Phase I/II of Neoadjuvant Accelerated Short Course Radiation Therapy With Proton Beam and Capecitabine for Resectable Pancreatic Cancer
Phase: PHASE1
Conditions: Pancreatic Cancer
Sponsor: Massachusetts General Hospital



Pa ge 1 of 3 4 
Versi o n date:  1 2/ 2 0 1 0 
D a n a F ar ber / H ar v ar d C a ncer Ce nter: 
M ass ac h usetts Ge ner al H os pit al, D a n a F ar ber C a ncer I nstit ute 
P hase I/II St u d y of Ne oa dj u va nt Accelerate d S h ort C o urse Ra diati o n T hera p y wit h Pr ot o n Bea m a n d 
Ca pecita bi ne f or Resecta ble Pa ncreatic Ca ncer 
St u d y Tre at me nt: 
Pr ot o n Bea m Ra di ot hera p y 
Ca pecita bi ne 
Pa ncreatect o m y 
S u p p ort Pr o vi de d B y: 
 P O- 1 
M G H De part me nt of Ra diati o n O nc ol o g y 
M G H De part me nt of N uclear Me dici ne 
Pri nci pal I n vesti gat or: 
T he o d ore S. H o n g, M D ( M G H)  
Site Pri nci p al I n vesti g at ors: 
Har ve y Ma m o n, M D, P h D ( D F CI) 
C o-I n vesti gat ors: 
Carl os Fer na n dez- del Castill o, M D  
La wre nce Blasz k o ws k y, M D  
Mic hael Bla ke, M D  
T h o m as De L a ne y, M D 
Al a n Fisc h m a n, M D 
A n dre w W ars h a w, M D 
Jeffre y Clar k, M D 
E u nice K wa k, M D, P h D 
Da vi d R ya n, M D 
A n dre w Z h u, M D, P h D 
Jill Alle n, M D 
Ara m Hezel, M D 
Jeffre y Me yer har dt, M D 
R o bert J Ma yer, M D 
Crai g Earle, M D 
C harles F uc hs, M D 
Peter E nzi n ger, M D 
Matt he w K ul ke, M D 
Pa n kaj B har ga va, M D 
D us h ya nt Sa ha ni, M D 
Bi n d u Sett y, M D 
Na garaj H olal kere, M D 
Je n nifer W o, M D  
Ra kes h K. Jai n, P h D  
Ga briel Da n D u da, D M D, P h D  
Researc h C o or di nat ors:  
A d diti o nal St u d y Staff: 
 
Res p o nsi ble D at a M a n a ger 

 
Pa ge 2 of 3 4 
 
  
 
St u d y N u m ber:  0 6- 2 4 8 
 

 
Pa ge 3 of 3 4 
S C H E M A 
 
P h ase I/II St u d y of Ne o a dj u v a nt Acceler ate d S h ort C o urse R a di ati o n T her a p y wit h Pr ot o n Be a m a n d 
C a pecit a bi ne f or Resect a ble P a ncre atic C a ncer wit h  1 8 F-l a bele d-fl u or ot h y mi di ne P ositr o n E missi o n 
T o m o gr a p h y Bi oi m a gi n g 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P h ase I:  3 p atie nts per le vel, 6 p atie nts at le vel 4 
P hase II: 2 5 patie nts at M T D 
 
R a di ati o n Acceler ati o n Sc he m a ( D ose Le vels): 
Da ys 1- 1 4:  
Pr ot o n Bea m Ra diati o n will be deli vere d i n a pr o gressi vel y accelerate d as bel o w: 
 
D ose 
L e vel 
e a d-i n 
h ase 
D ose/fr ac ti o n  
# T x  
Fr acti o n ati o n  
Sc he d ule 
T ot al 
D ose 
Wee k 1 
Sc he d ule 
Wee k 2 
Sc he d ule 
T ot al D a ys 
1  
1  
3 C G E  
1 0  
Q D 
3 0  
M T W T h Fri  
M T W T h Fri  
1 2 
  
Ste p 2  
D ose/fr acti o n  
# T x  
Fr acti o n ati o n  
Sc he d ule 
T ot al 
D ose 
Wee k 1 
Sc he d ule 
Wee k 2 
Sc he d ule 
T ot al D a ys 
2  
1  
5 C G E  
5  
Q D 
2 5  
M W F  
T T h  
1 1 
3  
2  
5 C G E  
5  
Q D 
2 5  
M T T h Fri  
M 
8 
4  
3  
5 C G E  
5  
Q D 
2 5  
M T W T h Fri  
- 
5 
 
Ca pecita bi ne will be a d mi nistere d orall y dail y i n t w o di vi de d d oses.  T he d ose of ca pecita bi ne is fi xe d at 
8 2 5 m g/ m 2 P O BI D f or a t otal of 1 0 da ys ( M- F) 2 wee ks. 
Bi o ps y pr o ve n 
resecta ble pa ncreatic 
ca ncer 
- 
n o metastatic 
disease o n C T 
- 
la p or osc o p y 
ne gati ve 
- 
la b orat or y 
e val uati o n 
- 
si g ne d 
c o nse nt 
 
Accelerate d pr ot o n 
bea m ra diati o n wit h 2 
wee ks of ca pecita bi ne 
At 3- 6 wee ks 
- Re-sta gi n g C T  
 
Pa ncreatic o d u o de nect o m y wit hi n 2- 7 wee ks of 
c o m pleti n g R T if n o metastatic disease 
Ge mcita bi ne base d c he m ot hera p y 
x 4- 6 c ycles 
  O R
Pa ncreatic o-
d u o de nect o m y 
wit hi n 2- 4  wee ks 
of c o m pleti n g R T. 
 
Patie nts w h o 
select t his o pti o n 
will n ot get re-
sta gi n g C T sca n. 

 
Pa ge 4 of 3 4 
T A B L E O F C O N T E N T S 
S C H E M A............................................................................................................................ 2 
1. 0  O BJ E C TI V E S ............................................................................................................ 4  
2. 0  B A C K G R O U N D ....................................................................................................... 4  
3. 0  P A TI E N T  E LI GI BI LI T Y .......................................................................................... 1 5  
4. 0  T R E A T M E N T ........................................................................................................... 1 7  
5. 0  P R E- T R E A T M E N T, O N- S T U D Y A N D P O S T- T R E A T M E N T E V A L U A TI O N S . 2 3 
6. 0  R E Q UI R E D  D A T A  T A B L E ..................................................................................... 2 4  
7. 0  D E T E R MI N A TI O N O F M T D A N D D L Ts .............................................................. 2 5 
8. 0  T O XI CI TI E S A N D D O S E M O DI FI C A TI O N .......................................................... 2 6 
9. 0  A D V E R S E  E V E N T S................................................................................................. 2 7  
1 0. 0  E V A L U A TI O N O F R E S P O N S E .............................................................................. 2 7 
1 1. 0  S T A TI S TI C A L  C O N SI D E R A TI O N S....................................................................... 2 9  
1 2. 0  R E T E N TI O N O F R E C O R D S.................................................................................... 3 0 
1 3. 0  R E F E R E N C E S .......................................................................................................... 3 1  

 
Pa ge 5 of 3 4 
 
1. 0  
O bjecti ves 
1. 1
 Pri mar y
  
1. 1. 1  
P hase I:  T o deter mi ne t he feasi bilit y a n d t ole ra bilit y of ra diati o n t hera p y deli vere d wit h pr ot o n 
bea m i n a o ne wee k accelerate d sc he d ule wit h c o nc urre nt ca pecita bi ne f or pa ncreatic ca ncer. 
1. 1. 2  
P hase II: T o de m o nstrate a gra de 3 or greater (a n y) t o xicit y rate of less t ha n 2 0 %. 
1. 2  
Sec o n dar y:  
1. 2. 1   
T o deter mi ne t he c o m plete pat h ol o gic res p o nse rate of pre o perati ve ca pecita bi ne a n d pr ot o n bea m 
ra diati o n t hera p y i n patie nts u n der g oi n g pa ncreatic o d u o de nect o m y.  
1. 2. 2  
T o deter mi ne t he pr o gressi o n-free s ur vi val i n patie nts treate d wit h pre o perati ve ca pecita bi ne a n d 
pr ot o n bea m ra diati o n t hera p y.  
1. 2. 3  
T o deter mi ne t he t o xicit y of ca pecita bi ne a n d pr ot o n bea m ra diati o n t hera p y i n patie nts wit h 
pa ncreatic ca ncer.   
1. 2. 4  
T o deter mi ne t he s ur gical m or bi dit y i n patie nts u n der g oi n g pa ncreatic o d u o de nect o m y w h o 
recei ve d pre o perati ve ca pecita bi ne a n d e xter nal bea m ra diati o n t hera p y. 
1. 2. 5  
T o deter mi ne 3 0- da y p ost- o perati ve m ortalit y after pa ncreatic o d u o de nect o m y i n patie nts w h o 
recei ve pre o perati ve ca pecita bi ne a n d e xter nal bea m ra diati o n t hera p y. 
2. 0  
B ac k gr o u n d  
2.. 1  
Ne o a dj u v a nt T her a p y 
Pr os pecti ve a n d retr os pecti ve data s u g gest t hat c o m pare d wit h s ur ger y al o ne, t he c o m bi nati o n of 
pa ncreatic o d u o de nect o m y wit h p ost o perati ve fl u or o uracil ( 5- F U) a n d e xter nal- bea m ra diati o n t hera p y ( E B R T) 
i m pr o ves s ur vi val d urati o n a n d l ocal-re gi o nal c o ntr ol.1, 2  H o we ver, t he m or bi dit y a n d ofte n pr ol o n ge d rec o ver y ti me 
ass ociate d wit h pa ncreatic o d u o de nect o m y pre ve nt t he ti mel y deli ver y of p ost o perati ve c he m ot hera p y a n d E B R T i n 
at least 2 0 % of eli gi ble patie nts. 3 T he ris k of dela yi n g p ost o perati ve a dj u va nt c he m ora diati o n has pr o m pte d 
i n vesti gat ors t o assess t he efficac y of c he m ot hera p y a n d E B R T bef ore pa ncr eatic o d u o de nect o m y i n patie nts wit h 
p ote ntiall y resecta ble a de n ocarci n o ma of t he pa ncreas.  Se veral c o nsi derati o ns s u p p ort t he use of pre o perati ve 
c he m ot hera p y a n d E B R T.  First, p ositi ve gr oss or micr osc o pi c mar gi ns of resecti o n al o n g t he ri g ht lateral b or der of 
s u peri or mese nteric arter y ( S M A) are c o m m o n f oll o wi n g pa ncreatic o d u o de nect o m y, s u g g esti n g t hat s ur ger y al o ne 
ma y be a n i na de q uate strate g y f or l ocal t u m or c o ntr ol.
4 Sec o n d, beca use c he m ora diati o n is gi ve n bef ore s ur ger y, 
dela ye d p ost o perati ve rec o ver y d oes n ot affect t he deli ver y of m ulti m o dalit y t hera p y.  T hir d, patie nts wit h 
disse mi nate d disease e vi de nt o n resta gi n g st u dies afte r c he m ora diati o n are n ot s u bjecte d t o a n u n necessar y 
la par ot o m y as s ur ger y w o ul d n ot be nefit t hese i n di vi d uals.   
St u dies fr o m t he M D A n ders o n H os pital first use d a sta n dar d-fracti o nati o n treat me nt sc he ma of 
pre o perati ve c he m ora diati o n a n d pa ncreatic o d u o de nect o m y. 5- 8 Ra diati o n t hera p y was deli vere d 5 da ys/ wee k o ver 
5. 5 wee ks deli veri n g a t otal d ose of 5 0. 4 G y i n 2 8 fracti o ns.  5- F U was gi ve n c o nc urre ntl y b y c o nti n u o us i nf usi o n at 
a d osa ge of 3 0 0 m g/ m 2 per da y, 5 da ys per wee k, t hr o u g h a ce ntral ve n o us cat heter.  T hirt y-ei g ht patie nts were 
e val ua ble f or a nal ysis of patter ns of treat me nt fail ure ; 1 peri o perati ve deat h occ urre d.  T u m or rec urre nce was 

 
Pa ge 6 of 3 4 
d oc u me nte d i n 2 9 patie nts: 8 rec urre nces ( 2 1 %) were l ocal-re gi o nal (i n t he pa ncreatic be d a n d/ or perit o neal ca vit y), 
a n d 3 0 ( 7 9 %) were dista nt (i n t he l u n g, li ver, a n d/ or b o ne).  T he li ver was t he m ost fre q ue nt site of t u m or 
rec urre nce, a n d li ver metastases were a c o m p o ne nt of fail ure i n 5 3 % of patie nts ( 6 9 % of all patie nts w h o ha d 
rec urre nces).  Is olate d l ocal or perit o neal rec urre nces were d oc u me nte d i n o nl y 4 patie nts ( 1 1 %).  I n c o ntrast, 
pre vi o us re p orts of pa ncreatic o d u o de nect o m y al o ne f or a de n ocarci n o ma of t he pa ncreas d oc u me nte d l ocal 
rec urre nce i n 5 0 t o 8 5 % of patie nts.9, 1 0 T he i m pr o ve me nt i n l ocal-re gi o nal c o ntr ol wit h pre o perati ve c he m ora diati o n 
was see n e ve n t h o u g h 1 4 of 3 8 e val ua ble patie nts ha d u n der g o ne la par ot o m y wit h t u m or ma ni p ulati o n a n d bi o ps y 
pri or t o referral f or c he m ora diati o n a n d re o perati o n.  E xcl u di n g t hese 1 4 patie nts, l ocal or perit o neal rec urre nce was 
a c o m p o ne nt of treat me nt fail ure i n o nl y 2 patie nts ( 8 %).  H o we ver, t his 5. 5- wee k c he m ora diati o n pr o gra m was 
ass ociate d wit h gastr oi ntesti nal t o xicit y ( na usea, v o miti n g,  a n d de h y drati o n) t hat re q uire d h os pital a d missi o n of o ne 
t hir d of patie nts. M ore o ver, i n a n E CO G trial e val uati n g pre o perati ve c he m or a diati o n f or pa ncreatic ca ncer patie nts, 
5 1 % of patie nts re q uire d h os pital a d missi o n f or t o xicit y of treat me nt d uri n g or wit hi n 4 wee ks after c o m pleti n g 
c he m ora diati o n. 1 1 
T hese fi n di n gs pr o m pte d a c ha n ge i n t he deli ver y of  pre o perati ve c he m ora diati o n at t he M D A n ders o n i n 
fa v or of s h ort c o urse E B R T.  I n a series of pr os pecti ve trials, i n vesti gat ors at M D A n ders o n treate d 6 0 patie nts wit h 
eit her pre o perati ve sta n dar d c o urse R T at a t otal d ose of 5 0. 4 G y ( 1. 8 G y/ Fracti o n, 2 8 fracti o ns, 5 da ys/ wee k), s h ort 
c o urse R T at a t otal d ose of 3 0 G y ( 3 G y/fracti o n, 1 0 fracti o ns, 5 da ys/ wee k), or p ost o perati ve sta n dar d c o urse R T at 
a t otal d ose of 5 0. 4 G y. 1 2   5- F U was gi ve n c o nc urre ntl y b y c o nti n u o us i nf usi o n 5- F U at a d osa ge of 3 0 0 m g/ m 2 per 
da y, 5 da ys/ wee k.  T his s h ort c o urse c he m ora diati o n pr o gr a m was desi g ne d t o a v oi d t he gastr oi ntesti nal t o xicit y 
see n wit h sta n dar d-fracti o nati o n c he m ora diati o n ( 5. 5 wee ks) w hile atte m pti n g t o mai ntai n t he e xcelle nt l ocal t u m or 
c o ntr ol ac hie ve d wit h m ulti m o dalit y t hera p y.  As wit h ot her ne oa dj u va nt treat me nt sc he mas, resta gi n g wit h c hest 
ra di o gra p h y a n d a b d o mi nal C T was perf or me d 4 wee ks f oll o wi n g c o m pleti o n of c he m ora diati o n i n pre parati o n f or 
pa ncreatic o d u o de nect o m y.   T he s h ort c o urse R T was ass ociat e d wit h fe wer gra des 3 t o xi cit y t ha n sta n dar d c o urse 
R T ( 7 % vs 1 9 %).  N o differe nce i n efficac y c o ul d be ascertai ne d as n o patie nt treate d wit h pre o perati ve 
c he m ora diati o n w h o u n der we nt R 0 resec ti o n e x perie nce d a l ocal rec urre nce. 
  
M ore rece ntl y, data fr o m 1 3 2 c o nsec uti ve patie nts w h o recei ve d pre o perati ve c he m ora diati o n a n d 
pa ncreatic o d u o de nect o m y f or a de n ocarci n o ma of t he pa ncreas als o s u p p orte d t he use of ra pi d-fracti o nati o n 
c he m ora diati o n. 1 3 F ort y-f o ur patie nts recei ve d sta n dar d fracti o nati o n ( 4 5- 5 0 G y, 1. 8 G y/fracti o n/ da y) E B R T a n d 8 8 
patie nts recei ve d s h ort c o urse E B R T ( 3 0 G y, 3 G y/fracti o n per da y).  T he me dia n o verall s ur vi val fr o m t he ti me of 
tiss ue dia g n osis was 2 1 m o nt hs.  S ur vi val d urati o n was n ot i nfl ue nce d b y t he d ose of pre o perati ve E B R T a n d 
c he m ot hera p y use d.  T he data s u g geste d t hat s h ort c o urse c he m ora diati o n ( 3 0 G y i n 2 wee ks) c o m bi ne d wit h 
pa ncreatic o d u o de nect o m y perf or me d o n acc uratel y sta ge d patie nts mi g ht be e q ui vale nt t o sta n dar d-fracti o nati o n 
c he m ora diati o n ( 4 5- 5 0 G y i n 5- 6 wee ks). 
2. 2  
C a pecit a bi ne a n d R a di ati o n T her a p y  
Ca pecita bi ne is a rati o nall y desi g ne d oral fl u or o p yri mi di ne. 1 4, 1 5 gi ve n its lac k of a nee d f or a n i m pla nta ble 
access de vice or p orta ble i nf usi o n p u m p a n d patie nt c o n ve nie nce, it has bec o me a n attracti ve a ge nt t o be c o m bi ne d 
wit h ra diati o n t hera p y.  Ca pecita bi ne u n der g oes t hree st e ps of e nz y matic acti vati o n bef ore c o n verti n g t o t he acti ve 

 
Pa ge 7 of 3 4 
dr u g.  It is rea dil y a bs or be d fr o m t he gastr oi ntesti nal tr act. I n t he li ver, a 6 0 k Da car b o x yesterase h y dr ol yzes m uc h 
of t he c o m p o u n d t o 5’- de o x y- 5-fl u or oc yti di ne ( 5’- D F C R). C yti di ne dea mi nase, a n e nz y me f o u n d i n m ost tiss ues, 
i ncl u di n g t u m ors, s u bse q ue ntl y c o n verts 5’- D F C R t o 5’- de o x y- 5-fl u or o uri di ne ( 5’- D F U R). T he e nz y me, t h y mi di ne 
p h os p h or ylase ( d T h d Pase), t he n h y dr ol yzes 5’- D F U R t o t he acti ve dr u g 5- F U. Ma n y tiss ues t hr o u g h o ut t he b o d y 
e x press t h y mi di ne p h os p h or ylase . S o me  h u ma n carci n o mas e x press t his e nz y me i n hi g her c o nce ntrati o ns t ha n 
s urr o u n di n g n or mal tiss ues.  Ca pecita bi ne is ra pi dl y a n d e xte nsi vel y a bs or be d wit h t he pea k plas ma c o nce ntrati o ns 
f or t he dr u g a n d its t w o mai n meta b olites occ urri n g s hortl y ( 0. 5 - 1. 5 h o urs) after a d mi nistrati o n.  T he n 
c o nce ntrati o ns decli ne e x p o ne ntiall y wit h a half-life of 0. 5 - 1 h o ur.   Plas ma c o nce ntrati o ns of t he c yt ot o xic m oiet y 
5- F U are ver y l o w.  
Ca pecita bi ne is ge nerall y well t olerate d.  Maj or si de effects i ncl u de diarr hea, na usea, ha n d-a n d-f o ot 
s y n dr o me, v o miti n g, fati g ue, a n d st o matitis.  T he m ost fre q u e nt gra de 3 or 4 la b orat or y a b n or malit y was ele vate d 
t otal bilir u bi n a n d al kali ne p h os p hatase, or a b n or mal li ver f u ncti o n tests.  M yel os u p pressi o n has bee n  rarel y 
re p orte d ( < 2 %). 
Its r ole as a ra di ose nsitizer has bee n m ost st u die d i n rectal ca ncer.  D u nst et al re p orte d t he res ults of a 
p hase I st u d y usi n g ca pecita bi ne i n T 3 a n d T 4 rectal ca ncer. 1 6 T hirt y-si x patie nts wit h rectal ca ncer recei ve d 
treat me nt i n t he a dj u va nt, ne oa dj u va nt, or palliati ve setti n g wit h a t otal ra diati o n d ose of 5 0. 4 G y.  Ca pecita bi ne was 
a d mi nistere d at escalati n g d oses fr o m 2 5 0 t o 1, 2 5 0 m g/ m 2 t wice a da y c o nc urre ntl y wit h ra diati o n.  T he y were a ble 
t o escalate t he ca pecita bi ne d ose t o 8 2 5 m g/ m2 t wice a da y.  D ose-li miti n g gra de 3 ha n d-a n d-f o ot s y n dr o me was 
o bser ve d i n t w o of si x patie nts treate d at 1, 0 0 0 m g/ m 2 bi d.  Ot her t o xicities were ge nerall y rare a n d/ or mil d.  O ne 
pat h ol o gic c o m plete re missi o n of a T 3 N 1 t u m or a n d ni ne partial re missi o ns were o bser ve d i n 1 0 patie nts treate d i n 
t he ne oa dj u va nt setti n g.  I n a n ot her st u d y, ca pecita bi ne was a d mi nistere d c o nc urre ntl y wit h ra di ot hera p y i n l ocall y 
a d va nce d rectal ca ncer. 1 7  T he treat me nt c o nsiste d of 2 c ycles of 1 4- da y oral ca pecita bi ne ( 8 2 5 m g/ m 2 BI D) a n d 
le uc o v ori n ( 1 0 m g/ m2 BI D), eac h of w hic h was f oll o we d b y a 7- da y rest peri o d.  T he o verall d o w nsta gi n g rate, 
i ncl u di n g b ot h pri mar y t u m or a n d n o des, was 8 4 %. A pat h ol o gic c o m plete res p o nse was ac hie ve d i n 3 1 % of 
patie nts. T we nt y- o ne patie nts ha d t u m ors l ocate d i nitiall y 5 c m or less fr o m t he a nal ver ge; a m o n g t he 1 8 treate d 
wit h s ur ger y, 7 2 % recei ve d s p hi ncter- preser vi n g s ur ger y.   Gra de 3 t o xicities i ncl u de d ha n d-f o ot s y n dr o me ( 7 %), 
fati g ue ( 4 %), diarr hea ( 4 %), a n d ra diati o n der matitis ( 2 %).   N S A B P is pla n ni n g a pr ospecti ve ra n d o mize d trial t o 
c o m pare ca pecita bi ne wit h i nf usi o nal 5- F U i n patie nts u n der g oi n g pre o perati ve ra diati o n t hera p y.  Preli mi nar y 
res ults fr o m a trial c o m bi ni n g ca pecita bi ne wit h ra diatio n t hera p y i n patie nts wit h l ocall y a d va nce d pa ncreatic 
ca ncer de m o nstrate d t he c o m bi nati o n t o be safe a n d t olera ble at a d ose of 8 2 5 m g/ m 2 t wice dail y. 1 8 
2. 3  
Pr ot o n Be a m R a di ati o n T her a p y 
T here ha ve bee n u n pr ece de nte d eff orts i n ra diati o n o nc ol o g y t o de vel o p a n d us e s o p histicate d, c o nf or mal 
p h ot o n tec h ni q ues i n or der t o i m pr o ve t he o utc o me f or ca ncer patie nts. T he ai m of t hese ne w tec h ni q ues is t o 
c o nce ntrate t he ra diati o n d ose distri b uti o n m ore c o m pletel y  o n t he disease tar get, t here b y s pari n g critical n or mal 
tiss ues a n d i ncreasi n g t he tar get d ose. T o war d t his e n d, ma n y a d va nces ha ve bee n ma de a n d e xa m ples of ne w 
de vel o p me nts i ncl u de T o m ot hera p y a n d i nte nsit y m o d ulate d p h ot o n t hera p y. At t he sa me ti me, hea v y, c har ge d-
particle pr o gra ms, partic ularl y t h ose f or pr ot o n t hera p y, ha ve bee n de vel o pe d. Pr ot o n t hera p y d ose distri b uti o ns are 

 
Pa ge 8 of 3 4 
Fi g ure O- 1. Pr ot o n ( Br a g g pe a k a n d m o d ul ate d 
Pe a k) a n d 1 0 M V de pt h d ose c ur ves. 
 
s u peri or t o t h ose of p h ot o n t hera p y a n d t his pr o vi des t he p ote ntial t o f urt her i m pr o ve cli nical o utc o mes. Se veral 
i nstit uti o ns ha ve c o m mitte d t o b uil d de dicate d pr ot o n t hera p y ce nters s uc h as t he Fra ncis H. B urr Pr ot o n T hera p y 
Ce nter ( F H B P T C) at t he Massac h usetts  Ge neral H os pital ( M G H) a n d t he L o ma Li n da U ni versit y Me dical Ce nter 
pr ot o n t hera p y facilit y. Se veral m ore pr ot o n t her a p y ce nters are i n t he fi nal pla n ni n g sta ge. 
2. 3. 1  
T he A d v a nt a ges of Pr ot o ns f or Deli ver y of C o nf or m al T her a p y 
C haracteristics of Pr ot o n Bea ms  
T he basis f or t he a d va nta ges of pr ot o n 
bea ms lies i n t he p h ysical la ws t hat deter mi ne 
t he a bs or pti o n of e ner g y i n tiss ues e x p ose d t o 
p h ot o n or pr ot o n bea ms.  I n a s pecific tiss ue, 
p h ot o ns are a bs or be d e x p o ne ntiall y w hereas 
pr ot o ns ha ve a fi nite ra n ge de pe n de nt u p o n t he 
i nitial pr ot o n e ner g y. T heref ore, t he de pt h d ose 
c haracteristics of t he t w o bea ms are 
q ualitati vel y differe nt (see Fi g ure O- 1). Pr ot o ns 
l ose t heir e ner g y i n tiss ue m ostl y b y c o ul o m bic 
i nteracti o ns wit h electr o ns i n t he c o nstit ue nt 
at o ms; h o we ver, a s mall fracti o n of e ner g y is 
tra nsferre d t hr o u g h n uclear c ollisi o ns. T he 
e ner g y l oss per u nit pat h le n gt h is relati vel y 
s mall a n d c o nsta nt as t he pr ot o n tra verses t he 
tiss ue u ntil near t he e n d of t he pr ot o n ra n ge 
w here t he resi d ual e ner g y is l ost o ver a s h ort dista nce (a p pr o xi matel y 0. 7 c m i n wi dt h at 8 0 % of t he ma xi m u m d ose) 
a n d t he pr ot o n c o mes t o rest, res ulti n g i n a disti ncti ve s har p rise i n t he tiss ue a bs or be d d ose (e ner g y a bs or be d per 
u nit mass) - k n o w n as t he Bra g g pea k (see t he c ur ve la bele d " u n m o d ulate d pr ot o n bea m" i n Fi g ure O- 1). I n p h ysical 
ter ms, t he ma g nit u de of t he tra nsfer of e ner g y t o tiss ue per u nit pat h le n gt h tra verse d b y t he pr ot o ns is i n versel y 
pr o p orti o nal t o t he s q uare of t he pr ot o n vel ocit y. T he l o w d ose re gi o n bet wee n t he e ntra nce a n d t he Bra g g pea k is 
calle d t he platea u of t he d ose distri b uti o n a n d t he d o se t here is 3 0- 4 0 perce nt of t he ma xi m u m d ose.  
T he Bra g g pea k is t o o narr o w i n e xte nt t o irra diate a n y b ut t he s mallest of tar gets, a blati o n of t he pit uitar y 
gla n d f or e xa m ple. F or t he irra diati o n of lar ger tar gets /t u m ors t he bea m e ner g y is m o d ulate d - se veral bea ms of 
cl osel y s pace d e ner gies (ra n ges) are s u pe ri m p ose d t o create a re gi o n of u nif or m d ose o ver t he de pt h of t he tar get. 
T hese e xte n de d re gi o ns of u nif or m d ose are calle d "s prea d- o ut Bra g g pea ks" ( S O B P). T his is s h o w n i n Fi g ure O- 1 
as t he “ m o d ulate d pr ot o n bea m”.  

 
       
X- R A Y S
P R O T O N S
M E D U L L O B L A S T O M A
  
Fi g ure O- 2. P osteri or, si n gle- be a m tre at me nt of t he s pi n al a xis. 
 F or c o m paris o n, Fi g ure  O - 1 als o s h o ws t he de pt h- d ose c ur ve f or a 1 0 M V x-ra y bea m, a n x-ra y e ner g y 
c o m m o nl y use d t o treat dee p  seate d  t u m ors. N ote 
t hat t he x-ra y bea m d ose rises t o a ma xi m u m val ue 
at relati vel y s hall o w de pt hs, t he n falls off 
e x p o ne ntiall y t o l o wer d oses at t he treat me nt 
de pt h.  A cli nical c o m paris o n of si n gle- bea m 
pr ot o n a n d p h ot o n bea ms is s h o w n i n Fi g ure O- 2 
w here a si n gle p osteri or bea m is use d f or t he 
treat me nt of t he s pi nal a xis i n t he treat me nt of 
me d ull o blast o ma. N ote t hat, f or t he p h ot o n 
treat me nt, t he heart, me diasti n u m, es o p ha g us, l u n g 
a n d s pi nal c or d are irra diate d b y t he treat me nt 
bea m w hereas f or t he pr ot o n treat me nt, t he bea m 
st o ps a br u ptl y distal t o t he tar get v ol u me a n d t here 
is n o irra diati o n of t he tiss ues a n d or ga ns distal t o 
t he tar get v ol u me.   
I n t he us ual cli nical sit uati o n, m ore t ha n o ne ra diati o n bea m is use d i n b ot h x-ra y a n d pr ot o n treat me nts. 
H o we ver, t he a d va nta ge s h o w n f or pr ot o ns usi n g si n gle bea ms is prese nt f or eac h a n d e ver y bea m use d. T heref ore, 
o ne ca n n ot o verc o me t he p h ysical disa d va nta ge of x-ra ys b y t he use of m ulti ple bea ms or c o m ple x bea m 
arra n ge me nts. I n m o der n pr ot o n t hera p y facilities, w hic h ha ve is oce ntric ga ntries a n d s o p histicate d bea m deli ver y 
a n d c o ntr ol s yste ms, pr ot o n t hera p y ca pa bilities are e q ui vale nt t o t h ose f or state- of-t he-art, c o nf or mal t hera p y usi n g 
x-ra ys wit h res pect t o n u m bers of bea ms, bea m direc ti o ns a n d c o m ple x deli ver y tec h ni q ues s uc h as i nte nsit y 
m o d ulati o n.  
I nte nsit y M o d ul ate d 
R a di ati o n T her a p y 
I nte nsit y- m o d ulate d 
x-ra y t hera p y (I M X T) – t he 
use of x-ra y bea ms eac h of 
w hic h is p ur p osel y ma de n o n-
u nif or m o ver its cr oss-secti o n 
– pr o vi des a ne w de gree of 
free d o m i n treat me nt deli ver y 
a n d ca n lea d t o m ore 
c o nf or mal d ose distri b uti o ns.  
Pr ot o ns, t o o, ca n be use d i n 
a n i nte nsit y m o d ulate d m o de 
(I M P T) si milar t o t hat f or 
Fi g ure O- 3:  Para nasal si n us t u m or treate d w it h I M P T (left) a n d I M X T (ri g ht).  D ose 
differe nce distri b uti o n bel o w. 
P R O T O N S 
DI F F E R E N C E 
( x-r a y s - pr ot o n s) 

 
Pa ge 1 0 of 3 4 
p h ot o ns a n d, i n a n a d diti o nal de gree of free d o m, are als o ma de n o n- u nif or m i n de pt h. T he a d va nta ge t hat si n gle 
bea ms of pr ot o ns ha ve o ver si n gle bea ms of x-ra ys, w hic h is mai ntai ne d w he n m ulti ple cr oss-firi n g bea ms of 
u nif or m i nte nsit y are e m pl o ye d, is si milarl y mai n tai ne d w he n i nte nsit y m o d ulati o n is e m pl o ye d. 
I n I M X T, t he d ose ca n be ma de t o c o nf or m t o t he tar get v ol u me w hile a v oi di n g selecte d a djace nt se nsiti ve 
str uct ures (alt h o u g h t he d ose u nif or mit y wit hi n t he tar get v o l u me is str o n gl y i nfl ue nce d b y s uc h selecti ve a v oi da nce 
a n d is ofte n of u n desira ble ma g nit u de). H o we ver, I M X T d oes n ot re d uce t he i nte grate d d ose deli vere d o utsi de t he 
tar get v ol u me (as c o m pare d t o sta n dar d c o nf or mal p h ot o n t hera p y); it o nl y, i n ge neral, s prea ds t hat e ner g y o ut o ver 
a lar ger v ol u me. I n o ur treat me nt pla n ni n g i nterc o m paris o ns (i n nas o p har y n x, para nasal si n us, l u n g a n d E wi n g’s 
sarc o ma) we ha ve f o u n d t hat t he i nte gral d ose f or I M P T is a fact or of t w o ( o n t he a vera ge) less t ha n f or I M X T. 
M ore o ver, w hate ver i m pr o ve me nt I M X T  ac hie ves o ver sta n dar d c o nf ormal x-ra y t hera p y, a c o m para ble 
i m pr o ve me nt is ac hie ve d w he n I M P T is c o m pare d t o sta n dar d c o nf or mal pr ot o n t hera p y. 
Fi g ure O- 3 de m o nstrates t he a b o ve p oi nts.  It is a c o m paris o n of t w o I M R T pla ns, o ne wit h x-ra ys a n d o ne 
wit h pr ot o ns, desi g ne d t o treat a para nasal si n us t u m or ( wit h t hree tar get v ol u mes recei vi n g 7 6, 6 6, a n d 5 6 G y, 
res pecti vel y). T he t w o pla ns were su bject t o i de ntical d ose c o nstrai nts o n n or mal tiss ues. T he pr ot o n d ose 
distri b uti o n (left) is clearl y e xcelle nt; t he p h ot o n distri b uti o n o n t he ri g ht is als o ver y g o o d.  H o we ver, t he 
prese ntati o n of t he d ose i n t he t o p pa nels d oes n ot a de q uatel y re veal t he si g nifica nt differe nces bet wee n t he t w o 
distri b uti o ns.  T he l o wer pa nels s h o w t he d ose differe nce  bet wee n t he pla ns. X-ra ys deli ver a n a d diti o nal “ bat h” of 
fr o m 5 t o 1 5 G y t hr o u g h o ut t he brai n a n d, i n t he re gi o n of t he ri g ht e ye ( w hic h is ma g nifie d i n t he l o wer left), u p t o 
4 0 G y m ore t ha n t he pr ot o ns.  ( T he c o nstrai nt o n t he ri g ht e ye’s reti na was 5 0 G y; ha d it bee n re d uce d, x-ra ys c o ul d 
certai nl y ha ve re d uce d t he d ose i n t hat re gi o n – b ut at t he price of i ncrease d d ose else w her e a n d, per ha ps, of greater 
n o n- u nif or mit y of d ose i n t he tar get v ol u mes.) 
Pa ncreatic t u m ors als o ha ve a n u m ber of n or mal str uct ures i n cl ose pr o xi mit y t hat ha ve li mite d ra diati o n 
t olera nce i ncl u di n g ki d ne ys, li ver, s pi nal c or d a n d st o mac h.  T he lac k of e xit d ose fr o m pr ot o n bea m ra diati o n ca n 
all o w f or re d uce d d ose t o t hese a n d ot her n or mal tiss ues 
2. 4  
Rati o nale f or S h ort C o urse Ra diati o n T hera p y 
2. 4. 1  
Pr ojecte d cli nical efficac y 
T he r ole of ne oa dj u va nt a n d a dj u va nt ra diati o n t hera p y f or resecta ble pa ncreatic ca ncer is t o i m pr o ve 
l oc ore gi o nal c o ntr ol b y sterilizi n g micr osc o pic disease t hat ma y n ot be re m o ve d wit h s ur ger y.  He nce, t here ma y n ot 
be a clear be nefit t o hi g her d oses of ra diati o n t hera p y i n t his setti n g.  T his is s u p p orte d b y t he M D A n ders o n 
e x perie nce (see 2. 1), w hic h s u g gest t hat s h ort c o urse  c he m ora diati o n ( 3 0 G y i n 2 wee ks) c o m bi ne d wit h 
pa ncreatic o d u o de nect o m y perf or me d o n acc uratel y sta ge d patie nts ma y be e q ui vale nt t o sta n dar d-fracti o nati o n 
c he m ora diati o n ( 4 5- 5 0 G y i n 5- 6 wee ks). 1 3   
T he sc he d ule of 5 G y x 5 has bee n e xte nsi vel y teste d  i n rectal ca ncer i n n u mero us ra n d o mize d E ur o pea n 
cli nical trials 1 9- 2 1.  T hese trials de m o nstrate d t hat t he re gi me n is ver y t olera ble wit h a n ass ociate d i m pr o ve me nt i n 
l ocal c o ntr ol.  B uj k o a n d c ollea g ues f or mall y c o m pare d 5 G y x 5 vs. c o n ve nti o nal c he m ora diati o n t o 5 0. 4 G y wit h 
5- F U c he m ot hera p y f or l o w-l yi n g rectal ca ncers i n a ra n d o mize d trial a n d di d n ot fi n d a differe nce i n rates of 
s p hi ncter preser vati o n 2 1.   L ocal c o ntr ol was n ot re p orte d i n t his earl y a nal ysis.   

 
Pa ge 1 1 of 3 4 
A sc he d ule of 2 5 G y i n 5 fracti o ns of 5 G y has a si milar a ntici pate d efficac y t o t he 3 0 G y sc he d ule 
me nti o ne d a b o ve. Usi n g li near- q ua dratic f or m ulati o n
2 2, t he t u m or effect of t he 2 5 G y s h o ul d be al m ost e q ui vale nt t o 
t he 3 0 G y sc he d ule. 
 
Ta ble 1  Efficac y C o m paris o n of c o n ve nti o nal, M D A n ders o n S h ort C o urse, a n d pr o p ose d sc he d ule 
S c he d ule  
D ose/fr acti o n  
# T x  
T ot al 
D ose 
* B. E. D ( G y) 
( n o ti me 
c orrecti o n) 
* * N. T. D ( G y) 
( n o  ti me  
c orrecti o n) 
* B. E. D. ( G y) 
(ti me c orrecti o n) 
* * N. T. D. ( G y) 
(ti me c orrecti o n) 
C o n ve nti o nal
 1. 8
 
G y
  
2 8
  
5 0. 4
  5 0. 4
  
5 9. 5
  
4 6. 8
 
3 9
 
M D A C C
 3
 
G y
  
1 0
 3 0
 3 9
  
3 2. 5
  
3 9
  
3 2. 5
 
M G H Pr ot o n  
5 C G E * * *  
5  
2 5  
3 7. 5  
3 1. 3 
3 7. 5 
3 1. 3 
* B. E. D. – Bi ol o gicall y e q ui vale nt d ose 
* * N. T. D. – N or malize d T otal D ose, or e q ui vale nt p h ysical d ose if deli vere d i n 2 G y fracti o ns. 
* * * C G E – C o balt Gra y E q ui vale nt, ass u mi n g a Relati ve Bi ol o gical Effecti ve ness of 1. 1. 
 
N o re p o p ulati o n ( n o ti me c orrecti o n): 
 
B. E. D = n d( 1 + d /) 
 
Wit h re p o p ulati o n (ti me c orrecti o n): 
 
B. E. D = n d( 1 + d /) – (T- T k)(l n 2/(T p ot)) 
 
W here: 
 
n = n u m ber of fracti o ns 
d = d ose per fracti o n 
n d = t otal d ose 
T = t otal ti me of treat me nt i n da ys 
T k  = ti me after start of treat me nt re p o p ulati o n be gi ns 
T p ot = p ote ntial d o u bli n g ti me 
 
Ass u mi n g: 
 
= 1 0   
 = 0. 3 5 T = ass u mi n g treat me nt starts o n a M o n da y wit h n o brea ks d uri n g treat me nt 
T k  = 2 8 d  
T p ot = 5 da ys  
 
 
N. T. D. = B. E. D./ ( 1 + 2/ 
 
As ca n be see n i n Ta ble 1, t he reas o n f or si milar cli n ical o utc o mes bet wee n a c o n ve nti o nal sc he d ule a n d t he M D 
A n ders o n 3 0 G y s h ort c o urse ma y be d ue t o b ot h t he lar ger  fracti o n size a n d s h orter treat me nt ti me.  Si milarl y, i n 
l o o ki n g at t he 2 5 G y sc he d ule, o ne w o uld e x pect ver y si mila r cli nical efficac y. 

 
Pa ge 1 2 of 3 4 
2. 4. 2  
Pr ojecte d cli nical t o xicit y 
Wit h alterati o n of a ra diati o n sc he d ule, t here is al wa ys c o ncer n t hat t he t o xicit y of  treat me nt ma y i ncrease.  
H o we ver, w he n i n vesti gat ors at M D A n ders o n m o ve d fr o m a c o n ve nti o nal sc he d ule t o a s h ort c o urse, t he cli nical 
t olera bilit y i n fact i m pr o ve d.   F urt her m ore, wit h lar ger fracti o n sizes, t here is als o a c o ncer n f or i ncrease d late 
effects.  Usi n g li near- q ua dratic f or m ulati o n, t he ris k f or late  effects a p pears t o be l o wer f or late effects t ha n wit h a 
c o n ve nti o nal sc he d ule. 
T a ble 2 
L ate Effect  C o m p aris o n of c o n ve nti o n al, M D A n ders o n S h ort C o urse, a n d pr o p ose d sc he d ule ( 
= 3) 
S Sc he d ule  
D ose/fr acti o n  
# T x  
T ot al D ose  
B. E. D ( G y) 
 
* * N. T. D. ( G y) 
C o n ve nti o nal
 1. 8
 
G y
  
2 8
  5 0. 4
  
8 0. 6
  
4 8. 4
 
M D A C C
 3
 
G y
  1 0
 
3 0
  
6 0
  
3 6
 
M G H Pr ot o n  
5 C G E  
5  
2 5 
6 6. 7 
4 0 
 
F or t he a b o ve me nti o ne d ra n d o mize d trial f or l o w- l yi n g rectal ca ncers c o m pari n g c o n ve nti o nal fracti o n 
wit h 5 G y x 5, a n a nal ysis of peri o perati ve c o m plicati o ns was als o perf or me d 2 3.  T here were n o differe nces i n t he 
rates of c o m plicati o ns or i n se vere c o m plicati o ns.  T hese res ults s u g gest t hat t here s h o ul d n ot be a n i ncrease i n 
s ur gical c o m plicati o ns wit h t his sc he d ule. 
Rec o m me n de d d ose li mits f or b ot h ac ute a n d late eff ects ca n be a dj uste d f or t he accelerate d sc he d ule. 
H o we ver, t he fe wer n u m ber of fracti o ns  re n der t he c o nstrai nts si g nifica ntl y m ore stri n ge nt.  Wit h pr ot o ns, greater 
d ose c o nf or malit y ca n be ac hie ve d.  It is t he g oal of t his pr ot oc ol t o de m o nstrate t he feasi bilit y a n d t olera bilit y of t he 
5 C G E x 5 re gi me n f or pa ncreatic ca ncer. 
2. 4. 3  
H y p ofracti o nati o n a n d ra di ose nsitizati o n wit h ca pecita bi ne 
Ra diati o n t hera p y has bee n c o n ve nti o nall y i n 1. 8- 2 G y fracti o ns.  H o we ver, f or a wi de variet y of p utati ve 
ra di ose nsitizers a n d cell li nes, ra di ose nsitizati o n is n ot see n u ntil lar ger fracti o n sizes.  F or e xa m ple, as st u d y fr o m 
M D A n ders o n ca ncer ce nter assessi n g t h e 5- F U-ra diati o n i nteracti o ns i n h u ma n  c ol o n a de n ocarci n o ma cells di d n ot 
s h o w si g nifica nt ra di ose nsitizati o n at 2 G y/fracti o n b ut di d at 4 a n d 6 G y/fracti o ns 2 4.  
Fi g ure O- 4  I ncre ase d r a di ose n sitiz ati o n wit h l ar ger fracti o n sizes wit h 5- F U 

 
Pa ge 1 3 of 3 4 
 
Fr o m B uc h h olz DJ (ref 2 4)  Ra diati o n s ur vi val c ur ves f or platea u p hase Cl o ne A cells irra diate d o n ice wit h bet wee n 
2 a n d 8 G y wit h x-ra ys wit h (s oli d circ les) or wit h o ut (e m pt y circles) 5 F U. 
Ot hers ha ve ge nerate d si milar s ur vi val c ur ves de m o nstrati n g greater ra di ose nsitizati o n wit h lar ger fracti o n 
size wit h 5- F U 2 5, 2 6 .  T his p he n o me n o n has als o bee n de m o nstrate d wit h ot her ra di ose nsitizers i ncl u di n g b ut n ot 
li mite d t o cet u xi ma b2 7 a n d H D A C i n hi bit ors2 8.  T he 5 G y fracti o n size is partic ularl y of i nterest w he n use d wit h 
ca pecita bi ne i n li g ht of t he st u d y b y Sa wa da a n d c ollea g ues 2 9.  I n t his st u d y, 5 G y of x-ra y irra diati o n i n se veral 
h u ma n ca ncer xe n o grafts pr o d uce d u pre g ulati o n of t h y mi di ne p h os p h or ylase, t he ke y e nz y me i n c o n verti n g t he 
ca pecita bi ne t o 5- F U i n t u m ors.  T hese i n vesti gat ors c orres p o n di n gl y f o u n d t hat 5 G y c o m bi ne d wit h ca pecita bi ne 
ha d greater a nti-t u m or effect t ha n e ve n 5 G y wit h  5- F U.  Fi g ure O- 5 bel o w s u m marizes t heir res ults. 
Fi g ure 5 
A ntit u m or acti vit y of  t he c o m bi n ati o n of X-r a y irr a di ati o n a n d fl u or o p yri mi di nes o n t he gr o wt h of Wi Dr 
h u m a n c ol o n c a ncer xe n o gr aft i n n u de mice 2 9. 
 
It re mai ns u n k n o w n if t his i ncrease d ra di ose nsitizatio n wit h lar ger fracti o n sizes will be see n i n patie nts 
wit h pa ncreatic ca ncer. H o we ver, it is u nli kel y t o be less t ha n see n wit h c o n ve nti o nal fracti o nati o n. 
2. 4. 4  
Patie nt a n d s ocietal c ost wit h s h ort c o urse pr ot o n bea m t hera p y. 
Wit h t he a p plicati o n of a n y ne w tec h n ol o g y, patie nt a n d s ocietal c osts m ust be c o nsi dere d.  T he be nefit t o 
t he patie nt is si m ple- fe wer visits f or ra diati o n t hera p y.  As l o n g as t he si de effect pr ofile is n ot greater t ha n wit h 
c o n ve nti o nal t hera p y, t he patie nt will s pe n d less ti me tra ve li n g f or ra diati o n t hera p y a n d s u bse q ue ntl y greater q ualit y 

 
Pa ge 1 6 of 3 4 
2. 5  
S u m m ar y of P h ase I Res ults a n d Deter mi n ati o n of P h ase II D osi n g 
 
T he P hase I p orti o n of t his P hase I/II st u d y c o m plete d accr ual i n Se pte m ber, 2 0 0 8.  All s u bjects e nr olle d i n 
P hase I ( n = 1 5) ha ve c o m plete d st u d y treat me nt.  Preli mi nar y a nal ysis of ac ute t o xicit y data de m o nstrates t he m ost 
c o m m o n t o xicities were fati g ue a n d na usea ( b ot h re p orte d b y  8 0 % of s u bjects; all na usea e ve nts were gra de 1; all 
fati g ue e ve nts were gra de 1 or 2).  Pai n was re p orte d b y 6 0 % of t he P hase I s u bjects, f oll o we d b y a n ore xia re p orte d 
b y 4 7 %.  Ot her t o xicities re p orte d b y 2 0 % or m ore of t he s u bjects i ncl u de d v o miti n g ( 3 3 %), i n di gesti o n ( 2 7 %) a n d 
diarr hea ( 2 0 %).  All of t he a b o ve e ve nts were gra de 1 or 2.  T here were si x gra de 3 e ve nts re p orte d i n t he P hase I, 
occ urri n g i n f o ur of t he s u bjects.  All gra de 3 e ve nts we re u nrelate d or u nli kel y relate d t o st u d y treat me nt. Gra de 3 
e ve nts  i ncl u de d bl oc ke d biliar y ste nts ( 2 e ve nts), ele vate d bilir u bi n ( 2 e ve nts), i nfecti o n ( 1 e ve nt) a n d p ositi o nal 
s h o ul der pai n ( 1 e ve nt).  T here were n o relate d a d verse e ve nts or gra de 4 or 5 t o xicities. 
  
T he fi nal d ose le vel (le vel 4; 5 G y x 5 i n 5 da ys) was ac hie ve d i n t he P hase I p orti o n of t he st u d y wit h o ut 
a n y d ose li miti n g t o xicities.   T h us, t his will be t he pl a n ne d d ose le vel f or t he P hase II p orti o n of t he st u d y. 
 
2. 5. 1  
C orrel ati ve St u dies B ac k gr o u n d 
T he searc h f or ne w bi o mar kers of res p o nse t o s h ort c o urse ne oa dj u va nt ra diati o n will i n v ol ve a n 
e xa mi nati o n of t he m olec ular a n d ge netic c haracteristics of t u m or s peci me ns. T his a nal ysis will be gi n wit h t he 
pri mar y t u m or after t he c o urse of treat me nt a n d ma y al s o i ncl u de a nal ysis of t he i nitial bi o ps y s peci me ns. T o 
c haracterize t he t u m ors at t he ge netic le vel, m utati o nal a nal ysis of t he treate d t u m or will be perf or me d usi n g a 
c ust o mize d S N A P S H O T platf or m t hat e xa mi nes t he t u m or f or a p pr o xi matel y 1 0 0 s pecific ge netic m utati o ns.  We 
will als o a nal yze D P C 4, S D F 1, C X C R 4, I L- 6, c- M E T a n d S H H stat us of t he t u m or s peci me ns. T u m or a nal ysis  
st u dies will be c o n d ucte d o n t he pa ncreatic o d u o de nect o m y s peci me ns a n d ma y als o be c o n d ucte d o n t he i nitial 
bi o ps y s peci me ns.     
I n a d diti o n t o t u m or a nal ysis, bl o o d sa m ples will als o be e val uate d t o scree n bi o mar kers i n or der t o assess 
w hat effects ra diati o n has i n t he bl o o d.  Bl o o d will be o bta i ne d via ve ni p u nct ure wit hi n t w o wee ks pri or t o t he start 
of c he m o-ra di ot hera p y a n d pri or t o s ur ger y d uri n g r o uti ne cli nical m o nit ori n g . Bl o o d sa m ples (a p pr o xi matel y 1 
teas p o o n) will be c ollecte d i n plas ma E D T A ( p ur ple t o p) vac utai ners. Plas ma  will be pre pare d i n sta n dar d met h o d 
b y Steele La b pers o n nel u n der t he s u per v isi o n of Da n G. D u da, D. M. D., P h D a n d st ore d at - 7 8 de grees Celsi us u ntil 
a nal ysis. F oll o wi n g c o m plete patie nt accr ual , V E G F, Pl G F, s V E G F R 2, s V E G F R 1, b F G F, S D F 1α , I L- 1, I L- 6, I L- 8, 
T N F- α , sI C A M 1, c olla ge n I V a n d s V C A M 1 le vels will be meas ure d.  
 
3. 0  
P atie nt Eli gi bilit y. 
3. 1
 I ncl usi o n
 
Criteria:
 
1  
C yt ol o gic of hist ol o gic pr o of pa ncreatic d uctal carci n o ma is re q uire d pri or t o treat me nt.   
2.  
N o e vi de nce of metastatic disease as deter mi n e d b y c hest C T sca n, a b d o mi nal C T sca n ( or M RI 
wit h ga d oli ni u m a n d/ or ma n ga nese), sta gi n g la par osc o p y a n d all patie nts m ust be sta ge d wit h a 
p h ysical e xa m, c hest C T, a b d o mi nal C T wit h i ntra ve n o us c o ntrast ( or A b d M RI wit h ga d oli ni u m 
a n d/ or ma n ga nese) a n d la par osc o p y.  O nl y p ote ntiall y resecta ble patie nts are eli gi ble.  P ote ntiall y 
resecta ble is defi ne d as: a). n o e xtra pa ncreatic disease, b) n o e vi de nce ( o n C T) of i n v ol ve me nt of 
t he celiac a xis or S M A,  c) n o e vi de nce ( CT or M RI) of occl usi o n of t he S M V or S M P V 
c o nfl ue nce, a n d d) n o e vi de nce  of dista nt metastases o n sta gi n g la par osc o p y.   

 
Pa ge 1 7 of 3 4 
3.  
Patie nts m ust be 1 8 years ol d or ol der. T here will be n o u p per a ge restricti o n; patie nts wit h 
E C O G- 4. Perf or ma nce Stat us of 0 or 1 are eli gi ble. 
5.  
W o me n of c hil d beari n g p ote ntial m ust a gree t o  practice a de q uate c o ntrace pti o n a n d t o refrai n 
fr o m breast fee di n g, as s pecifie d i n t he i nf or me d c o nse nt fr o m ti me of st u d y e ntr y u ntil 3 0 da ys 
after last c he m ot hera p y.  Fe male patie nts m ust ha ve a ne gati ve pre g na nc y test wit hi n 7 da ys of 
treat me nt or be cate g orize d as n ot of c hil d- beari n g p ote ntial. W O C P m ust a gree t o use a de q uate 
c o ntrace pti o n a n d t o refrai n fr o m breast fee di n g u ntil 3 0 da ys after last c he m ot hera p y. 
6.  
Patie nts m ust si g n a st u d y-s pecific c o nse nt f or m, w hic h is attac he d t o t his pr ot oc ol. 
7.
 La b
 
Val ues
 
A N C  1 5 0 0 cells/ m m 3 
Platelet c o u nt at least 1 0 0, 0 0 0 cells/ m m 3.    
A S T a n d A L T  2. 5 x u p per li mit of n or mal 
T otal Bilir u bi n  2. 5 x u p per li mit of n or mal if patie nt is s/ p biliar y ste nti n g 
T otal Bilir u bi n  1. 5 x u p per li mit of n or mal if n o biliar y ste nti n g was d o ne 
  
  
Ser u m Creati ni ne wit hi n n or mal ra n ge ( 0. 6- 1. 5 m g/ dl) 
 Creati ni ne Cleara nce  3 0 ml/ mi n (as esti mate d b y C oc kr oft Ga ult E q uati o n):  
( 1 4 0 - a ge [ yrs]) ( b o d y wt [ k g]) 
Creati ni ne cleara nce f or males =   
— — — — — — — — — — — — 
( 7 2) (ser u m creati ni ne [ m g/ d L]) 
Creati ni ne cleara nce f or fe males =   0. 8 5 x male val ue  
3. 1  
E xcl usi o n Criteri a:  
Patie nts w h o f ulfill a n y of t he f oll o wi n g criteria will be e xcl u de d: 
1.  
T u m ors i n t he b o d y or tail of t he pa ncreas (t o t he left of t he p ortal- S M V c o nfl ue nce) are n ot 
eli gi ble. L ocati o n at t he p ortal – S M V c o nfl ue nce is all o we d. 
2.  
Patie nts ca n n ot ha ve he patic or perit o neal metastases detecte d b y i ma gi n g or la par osc o p y pri or t o 
c he m ora diati o n.  Patie nts wit h p ositi ve perit o neal c yt ol o g y (fr o m was hi n gs at t he ti me of 
la par osc o p y) will n ot be eli gi ble. 
3.  
Seri o us c o nc o mita nt s yste mic dis or ders i nc o m pa ti ble wit h t he st u d y (at t he discreti o n of t he 
i n vesti gat or), s uc h as si g nifica nt car diac or p ul m o nar y m or bi dit y, o n g oi n g i nfecti o n as ma nifeste d 
b y fe ver.  
4.  
Pre g na nt or lactati n g w o ma n. W o ma n of c hil d be ari n g p ote ntial wit h eit her a p ositi ve or n o 
pre g na nc y test (ser u m or uri ne) at baseli ne. W o ma n / me n of c hil d beari n g p ote ntial n ot usi n g a 
relia ble a n d a p pr o priate c o ntrace pti ve met h o d. ( P ost me n o pa usal w o ma n m ust ha ve bee n 
a me n orr heic f or at least 1 2 m o nt hs t o be c o nsi d ere d of n o n-c hil d beari n g p ote ntial).  Patie nts will 
a gree t o c o nti n ue c o ntrace pti o n f or 3 0 da ys fr o m t he date of t he last st u d y dr u g a d mi nistr ati o n 
5.  
Life e x pecta nc y < 3 m o nt hs. 
6.  
Seri o us, u nc o ntr olle d, c o nc urre nt i nfecti o n(s). 
7.  
A n y pri or c he m ot hera p y or ra diati o n f or treat me nt of t he patie nt’s pa ncreatic t u m or.  

 
Pa ge 1 8 of 3 4 
8.  
Treat me nt f or ot her carci n o mas wit hi n t he last fi ve years, e xce pt c ure d n o n- mela n o ma s ki n a n d 
treate d i n-sit u cer vical ca ncer.   
9.  
Cli nicall y si g nifica nt car diac dis ease (e. g. c o n gesti ve heart fail ure, s y m pt o matic c or o nar y arter y 
disease a n d car diac arr h yt h mias n ot well c o ntr olle d wit h me dicati o n) or m y ocar dial i nfarcti o n 
wit hi n t he last 1 2 m o nt hs. 
1 0.  
Ot her seri o us u nc o ntr olle d me dical c o n diti o ns t hat t he i n vesti gat or feels mi g ht c o m pr o mise st u d y 
partici pati o n. 
1 1.  
Lac k of p h ysical i nte grit y of t he u p per gastr oi ntesti nal tract or mala bs or pti o n s y n dr o me. 
1 2.  
K n o w n, e xisti n g u nc o ntr olle d c oa g ul o pat h y. 
1 3.  
U n willi n g ness t o partici pate or i na bilit y t o c o m pl y wit h t he pr ot oc ol f or t he d urati o n of t he st u d y. 
1 4.  
A n y pri or fl u or o p yri mi di ne t hera p y ( u nless gi ve n i n a n a dj u va nt setti n g a n d c o m plete d at least 6 
m o nt hs earlier). 
1 5.  
Pri or u na ntici pate d se vere reacti o n t o fl u or o p yri mi di ne t hera p y, or k n o w n h y perse nsiti vit y t o 5-
fl u or o uracil or k n o w n D P D deficie nc y. 
1 6.  
Partici pati o n i n a n y i n vesti gati o nal dr u g st u d y wit hi n 4 wee ks prece di n g t he start of  st u d y 
treat me nt. 
1 7.  
Hist or y of u nc o ntr olle d seiz ures, ce ntral ner v o us s y ste m dis or ders or ps yc hiatric disa bilit y j u d ge d 
b y t he i n vesti gat or t o be cli nicall y si g nifica nt, precl u di n g i nf or me d c o nse n t, or i nterferi n g wit h 
c o m plia nce or oral dr u g i nta ke. 
1 8.  
Maj or s ur ger y, e xcl u di n g la p or osc o p y, wit hi n 4 wee ks of t he start of st u d y treat me nt, wit h o ut 
c o m plete rec o ver y. 
1 9.  
Patie nts s h o ul d n ot be o n ci meti di ne as it ca n d ecrease t he cleara nce of 5- F U .  A n ot her H 2- bl oc ker 
or pr ot o n p u m p i n hi bit or ma y be s u bstit ute d bef ore st u d y e ntr y. 
4. 0  
Tre at me nt  
4. 1  
C a pecit a bi ne:  
4. 1. 1
 Descri pti o n:
 
Ca pecita bi ne ( Xel o da) is a c o m merciall y a vaila ble fl u or o p yri mi di ne car ba mate wit h a nti ne o plastic 
acti vit y.  It is a n orall y a d mi nistere d s yste mic pr o dr u g of 5’- de o x y- 5-fl u or o uri di ne ( 5’- D F U R) w hic h is 
c o n verte d t o 5-fl u or o uracil.  T he c he mical na me f or ca pecita bi ne is 5’- de o x y- 5-fl u or o- N-
[( pe nt yl o x y)car b o n yl]-c yti di ne a n d has a m olec ular wei g ht of 3 5 9. 3 5. 
Ca pecita bi ne is a w hite t o off- w hite cr ystalli ne p o w der wit h a n a q ue o us s ol u bilit y of 2 6 m g/ m L at 
2 0 o C.  Ca pecita bi ne is s u p plie d as bic o n ve x, o bl o n g fil m-c oate d ta blets f or oral a d mi nistrati o n.  Eac h li g ht 
peac h-c ol ore d ta blet c o ntai ns 1 5 0 m g of ca pecita bi ne a n d eac h p eac h-c ol ore d ta blet c ontai ns 5 0 0 m g of 
ca pecita bi ne.  T he i nacti ve i n gre die nts i n ca pecita bi ne i ncl u de:  a n h y dr o us lact ose, cr oscar mell ose s o di u m, 
h y dr o x y pr o p yl met h ylcell ul ose, micr ocr ystalli ne cell ul o se, ma g nesi u m stearate, a n d p urifie d water.  T he 
peac h or li g ht peac h fil m c oati n g c o ntai ns h y dr o x y pr o p yl met h ylcell ul ose, talc, tita ni u m di o xi de, a n d 
s y nt hetic yell o w a n d re d ir o n o xi des. 

 
Pa ge 1 9 of 3 4 
4. 1. 2
 Dr u g
 
A d mi nistrati o n:
 
T he d ose of ca pecita bi ne will be gi ve n orall y 8 2 5 m g/ m 2 BI D (t otal 1 6 5 0 m g/ m 2 per da y) f or a 
t otal of 1 0 da ys ( M- F) 2 wee ks.  T he first d ose of ca pecita bi ne will start o n t he first da y of ra diati o n 
t hera p y.  T he d ose of ca pecita bi ne will be fi xe d u nless t here are d ose le vel re d ucti o ns. T he dail y d ose will 
be a d mi nistere d i n t w o di vi de d d oses a p pr o xi matel y 1 2 h o urs a part.  T he me dicati o n s h o ul d be gi ve n 
wit hi n 3 0 mi n utes after t he e n d of a meal or s nac k a n d s wall o we d wit h a b o ut 8 oz. of water.  T he d ose of 
ca pecita bi ne will be calc ulate d o n t he basis of milli gra ms of dr u g per s q uare meter of b o d y s urface area 
( B S A).   
D oses will be r o u n de d t o t he nearest m ulti ple of w h ole ta blets.  Ca pecita bi ne ta blets are eit her 1 5 0 
or 5 0 0 m g i n size, s o t he d ose gi ve n will be r o u n de d t o t he nearest 1 5 0 m g ta blet.  T he B S A will be 
r o u n de d t o t he nearest te nt h a n d t he i n vesti gat or will prescri be ca pecita bi ne acc or di n g t o t he f oll o wi n g 
c hart.  T he d ose of ca pecita bi ne will n ot e xcee d 2 0 0 0 m g p o bi d.  
A dr u g diar y will be pr o vi de d t o d oc u me nt a p pr o priate a d mi nistrati o n. 
 
D oes M o dificati o ns:  See secti o n 8. 2. 
 
T a ble 4 
Treat me nt wit h ca pecita bi ne will be gi ve n f or a t otal of 1 0 da ys ( M- F) 2 wee ks. 
B S A ( m 2)
 D ose
 
BI D
 
( T otal m g per d ose) 
5 0 0 m g ta bs  
1 5 0 m g ta bs 
1. 0
 8 0 0
  
1
  2
 
1. 1
 1 0 0 0
  
2
  0
 
1. 2
 1 0 0 0
  
2
  0
 
1. 3
 1 0 0 0
  
2
  0
 
1. 4
 1 1 5 0
  
2
  1
 
1. 5
 1 3 0 0
  
2
  2
 
1. 6
 1 3 0 0
  
2
  2
 
1. 7
 1 5 0 0
  
3
  0
 
1. 8
 1 5 0 0
  
3
  0
 
1. 9
 1 5 0 0
  
3
  0
 
2. 0
 1 6 5 0
  
3
  1
 
2. 1
 1 8 0 0
  
3
  2
 
2. 2
 1 8 0 0
  
3
  2
 
2. 3
 2 0 0 0
  
4
  0
 
2. 4
 2 0 0 0
  
4
  0
 
2. 5
 2 0 0 0
  
4
  0
 
 

 
Pa ge 2 0 of 3 4 
4. 1. 3  
St ora ge a n d Sta bilit y: 
St ore at 2 5 o C ( 7 7o F); e xc ursi o ns per mitte d t o 1 5o t o 3 0o C ( 5 9o t o 8 6o F), kee p b ottles or st ora ge de vices 
ti g htl y cl ose d. 
4. 1. 4  
 A ncillar y T hera p y:  
Patie nts s h o ul d recei ve f ull s u p p orti ve care, i ncl u di n g tra nsf usi o ns of bl o o d a n d bl o o d pr o d ucts, a nti bi otics, 
a ntie metics, etc. w he n a p pr o priate.  T he reas o n(s) f or treat me nt, d osa ge, a n d t he dates of treat me nt s h o ul d be 
rec or de d o n t he fl o w s heets.  Er yt hr o p oieti n is all o we d.  M yel oi d gr o wt h fact ors s h o ul d n ot be use d pr o p h ylacticall y 
b ut ma y be utilize d t o treat gra de 4 ne utr o pe nia ( A N C < 5 0 0) wit h or wit h o ut fe ver. 
4. 1. 5
 C o nc o mita nt
 Me dicati o ns:
  
Patie nts ma y recei ve all c o nc o mita nt t hera p y dee me d necessar y t o pr o vi de a de q uate s u p p ort.  N o ot her 
c yt ot o xic t hera p y or ra di ot hera p y ma y be use d d uri n g t hera p y. 
Ca pecita bi ne a n d s o me of its meta b olites are c o n verte d pr i nci pall y b y li ver e nz y mes (car b o x ylesterase a n d c yti di ne 
dea mi nase a n d T P i n t u m or tiss ues). At prese nt, it is u n k n o w n w het her t his meta b olis m is li kel y t o be i nfl ue nce d b y 
ot her treat me nts or alc o h ol, w hic h eit her i n d uce or i n hi bit certai n li ver e nz y mes. 
All o p uri n ol:   O x y p uri n ol, a meta b olite of all o p uri n ol, ca n p ote ntiall y i nterfere wit h 5- F U a na b olis m via or otate 
p h os p h ori b os yltra nsferase.  Alt h o u g h t h is was ori gi nall y use d as a strate g y t o pr otect n or mal tiss ues fr o m 5- F U-
ass ociate d t o xicit y, f urt her la b orat or y st u dies s u g geste d p ossi ble a nta g o nis m of t he a n tica ncer acti vit y of 5- F U i n 
s o me t u m or m o dels.  If a patie nt is recei vi n g all o p uri n ol, t he nee d f or ta ki n g t his me dici ne s h o ul d be ascertai ne d.  If 
p ossi ble, all o p uri n ol s h o ul d be disc o nti n ue d pri or t o starti n g o n t his re gi me n, a n d a n ot her a ge nt s u bstit ute d f or it. 
S ori v u di ne a n d Bri v u di ne : A meta b olite of t he a b o ve t w o i n vesti gati o nal a nti viral a ge nts, 
5- br o m o vi n yl uracil, is a p ote nt i n hi bit or of di h y dr o p yri mi di ne de h y dr o ge nase, t he e nz y me t hat cata b olizes 5- F U.  
Patie nts s h o ul d n ot recei ve c o nc urre nt t h era p y wit h eit her of t hes e a nti viral a ge nts w hile recei vi n g ca pecita bi ne.  If  
a patie nt has recei ve d pri or s ori v u di ne or  bri v u di ne, t he n at least f o ur wee ks m ust ela pse bef ore t he patie nt recei ves 
ca pecita bi ne t hera p y 
A ntic oa g ula nts : See W ar ni n gs a n d Preca uti o ns Secti o n 6. 9 I n a dr u g i nteracti o n st u d y wit h si n gle d ose 
warfari n a d mi nistrati o n, t here was a si g nifica nt i ncrease i n t he mea n A U C of S- warfari n. T he ma xi m u m o bser ve d 
I N R val ue i ncrease d b y 9 1 %. T his i nteracti o n is pr o ba bl y d ue t o a n i n hi biti o n of c yt oc hr o me P 4 5 0 2 C 9 b y 
ca pecita bi ne a n d/ or its meta b olites.   
P he n yt oi n:  I ncrease d p he n yt oi n plas ma c o nce ntrati o ns ha ve bee n re p orte d d uri n g c o nc o mita nt use of 
Xel o da  wit h p he n yt oi n, s u g gesti n g a p ote ntial i nteracti o n. Patie nts ta ki n g p he n yt oi n c o nc o mita ntl y wit h Xel o da  
s h o ul d be re g ularl y m o nit ore d f or i ncrease d p he n yt oi n plas ma c o nce ntrati o ns a n d ass ociate d cli nical s y m pt o ms. 
La xati ves :  T he use of dr u gs wit h la xati ve pr o perties s h o ul d be a v oi de d. 

 
Pa ge 2 1 of 3 4 
4. 1. 6
 War ni n gs
 
a n d
 
Preca uti o ns:
 
Re nal I ns ufficie nc y : Patie nts wit h m o derate re nal i m pair me nt as meas ure d b y ser u m creati ni ne ( > 1. 3) at 
b aseli ne re q uire d ose re d ucti o n. Patie nts wit h mil d a n d m o derate re nal i m pair me nt at baseli ne s h o ul d be caref ull y 
m o nit ore d f or a d verse e ve nts. Pr o m pt i nterr u pti o n of t hera p y wit h s u bse q ue nt d ose a dj ust me nts will be ma de if a 
patie nt de vel o ps a gra de 2 t o 4 a d verse e ve nt.  Ca pecita bi ne is c o ntrai n dicate d i n patie nts wit h a calc ulate d 
creati ni ne cleara nce of < 3 0 ml/ mi n.  Creati ni ne le vel w ill be c hec ke d a n d creati ni ne cleara nce calc ulate d o n St u d y 
Da y 8 f or all s u bjects t o e ns ure safet y of c o nti n ue d a d mi nistrati o n of ca pecita bi ne.  
Pre g na nc y/ N ursi n g:  Ca pecita bi ne ma y ca use fetal har m w he n gi ve n t o a pre g na nt w o ma n. If t he dr u g is 
use d d uri n g pre g na nc y, or if t he patie nt bec o mes pre g na nt  w hile recei vi n g t his dr u g, t he patie nt s h o ul d be a p prise d 
of t he p ote ntial hazar d t o t he fet us. W o me n of c hil d beari n g p ote ntial s h o ul d be a d vise d t o a v oi d bec o mi n g pre g na nt 
w hile recei vi n g treat me nt wit h ca pecita bi ne. Beca use of t he p ote ntia l f or seri o us a d verse reacti o ns i n n ursi n g i nfa nts 
fr o m ca pecita bi ne, t he patie nt will be i nstr ucte d t hat n ursi n g m ust be disc o nti n ue d w he n recei vi n g ca pecita bi ne 
t hera p y. 
C oa g ul o pat h y : Patie nts recei vi n g c o nc o mita nt ca pecita bi ne a n d oral c o u mari n- der i vati ve a ntic oa g ula nt 
t hera p y s h o ul d ha ve t heir a ntic oa g ula nt res p o nse (I N R or pr ot hr o m bi n ti me) m o nit ore d fre q ue ntl y i n or der t o a dj ust 
t he a ntic oa g ula nt d ose acc or di n gl y. A cli nicall y i m p orta nt Ca pecita bi ne- Warfarin dr u g i nteracti o n was de m o nstrate d 
i n a cli nical p har mac ol o g y trial. Altere d c oag ulati o n para meters a n d/ or blee di n g, i ncl u di n g de at h , ha ve bee n 
re p orte d i n patie nts ta ki n g ca pecita bi ne c o nc o mita ntl y wit h c o u mari n- deri vati ve a ntic oa g ula nts s uc h as warfari n a n d 
p he n pr oc o u m o n. P ost mar keti n g re p orts ha ve s h o w n cli nicall y si g nifica nt i ncreases i n pr ot hr o m bi n ti me ( P T) a n d 
I N R i n patie nts w h o were sta bilize d o n a ntic oa g ula nts at t he ti me ca pecita bi ne was i ntr o d uce d. T hese e ve nts 
occ urre d wit hi n se veral da ys a n d u p t o se veral m o nt hs after i nitiati n g ca pecita bi ne t hera p y a n d, i n a fe w cases, 
wit hi n o ne m o nt h after st o p pi n g ca pecita bi ne. T hese e ve nts occ urre d i n patie nts wit h a n d wit h o ut li ver metastases. 
A ge greater t ha n 6 0 a n d a dia g n osis of ca ncer i n de pe n de ntl y pre dis p ose patie nts t o a n i ncrease d ris k of 
c oa g ul o pat h y. 
Car di ot o xicit y:  T he car di ot o xicit y o bser ve d wit h ca pecita bi ne i ncl u des m y ocar dial i nfarcti o n/isc he mia, 
a n gi na, d ysr h yt h mias, car diac arre st, car diac fail ure, s u d de n deat h, electr ocar di o gra p hic c ha n ges, a n d 
car di o m y o pat h y.  T hese a d verse e ve nts ma y be m ore c o m m o n i n patie nts wit h a pri or hist or y of c or o nar y arter y 
disease. 
T his treat me nt is f oresee n as a self-a d mi nistere d o ut- patie nt treat me nt, a n d i n certai n circ u msta nces a d verse 
e ve nts t hat c o ul d occ ur, s uc h as diarr hea, or ha n d-f o ot s y n dr o me ca n ra pi dl y bec o me seri o us. I n t he case w here a 
patie nt e x perie nces a n y t o xicit y bet wee n sc he d ule d visits, t he patie nt will be i nstr ucte d t o c o ntact t he cli nic as s o o n 
as p ossi ble, f or f urt her directi o ns, disc o nti n uati o n of st u d y me dicati o n, a n d/ or treat me nt. 
4. 2  
R a di ati o n T her a p y. 
T R E A T M E N T P L A N  
4. 2. 1  
Si m ul ati o n a n d Pl a n ni n g 
T u m or v ol u me will be defi ne d o n t he basis of C T a n d M RI i ma gi n g fi n di n gs a n d o perati ve n otes a n d 
fi n di n gs.  P ositi o n of ste nts a n d s ur gical cli ps, if a n y, a n d c h ola n gi o gra p h y ma y als o be utilize d.  S pecificall y, a cli p 

 
Pa ge 2 2 of 3 4 
will be place d at t he sec o n d p orti o n of  t he d u o de n u m f or i ma ge g ui da nce.  T he pri mar y t u m or a n d a n y cli nicall y 
e nlar ge d l y m p h n o des will be treate d wit h a mar gi n of 2 c m t o i ncl u de peri pa ncreatic n o des.  T he p orta he patis, 
celiac a xis, s u peri or mese nteric arter y ( S M A) r o ot, a n d t he pa ncreatic o d u o de nal n o des will als o be treate d.  I n ste p 1 
( d ose le vel – 1), t otal d ose will be prescri be d t o t he 9 5 % iso d ose a n d will be 3 0 C G E i n 1 0 fracti o ns ( 3 G y/ da y) wit h 
m ultifiel d tec h ni q ues.  I n ste p 2, t otal d ose will be pres cri be d t o t he 9 5 % is o d ose a n d will be 2 5 C G E i n 5 fracti o ns 
( 5 G y/ da y) wit h m ultifiel d tec h ni q ues.   
Patie nts will be si m ulate d s u pi ne. I ntra ve n o us a n d or al c o ntrast will be a d mi nistere d per sta n dar d 
de part me nt pr ot oc ol.   If t olerate d, t he B o d y Fi x s yste m will be use d.  T he B o d y Fi x s yste m is a n F D A a p pr o ve d 
s yste m.  Wit h t his s yste m preli mi nar y e x perie nce de m o nstrates t hat c hest wall m oti o n is li mite d t o a p pr o xi matel y 2 
m m i n t he A P directi o n.  If t he B o d y Fi x is n ot feasi ble, n o restricti ve de vice will be use d.  4- D pla n ni n g C T will be 
o btai ne d f or treat me nt pla n ni n g t o ascertai n t he e xte nt of t u m or m oti o n.  
T he Gr oss T u m or V ol u me ( G T V) is defi ne d as t he gr oss pri mar y t u m or a n d a n y l y m p h n o des e nlar ge d o ver 
1 c m d uri n g si m ulati o n usi n g c o ntrast gi ve n d uri n g C T or M RI.  T he cli nical tar get v ol u me ( C T V) will als o i ncl u de 
t he f oll o wi n g at-ris k n o dal basi ns: p orta he patis, celiac a xis, s u peri or mese nteric arter y, a n d pa ncreatic o d u o de nal 
n o des as defi ne d b y t he i n ner-t hir d of  t he d u o de n u m.  Pla n ni n g tar get v ol u me ( P T V): Beca use da il y l ocalizati o n a n d 
gati n g a n d/ or B o d y Fi x I m m o bilizati o n will be use d, a 1 c m mar gi n i n t he i n all directi o ns e xce pt 0. 5 c m p osteri orl y.  
T he P T V m ust be di gitize d or dra w n o n t he pla n ni n g C T sca n D R Rs. 
C o m p uterize d d osi metr y is re q uire d if m ore t ha n t w o fiel ds are use d. All fiel ds m ust be si m ulate d usi n g a 
mac hi ne t hat d u plicates t he ge o metr y of t he act ual treat me nt mac hi ne.  Pa tie nt c o nt o urs a n d is o d ose pl ots are 
re q uire d.  Is o d ose pl ots m ust acc o u nt f or t he effect of all treate d fiel ds, i ncl u din g a n y bl oc ki n g use d.   
Ra diati o n t hera p y will be gi n o n Da y 1.  Treat me nt m ust be gi n o n a M o n da y. 
I n ste p 1, fiel ds will recei ve a t otal d ose of 3 0 C G E at 3 C G E per fracti o n 5 da ys per wee k o ver 2 wee ks.  I n ste p 2, 
fiel ds will recei ve a t otal d ose of 2 5 C GE at 5 C G E per fracti o n as o utli ne d bel o w. 
Ta ble 5 
Ra diati o n D ose Sc he d ule 
D ose 
L e vel 
te p 1 
e a d-i n 
h ase 
D ose/f r acti o n  
# 
T x 
Fr acti o n ati o n  
Sc he d ule 
T ot al 
D ose 
Wee k 1 
Sc he d ule 
Wee k 2 
Sc he d ule 
T ot al D a ys 
1  
1  
3 C G E 
1 0  
Q D 
3 0  
M T W T h Fri  
M T W T h Fri  
1 2 
  
Ste p 2  
D ose/fr acti o n  
# 
T x 
Fr acti o n ati o n  
Sc he d ule 
T ot al 
D ose 
Wee k 1 
Sc he d ule 
Wee k 2 
Sc he d ule 
T ot al D a ys 
2  
1  
5 C G E 
5  
Q D 
2 5  
M W F  
T T h  
1 1 
3  
2  
5 C G E 
5  
Q D 
2 5  
M T T h Fri  
M 
9 
4  
3  
5 C G E 
5  
Q D 
2 5  
M T W T h Fri  
- 
5 
 

 
Pa ge 2 3 of 3 4 
4. 2. 2  
Tre at me nt 
All c har ge d particle treat me nt will be gi ve n wit h t he patie nt at t he Fra ncis H. B urr Pr ot o n T hera p y Ce nter.  Fil m 
or di gital i ma ges will be ta ke n pri or t o eac h treat me nt i n  acc or da nce wit h t he pr ot o n ce nter's sta n dar d practice 
f or all patie nts.  T hese i ma ges are use d t o verif y t he p ositi o n of t he patie nt a n d t he a pert ure.  T hese di gital 
i ma ges are per ma ne ntl y st ore d electr o nicall y f or eac h patie nt. 
. All patie nts will be treate d wit h res pirat or y gati n g t o acc o u nt f or res pirat or y e xc ursi o n if t u m or m oti o n is 
> 5 m m.  Treat me nt m ust start o n a M o n da y 
4. 2. 3  
N or m al tiss ue v ol u me a n d d ose c o nsi der ati o ns 
N or mal tiss ue g ui deli nes are as o utli ne d bel o w. I n ste p 1 (lea d-i n p hase), t he 1 0 fracti o n c o nstrai nts will be 
use d.  I n ste p 2, t he 5 fracti o n c o nstrai nts will be use d. 
 
Ta ble 6 
Pla n ni n g G oals - N or m al tiss ue c o nstrai nts 
 
O R G A N  
T hres h ol d D ose 
C o n ve nti o n al 
2 8 fr acti o n 
Sc he d ule 
N or m alize d 
T ot al D ose 
( 2 G y e q ui v ale nts) 
 
T hres h ol d D ose- 
Ste p 1- 1 0 
fr acti o n sc he d ule 
( C G E) 
T hres h ol d D ose- 
Ste p 2- 5 fr acti o n 
sc he d ule 
( C G E) 
% A b o ve t hres h ol d 
Li ver 
3 0 G y 
2 3. 0 G y 2 2 2
  1 7. 5
  
3 0 %
 
Ki d ne y 
2 0 G y 
1 4. 8 G y 3 1 6
  1 3
  
3 0 %
 
S pi nal C or d  
4 5 G y 
4 0. 6 G y 2 3 1
  2 4
  
0 %
 
St o mac h 
4 0 G y 
3 8 G y 1 0 1 8 *
  7
  
1 0 %
 
Ass u me d  i n s u bscri pts 
 
*  If p ossi ble -  St o mac h d ose t hres h ol d is t o pre ve nt na usea, a n ac ute effect. N o esta blis he d g ui deli nes 
e xist. H o we ver, i n t he preli mi nar y M G H I M R T e x perie n ce, t he a b o ve d ose t hres h ol d is ass ociate d wit h ~ 
1 0 % rate of A N Y a nti-e metic use.  T he dail y N T D of t he c o n ve nti o nal sc he d ule is 1. 3 6 G y.  T his mea ns 
t hat t hat t he t hres h ol d d ose ( N T D) f or a fi ve fracti o n sc he d ule is 6. 8 G y ( 2 G y e q ui vale nts) a n d c orrelates 
wit h t he liste d d ose t hres h ol d. 
Treat me nt pla n ni n g s h o ul d be a dj uste d f or decrease d re nal f u ncti o n base d o n a n ele vate d ser u m creati ni ne, a 
hist or y of u nilateral or bilateral re nal disease, a n d a b n or ma lities i n baseli ne la b orat or y or ra di o gra p hic st u dies.  
A d diti o nal st u dies t o assess re nal f u ncti o n will be perf or me d as nee de d.  
4. 3  
S ur ger y 
4. 3. 1  
S ur ger y will be perf or me d 2- 7 wee ks after ra diati o n t hera p y if n o metastatic disease o n re-sta gi n g.   
Patie nts w h o recei ve s ur ger y 2- 4 wee ks after c o m ple ti n g R T will n ot be resta ge d pri or t o s ur ger y. 
4. 3. 2  
At la par ot o m y, t he li ver a n d pa ncreas will be e xa mi ne d b y pal pati o n a n d i ns pecti o n. 
4. 3. 3  
I n t he a bse nce of metastases, t u m or m o bilizati o n a n d s ur gical resecti o n will be perf or me d.  A 
pa ncreatic o d u o de nect o m y ( W hi p ple pr oce d ure) wit h sta n dar d l y m p ha de nect o m y will be d o ne.  T his 
i n v ol ves dissecti o n u p t o t he s u peri or mese nteric arter y, wit h s kelet o nizati o n of t he ri g ht lateral a n d a nteri or 
as pects of t he vessels.  
4. 3 4  
Fee di n g jej u n ost o m y a n d gastr ost o m y t u bes ma y be place d at t he discreti o n of t he o perati n g s ur ge o n. 

 
Pa ge 2 4 of 3 4 
4. 4  
P at h ol o g y 
Pr ocessi n g t he s peci me n a n d pat h ol o g y will be re p orte d acc or di n g t o t he AJ C C Ca ncer Sta gi n g Ma n ual, 6 t h 
E diti o n.  Pa ncreatic tra nsecti o n mar gi n, a n d t he bile d uct ma r gi n will be e val uate d o n fr oze n secti o n.  Rec or de d o n 
per ma ne nt secti o n will be: t u m or size, de gree of differe ntia ti o n ( well, m o derate, p o or), l y m p h n o de stat us, mar gi n 
stat us, a n d de gree of treat me nt effect.   
4. 4. 1 Bi o m ar kers of Res p o nse  
T he searc h f or ne w bi o mar kers of res p o nse t o s h ort c o urse ne oa dj u va nt ra diati o n will i n v ol ve a n 
e xa mi nati o n of t he m olec ular a n d ge netic c haracteristics of t he t u m or s peci me ns. T his a nal ysis will be gi n wit h t he 
pri mar y t u m or after t he c o urse of treat me nt a n d ma y al s o i ncl u de a nal ysis of t he i nitial bi o ps y s peci me n. T o 
c haracterize t he t u m ors at t he ge netic le vel, m utati o na l a nal ysis of t he s peci me ns will be perf or me d usi n g a 
c ust o mize d S N A P S H O T platf or m t hat e xa mi nes t he t u m or f or a p pr o xi matel y 1 0 0 s pecific ge netic m utati o ns. 
Fi n di n gs fr o m t he m olec ular a n d ge netic st u dies will be a nal yze d i n t he c o nte xt of c ha n ges a p preciate d i n t he 
hist ol o gical a n d i m m u n o hist oc he mical c ha n ges f o u n d i n t u m or tiss ue secti o ns i n or der t o vali date k n o w n mar kers of 
ra diati o n se nsiti vit y a n d defi ne ne w bi o mar kers of treatme nt res p o nse.  All c orrelati ve st u dies are o pti o nal.  
5. 0  
Pre-tre at me nt, O n- St u d y, a n d P ost Tre at me nt E v al u ati o ns  
5. 1  
Pri or t o St u d y E nr oll me nt:  Pri or t o st u d y e nr oll me nt patie nts m ust u n der g o t he f oll o wi n g e val uati o ns: 
Wit hi n 4 2 d a ys of e nr oll me nt:   la par osc o p y, C hest C T, A b d o mi nal- pel vic C T ( or M RI), 
Wit hi n 2 8 d a ys of e nr oll me nt:   Si g ne d i nf or me d c o nse nt,  
Wit hi n 7 d a ys of e nr oll me nt: P h ysical e xa m, La b st u dies ( C B C wit h  diff, Na, K, B U N, Cr, Gl uc ose, 
P h os p h or o us, Calci u m, Al b u mi n, A S T, A L T, T otal b ilir u bi n, Al kali ne p h os p hatase, C A 1 9- 9, C E A, a n d a 
uri ne or ser u m H C G f or w o me n of c hil d beari n g p ote ntial). 
5. 2  
E v al u ati o n D uri n g St u d y: O n tre at me nt d a ys 8 a n d 1 5 , t he patie nts will be assesse d as f oll o ws: 
a)  C o m plete bl o o d c o u nt ( C B C: he m o gl o bi n, he mat ocrit,  re d bl o o d cells, W B C, platelets, a n d differe ntial 
bl o o d c o u nts) wee kl y. 
b)  Bl o o d c he mistries ( Na, K, B U N, Cr, Gl uc ose, , Calci u m, Al b u mi n, A S T, A L T, T otal bilir u bi n, Al kali ne 
p h os p hatase)  
c)  Hist or y, p h ysical e xa m, a n d vital si g ns  
d)  After c o m pleti o n of ca pecita bi ne a n d ra diati o n t her a p y, patie nts will ha ve a 3 t o 6 wee k rest peri o d 
f oll o we d b y a resta gi n g C hest C T, A b d C T ( or M RI), C E A, C A 1 9- 9 S ur ger y will be perf or me d 4 t o 7 wee ks 
after c o m pleti o n of ne oa dj u va nt t hera p y. 
5. 3  
P ost Tre at me nt e v al u ati o n 
After c o m pleti o n of t hera p y a n d s u r ger y, patie nts will be f oll o we d f or 3 0- da y m or bi dit y a n d m ortalit y 
e val uati o n.  It is rec o m me n de d (alt h o u g h n ot ma n date d) t hat patie nts u n der g oi n g R 0 resecti o ns s h o ul d recei ve 
a dj u va nt treat me nt wit h 4 c ycles of ge mcita bi ne- base d t hera p y.  Patie nts s h o ul d be c o ntacte d eit her b y tele p h o ne or 
cli nic visit e ver y 6 m o nt hs f or 5 years after s ur ger y i n or der t o f oll o w pr o gressi o n-free a n d o verall s ur vi val stat us. 

 
Pa ge 2 5 of 3 4 
6. 0  
Re q uire d D at a ( als o see secti o ns 5. 1 – 5. 3) 
 
T a ble 7 
Re q uire d Data Ta ble 
Tests a n d O bser vati o n  
Pri or t o 
St u d y 
Da ys 1, 8, 1 5  
Pre o p * *  
P ost- o p F/ U 
Si g ne d i nf or me d c o nse nt  
A 
 
 
 
Hist or y
 X
 
 
 
 
P h ysical
 
E xa mi nati o n
 X
 X
 X
 
 
Vital Si g ns a n d perf or ma nce 
stat us 
X
 
  X
 
 
Hei g ht/ W ei g ht/ S urface Area  
X 
 
 
 
Dr u g T o xicit y 
 
X 
X  
 
La b orat or y *: ( wit hi n 7 da ys of 
e nr oll me nt) 
 
 
 
 
C B C/ plts/ diff
  
X
 X
 X
 
 
Ser u m c he mistries ( Na, K, 
B U N, Cr, Gl uc ose, , Calci u m, 
Al b u mi n, A S T, A L T, T otal 
bilir u bi n, Al kali ne 
p h os p hatase) 
X
 X
 X
 
 
Creati ni ne cleara nce 
calc ulati o n ( C oc kr oft Ga ult) 
X 
X ( da ys 1 a n d 
8 o nl y) 
 
 
C A 1 9- 9
 X
 
 
X
 
 
C E A
 X
 
 
X
 
 
Pre g na nc y test * 
A 
 
 
 
O pti o nal Researc h Bl o o d   
G 
 
G  
 
Sta gi n g:
 
 
 
 
 
 
C hest C T A b d- pel vic C T ( or 
M RI) 
A
 
  X,
 
F
 
D
 
 
 
 
 
 
La par osc o p y
 B
 
 
 
 
Ra diati o n Pla n ni n g 
A 
 
 
 
A dj u va nt
 
t hera p y
 
 
 
 C
 

 
Pa ge 2 6 of 3 4 
* La b orat or y val ues nee d t o be o btai ne d wit hi n 7 da ys of st u d y e ntr y 
* * Pre o p e val uati o ns s h o ul d ta ke place 3- 6 wee ks after c o m pleti n g X R T a n d ca pecita bi ne 
A:  Sta gi n g C T or M RIs nee d t o be o btai ne d wit h 4 2 da ys of st u d y e ntr y   
B:  La par osc o p y nee ds t o be o btai ne d w it hi n 4 2 da ys of st u d y e ntr y.  Cli p will be place d i n sec o n d p orti o n of 
d u o de n u m. 
C:  It is rec o m me n de d t hat all patie nts w h o u n der g o R 0 res ecti o ns recei ve 4 c ycles of ge mcita bi ne- base d t hera p y.  
Cli nic visits a n d/ or p h o ne calls are re q uire d e ver y 6 m o nt hs f or 5 years after W hi p ple or u ntil deat h. 
D. C T sca ns will be perf or me d at least e ver y 6 m o  f or t he first 2 years a n d yearl y f or years 3- 5. 
F.  Patie nts recei vi n g s ur ger y 2- 4 wee ks afte r c o m pleti n g R T will n ot ha ve pre- o p sca ns. 
G. O pti o nal researc h bl o o d sa m ples will be o btai ne d at baseli ne a n d pri or t o s ur ger y. Please refer t o secti o n 2. 5. 1 f or 
s pecific i nstr ucti o ns.  
7. 0   
Deter mi n ati o n of M T D a n d D L Ts:  
7. 1 
P h ase I Deter mi n ati o n of M T D 
T he Ma xi m u m T olerate d D ose ( M T D) will be deter mi ne d as f oll o ws.   T he d ose li miti n g t o xicities ( D L T) 
are defi ne d i n 7. 2 wit hi n t hree wee ks of t he start of ra dia ti o n t hera p y. Patie nts will be e val ua ble f or D L T w het her or 
n ot t he y u n der g o s ur ger y f oll o wi n g t he ne oa dj u va nt t hera p y. Be gi n ni n g at le vel 1 of t he lea d-i n ste p 1, 3 patie nts 
will be treate d i nitiall y acc or di n g t o eac h of t he accelerate d  d ose sc he d ules i n 4. 2, Ta ble 5. If n o D L T were 
o bser ve d, t he pr ot oc ol will pr ocee d t o t he ne xt le vel of d ose sc he d ule. If at l east 2 of t he m were t o e x perie nce D L T, 
t he pre vi o us le vel will c o nsi dere d t he ma xi mall y t olerate d d ose ( M T D) sc he d ule.  If 2 patie nts at d ose le vel 1 are 
o bser ve d t o ha ve D L Ts, t he st u d y will be cl ose d. If e xactl y 1 of t he i nitial 3 patie nts were t o ha ve D L T at a gi ve n 
le vel, 3 m ore patie nts will be treate d usi n g t he sa me d ose sc he d ule. If n o f urt her D L T were t o occ ur, t he ne xt le vel 
of d ose sc he d ule will be gi n e nr oll me nt. If 1 or m ore of t he a d diti o nal 3 patie nts were t o e x perie nce D L T, t he 
pre vi o us le vel will  be c o nsi dere d t he M T D sc he d ule. If n o ne  of t he first 3 patie nts treate d at le vel 4 or o nl y 1 of 6 
patie nts were t o ha ve D L T, le vel 4 will be declare d as t he M T D sc he d ule. 
7. 2  
D ose Li miti n g T o xicities ( D L Ts).   D L T will be defi ne d as occ urri n g wit hi n 3 wee ks of t he start of 
ra diati o n t hera p y: 
a)  
A n y gra de 3 n o n- he mat ol o gic or he mat ol o gic t o xicit y re q uiri n g a greater t ha n 7 da y i nterr u pti o n i n 
t hera p y (e xcl u di n g al o pecia a n d na usea/ v o miti n g n ot c o ntr olle d b y  o pti mal s u p p orti ve care or  
b)  
A n y gra de 4 n o n- he mat ol o gic t o xicit y or 
c)  
A n y gra de 4 ne utr o pe nia or t hr o m b oc yt o pe nia as defi ne d b y N CI C T C v 3. 0. ( See secti o n 7. 2. 1 f or 
d ose m o dificati o ns). 
T o xicities n ot d ue t o c he m ora diati o n, s uc h as c h ola n gitis fr o m a bl oc ke d biliar y ste nt, or s y m pt o ms t h o u g ht 
t o be fr o m t u m or pr o gressi o n s uc h as pai n or b owel o bstr ucti o n, will n ot be classifie d as D L Ts.  

 
Pa ge 2 7 of 3 4 
A n y D L T s h o ul d be re p orte d t o t he pri nci ple i n vesti g at or or t he st u d y d at a m a n a ger wit hi n 7 2 h o urs.   
7. 3 P h ase II D osi n g 
  
As descri be d i n Secti o n 2. 5, a b o ve, t here were n o D L Ts o bser ve d i n t he P hase I st u d y s u bjects.  T he M T D 
reac he d was d ose le vel 4 ( 5 G y x 5 i n 5 da ys).  T h us, t his will be t he pla n ne d d ose le vel f or t he P hase II p orti o n of 
t he st u d y. 
 
8. 0  
T o xicities a n d D ose M o dific ati o ns 
8. 1  
C a pecit a bi ne a n d R a di ati o n T her a p y 
8. 1. 1.
 Ge neral
 T o xicities:
 
T he m ost c o m m o n t o xicities of ca pecita bi ne a n d ra diati o n t hera p y are fati g ue, na usea, a b d o mi nal pai n, 
diarr hea, i n di gesti o n, v o miti n g, wei g ht l oss a n d a n ore xia.   Ot her t o xicities ma y i ncl u de ne utr o pe nia, 
t hr o m b oc yt o pe nia, a ne mia, c uta ne o us eru pti o ns, al o pecia, fe ver, fl u-li ke s y m pt o ms, a n d urticarial reacti o ns.  M uc h 
less c o m m o n t o xicities c o ul d i ncl u de a na ph ylactic reacti o ns, peri p h eral ne ur o pat h y, arr h yt h mia, gastr oi ntesti nal 
blee di n g a n d b o wel o bstr ucti o n. 
8. 2  
D ose M o dific ati o ns:  
8. 2. 1  
He mat ol o gic a n d N o n- He mat ol o gic T o xicit y 
Ca pecita bi ne a n d ra diati o n t hera p y will be hel d f or a n y Gra de 3 or 4 t o xicit y (e xce pt f or al o pecia a n d 
na usea/ v o miti n g w hic h is c o ntr olle d wit h a nti-e metic t hera p y) .  After t o xicit y res ol ves t o < gra de 2, ca pecita bi ne 
will be res u me d at 6 0 0 m g/ m 2 BI D t o c o m plete t he 1 0  we e k da ys of t hera p y. Ca pecita bi ne ca n be hel d a ma xi m u m 
of 7 da ys.  If f urt her gra de 3 or 4 t o xicit y is n ote d at t he re d uce d d ose le vel, after t o xicit y res ol ves t o < gra de 2, 
ca pecita bi ne will be res u me d at 5 0 0 m g/ m 2 BI D t o c o m plete  t w o wee ks of t hera p y.  If t he sec o n d d ose re d ucti o n is 
n ot t olerate d, ca pecita bi ne will be st o p pe d.  Patie nts w ill kee p a ca pecita bi ne diar y a n d will rec or d t he n u m ber of 
ca pecita bi ne ta blets a n d t he ti me t hat t he y will ta ke t he ta blets.  N ote t hat patie nts ca n p ote ntiall y ha ve n o 
c o m bi nati o n t hera p y f or u p t o 3 da ys wit h o ut bei n g c o nsi dere d a D L T as n o t hera p y is pla n ne d f or da y 1 1 a n d 
c o m bi nati o n of c he m ora diati o n d oes n ot e xcee d 1 0 da ys.  Ra diati o n t hera p y will be hel d f or Gra de 3 or 4 na usea 
u ntil na usea res ol ves t o Gr 2 or less. 
 

 
Pa ge 2 8 of 3 4 
9. 0  
A d verse E ve nts 
9. 1  
A d verse E ve nt a n d Re p orti n g Defi niti o ns  
I n t he e ve nt of a n a d verse e ve nt t he first c o ncer n will be f or t he safet y of t he s u bject.   
 
Res ults i n deat h  
 
Is life-t hreate ni n g  
 
Re q uires or pr ol o n gs i n patie nt h os pitalizati o n  
 
Is disa bli n g  
 
Is a c o n ge nital a n o mal y/ birt h defect  
 
Is me dicall y si g nifica nt or re q uires me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes 
liste d a b o ve. 
9. 2  
Re p orti n g of Seri o us Tre at me nt E mer ge nt A d verse E ve nts  
All treat me nt e mer ge nt S A Es s h o ul d be rec or de d a n d fa xe d t o: 
 
St u d y C o or di nati o n Ce nter/ Pri nci pal I n vesti gat or 
C o ntact I nf or mati o n a n d fa x # 
T he o d ore S. H o n g, M D 
 
A N D:( T B D) 
I R B C o ntact i nf or mati o n a n d fa x # 
1 0. 0  
E V A L U A TI O N O F R E S P O N S E 
1 0. 1  
Res p o nse Criteria   
 
Res p o nse a n d pr o gressi o n will be e val uate d i n t his st u d y usi n g t he i nter nati o nal criteria pr o p ose d b y 
t he R E CI S T ( Res p o nse E val uati o n Criteria i n S oli d T u m ors) c o m mittee.  C ha n ges i n o nl y t he lar gest dia meter 
( u ni di me nsi o nal meas ure me nt) of t he t u m or lesi o ns are use d i n t he R E CI S T criteria. 
1 0. 1. 1  Ra di o gra p hic Res p o nse   
Defi niti o n of Res p o nse:  O verall t u m or res p o nse will be base d o n a n i nte grati o n of t he e val uati o n of tar get, 
n o n-tar get, a n d ne w lesi o ns, as descri be d bel o w: 
E val uati o n of tar get le si o ns ( pa ncreatic mass): 
C o m plete Res p o nse ( C R):    Disa p peara nce of all cli nical a n d radi ol o gical e vi de nce of tar get lesi o ns. 
P arti al Res p o nse ( P R):   A 3 0 % or greater decrease d i n t he s u m of L D of all lesi o ns i n refere nce t o t he 
baseli ne s u m L D. 
St a ble Dise ase ( S D):   Neit her s ufficie nt i ncrease t o q ualif y f or P D n or s ufficie nt s hri n ka ge t o q ualif y f or 
P R. 
Pr o gressive Dise ase ( P D):   A 2 0 % or greater i ncrease i n t he s u m of  L D of all tar get lesi o ns, ta ki n g as 
refere nce t he s mallest s u m L D rec or de d si nce baseli ne. 

 
Pa ge 2 9 of 3 4 
T o be assi g ne d a stat us of P R or C R, c ha n ges i n  t u m or meas ure me nts m ust be c o nfir me d b y re peat 
e val uati o ns w hic h s h o ul d be perf or me d n o less t ha n 4 wee ks after t he criteria f or res p o nse are first met. 
E val uati o n of n o n-tar get lesi o ns:  
 
Pr o gressive Dise ase ( P D):   t he de vel o p me nt of ne w lesi o n(s). 
E val uati o n of ne w lesi o ns: 
N o:   
T here are n o ne w lesi o ns. 
Yes:   
Ne w lesi o ns are prese nt.  N ote:  If ne w lesio ns are prese nt, t he patie nt is c o nsi dere d t o 
ha ve pr o gressi ve disease o verall. 
O verall Res p o nse: 
O verall res p o nse will be deter mi ne d as ta b ulate d bel o w, base d o n t he e val uati o n of tar get, n o n-tar get, a n d 
ne w lesi o ns: 
Tar get lesi o ns  
N o n- Tar get lesi o ns  
Ne w Lesi o ns  
O verall res p o nse 
C R
 C R
  
N o
 C R
 
C R
 I nc o m plete
 
res p o nse/ S D
 
N o
 P R
 
P R
 N o n- P D
 N o
 P R
 
S D
 N o n- P D
 N o
 S D
 
P D 
A n y 
Yes or N o 
P D 
A n y 
P D 
Yes or N o 
P D 
A n y
 A n y
  
Yes
 P D
 
 
E ver y eff ort s h o ul d be ma de t o d oc u me nt t u m or meas ure me nts a n d e xte nt of disease, e ve n after 
disc o nti n uati o n of t hera p y, i n or der t o classif y patie nts f o r o verall res p o nse as descri be d a b o ve.  Patie nts w h o d o n ot 
ha ve t u m or res p o nse assess me nt d ue t o ra pi d pr o gressi o n or  t o xicit y will be c o nsi dere d as n o n-res p o n ders, will be 
i ncl u de d i n t he de n o mi nat or f or t he res p o nse rate, a n d will be classifie d i nt o o ne of t he f oll o wi n g cate g ories: 
 
deat h attri b ute d t o disease pr o gressi o n 
 
deteri orati o n attri b ute d t o disease pr o gressi o n 
 
deat h attri b ute d t o dr u g t o xicit y 
 
earl y disc o nti n uati o n attri b ute d t o dr u g t o xicit y 
1 0. 2
 Pat h ol o gical
 
Res p o nse
 
All patie nts will u n der g o a f ull pa t h ol o gical re vie w of t heir pa ncreatic o d u o de nect o m y s peci me n acc or di n g 
t o t he AJ C C Sta gi n g Classificati o n, 6t h.  I nitial gr oss e val uati o n a n d i de ntificati o n of resecti o n mar gi ns will be 
perf or me d j oi ntl y b y t he s ur ge o n a n d t he pat h ol o gist.  Pat h ol o gical c o m plete res p o nse will be defi ne d as t he a bse nce 
of a n y via ble t u m or cells wit hi n t he pat h ol o gic s peci me n. 
1 0. 3  
Ti me t o t u m or pr o gressi o n 
Ti me fr o m date of pr ot oc ol e ntr y t o first o bjecti ve d oc u me ntati o n of pr o gressi ve disease or deat h.  Patie nts 
w h o die wit h o ut a re p orte d pri or pr o gressi o n will be c o nsi dere d t o ha ve pr o gresse d o n t he da y of t heir deat h.  

 
Pa ge 3 0 of 3 4 
1 0. 4  
Ti me t o deat h 
Ti me fr o m date of pr ot oc ol e ntr y t o date of deat h 
1 0. 5  
Ti me t o l ocal rec urre nce 
  
A l ocal rec urre nce will be defi ne d as a n y e vi de nce of t u m or rec urre nce wit hi n t he ra diati o n fiel d.  T he ti me 
t o l ocal rec urre nce will be fr o m t he date of pr ot oc ol e ntry t o t he first o bjecti ve d oc u me ntati o n of a l ocal rec urre nce. 
1 1. 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  
1 1. 1  
P hase 1  
T he d ose li miti n g t o xicities ( D L T) are defi ne d i n 6. 2 w it hi n t hree wee ks of t he start of ra diati o n t hera p y. 
Patie nts will be e val ua ble f or D L T w het her or n ot t he y u n der g o s ur ger y f oll o wi n g t he ne oa dj u va nt t hera p y. 
Be gi n ni n g at le vel 1 of t he lea d-i n ste p 1, 3 patie nts will be treate d i nitiall y acc or di n g t o eac h of t he accelerate d d ose 
sc he d ules i n 4. 2, Ta ble 5. If n o D L T were o bser ve d, t he pr ot oc ol will pr ocee d t o t he ne xt le vel of d ose sc he d ule. If 
at least 2 of t he m were t o e x perie nce D L T, t he pre vi o us  le vel will c o nsi dere d t he ma xi mall y t olerate d d ose ( M T D) 
sc he d ule. If e xactl y 1 of t he i nitial 3 patie nts were t o ha ve D L T at a gi ve n le vel, 3 m ore patie nts will be treate d usi n g 
t he sa me d ose sc he d ule. If n o f urt her D L T were t o occ ur, t he ne xt le vel of d ose sc he d ule will be gi n e nr oll me nt. If 1 
or m ore of t he a d diti o nal 3 patie nts were t o e x perie nce D L T, t he pre vi o us le vel will c o nsi dere d t he M T D sc he d ule. 
If n o ne of t he first 3 patie nts treate d at le vel 4 or o nl y 1 of 6 patie nts were t o ha ve D L T, le vel 4 will be declare d as 
t he M T D sc he d ule.  
F oll o wi n g t he escalati o n al g orit h m, t he pr o ba bilit y of pr o gressi n g t o t he ne xt le vel of d ose sc he d ule is 
gi ve n bel o w u n der a ra n ge of t he tr ue D L T rate. F or e xa m ple, if a d ose sc he d ule were ass ociate d wit h a n u n derl yi n g 
D L T rate of 5 0 %, t he pr o ba bilit y of escalati n g is 1 7 % s o t hat t he pr ot oc ol is u nli k el y t o pr ocee d t o t he ne xt le vel. As 
3- 6 patie nts will be e nr olle d at eac h le vel of pr o gressi vel y accelerate d d ose sc he d ule, accr ual t o t he escalati o n p hase 
ma y be u p t o 2 4 patie nts.  
Tr ue D L T rate  
Pr o ba bilit y of escalati o n 
1 0 %
 9 1 %
 
2 0 %
 7 1 %
 
3 0 %
 4 9 %
 
4 0 %
 3 1 %
 
5 0 %
 1 7 %
 
6 0 %
 8 %
 
 
1 1. 1  
P hase 2  
Accr ual will be e x pa n de d s o t hat a n ot her 2 5 patie nts will be treate d at t he M T D le vel i n or der t o deter mi ne 
t he rate of a n y gra de 3 or greater t o xicit y ass ociate d wit h t he accelerate d d ose a n d t o i n vesti gate t he sec o n dar y 
e n d p oi nts.  T o xicit y will be defi ne d acc or di n g t o t he N CI C o m m o n Ter mi n ol o g y Criteria ( versi o n 3). T he M D 
A n ders o n data de m o nstrate d 1 9 % gra de 3 t o xicit y usi n g t he sta n dar d c o urse of pre o perati ve ra diati o n at a t otal d ose 

 
Pa ge 3 1 of 3 4 
of 5 0. 4 G y c o nc urre ntl y wit h c o nti n u o us i nf usi o n 5- F U. If gra de 3 or greater t o xicit y were o bser ve d a m o n g at least 3 
of 2 5 patie nts, t he e xact 9 0 % o ne-si de d  u p per b o u n d will e xcee d 2 0 %. If t he un derl yi n g rate of gra de 3 or greater 
t o xicit y relate d t o t he M T D sc he d ule were 6 % t hat is c om para ble t o t he M D A s h ort-c o urse sc he d ule, t he decisi o n 
r ule is ass ociate d wit h 8 1 % pr o ba bilit y of r uli n g o ut rates hi g her t ha n 2 0 % at a o ne-si de d si g nifica nce le vel of 1 0 %. 
A sa m ple size of 2 5 patie nts treate d at t he M T D sc he d ule will pr o vi de a n e xact 9 0 % c o nfi de nce i nter val of wi dt h n o 
m ore t ha n +/- 0. 1 8 f or t he esti mati o n of t o xicit y, s ur gical m or bi dit y a n d pat h ol o gic c o m plete res p o nse. Patie nts w h o 
d o n ot u n der g o s ur ger y will be c o nsi dere d as fail ures i n t he esti mati o n of pat h ol o gical c o m plete res p o nse. 
Hist oricall y, pat h ol o gic c o m plete res p o nses are rarel y o bser ve d wit h ne oa dj u va nt ra diati o n a n d c o nc urre nt 5- F U. 
T h us a n y pat h ol o gic c o m plete res p o nse will be dee me d as  si g nifica nt. Pr o gressi o n-free s ur vi val will be esti mate d 
usi n g t he Ka pla n- Meier met h o d. Accr ual is pr ojecte d t o ta ke a b o ut 1 8 m o nt hs f or eac h p hase. If a patie nt is f o u n d t o 
be i neli gi ble o nce re gistere d a n d t heref ore ta ke n off st u d y a n d e xcl u de d fr o m a nal ysis, a n a d diti o nal patie nt ma y be 
e nr olle d a n d i ncl u de d i n a nal ysis. 
 
1 2. 0  
R E T E N TI O N O F R E C O R D S 
All d oc u me ntati o n of a d verse e ve nts, rec or ds of st u d y dr u g recei pt a n d dis pe nsati o n, a n d all I R B 
c orres p o n de nce will be retai ne d f or at least 2 years after t he i n vesti gati o n is c o m plete d. 
 

 
Pa ge 3 2 of 3 4 
1 3. 0  
Refere nces  
1.  
Kalser M H, Elle n ber g S S. Pa ncreatic Ca ncer. A dj u va nt C o m bi ne d Ra diati o n a n d C he m ot hera p y 
F oll o wi n g C urati ve Resecti o n [ P u blis he d Errat u m A p pears i n Arc h S ur g 1 9 8 6 Se p; 1 2 1( 9): 1 0 4 5]. 
Arc h S ur g 1 9 8 5; 1 2 0( 8): 8 9 9- 9 0 3. 
2.  
Li m J E, C hie n M W, Earle C C. Pr o g n ostic fact or s f oll o wi n g c urati ve resecti o n f or pa ncreatic 
a de n ocarci n o ma: a p o p ulati o n- base d, li n ke d data base a nal ysis of 3 9 6 patie nts. A n n S ur g 
2 0 0 3; 2 3 7( 1): 7 4- 8 5. 
3.  
Kli n ke n bijl J H, Jee kel J, S a h m o u d T, et al. A dj u va nt ra di ot hera p y a n d 5-fl u or o uracil after c urati ve 
resecti o n of ca ncer of t he pa ncreas a n d peria mp ullar y re gi o n: p hase III trial of t he E O R T C 
gastr oi ntesti nal tract ca ncer c o o perati ve gr o u p. A n n S ur g 1 9 9 9; 2 3 0( 6): 7 7 6- 8 2; disc ussi o n 8 2- 4. 
4.  
Willett C G, Le wa n dr o ws ki K, Wars ha w A L, Ef ir d J, C o m pt o n C C. Resecti o n mar gi ns i n 
carci n o ma of t he hea d of t he pa ncreas. I m plicati o ns f or ra diati o n t hera p y. A n n S ur g 
1 9 9 3; 2 1 7( 2): 1 4 4- 8. 
5.  
Ric h T A, E va ns D B, C urle y S A, Aja ni J A. A dj u va nt ra di ot hera p y a n d c he m ot hera p y f or biliar y 
a n d pa ncreatic ca ncer. A n n O nc ol 1 9 9 4; 5( S u p pl 3): 7 5- 8 0. 
6.  
Stale y C A, Lee J E, Clear y K R, et al. Pre o pe rati ve c he m ora diati o n, pa ncreatic o d u o de nect o m y, a n d 
i ntra o perati ve ra diati o n t hera p y f or a de n ocarcin o ma of t he pa ncreatic hea d. A m J S ur g 
1 9 9 6; 1 7 1( 1): 1 1 8- 2 4; disc ussi o n 2 4- 5. 
7.  
E va ns D, A b br uzzese J, L ee J, Clear y K,  Ric h T. Pre o perati ve c he m ora diati o n a n d 
pa ncreatic o d u o de nect o m y f or a de n ocarci n o ma of t he pa ncreas ( Meeti n g a bstract). Pr oc A n n u Meet 
A m S oc Cli n O nc ol 1 9 9 4; 1 3: A 6 9 2. 
8.  
E va ns D B, Pisters P W. Pre o perati ve c he m ora diati o n t hera p y f or pa ncreatic ca ncer. S ur g Cli n N ort h 
A m 2 0 0 1; 8 1( 3): 7 0 9- 1 3. 
9.  
Te p per J E. A dj u va nt Irra diati o n of Gastr oi ntesti nal Mali g na ncies: I m p act O n L ocal C o ntr ol a n d 
T u m or C ure. I nt J Ra diat O nc ol Bi ol P h ys 1 9 8 6; 1 2( 4): 6 6 7- 7 1. 
1 0.  
W hitti n gt o n R, Br y er M P, Haller D G, S oli n LJ, R osat o E F. A dj u va nt T hera p y of Resecte d 
A de n ocarci n o ma of t he Pa ncreas. I nt J Ra diat O nc ol Bi ol P h ys 1 9 9 1; 2 1( 5): 1 1 3 7- 4 3. 
1 1.  
H off ma n J P, Li psitz S, Pisa ns k y T, Weese J L, S oli n L, Be ns o n A B, 3r d. P hase II trial of 
pre o perati ve ra diati o n t hera p y a n d c he m ot hera p y f or patie nts wit h l ocalize d, resecta ble 
a de n ocarci n o ma of t he pa ncreas: a n Easter n C o o perati ve O nc ol o g y Gr o u p St u d y. J Cli n O nc ol 
1 9 9 8; 1 6( 1): 3 1 7- 2 3. 
1 2.  
S pitz F R, A b br uzzese J L, Lee J E, et al. Pre o pera ti ve a n d p ost o perati ve c he m ora diati o n strate gies i n 
patie nts treate d wit h pa ncreatic o d u o de nect o m y f or a de n ocarci n o ma of t he pa ncreas. J Cli n O nc ol 
1 9 9 7; 1 5( 3): 9 2 8- 3 7. 

 
Pa ge 3 3 of 3 4 
1 3.  
Bresli n T M, Hess K R, Har bis o n D B, et al. Ne oa dj u va nt c he m ora di ot hera p y f or a de n ocarci n o ma of 
t he pa ncreas: treat me nt varia bles a n d s ur vi val d urati o n. A n n S ur g O nc ol 2 0 0 1; 8( 2): 1 2 3- 3 2. 
1 4.  
Ni n o mi y a I, Tera da I, Y os hiz u mi T, et al. A n ti- metast atic effect of ca pecita bi ne o n h u ma n c ol o n 
ca ncer xe n o grafts i n n u de m o use rect u m. I nt J Ca ncer 2 0 0 4; 1 1 2( 1): 1 3 5- 4 2. 
1 5.  
Mi wa M, Ura M, Nis hi da M, et al. Desi g n of a n o vel oral fl u or o p yri mi di ne car ba mate, 
ca pecita bi ne, w hic h ge nerates 5-fl u or o uracil selecti vel y i n t u m o urs b y e nz y mes c o nce ntrate d i n 
h u ma n li ver a n d ca ncer tiss ue. E ur J Ca ncer 1 9 9 8; 3 4( 8): 1 2 7 4- 8 1. 
1 6.  
D u nst J, Reese T, S utter T, et al. P hase I trial e val uati n g t he c o nc urre nt c o m bi nati o n of 
ra di ot hera p y a n d ca pecita bi ne i n rectal ca ncer. J Cli n O nc ol 2 0 0 2; 2 0( 1 9): 3 9 8 3- 9 1. 
1 7.  
Ki m J S, Ki m J S, C h o MJ, S o n g K S, Y o o n W H. Pre o perati ve c he m ora diati o n usi n g oral 
ca pecita bi ne i n l ocall y a d va nce d rectal ca ncer. I nt J Ra diat O nc ol Bi ol P h ys 2 0 0 2; 5 4( 2): 4 0 3- 8. 
1 8.  
Be n-J osef E, S hiel ds A F, Vais ha m p a y a n U, et al. I nte nsit y- m o d ulate d ra di ot hera p y (I M R T) a n d 
c o nc urre nt ca pecita bi ne f or pa ncreatic ca ncer. I n t J Ra diat O nc ol Bi ol P h ys 2 0 0 4; 5 9( 2): 4 5 4- 9. 
1 9.  
A n o n y m o us. I m pr o ve d s ur vi val w it h pre o perati ve ra di ot hera p y i n resecta ble rectal ca ncer. S we dis h 
Rectal Ca ncer Trial.[see c o m me nt][errat u m a p pe ars i n N E n gl J Me d 1 9 9 7 Ma y 2 2; 3 3 6( 2 1): 1 5 3 9]. 
Ne w E n gla n d J o ur nal of Me dici ne 1 9 9 7; 3 3 6( 1 4): 9 8 0- 7. 
2 0.  
Ka piteij n E, Marij ne n C A, Na gte gaal I D, et al . Pre o perati ve ra di ot hera p y c o m bi ne d wit h t otal 
mes orectal e x cisi o n f or resecta ble rectal ca ncer.[ see c o m me nt][s u m mar y f or patie nts i n Ca n J S ur g. 
2 0 0 3 Fe b; 4 6( 1): 5 4- 6; P MI D: 1 2 5 8 5 7 9 8]. Ne w E n gla n d J o ur nal of Me dici ne 2 0 0 1; 3 4 5( 9): 6 3 8- 4 6. 
2 1.  
B uj k o K, N o wac ki M P, Nasier o ws ka- G utt mej er A, et al. S p hi ncter preser vati o n f oll o wi n g 
pre o perati ve ra di ot hera p y f or rectal ca ncer: re p ort of a ra n d o mise d trial c o m pari n g s h ort-ter m 
ra di ot hera p y vs. c o n ve nti o nall y fracti o nate d radi oc he m ot hera p y. Ra di ot her O nc ol 2 0 0 4; 7 2( 1): 1 5-
2 4. 
2 2.  
F o wler J F. Brief s u m mar y of ra di ol o gical pri nci ples i n fracti o nate d ra diati o n t hera p y. Se mi n Ra diat 
O nc ol 1 9 9 2; 2: 1 6- 2 1. 
2 3.  
B uj k o K, N o wac ki M P, Ke p ka L, et al. P ost o pe rati ve c o m plicati o ns i n patie nts irra diate d pre-
o perati vel y f or rectal ca n cer: re p ort of a ra n d o mise d  trial c o m pari n g s h ort-ter m ra di ot hera p y vs 
c he m ora diati o n. C ol orectal Dis 2 0 0 5; 7( 4): 4 1 0- 6. 
2 4.  
B uc h h olz DJ, Le pe k KJ, Ric h T A, M urra y D. 5- Fl u or o uracil-ra diati o n i nteracti o ns i n h u ma n c ol o n 
a de n ocarci n o ma cells. I nt J Ra diat O nc ol Bi ol P h ys 1 9 9 5; 3 2( 4): 1 0 5 3- 8. 
2 5.  
S malle y S R, Ki mler B F, E va ns R G, Dalziel W C. Het er o ge neit y of 5-fl u or o uracil ra di ose nsiti vit y 
m o d ulati o n i n c ult ure d ma m malia n cell li nes. I nt J Ra diat O nc ol Bi ol P h ys 1 9 9 2; 2 4( 3): 5 1 9- 2 5. 
2 6.  
La wre nce T S, Da vis M A, Ma y ba u m J. De pe n de nce of 5-fl u or o uracil- me diate d ra di ose nsitizati o n 
o n D N A- directe d effects. I nt J Ra diat O nc ol Bi ol P h ys 1 9 9 4; 2 9( 3): 5 1 9- 2 3. 

 
Pa ge 3 4 of 3 4 
2 7.  
H ua n g S M, B oc k J M, Harari P M. E pi der mal gr o w t h fact or rece pt or bl oc ka de wit h C 2 2 5 m o d ulates 
pr oliferati o n, a p o pt osis, a n d ra di ose nsiti vit y i n s q ua m o us cell car ci n o mas of t he hea d a n d nec k. 
Ca ncer Res 1 9 9 9; 5 9( 8): 1 9 3 5- 4 0. 
2 8.  
C hi n nai y a n P, Valla b ha ne ni G, Ar mstr o n g E,  H ua n g S M, Harari P M. M o d ulati o n of ra diati o n 
res p o nse b y hist o ne deacet ylase i n hi biti o n. I nt J Ra diat O nc ol Bi ol P h ys 2 0 0 5; 6 2( 1): 2 2 3- 9. 
2 9.  
Sa wa da N, Is hi ka wa T, Se ki g uc hi F, Ta na ka Y, Is hits u ka H. X-ra y irra diati o n i n d uces t h y mi di ne 
p h os p h or ylase a n d e n ha nces t he efficac y of ca pec ita bi ne ( Xel o da) i n h u ma n ca ncer xe n o grafts. 
Cli n Ca ncer Res 1 9 9 9; 5( 1 0): 2 9 4 8- 5 3. 
 
.