"PS 1 ßS"åö#ìL£/Ó("åö#ìL£/Ó¨)Q÷D`4|lx~S½¬0.|lx~QJ="Ó0ª"ÏM,IN Grade 3 ßSGÍÞS1Ýá§STQJ7L|r}m
vjpfuQícºIF!M>S|lx~T¼RÓ¨MT UFT'LV(*bevacizumab$ bev)5Q"Xeloda 1
Q"XELOX(*bev)5Q"FOLFOX(*bev)0Q"ESô.Q""åö#ìL£/Ó¨MT XELOX(*bev)4QM6
IF!Grade 3 ßSGÍÞc-ZFÓN-ZP;IFÓM0ªNÏM,Ic3BF­"GÍÞS1ìNGQTS6`ÊNBL"ïöMTé;(úé)"BUN ¼û"9Ê4$ESÇK<"¼RÓ¨MTé;(úé)
N BUN"AST¼û<ý×AaF!=""åö#ìL£/Ó¨Q:7LTGÍÞS1ìNGQTS6`Êcý×M=P;IF!

$ " & #
øÿQ÷D`M>Sæ<TþB>"îÚ5/Sæº#Á1øÿT5FU"CPT11"lOHP P
OS¹ÄQ]`õÄ:KM>"Bevacizumab"Cetuximab"Panitumumab POS9Ê4$E"WF@a^SÏMQ#¹éNPIFÝQc÷ÞNBF Regorafenib"TAS102 Q]`ÏMPOQ]_ìó¢S
üûT Best Supportive Care SXSD4;®;^D/.WM!BL=L7`.)!B;B"@a^SÏ
M>S¿¥NPIL7`4Ø$M>Shtq~mT3$.R<Ô>"åö#ìL£/<N¶PÓ¨c÷ÞNBLÒËAaFPÛÌ±S­Q

K>[S<VNdOM6`!="ÒÃSPÛSàQ:?

`ÏM÷ÞT"YBbESJPÝQU;_MTP7!¼RÓ"åö#ìL£/S"BFÓQ÷BL["Õ%S·6c9P<^ÏMBL7`S<³áM6`!øÿ°¤<ÆêBL7`øÿÏMigsy
g~cTCZND`Õigsyg~Q:7LT"¦OPÏM<%NP^P7ÓQ÷D`M>Se{kznw[ÐAaL7`/)!B;B"¼RÓ"åö#ìL£/S"BFÓQ÷D`M>SïéQHD`q&oT?B>"@SJPÓQ:7L"OSJPÏM<%NP`;S2ùT´%SPÛ

Q\GR^aL7`S<³ÒM6`!¾S°¤MT"¼RÓ"åö#ìL£/S"BFÓSq&ocíB"GÍÞS1ìNTD`ÊcB^;QD`@NcC$NBF!
*)!'%+,)Q:7L/--4.+/-.1SQîÚ5/Sæº#Á1øÿQ÷BLM><ËºAaFÓS8
H"32ÂSßSÓ/.ç"PS 1 ßSÓ4çS¬/5Ac÷ÞNBF!¯*T32ÂSßS¼RÓQ÷D`/0|lx~"PS 1 ßS"åö#ìL£/ÓQ÷D`4|lx~S½¬0.|lx~c÷ÞNB
F!Ó0ª(.R"é;"ECOGPerformance Status(PS)":óÝ"Õò£/"Á1'Ù1"²
18"²1ñSG@(ÏMÉÎ)"&ñ"ðâ©"CEA"M>S)"ÏM,I(ÇKEÄ"ÏM¢"ÏMµ(RECIST))N Grade 3 ßSGÍÞS1Ýá§(CTCAE)STQJ7L|r}
mvjpfuQícºIF!32ÂßS¼RÓQ÷D`/0|lx~(¼RÓ¨)"PS 1 ßS"åö#,øÅøø «°¤ ÝéÿÑÏM¡7»À"+ »ÀÜ
,,øÅøø «°¤ »ÀÜ

9 N o ¢ D 6 I F}

bqMxB<>4SPRT(z$}47bqc)CHdMg?>!

&'!!"%)#
¥DZ(W)E32k(00k+42k)(h¥qc%33k(31k+42k)"z$}

bqc%

24#
1k(00k+3.k))"|E|.,¤"u|--¤(h¥qc%|-2¤"u|3¤"z$}bqc%|0¤"u|0¤)A6?>!h¥qcAE PS 0 -4¤"PS 1 1¤C<"z$}b

qcD PS E4¤¤9 PS 1 A6?>!wE-0¤AGJL"h¥qcAE-,¤"z$}b

qcAE0¤A6?>!i¤9..¤"t¤(nXw¤)95¤(h¥qc%iw¤-5¤"t¤0¤"z$}bqc%iw¤/¤"t¤1¤)A6?>!Y_XV(r6K)Ea9-4'/-¤BjH:"h¥qc"z$}bqcAH-0'./¤"0'4¤BA6?>!o¢]lnCe9~v;L@7>w¤E.4'/-¤(h¥qc%.-'./¤"z$}bqc%3'4¤)A6?>!\`¢]lD CEA DZ(W)Eh¥qcA..#/ng'ml(.ng'ml+005/ng'ml)"
PS 1 UycA3#
1ng'ml(.ng'ml+3.ng'ml)A6?>(-)!
&! "$%#

Zj$V5U!^3%OS$n&*(%?jD<$n&)*%WKS"Mh:[D<
$n&+%

32
(00+42)33(31+42)24#
1(00+3.)

Lc$T#H%

.,'--

-2'3

0'0

PS$'#(#)%-4'-/',-4'1',,'4',

bRI$g#e%

-0'-3

-,'-/

0'0

BMI$V5U%

.
(-2#
.+.1#
1)
.-#

4
(-2#
1+..#
1)
.-#

(-2#
.+..#
,)
.,

..'5

-5'0

/'1

-'4'-','-.'5-'3',','-,'1,'-'-','.'0',

/'.4

.'.-

-'3

-4'5'0'0-0'5'.'.

0','.'.

1'-.'3'3/'4'3'1.'0','.

CEA$V5U!^3%

1(.+005/)--#/(.+005/)..#

1(.+3.)
3#

68idk$g#e%

5'..

3'-2

.'2

@]#F]$YBLX4%>]`2$Ce#A#T#D#S#R%>]Q-ge$Ci7AB%$g#e%
X4Q$Ea,.%$9#\#01/N#;G%
PJ=$tub1#tub2#por,muc#_f%"!$+(*\`¢DSPRTEh¥qcAE UFT'LV(*bevacizumab%U[ bev)5¤"Xeloda 1¤"XELOX(*bev)5¤"FOLFOX(*bev)/¤"=D-¤"z$}bqcAE XELOX(*bev)4¤

A6?>!lOHP DE¡cBHs£8J-^f£D-,,mg'm. 8JD]l;L@7>!p
mO&Q{DZ(W)Eh¥qcA2#
1O&Q(.O&Q+/2O&Q)z$}
O&Q(/O&Q+/.O&Q)A6?>(.)!

bqcA1#
1

48

PoS"cY^#[jJeS7_1>`bICFmg8@]Z7Hi1>AQ8D\-! '0+/

Lndj[^&n*-+'

HoN?
&n*,-'bX^"Zl=eN?
&n*0'

)
,
'
'&
'
(
'

)
,
'
+
*
'
(
'

&
&
&
,
(
&
&
&

.
&,)-/'/!
.
&,)-/'.!
.
&-)-,'

'
.
+
'-

&
*
)
',

'
*
(
'

UFT%LV
UFT%LV(Bev
XelodaXELOXXELOX(Bev
FOLFOXFOLFOX(Bev12]
MJ3$4Y#a6`
LnhGKE9fc
CR
PR
SD
PD

hERW9 peak grade 4 Grade 1 (n"Grade 2 17n"Grade 3 ,n4/32!PoSL49 Grade1 2 n"Grade 2 '(n"Grade 3 +n"cY^#[jJeSL49 Grade 2 +n"Grade 3 'nd4
/32!Grade 4"Grade 5 8hERW9lL5<7d;6032$f)%!Grade 3 8hERW9Bk(n"?X'n"VCGTM(n"OaKNU(n4/="PoSL49Bk'n"?X'n"VCGTM(n"OaKNU(n"cY^#[jJeSL49Bk'n8:4/32$f*%!
-" .$&(,*)%

gIk[^&n*-+'

HoN?
&n*,-'bX^"Zl=eN?
&n*0'

,
(
',
&
&

*
(
'(
+
&
&

(
&
+
'
&
&

G0
G1
G2
G3
G4
G5

-# .$&(,*)%

HoN?
&n*,-'[^&n*-+'bX^"Zl=eN?
&n*0'

G2

G3

G2

G3

G2

G3

7m
5V
5V
B_;
iRW@U:
O\TD?
S8<PA
Fa>CQ
12]

,
(
(
)
*
+
&
)
(

(
'
&
&
&
&
(
(
&

,
'
(
'
(
*
&
(
&

'
'
&
&
&
&
(
(
&

&
'
&
(
(
(
&
&
(

'
&
&
&
&
&
&
&
&

peak grade

'-

,

'(

+

+

'

49

6 I [ z A 2 E C!!($&'"#%)
Grade 3 J_AvOZ^HkD:Q\>kD?5;:Q\=mU>[zjwHoP9:VN"vOZ^
Anb>vK@R|A2FMY>9<"cd=Bas&ea'"BUN Wf"rYpiuAXx6&q-'"
W{\T=Bas&ea'> BUN"AST Wf6g]8G:&q.'!Lt"h`d$bySl\T@4
3<BvOZ^Anb>vK@R|A2FMYHg]=7?5;:&q/'!
;( =/46!$G3"+0@*,-3!:<>.7"89!n#'%"

AM"/.71;!HG#=E"?!:#
PS"P&*!P)+#
BMI"),,!,,'#
94!6B
35LFN"K!I#
WBC"><!2<#Hb"><!2<#
Plt"><!2<#
AST"><!2<#
ALT"><!2<#
Bil"><!2<#
BUN"><!2<#Cr"><!2<#
CEA"><!2<#
CA+0%0"><!2<#
LOHP"$!%#
D8C@J"$!%#

G(,

G)-

P

/%)0
),%))
),%))
)*%)+
.%)1
/%)0
*,%)
)/%0
**%+
*,%)

.%(
.%(
,%*
)%+%+
*%,
.%(
*%,
.%(
,%*
,%*
.%(
+%+
-%)
*%,
+%+
-%)
-%)

(#
-(),
(#
.+
(#
),
(#
**
(#
/1
(#
(#
1(#
*,
(#
(-(#
(-(#
*,
(#
((/
(#
-,
(#
1(#
/1
(#
+,
(#
(+
(#

*,%)
**%+
*,%)
*+%*
0%)/
))%),
).%1
1%).

;) =/46!$G3"+0@*,-3!:<>.7"2?51!n#&'"=E"?!:#
BMI"),,!,,'#
94!6B
35LFN"K!I#
WBC"><!2<#Hb"><!2<#
Plt"><!2<#
AST"><!2<#
ALT"><!2<#
Bil"><!2<#
BUN"><!2<#Cr"><!2<#
CEA"><!2<#
CA199"><!2<#
LOHP"$!%#
D8C@J"$!%#

G(,

G)-

P

))%/
))%/
*%).
-%)+
)0%(
),%,
),%,
)0%(
)0%(
)/%)
)/%)
).%*
*%)+
-%)(
0%)(
0%)(

-%(
)%,
*%+
)%,
-%(
+%*
-%(
+%*
-%(
-%(
*%+
-%(
)%+
)%+
,%)
,%)

(,
(#
(1
(#
).
(#
/*
(#
)/
(#
*0
(#
()
(#
,(#
(()
(#
+*
(#
-.
(#
/.
(#
)(#
),
(#

ü¤"Í³Á$·ôØ¤KÂAXÆÌr|öçMf»¶KîAXmMv¸

50<& >-24"%G3#).A(*+1"9=@,7#:58!6?/;30"n$'#18"3!/#
BMI"%22!22>#.*/,5)+=9>"<!:#
WBC"20!(0#Hb"20!(0#Plt"20!(0#AST"20!(0#ALT"20!(0#Bil"20!(0#BUN"20!(0#Cr"20!(0#CEA"20!(0#CA199"20!(0#7-64;"+!#

G$&

G%'

P

-%.
+%0
.%,%/
0%+
/%,
0%+
1%*
0%+
0%+
0%+
1%*
-%.
-%.
+%0

+%*
*%+
+%*
*%+
+%*
+%*
+%*
+%*
+%*
+%*
+%*
+%*
*%+
+%*
+%*

,+
*#
/3
*#
-+
*#
.*#
/3
*#
.*#
/3
*#

"

/3
*#
/3
*#
/3
*#
-+
*#
,+
*#
*1
*#

!

ÆÌ©Ù®ûKÂAX¢öNxtÏ¹ª§:Çl¡ºÈG4W"¢ë¹ª§:?YX!@9@"©Ù

9Vo{Ñj[ìAX®ûT¢ë¹ªÙ[;CA®ûS¬J<J5!BYVM®ûK85FN¹ªsØG4YOxtÏ¹ª§:ºÈ?YX:"¹ªáØJ²nèu[Ä@Cr|öçJIM»³
öç:ºÈ?YX!¢ë¹ªáØJ´$ÙÆÌM+¡¢öK85F"

ùJ¢ö[×ïG;X}¤

KÂ@FN"FOLFOX öç&FOLFOX4 öç8UP mFOLFOX6 öçJI'T XELOX öç"FOLFIRIöçHãßÏ¢öêHMäñ:+¡¢öMß¨¢öH@Fµ«?YF5X-'(/'!@9@">MðJ»³r|öçKÚDF"¬J9VLàÓGìy°:Ù·AX!¦ÖJìy°N97DF}¤M QOL [¿J6>HHJW"²KUDFN·è[9AU6JÅHJX>HS4X!ñAXêTr|öç
c]adKUW"IMðJìy°MàÓ:59KE5FNÜzÏ÷<ÊVYF5X:"IMðJ}¤Kìy°MàÓ:59KE5FN4QW÷<ÊVYF5J5!ìy°Mí½KE5FN"UGT1A1
kÒåi: CPT11 KUXìy°HýAX>H:ÊVYF5XÎÓG4X!ü¤TÍ³Á$·ôØ¤JIGN¦ÖJìy°:>DC²"·è:9?YXb^\:5CR"£Mú­M²
K85FNìy°Ù·àÓM5êTr|öçc]adMñ[7CW"ñAXêø[ø@F¢öMÓ[óH@CWAXJIMâ:ZYF5X!@9@"ìy°MÙ·[í½@"b^\:Í5HÛÉ?YC}¤K¥ãJ¢ö[6>H:G;YO"}¤KHDFMab_`NÆ;5H7VYX!
ü¤TÍ³Á$·ôØ¤[Â°H@Cú­MæH@FN"ü¤K85F5FU : Best Supportive Care UWìG4X>HNAGK¯é?YF8W"Ýü¤HÕðM¼õH·¾~:ÄG;X>H:æ?YF5X0'!Àäñr|öçK@FS"ÃïsØJ}¤[ºÈAYO"Ýü¤HÕðK£sØG4WuSÄG;XHMæ:4X1'!@9@"ürKÚ6³Á$·ôØMÍq"Àäñr|ñç:¦ÖJìy°HýAXHMæS4W2'"£Mú­M²K8=XÐpKNËh
:ÞòG4X!wMÔGÀ<£?YF5C UFT%LV öçK@FN"Hochster VKUX1/g±
Mü¤[Â°H@C ECOG +,33K85F"¼õ,+#2)"Time To Progression&TTP'.#0e"Median Survival Time&MST'+-#*eH÷JuG4DCHæ?YF5X3'!ZYZYN>YQ

= a » < P 8 Y U

51

KO­@¿PÒ¬$®#çî`æËLBF<.P>È¸¢`½·BJ>F/.)//)!0..2ÿ+0..7ÿO
1.?P­@¿`æËLBJ½·BF UFT'LV <.Pè!à>È¸¢KQ52+66°(íë6/#3°)P­@¿=óBA^"ß§9/5#
7-"ÁDÓ¦931#
4-"Öãíë01#
3yK8HF!4¹ËQ Grade
3 =0?(5-)"Grade 4 =/?(2-)K8\"Grade 3 }ÌPò4¹Ë`þVN<HF!@P¸¢`Â?J UFT'LV <.OæD] Bevacizumab PÌÍE§`øD]¸¢`2.?P­@¿(53+7.°(íë6/°))`æËLBJ½·BF!4§ÔOBJQß§90.#.-"ÁDÓ¦953#.-"
Öãíë0/#
5y"0ázÖã6#
7yK8HF!4¹ËQ Grade 3 P¨í¤Ç`/?
(1-)OþVF="Grade 3 }ÌP&ò4¹ËQ/.-}

K8HF!@^[ûIP¸¢PÞÖã=RSù÷K8]@L`«:]L"ÉÅ$Ý©XÜ¯ÜÊ"­{"é"ýNMú4P4
¹Ë=ì[^J9] Bevacizumab `,ãÊPä9­@¿P<.O,6D]sujl"ksujl
OI9JQ">â>ø='7K8]L«:[^]!TF"_^_^Qù¡ev&pO;9J¥³

ECOG Performance Status(PS)
12 P¿`æËLBF>È¸¢(»3ÚÆ)!$Ò¬®#çîO;?]/º»<LBJP XELOX(LOHP%/..mg'm0)*qngiro,6<.OD]4§ÔP(UMIN.....5440"óBÃ;"ðÙí)W½·BJ;\"­@¿"Ñå$Ö8!PñøBF¿OæD

]<.PÕØ`Ä×BJ9]!/¸¢OÛ:G"0./.ÿ/<[/0TKP/ÿOÒ¬®#çîP/º»<LBJ XELOX,qngiro<.`·¬BF±Pô5ÐOD]bxf&l`½·B"ü
Ï>ÈLBJPô5Ð`þBF!LBJ"ÞåP35#
3-K lOHP P¤=="04#0-K»<
Pï=¬_^J;\"½±P>ÈPÎO;9JQ¿PÐOCFæ=À[^J9]@L=$1B
J9]!
! $ # "
öO;?]

øKQ"­@¿XñÑå$Ö8!¿OæBJW"whsxX2²ô5=Pª*OZ\"|ÞO<.½·=!K8HF!Grade 3 }ÌP4¹Ë#ÖLêÔ"BUN ­ë(Þå"­@¿)"+µ(ò2´6(Þå)"AST ­ë(­@¿)PA`þVF!
&%/)Simmonds PC : Palliative chemotherapy for advanced colorectal cancer : systematic review andmetaanalysis. Colorectal Cancer Collaborative Group. BMJ 321%31/+313 0...#0)C3<.#çî»<dcmtcx(çî¡-)"~¶60./2ÿ%"06+13"£Å%
¼¾"õ"0./2
1)Douillard JY, Cunnungham D, Roth AD, et al : Irinotecan combined with fluorouracil comparedwith fluorouracil alone as firstline treatment for metastatic colorectal cancer : a multicentre randomized trial. Lancet 355%/.2/+/.25"0...#2)Tournigand C, Andre T, Achille E, et al : FOLFIRI followed by FOLFOX6 or the reverse sequencein advanced colorectal cancer : a randomized GERCOR study. J Clin Oncol 22%007+015"0..2#
3)Cassidy J, Tabernero J, Twelves C, et al : XELOX(capecitabine plus oxaliplatin)%active firstline
therapy for patients with metastatic colorectal cancer. J Clin Oncol 22%0.62+0.7/"0..4#4)Folprecht G, Cunningham D, Ross P, et al : Efficacy of 5fluorouracilbased chemotherapy in elderly patients with metastatic colorectal cancer : a pooled analysis of clinical trials. Ann Oncol 15%/11.+/116"0..2#5)Aparicio T, Desrame J, Lecomte T, et al : Oxaliplatin or irinotecanbased chemotherapy for metastatic colorectal cancer in the elderly. Br J Cancer 89%/217+/222"0..1#

ASC!MDI#FQ@NC6J58KL?;=RO79HE6>P58:B7<G

52

3'Aparicio T, Jouve JL, Teillet L, et al : Geriatric factors predict chemotherapy feasibility : ancillary
results of FFCD 200102 phase ! study in firstline chemotherapy for metastatic colorectal cancer in elderly patients. J Clin Oncol 31$,/1/(,/2+!-+,."
4'Hochster HS, Luo W, Popa EC, et al : Phase " study of uraciltegafur with leucovorin in elderly&* or ) 75 years old'patients with colorectal cancer : ECOG 1299. J Clin Oncol 25$0.42(
0/+-!-++2",+'Murata K, Yamamoto H, Fukunaga M, et al : Survival benefit of oral tegafur%uracil and leucovorin
as a first line therapy for elderly patients with advanced or metastatic colorectal cancer. Hepatogastroenterology 61$4/(43!-+,/",,'Mizushima T, Tamagawa H, Matsuda C, et al : Phase " Study of Oral Tegafur%Uracil and Leucovorin plus Bevacizumab as a FirstLine Therapy for Elderly Patients with Advanced or Metastatic Colorectal Cancer. Oncology 89$,0-(,03!-+,0"

$"#!*&(')+%! SÅNE+)ý4+*c³×EMD:!

"

?

¹

400¼

.

4

+

400¼

. 105

15

¿Ò$Õ%

105}ü)¿ÒTvqiz*

>+

10~

¨Trnk{cC¸>SÎ"Ü;>¤}T÷>¼"¡æ=QL=:),>Q*c>:",8ARûóTØR<É?D:!15R20¼.20ªOE"ªcN?`K@9@Mtw{pegpEMD:!XJ"CD-ROM"DVD-ROM ø)ohmp¾0ã*c¸>Ã"nsp7c8SÎÈR<à_D:!

# =&SÊ&7)+*Tç+¼"7"#7TË+¼N±D:!
$ Ö¼T·>Ö¼c>:"õB«ë~T CGS ë~N m"cm"mm"cm2"ml"l"dl"kg"g"mg QP
OEMD:!
% ¿ÒTÂ´}ÎSç?DNÞ8N9`BO"+¼\<c­G`Ï®Tpy&l{ju&r&c=@JÎR8EMD:!
&¨TáOEM/:JEXHd!¿Ò"ÕQPN/c?G`[SRTIS¹8EMD:!

' +T4+ïR>DaJ[SSYc9AMD:!4+ïS>¢ÇRT$­c(EMD:!
( +SÉ?1T½S];RùEMD:!
>+"ðÁ7T3ÔXNE"Ia}ÎT+ä,+et al,OEMD:!
¯+S±¾T Index Medicus Ç±RÅFMD:!
µ»SÏ®/>$­*ðÁ7%E+é7"µ»7"Ö"-Ö)ÙDþ­*ëª4SÏ®/>$­*ðÁ7%E+é7"É7).Á7*"""-"!ªÇ7"!ªî")ÙDþ
­*C

1*ô¥Fí"£§ Ì"ò

9"ä%S@2#O@2 7)12*%108-114"1870#

2*6ü'"ñêÝÿ"¶²

Ñ%°3SßÓì2#gfxm=^°3W)*)

Ð.*"è2""308'327"O@2À"ö"1872#

3*Umezawa H, Aoyagi T, Suda H, et al : Bestatin, an inhibitor of aminopepitidase B, produced by Actinomycetes. J. Antibiotics 29 :86-88"1865#)+úT"TFZRNTFX_"<b_RNV!

*

E+T?¹-TFZR-)åÍ-12-×Ú*-©|-<b_R-+-%-ÕSÛ8-ÕSÆR
¨c¦×EMD:!Õ<]U%RT+ïRÄ`Æ$R$­c(EMD:!

+¬:T½S];Q­c>:XG!
-#

,

((1#

((1*

((a

¨RT%ºc(E"%é"ðÁ7"Çâ"7" ¨5Ö"Õ%óÖc8EMD:!

#-&%()'#.!,$+*"%+*%ªò¾6)#S²BýBß$Çz)#éAÊ²Bï:?B_O$#%C$Ãñ

6¯#Îë²B2Bß$¯Ä*ø#1¸`,-.0/"$>ÉÂ)#Ä²B2Bß$@Í#oÿîd<Ù8$Ef~Õ¡#ÇP²B2?B_O$¤í¡#}Æ²B2Bß$òëJNø#S²B2Bß$ÈN#Û#¾t²B2Bß$äþ¸Ï#ÇA²B2Bß$

ÞÁ#²s²B2Bß$LÄ

#PÅ²B2Bß$

ö3ªò¾6)#S²BýBß$3®

÷Û#PÅ²B2Bß$#&C$A(î³v) #Çé²B2Bß$d@#¿²B2Bß${Ä

Yv#XÒ²B2Bß$»¤

Ö#éAÊ²B2Bß$
j·#S²B£°èe2B_O$

%+*&

w
õÄ

-Û#ÇPÅÿTpÙ8$ma´÷L#¨ù²B2Bß$

ÓI#²sÜÿ

Ù.0/"$

ç#îd<²B2Bß$

#Çé²BkxRÙ_O$Æ¶Û#ÇP²B2Bß$ÒÉë

ð·#1¸2?²B$r©·#éAÊ²B2Bß$.

²#Çé²BkxRÙ_O$Ä

¼K#ÇPÅÿTpÙ8$vg

ôÛ#m¸2?²B$¹Ä

Z6#S²B2Bß$¥7

Nó#[+K²B2Bß$#'C$ñ®

4)#;w²B2Bß$Vò

×#²á2?²B$cn×#wü2?²B$

mN

yì#ÇP²B2Bß$

M

Þ×#Çé²BkxRÙ_O$ú&9)#ËÆ²B2Bß$¤âÂ)#Çé²B2Bß$ò®

0Û#oÿÙ8S,-.0/"$Éc²Ö#²s²B2Bß$«Äl#Uë²B2Bß$

vQ

#N!ã²B2Bß$µÌ

#uê2?²B$%+*'

wëvHÛ#S²B£°èe2B_O$
%+*(

²¤

n#S²B2Bß$ò~Û#ÇPÅÿTpÙ8$#(C$¦Ä

Wv#;w²B2Bß$/ë5bL#ºÑ²B'2B\$

½

Y¬#S²B2Bß$

Eq,Ú#oÿ,-.0/"_O$m]¢#Uë²B2Bß$ÀÕ"#G_!G=B%æ.0/"$à¤$#1Ø²B2Bß$

!Ä
c

%+*)

÷#éAÊ²B2Bß$±D#oÿÙ8S,-.0/"$«w

F#¿²B2Bß$wÄ

6¡#îd<²B2Bß$^w

Û#[+K²B2Bß$

#iÆ²BcÔåÐ2B_O$û·#ÇP²B2?B_O$é®

h×#²s²B2BßÝ­G_O|§$

&+*'

¯]

ÃÙ$F3EÓJ%$'M%"/!*$~7,-.0/#%
àÚ

&+*(

Èæ÷?$fÓJ3Jû%ÜÏ

5æ$a¤ÓJ3Jû%Þ$ü43EÓJ%¹)p{þ$ÛÓJ3Jû%pà$`ÔÓJ3Jû%äà°:$ÓÓJñÄýômX¬%"Æ

)×$]n7,-.0/#mX¬%±ÖGÄ$ãYá7cô7%

r¿¥5$~7ô73:.0/#%

Uàt½$õ±3EÓJ%Ó0

9$,qBÓJ3Jû%Ý?$ãYÓJ3Jû%ÿ0lì$Om!OCJ:$.0/#%

0 Z5$ãYÓJ3EJmX¬%/Ñ

oP$a¤ÓJÄÒ&r3JmX¬%

V!àÝ>$gBT©ÓJ3Jû%d)=-$(3EÓJ%4 !¸$ãYá7cô7%¡bÍ?$èâÓJ3Jû%àÚ¸×$ãYÓJ@3ñÄýmX¬%àÚ

hÃ$NÅ3EÓJ%Åà

Sö$_RÓJ3Jû%ê0 ½$YáÓJ3Jû%+$uâÓJpð#í3JmX¬%

2$ÛÓJ3Jû%[) ´$gBT©ÓJ3Jû%8Ä÷ö$ãY­3EÓJ³CQô.0/#%õA 6ì$ÓÓJ3JûúÐOmXÇ%Ìà

D?$ÜÓJ3Jû%[Óºwì$AÓJ3Jû%¯°ö$É4n,-.0/#%$)M%?Ñ

¦¾$äàJ>!k;ÄÓJ3Jû%
v$«ßåÓJ3Jû%®²¸ó$èâÓJ|ÎEJmX.0/#%Dä?$ÓÓJñÄýômX¬%`Ô

zë$¹KÓJ3Jû%)ª5$2Øn,-.0/#%ä£$2Øn,-.0/#%=/*?$ã'ÓJx^ômX¬%})$ãYá7cô7%

ç

Ý

ÚÑ

&+**

6$\3EÓJ%ÚÑ$(M%Aû

&+*)Ãö$~7,qBô7i<ô.0/#%¯;ÃAÞ$Óù7Á½ô.0/#%±) e$ÓÓJ3Jû%W"!$'IæÓJ3Jû%s%$É4ÓJ3JûïOmXÇ%Uà

AH$¹KÓJ3Jû%§·5$âÓJ3JûúÐ¢CmXÇ%Ë0.8$ãYÓJ3EJmX¬%ÕÄ$Yáù73EÓJ%A»T$Óù7Á½ô.0/#%µàÂ@$gBT©ÓJ3Jû%

yä

À

¯Ê

Zw$}Ø3EÓJ%Là

×$uâÓJpð#í3JmX¬%¼é/<$YáÓJ3Jû%¯më$§àÓJ3Jû%ä

Ã×$ãYÓJ3Jû%ÖÊ6ó$ü43EÓJ%$*M%1û

jè9î¶¾¸$ÓÓJñÄýômX¬%$uâÓJpð#í3JmX¬%¨$wÌÓJ3Jû%
kó$a¤ÓJÄÒ&r3JmX¬%
Þ$~71&;ÄmX¬%Ã$õ±3EÓJ%ø9þ0$\3EÓJ%k$ãYá7cô7%
Ãò$äàJ>!k;ÄÓJ3Jû%

&)()

/¸

@)#Ò\ÀG2Gì$²µ*#c÷ÀG2Gì$v#ö2BÀG$O8{#Àè"¬©å,.-"$¤Î%#0Äi*+,.-"h[$½Î

sq#0äÀG2Gì$>Î¨#øk?"ÀG2Gìî2Gh[$µÕþ#ÀÀG2Gì$Iµ .ç#Y#ðÀG2Gì$AÓÄx#0Äi*+,.-"$`ùß#}"*+,.-"å5$±Ó0ûØ#=æ"ÀG2Gì$z¤ÿ4#ÖÑÀG2Gì$Æ¼

#Ò\Ï"b~å5$

Ó÷V#zÄ2BÀG$ÇÎPYþ#^2BÀGº|2&,.-"$¡ü®S#ÒõÀG2Gì$

w3

ñù#0Äi*+,.-"$

Z÷

qÃ#dÞÀG2Gì$#yµ2BÀG$;Ó

nç#Ò\2BBÀG2Gìê»å5$«

ÌÕ#\ÏÀG2Gìê»å5$#)L$3&))%#&%L$Úü
¹&))&{#ÖÑÀG2Gì$ß#^2BÀGº|2&,.-"$

ûÂ¢ç#ÀÀGâ¯íåh[$ÅÎt#ÍÔÀG2Gì$ÑÊ

Yù#ÑÀG2Gì$ÎÆ$4#¦JÀGÝh[$Ð]

4e#Ë\ÀG2Gì$ÆÑ¶#øk?ÀG2Gì$¦Êÿ)#ö2BÀG$°¼¿#aÀG¯¾ôm2Gh[$F¯:#ÒDÀG2Gì$j¥Û#}"å5a*+,.-"$

Ó÷

úÃ#0Ä2BÀG$·jPã#aÀG2Gì$ªÂ

S#}"2&h[,.-"$
1Óç#0Äi*+,.-"h[$+#¥ÀG2Gì$

c¥ç#rÑÀGjàòÜ2Gh[$£ï#zÄ2BÀG$AÓû¼q)#Ò\2BÀG$Cü

ó#QéÀG2Gì$(û-#pÀG2Gì$ÎÆ'ù#Ò\Ï"b~å5$

ï3

YM#Ò\ÀG2Gì$§Tu#Àè"¬©å,.-"$

X#&&L$µ9

Ó8

R#aÀG¯¾ôm2Gh[$"#ö2BÀGê»*+h[$ÿ#Nh!Nh[$o#Àî2BÀG$áÑþ#Ù÷ÀG2Gì$×

#øk?ÀG2Gì$p­#\Ïè"2BÀG$ý'Ø)#øk?"ÀG2Gì$³Á

l#^i"*+,.-"$

sÛ#}"*+,.-"Æ<å5$#&'L$Ej¥ù#ÉÀG2Gì$

g¡

$Û#È

C¼

7Ø#õ!h[å5$WÅ

f#!e,*+,.-"$

û÷

1ã#ÀÀGâ¯íåh[ê»å5$KL/#õDÕÀG2Gìê»Nh[´$&))'ÀG2Gì$_6 'ã#\ÏÀG2Gì$Ó

U¯#Àî2BÀG$0ëSþ#`ÁÀG*+h[$´H¥x#Ò\Ï"b~å5$Î#¦JÀG2Gì$Ð3

#Àè"¬©å,.-"$

%++&

ïG ³>#êa7GGÔO7O!$

ÃÎ{#êMÔO7O!$#%&R$Cª|#dÕÔO7O!$]NÓ³#5tBÔO7O!ùÒ»wo`Æ$%++'H#"èpC7GÔO$ÔS

ÓE#AÔO7O!$#%'R$(nN#Â23.417GÔO$/è

½¡#jO[¦ÔO7O!$

gs

4#±MÔOþÍ-¤ù;$®Ú

L#Wo!Wo`¬$q

ô#àaÔO7O!$

5!

>ä

Á±#aæýC7GÔO$ÿYð#/MíÔO7O!þÍWo`Æ$ÖÎçä

F±#êaÔO7O!$

u8

JM#êaæCfù;$üäTû#cpC,-/40"o`¬$ÜÎ

b9#êa7GGÔO7O!$

Rä?%#Wo!WDOF+/40"$&Aá#ÔýC¼¸ù/40"$&A¶S#aæÔO7O!$

0­[#ê/ÔOEJ7Oo`¬$]ä²ð#5tBÔO7O!ùÒ»wo`Æ$Ë<

iK#Wo!WDOF+/40"$

Úä

L#C,-/40"Ü?ù;$#%(R$Î¾ñ#aæÔO7O!$

AäÉ#e¢ÔOÀÑ.w7Oo`¬$ÅPÁ9#ê/ÔO7O!$\Ù]#17GÔO7O!$®<

Øø#/MíÔO7O!$º2

â#_7GÔO$¿7r#dÕÔO,-o`¬$äÜn9#´QÔO7O!$

ßØ¡#5tBÔO7O!þÍù;$´äÓ#«ãìÔO7O!$úzí¼#5tBÔO7O!$²

;#ÛóÔOI°7Ol$

ë2£9#Ç@p,-/40"$<Q±û#Wo!Wo`¬$¨¡#è7GÔO$

]ä

%++(

%++)

A2

¯#5tBCÔO7O!$7Oo`¬$#%)R$ëÝöt#Chù;$
éä
äÜ
I8

#@úCÔO7O!$
yû#~èÔOsõ*ò7Oo`¬$#ÔýC¼¸ù/40"$

vë#MHpC7GÔO$Ê#êaæCfù;$¥Ì#àaÔOÀ#}Oo`/40"$ë|#àaÔO7O!$

ä

S#jO[¦ÔO7O!$

ÜÎ#ÞÔO7FZ§×XÔO!$ëä©#aæÔOÔO;7Oo`G$

36¾[#dÕÔO,-o`¬$U:ô#7GÔO7O!$µ

6L#êaÔO7GOo`¬$<È

T#e¢ÔOÔO;¹BOo`G$¡#aæÔO7Oo`G$ÄÈ#ÔýC¼¸ù/40"$

bx#^D'ÔO7O!$ÔÈMP îû#e¢ÔOÀÑ.w7Oo`¬$
%++*

=8

#%*R$6ê
®Q

k9#7GÔOm=7Oo`!8$

8
:

º2

Ö

¾ø#VÃåHù;$ë ;#ê/ÔOEJ7Oo`¬$,9#Wo!WDOF+/40"$

ÏA÷ML#·ïÈpC,-/40"$

û#ÛóÔOI°7Ol$ÐL#Ø7GÔO$²Î

nK#êaÔO7GOo`¬$)~#C,-/40"Ü?ù;$

&++(

M

#&(P$
&++)

=#Æú;GÆN;Nø$\²1#~I;GÆN;Nø$ZÂ¨ï#[6üÆN¸*GNi]¡$

Óu#}5,0475"i]¡$°ÿ

t=#&;GÆN$FÆ#8Ðj,0475"i]¡$ÙÒ

Jó#eÆN;Nø$=#}5q@¸>ANø$Þ¨#ÆÆN;Nø$Ö¸#Si!Si]¡$? ´±#vÞÆN;Nø$¹A#&)P$³m
Ìn

&++*

Ò¼l

ª#»3j,0475"$-Ù%<+#ß$ÆNÆN>;Nhi]G$©

£#&*P${në#}5,0475"ÒBð>$0#9¼;GÆN$0#ß^ÆNÆN>;Nhi]G$?-

7ë#Æô5´±ð475"$~à¦#&;GÆN;Nø$¥#}5ð>e,0475"$Ê

×æ#Æ5ÆN;Nø$ÒÞ)¼

w=#ß^ÆN;Nø$Ûêl¶ñ#ß^;GGÆNäRi]¡$

í·ï#;GÆN$òé¬>#8Ðj,0475"$½Ë

#Ø4./-¾Ï¡;Ni]¡$Â<¢#g@YÆN;Nø$:kq¶#a;GÆN;Nø$Æ«iå#ßKÆN;Nø$þ#ÆN;Nø$. 7ó#Si!SDN8"475"$
&+++

<«

ï#ÆÆNÆN>$#&+P$ÆÇ

#vÞÆNlì!ç;Ni]¡$

FIË/z#vÞÆN;Nø$H«

0#g@YÆN;NøºÍ;GNi]¡$¯L

2=#^ÜÆN2163i]¡${Ö#&;GÆN$ÙÒ

#$KáÆN;Nø$ÝÙ¶À#­OÆN;Nø$-Ùµ#ß^;GGÆNäRi]¡$(Å§W#^ÜÆN;Nø$sÙ

Ô#dÈÆN,0i]¡$®? [7#UõÆN;Nø$

ZX

ÉQ#I;GÆN$C-·7#cVÆN;Nø$

ÚC
'%%%

<«

÷#eÆN¸Ä#o;Ni]¡$¶#dÈÆN;Nø$#'%P$H- ûó#}5f'ð>$[ÿâ#g@YÆN;Nø$£¹

û1#;GÆNÆ\;8475"$~àë#dÈÆN,0i]¡$ÙÒ

y=#^ÜÆNÆN>$Ò- #eÆNÆN>$î-`ó#Si!Si]¡$

ù'

©Â

r

N#ß$ÆNF<;Ni]¡$
Eæ#vÞÆNlì!ç;Ni]¡$+#ÑèÆN;¤;Nh$

Z¼

#ÆÆNÆN>$ßû#g@YÆN;Nø$£:}ï#bj5,0475"$

BÕ_Tv#~I;GÆN${_#ß^ÆN;NøöÁð>$Ùlb,

Ó9#$KáÆNÆN>$

ZÙ
'%%&

°ã,¯4#ß^;GGÆN;N¿|i]G$

Ðæ#ß^;GÆN$Ã#Si!Si]¡$#'&P$ý- pÎ#eÆNÆN>$x#ß^ÆN;GNi]¡$

'%%&

à

#'&P$7è
ÐK
¡Â
'%%'

§å

À#×r=Û@ý;$ù#ÓÓMûÈ$ýq`¯$
Ì#éb°6FÓMõ¾o021"$'%%(

L#^>)ÓM6M"$·³º#h¤ÓM6@[«ÖVÓM"$2

ù~#16FÓM$?êÌ9#H6FÓM$Á#=./021"q`¯$¬#/JìÓMÓM;$#''P$O7 ¬X#®äëÓM6M"$
AÛè

Ä?#Ê6FÓM$c-#gÔÓM./q`¯$'ßÆ#Óÿ=Ã¿ý021"$¸2 ¹ñ#©ÓM6M"$±ËFE#/<ÓMéý;$c

m:#ébæ=iý;$xåÆù#mH\ªÓM6M"$±7I#ÚöÓMC²6Mn$#'(P$¾åÌ¹#ébÓM6M"$

uS

G7

ñ#;ÓM6M"$

Â

ðt

kó#Óÿ=Ã¿ý021"$'7

þ#Tq!Tq`¯$

0{

9#mH\ªÓM6M"$
z#èÓMý;$G7

E%#èÓMÓM;6MÍq`F$

kó#Tq!TDM@,021"$

:#h¤ÓMý;$åÛ%k#bæÓM6M"$

ÛèvÕ

F^#4×r./021"$Å½Æ£#h¤ÓMÈÒ.y6Mq`¯$

2jÕ

µ4#=Ã86@021"$

ô

Ý~#5BÓM6M"$#'*P$Gçã}#ébÓM6M"!Ïý;$

çC



(5

Qþ#gÔÓM6M"!Ïý;$øt:#e6FÓM$ÜÕÊ|Y#3vCÓM6M"!Ïý;$<ÈÓZ#Ó=ÓMÓM;$B»:#é/ÓM6M"$

ò7

Ió#Ó=ÓMÓM;$Ë2 ¥:#ÓÓMÓM;$7¸

k#×ÓM6M"$

Óé4#Óÿ=Ã¿ý021"$

©#ébæ=iý;$ÙïÎ#¾x6@021"$#B F6#&w6FÓM$ê7Æ¿#éb6@021"$

92¸7

Ç¹#Óÿ=Ã¿ý021"$

'%%)

a¨

#')P$Ç_

'%%*

'%%+

#'+P$Ñå
±B
Iå

'%%,

í#fWÛ@d"R021"$
#îAr=6FÓM$
4^#Óÿ=+*pÍ6@021"$:#ÜÓM6M"!M"!Ïý;$#',P$÷Ctp#Tq!84ý;$='%%-¶ü#ò26FÓM$â#U¢6FÓM6M"$­#mH\ªÓM6M"$
É#lr=Û@ý;$´#=./021"Û@ý;$#gÔÓMÓM;$Þ3¦:D#ébÓM6M"!Ïý;$¹á#ébæ=iý;$¼Ø

:ó#èÓM6M"!M"!Ïý;$s¶A#gÔÓM6M"!Ïý;$7

3v#=./021"Û@ý;$NØ]#h¤ÓMÓM;$úÕ>£#3vCÓM6M"$

Ùèº}#Tq!84ý;$#'-P$¼Ø :ó#èÓMÓM;$

'%%*

®Ä

ó#(,2354"Úè<$t$,#dÇ8GÆO$ZË;#dÇÆOÆO<$Ö4­ç#÷'ÆO8Oï$!

²z#ÌâÆOÆO<$lX#UíÆOÆO<$Í³ºà#Æ8+354"$o#Ú^ÆOÆO<$ðïùÕ

x/#Ú^×(fè<$\ÕÚµ#Æ8GÆO$¼¾

Já#Ý,s(8GÆO$§È

3#0Hs(8GÆO$ÐÕÛu

Xá#ÆÆOÆO<${0ÿ#UíÆO8Oï${?&#ÆÆOÆO<8Omr]G$YÊ>#k1X¤ÆO8Oï$Â;#gãÆOÆO<8Omr]G$ÛÈ

0º#(è<VÆ8+354"$ùºü#Æì(¸µè354"$\Õ|#ÎÆOè<$

\Õ

X

t9

Øç#Ú÷ÆOè<$En#÷'ÆO8Oï$=ù£*#c8GÆO$P»

0ä#T8GÆO8Oï$Û

#ø8GÆO$¥·/+1#e¢ÆOè<$#'*Q$!Õ
ÎÈ¾'%&%#(%Q$¬'%&&#(&Q$Ñ

'%&'#('Q$ª»#ÙÆOuåõ¿8GOr]©$

W#,2r]L#üè<$ö#k1X¤ÆO"Oï$ä#ÆÆOÆO<$#^×ì(8GÆO$´;#½%ÆOÆO<$#k1X¤ÆO8Oï$2þº}#6És,2354"Í@è<$a£Ó#Æì(¸µè354"$ÈB´¡#ñws(,2354"$

ùR«#Ú^×pÎ 8+354"r]©$®þ

M'#k1X¤ÆOè<$Ä¯?¡#dÇÆO¹iNG$

9¯

h#ÉÆO`:r]ï$C?#e¢ÆOè<$#((Q$Iq#ûvD(ÆOÆO<8Or]G$÷b¾~Ó#ÆÆOÆO<8Omr]G$ÕÒ.#[)òÆO8Oï$Ù

ýê#dÇ8GÆOÁ8Or]©$Ä_#y8+354"!Í,2354"$!°¦ô#ûvD(ÆOè<$

Sa

'%&(

'%&)

þE

#()Q$ª»a

#k1X¤ÆO8Oï$æ#Æì(¸µè354"$

O#Æì(¸µè354"$ª

7$#k1X¤ÆO8Oï$

W#,2r]L#üè<$úu

Xá#¨ÔÜÆO8Oï$±#Ú÷ÆOF-8Or]©$ÈÞ

jK#ÉÆO8OïîÃè<$ä[#Æ(ÆOÆO<8Or]G$ëÕÏµ#Aé(ÆOÆO<8Or]G$ÍÀßÈÅ¶#Ú^ÆO8OïîÃè<$ÎÈ¾Æ;/#ñws(-.0è<$

6Sw§D2KH+,_

*/+k*, Zv
*/+k+) q

"

q

!

#

o[t

6S{^w§mfts w | 4¢3rQ<E\cC4`33=:G;!
')+-&((.) hpidn)&*/&TUVW+1,-*.&.,0+¨$(+%

Zv~ XjZv
D¤DY2O3ER¡@"xba35BO
CL>?Jx#;O8AE"¦@IMP=rR
7"uz4LF}zDl¥D]CBNG;D@"£I
yDgReI?\93!