Clinical trial NCT00438256
Conditions: Pancreatic Cancer
Keywords: accelerated short course proton beam radiation
Sponsor: Massachusetts General Hospital
Start date: 2007-12-01; Completion date: 2017-12-01
Enrollment: 50 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
A standard treatment for pancreatic cancer is radiation therapy plus chemotherapy after surgery. Radiation therapy and chemotherapy are commonly given for up to six weeks. Previous research has suggested that giving the radiation and chemotherapy for a shorter amount of time (accelerated schedule) before surgery may be better tolerated. In this research study, different schedules of proton radiation therapy will be used. Each schedule will give about the same total dose of radiation. However, the total dose will be spread out over different time periods and different numbers of sessions. The purpose is to find the shortest schedule of radiation therapy that can be given without unacceptable side effects. Proton beam radiation is being used because of its unique ability to deposit its energy directly in the tumor, resulting in less radiation to normal tissue. A new type of PET scan is also being studied to see if it can help predict the response to pre-surgery treatment.

Detailed description:
* Not everyone who participates in this research study will receive the same schedule of radiation therapy. The schedule of radiation therapy will depend on the number of participants enrolled on the study and how well they have tolerated their radiation schedule. All patients will receive proton beam therapy.
* Here are the proposed schedules of radiation therapy. If at any point too many subjects experience too many unacceptable side effects, no subject will be enrolled to the next level. Dose Level 1: 10 radiation sessions given Monday-Friday for two weeks. Dose Level 2: 5 radiation sessions given Monday, Wednesday and Friday in Week 1 and Tuesday and Thursday in Week 2. Dose Level 3: 5 radiation sessions given Monday, Tuesday, Thursday and Friday in Week 1 and Monday in Week 2. Dose Level 4: 5 Radiation sessions given Monday through Friday in Week 1.
* In Dose Levels 2, 3 and 4, there are fewer radiation sessions, but the radiation dose given at each session is slightly higher than the dose given in each of the 10 sessions of Dose Level 1.
* Capecitabine will be given orally (pill form) starting on the first day of radiation therapy and will be taken for the two weeks that the participant receives radiation therapy.
* On days 1, 8 and 15 of each study cycle, the participant will be seen at the clinic for: physical examination, questions about side effects; and routine blood tests.
* After the last day of study treatment there will be up to a six-week rest period before surgery is performed.
* About three to six weeks after the participant has finished study treatment, the following procedures will be done: CT or MRI, physical examination; questions about side effects and blood tests.

Arms: arm 1: 10 Radiation Sessions over 2 weeks arm 2: 5 Radiation sessions: 3 in week 1 and 2 in week 2 arm 3: 5 Radiation sessions: 4 in week 1 and 1 in week 2 arm 4: 5 Radiation Sessions in one week
Interventions: intervention 1: Proton Beam Radiation intervention 2: Capecitabine
Intervention descriptions: intervention 1: Given over different schedules and duration intervention 2: Given orally starting on day one of radiation therapy for 2 weeks

Protocol documents:
Prot_SAP_000.pdf: 


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.  
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