Amwls of Oncology 12: 1711-1720.

2001
2001 Khmer Academic Publishers Printed in the Netherlands

Original article
Randomised trial of SIR-Spheres plus chemotherapy vs. chemotherapy alone
for treating patients with liver metastases from primary large bowel cancer
B. Gray, G.Van Hazel, M. Hope, M. Burton, P. Moroz, J. Anderson, V. Gebski
Royal Perth Hospital, Sir Charles Gairdner Hospital. University of Western Australia, Australia

Sum
mar
y
Pur
pos
e:
SIRSph
eres
are
radi
oact
ive
yttri
um9
0

micr
osph
eres
(SIR
Sph
eres
,
Sirte
x
Med
ical
Lim
ited,
Aust
ralia
)
used
to
sele
ctiv
ely
targ
et
high
leve
ls of
ioni
sing
radi
atio
n to
tum
ors
with
in
the
liver
.
This
trial
was
desi
gne
d to
mea
sure
any
increa
sed
pati
ent

bene
fit
by
addi
ng a
sing
le
adm
inist
ratio
n of
SIRSph
eres
to a
regi
men
of
regi
onal
hepa
tic
arter
y
che
mother
apy
(HA
C)
adm
inist
ered
as a
12
day
infu
sion
of
flox
uridi
ne
and
repe
ated
at
mon
thly
inter
vals,
vs.
the
sam
e
che
mot
hera
py
alon
e.
P
atie
nts
and
met
hod
s- A
phas
e III
rand
omi

sed
clini
cal
trial
ente
ring
74
pati
ents
was
und
erta
ken
on
pati
ents
with
biloba
r
nonrese
ctab
le
liver
met
asta
ses
fro
m
prim
ary
aden
ocar
cino
ma
of
the
larg
e
bow
el.
Pati
ent
bene
fit
crite
ria
asse
ssed
in
the
trial
wer
e
tum
or
resp
onse
,
time
to
dise
ase
prog
ressi
on
in
the
liver

,
over
all
surv
ival,
qual
ity
of
life,
and
treat
men
t
relat
ed
toxi
city.
Tum
or
resp
onse
was
mea
sure
d by
seria
l
chan
ges
in
both
cros
ssecti
onal
tum
or
area
s
and
total
tum
or
volu
mes,
prov
ided
any
resp
onse
laste
d
not
less
than
thre
e
mon
ths
as
well
as
chan
ges
in
seru
m
carc
inoemb

ryon
ic
anti
gen
(CE
A).
R
esul
ts:
The
part
ial
and
com
plet
e
resp
ons
e
rate
(PR
+
CR)
was
sign
ifica
ntly
grea
ter
for
pati
ents
rece
ivin
g
SIR
Sph
eres
whe
n
mea
sure
d by
tum
or
area
s
(44
%
vs.
17.6
%,
P =
0.01
)
tum
or
volu
mes
(50
%
vs.
24%
, P
=
0.03
)
and

CE
A
(72
%
vs.
47%
, P
=
0.00
4).
T
he
med
ian
time
to
dise
ase
prog
ressi
on
in
the
liver
was
sign
ifica
ntly
long
er
for
pati
ents
rece
ivin
g
SIRSph
eres
in
com
pari
son
to
pati
ents
rece
ivin
g
HA
C
alon
e
whe
n
mea
sure
d by
eith
er
tum
or
area
s
(9.7
vs.
15.9
mon

ths,
P 0.00
1),
tum
or
volu
mes
(7.6
vs.
12.0
mon
ths,
P =
0.04
) or
CE
A
(5.7
vs.
6.7
mon
ths,
P =
0.06
).
T
he
one,
two,
thre
e
and
five
year
surv
ival
for
pati
ents
rece
ivin
g
SIR
Sph
eres
was
72
%,
39
%.
17
%
and
3.5
%,
com
pare
d to
68
%,
29
%,,
6.5
%

and
0%
for
HA
C
alon
e.
Cox
regr
essi
on
anal
ysis
sug
gest
s an
imp
rove
men
t in
surv
ival
for
pati
ents
treat
ed
with
SIR
Sph
eres
who
surv
ive
mor
e
than
15
mon
ths
(P =
0.06
).
The
re
was
no
incr
ease
in
grad
e 34
treat
men
t
relat
ed
toxi
city
and
no
loss
of
qual
ity

of
life
for
pati
ents
rece
ivin
g
SIR
Sph
eres
in
com
pari
son
to
pati
ents
rece
ivin
g
HA
C
alon
e.
C
onc
lusi
onThe
com
bina
tion
of a
sing
le
inje
ctio
n of
SIR
Sph
eres

plus
HA
C is
subs
tanti
ally
mor
e
effe
ctiv
e in
incr
easing
tum
or
resp
ons
es
and
pro
gres
sion

free
surv
ival
than
the
sam
e
regi
men
of
HA
C
alon
e.
Key
wor
ds:
can
cer,
che
mot
hera
py,
live
r,
SIR
Sph
eres
.
SIR
T.
treat
men
t

Intr
odu

ctio
n
Can
cer
of
the
gast
rointe
stin
al
trac
t
com
mo
nly
met
asta
sise
s to
the
live
r as
a
resu
lt of
the
port
al
ven
ous
drai
nag
e of
the
gut
[1].
For
man
y
pati
ents
wit
h
diss
emi
nate
d
larg
e
bow
el
can
cer,
the
live
r
repr
ese
nts
eith
er

the
do
min
ant
or
onl
y
site
of
met
asta
ses,
and
is a
maj
or
cau
se
of
pati
ent
mor
talit
y
[2].
For
a
min
orit
y of
pati
ents
wit
h a
limi
ted
nu
mbe
r of
live
r
met
asta
ses,
som
e
for
m
of
loca
lly
abla
tive
trea
tme
nt
suc
h as
surg
ical
rem
oval
,

cry
othe
rap
y or
radi
ofre
que
ncy
abla
tion
can
offe
r
the
cha
nce
of
lon
g
ter
m
surv
ival
.
Ho
wev
er,
for
mos
t
pati
ents
wit
h
met
astati
c
live
r
can
cer,
the
dise
ase
is
well
bey
ond
any
for
m
of
loca
lly
abla
tive
trea
tme
nt
by
the
tim
e it

is
diag
nos
ed.
T
he
mai
nsta
y of
trea
tme
nt
for
adv
anc
ed
live
r
met
astase
s is
eith
er
syst
emi
c or
regi
onal
che
mot
hera
py.
Sys
tem
ic
che
mot
hera
py
usin
g 5fluo
rour
acil
and
leuc
ovo
rin
has
bee
n
exte
nsiv
ely
eval
uate
d
for
pati
ents
wit
h

advan
ced
colo
rect
al
can
cer
and
sho
wn
to
resu
lt in
tum
or
resp
ons
e
rate
s of
the
ord
er
of
10
%

20
%
and
a
sma
ll
surv
ival
ben
efit
[3,
4].
Mor
e
rece
nt
trial
evid
enc
e
has
sho
wn
that
the
resp
ons
e
rate
and
surv
ival
for
this
gro

up
of
pati
ents
can
be
furt
her
enh
anc
ed
by
the
addi
tion
of
new
er
age
nts
incl
udi
ng
irin
otec
an
[5,
6]
and
oxal
ipla
tin
[V].
R
egio
nal
trea
tme
nt
of
the
live
r by
hep
atic
arte
ry
che
mot
hera
py
(H
AC)
,
usu
ally
wit
h 5fluo
rour
acil
or

flox
urid
ine,
has
bee
n
use
d
for
man
y
dec
ade
s
for
trea
ting
adv
anc
ed
live
r
met
asta
ses.
Alt
hou
gh
man
y
trial
s
hav
e
rep
orte
d
hig
her
resp
ons
e
rate
s
for
HA
C,
ther
e
rem
ains
dou
bt
ove
r
whe
ther
this
for
m
of
regi
onal
che

mot
hera
py
con
fers
any
maj
or
addi
tion
al
surv
ival
adv
anta
ge
whe
n
com
pare
d to
syst
emi
c
che
mot
hera
py
[8].
The
re is
clea
rly
a
nee
d
for
mor
e
effe
ctiv
e
trea
tme
nts
for
this
larg
e
pati
ent
gro
up.
S
elec
tive
Inte
rnal
Rad
iati
on
The
rap
y

(SI
RT)
has
bee
n
dev
elop
ed
for
the
trea
tme
nt
of
adv
anc
ed
non
rese
ctab
le
pri
mar
y
and
met
asta
tic
live
r
can
cer.
The
tech
niq
ue
in-

17
12
vol
ves
emb
olisi
ng
radi
oact
ive
yttri
9
um
0

SIR
Sph
eres

into
the
arte
rial

blo
od
sup
ply
of
the
live
r.
Bec
aus
e
bot
h
pri
mar
y
and
met
asta
tic
tum
ors
wit
hin
the
live
r
are
sup
plie
d
alm
ost
enti
rely
by
blo
od
fro
m
the
hep
atic
arte
ry,
as
opp
ose
d to
the
nor
mal
live
r
pare
nch
yma
, the
SIR
Sph
eres

con
cent

rate
sele
ctiv
ely
in
the
tum
or
com
part
men
t
wit
hin
the
live
r
[9].
Thi
s
phy
siol
ogic
al
tum
or
targ
etin
g
can
be
enh
anc
ed
by
inje
ctin
g
Ang
iote
nsin
-2
into
the
hep
atic
arte
ry
im
med
iatel
y
bef
ore
the
adm
inis
trati
on
of
the
SIR
-

Sph
eres
.
For
a
peri
od
of
sev
eral
min
utes
the
Ang
iote
nsin
-2
cau
ses
the
nor
mal
live
r
arte
-rial
blo
od
vess
els
of
the
live
r to
con
stric
t,
but
not
thos
e
sup
plyi
ng
the
tum
or
[10]
. If
the
SIR
Sph
eres

are
inject
ed
duri
ng
this
tim
e,
they

will
furt
her
con
cent
rate
wit
hin
the
tum
or
mic
rov
asc
ulat
ure.
S
IRSp
her
es

(Sir
tex
Me
dic
al
Ltd
,
Au
stra
lia)
are
rad
ioa
ctiv
e
yttr
iu
90
m
mic
ros
phe
res
that
wer
e
dev
elo
ped
wit
h
opt
ima
l
cha
ract
eris
tics
for
ad
mi
nist

rati
on
of
Sel
ective
Int
ern
al
Ra
diat
ion
Th
era
py
(SI
RT
) to
pati
ent
s
wit
h
adv
anc
ed
non
res
ect
abl
e
live
r
can
cer.
Ear
lier
rep
orts
fro
m
bot
h
our
res
ear
ch
gro
up
and
oth
ers
hav
e
sho
wn
that
trea
tme
nt
wit
h
SI
R-

Sp
her
es

res
ults
in a
hig
h
res
pon
se
rate
for
pati
ent
s
wit
h
met
ast
atic
live
r
can
cer
[II,
12,
13]
.
Oth
er
sim
ilar
stu
die
s
hav
e
sho
wn
that
SI
RSp
her
es

are
als
o
eff
ecti
ve
in
cau
sin
g
reg
res
sio
n
and
inc
rea

sin
g
sur
viv
al
for
pati
ent
s
wit
h
pri
ma
ry
hep
ato
cellula
r
can
cer
[14
].
T
hes
e
hig
h
res
pon
se
rate
s
wer
e
the
bas
is
for
con
duc
ting
a
ran
do
mis
ed
con
trol
led
tria
l to
ass
ess
wh
eth
er a
sin
gle
inje
ctio
n

of
SI
RSp
her
es

cou
ld
inc
rea
se
the
tumo
r
res
pon
se
rate
,
tim
e to
dis
eas
e
pro
gre
ssi
on
in
the
live
r,
sur
viv
al,
and
to
me
asu
re
trea
tme
nt
rela
ted
tox
icit
y
or
cha
nge
in
qua
lity
of
life
.

Pat
ient
s

and
met
hod
s
Trial
desig
n
Pati
ents
with
nonrese
ctabl
e
liver
meta
stase
s
from
prim
ary
aden
ocarcino
ma
of
the
large
bow
el,
but
with
out
dista
nt
meta
stase
s.
were
rand
omis
ed
usin
g a
blin
ded
enve
lope
batc
h
meth
od
cont
rolle
d by
an
inde
pend
ent
pers
on
Trea
tmen
t
cons
isted
of
eithe
r a
regi
men
of
hepa

tic
arter
y
che
mot
hera
py
(HA
C)
with
flox
undi
ne
(FU
DR.
Cont
rol
Arm
) or
the
sam
e
che
mot
hera
py
plus
a
singl
e
injec
tion
of
SIRSphe
res
(Inv
estig
ation
al
Arm
).
The
trial
was
origi
nally
desi
gned
to
enter
95
patie
nts,
but
was
clos
ed
for
accr
ual
in
1997
after
enter
ing
74
patie
nts.
The
deci
sion
to
ceas
e

accr
ual
was
mad
e
due
to i)
incre
asin
g
reluc
tanc
e of
both
patie
nts
and
their
refer
ring
medi
cal
pract
ition
ers
to
have
patie
nts
rand
omis
ed
whic
h
resul
ted
in a
dimi
nishi
ng
accr
ual
rate,
ii)
abse
nce
of
ongo
ing
fund
ing
for
the
trial
and
in) a
state
ment
in
1996
by
the
Foo
d
and
Dru
g
Adm
inist
ratio
n
(FD
A)
that
treat

ment
relat
ed
resp
onse
and
time
to
dise
ase
prog
ressi
on
were
acce
ptabl
e
crite
ria
to
supp
ort a
Pre
Mar
ket
Appl
icati
on to
the
FDA
for
regis
trati
on
of
SIRSphe
res*
in
the
USA
.
T
he
Prin
cipal
Inve
stiga
tors
cons
idere
d
that
if
the
trial
were
to
sho
w a
signi
fican
t
impr
ove
ment
in
resp
onse
and/
or
time
to
dise
ase

prog
ression,
then
this
woul
d be
a
clini
cally
imp
orta
nt
outc
ome,
even
thou
gh
the
stud
y
woul
d be
unde
rpo
were
d to
sho
w
the
origi
nal
requ
ired
incre
ase
in
medi
an
survi
val
of
the
inve
stiga
tiona
l
arm
of
30%
over
the
cont
rol
arm
with
90%
pow
er
and
95%
conf
iden
ce.
The
deci
sion
to
ceas
e
accr
ual
at 74
patie
nts
was

supp
orte
d by
the
fact
that
this
num
ber
of
patie
nts
woul
d
still
allo
w
dete
ction
of an
incre
ase
in
resp
onse
from

20%
to
55%
with
80%
pow
er
and
95%
confi
denc
e and
an
incre
ase
in
medi
an
time
to
disea
se
prog
ressi
on
for
contr
ol
grou
p
patie
nts
of
4.5
mont
hs by
32%
with
80%
pow
er
and
95%
confi
denc
e.
Base

d on
a
samp
le
size
of 74
patie
nts,
the
pow
er to
detec
t an
absol
ute
30%
)
incre
ase
in
survi
val
at six
mont
hs
from
50%
to
80%
is
70%
with
a
95%
confi
denc
e
level
.
T
here
fore,
the
Trial
Coordi
nato
rs
cons
idere
d it
acce
ptabl
e to
redu
ce
the
chan
ce of
sho
wing
a
survi
val
impr
ove
ment
in
view
of
the
fact
that
resp
onse
and

time
to
dise
ase
prog
ressi
on
had
beco
me
prim
ary
outc
ome
mea
sure
s in
the
stud
y.
P
atien
ts
were
strati
fied
befo
re
rand
omis
ation
into
three
grou
ps
depe
ndin
g on
the
perc
enta
ge of
liver
invo
lved
with
tum
or
(viz;
<
25%
,
25%
50%
, >
50).
All
patie
nts
were
fully
infor
med
of
the
natu
re of
the
trial
and
sign
ed
infor
med
cons

ent
to
enter
the
stud
y.
The
trial
was
appr
oved
by
the
Hum
an
Ethi
cs
Com
mitt
ees
of
parti
cipat
ing
instit
utions
and
conf
orm
ed to
the
Aust
ralia
n
Nati
onal
Heal
th &
Med
ical
Rese
arch
Cou
ncil
State
ment
on
Hum
an
Exp
erim
entat
ion
and
the
Worl
d
Med
ical
Asso
ciati
on
Decl
arati
on
of
Hels
inki.

Patie
nts

All
patie
nts
had
unde
rgon
e
com
plete
surgi
cal
rese
ction
of a
prim
ary
aden
ocar
cino
ma
of
the
large
bow
el.
Only
patie
nts
with
nonrese
ctabl
e
meta
stase
s
limit
ed to
the
liver
and
lym
ph
node
s in
the
port
a
hepa
tis
were
inclu
ded
in
the
stud
y.
The
port
a
hepa
tis
lym
ph
node
s are
the
drai
ning
lym
ph
node
s of
the
liver

and
are
diffi
cult
to
asse
ss on
CAT
scan
but
are
occa
sion
ally
foun
d to
be
invo
lved
with
tum
or at
the
time
of
surg
ery.
Patie
nts
were
requ
ired
to
have
WH
O
perf
orm
ance
statu
s 02,
have
adeq
uate
hae
mato
logic
al
and
hepa
tic
func
tion
and
not
have
clini
cal
evid
ence
of
cirrh
osis
or
ascit
es.
Patie
nts
who
had
alrea
dy
recei
ved

syste
mic
che
mot
hera
py
for
treat
ment
of
their
meta
stase
s
were
eligi
ble
for
trial
entry
, but
were
excl
uded
if
they
had
recei
ved
radi
othe
rapy
to
the
liver.
All
patie
nts
had
biloba
r
liver
meta
stase
s
and
were
revie
wed
in a
surgi
cal
onco
logy
unit
to
conf
irm
that
the
meta
stases
were
so
adva
nced
that
they
were
unab
le to
be
treat

ed
by
any
form
of
local
ablat
ion.
Patie
nts
in
who
m
the
liver
meta
stase
s
coul
d be
treat
ed
by
any
form
of
local
ablat
ion
such
as
surgi
cal
rese
ction
or
cryo
thera
py
were
excl
uded
from
the
stud
y.

Inve
stiga
tions
Befo
re
trial
entry
, all
patie
nts
unde
rwen
t a
batte
ry of
serol
ogic
tests
to
deter
mine
hae
mato
logic
al,
renal
and

liver
func
tion
and
a
seru
m
CEA
.
Ima
ging
studi
es
were
unde
rtake
n to
deter
mine
the
exte
nt of
dise
ase
in
the
liver
and
to
look
for
evid
ence
of
extra
hepa
tic
mali
gnan
cy
Com
puls
ory
imag
ing
tests
inclu
ded
cont
rast
enha
nced
CAT
scan
s of
the
whol
e
abdo
men
and
pelvi
s.
CAT
scan
s of
the
lung
and
a
nucl
ear
medi
cine
bone

scan.
Patie
nts
unde
rwen
t a
trans
fem
oral
hepa
tic
arteriogr
am
to
aid
the
surgi
cal
plac
eme
nt of
the
acce
ss
cath
eter.
A
ll
patie
nts
unde
rwen
t a
full
lapar
oto
my
by
the
sam
e
surgi
cal
onco
logis
t in
orde
r to
conf
irm
the
nonrese
ctabl
e
statu
s of
the
meta
stases
,
look
for
evid
ence
of
intra
abdo
mina
l
spre
ad of
the
tum

or
and
to
inser
t an
hepa
tic
arter
y
cath
eter
and
port
thro
ugh
whic
h all
treat
ment
woul
d be
admi
niste
red.
Patie
nts
were
rand
omis
ed
after
inser
tion
of
the
hepa
tic
arter
y
cath
eter
and
port.
P
atien
ts
rand
omis
ed to
recei
ve
SIRSphe
res*
unde
rwen
t a
nucl
ear
medi
cine
scan
to
deter
mine
the
amo
unt
of
SIRSphe
res
that
woul
d
pass
thro

ugh
the
liver
and
lodg
e in
the
lung
s.
This
was
perf
orm
ed
by
injec
ting
tech
netiu
m99
label
led
macr
oaggr
egat
ed
albu
min
(MA
A)
into
the
port
and
mea
surin
g the
radi
oacti
vity
in
the
liver
and
lung
s
usin
g a
gam
ma
cam
era.
Area
s of
inter
est
were
draw
n
arou
nd
the
liver
and
lung
s
and
the
perc
enta
ge of
the
MA
A
that

lodg
ed in
the
lung
s
was
deter
mine
d as
a
fract
ion
of
the
total
amo
unt
of
MA
A in
both
lung
s
and
liver.
This
was
reco
rded
as a
'lung
brea
kthro
ugh
perc
enta
ge'
in
orde
r to
deci
de
whet
her
to
redu
ce
the
amo
unt
of
activ
ity
to
admi
niste
r to
the
patie
nt.
Prev
ious
expe
rime
nts
had
sho
wn
that
a
lung
brea
kthro
ugh
perc

enta
ge of
>10
%>
mig
ht
resul
t in
radia
tion
pneu
mon
itis
and
shou
ld be
acco
mpa
nied
by a
redu
ction
in
the
amo
unt
of
yttri
um-

1713

90
activi
ty
admi
nister
ed to
the
patie
nt
[15].
This
techn
ique
has
been
show
n to
be a
relia
ble
meth
od
for
deter
mini
ng
the
subse
quent
distri
butio
n of
SIRSphe
res.
T
he
tumo
r and
liver
volu
mes
were
calcu
lated
from
the
serial
slices
of
the
pretreat
ment
CAT
scan
and
recor
ded
as a
tumo
r/tota
l
liver
volu
me
ratio
as
descr
ibed
previ
ously
[16].

Data
hand
ling
and
recor
ding
of
respo
nse
All
sourc
e
data
for
this
trial
has
been
indep
ende
ntly
moni
tored
and
audit
ed
befor
e
being
subje
cted
to
analy
sis
and
inter
preta
tion.
A
s
respo
nse to
treat
ment
was a
prima
ry
end
point
of
this
trial,
sever
al
meth
ods
have
been
used
to
recor
d
these
event
s
Conv
entio
nal
meth
odolo
gy is
to
recor
d
serial
chan

ges in
both
tumo
r size
and
chan
ges in
seru
m
tumo
r
mark
ers.
The
most
com
mon
meth
od of
recor
ding
tumo
r size
is to
recor
d
chan
ges in
the
sum
of the
produ
cts of
cross
sectio
nal
diam
eters
of all
meas
urabl
e
lesio
ns
seen
on
serial
CAT
scans
from
whic
h the
total
tumo
r area
is
calcu
lated
and
whic
h is
then
used
to
deter
mine
respo
nse.
Sever
al
repor
ts
have
indic
ated
that
using

tumo
r
areas
calcu
lated
from
cross
sectio
nal
diam
eters
to
determine
respo
nse to
treat
ment
is not
optim
al in
asses
sing
respo
nse
of
liver
tumo
rs
and
have
advo
cated
the
use
of
serial
chan
ges in
tumo
r
volu
me as
a
more
accur
ate
meas
ure of
respo
nse
[16].
Our
exper
ience
supp
orts
this
assert
ion
and
theref
ore,
tumo
r
volu
mes
as
well
as
tumo
r
areas
have
been
indep
ende

ntly
recor
ded
in
this
trial.
I
n
order
to
decre
ase
obser
ver
error
when
recor
ding
tumo
r
volu
me
respo
nse,
two
medi
cal
practi
tioner
s not
assoc
iated
with
the
trial
indep
ende
ntly
and
blindl
y
evalu
ated
all
serial
CAT
scans
on all
patie
nts.
The
outlin
e of
all
tumo
rs on
the
serial
CAT
scans
were
manu
ally
trace
d and
the
tracin
gs
were
then
digiti
sed
by a
third
indep
ende
nt

opera
tor
using
a
graph
ics
tablet
.
Data
was
transf
erred
to a
comp
uteris
ed
datahandl
ing
packa
ge
that
calcu
lated
the
total
tumo
r and
liver
volu
mes
by
multi
plyin
g the
tracin
g
areas
by
the
thick
ness
of the
CAT
scan
slice.
By
addin
g the
volu
mes
for
each
CAT
scan
slice,
the
total
tumo
r
volu
me
and
liver
volu
me
can
be
calcu
lated.
As
part
of the
indep
ende
nt
valid
ation

mech
anis
m, if
one
obser
ver's
recor
d of a
tumo
r
volu
me
varie
d by
more
than
10%
from
the
mean
of the
two
obser
vers'
meas
urem
ents,
then
the
scans
were
indep
ende
ntly
trace
d by
a
third
obser
ver.
The
'avera
ge
tumo
r
volu
me'
was
then
taken
as the
mean
of the
two
close
st
value
s. In
additi
on,
chan
ges in
tumo
r area
were
indep
ende
ntly
evalu
ated
by a
third
obser
ver.
This
produ
ced a
furth

er
data
set to
evalu
ate
respo
nse to
treat
ment.
S
erial
chan
ges in
CEA
have
repea
tedly
been
show
n to
be a
reliab
le
correl
ate of
survi
val
for
patie
nts
with
disse
minat
ed
color
ectal
cance
r
under
going
treat
ment
[17,
18].
There
fore,
tumo
r
respo
nse
was
also
calcu
lated
from
chan
ges in
seru
m
CEA
levels
. As
the
assay
for
CEA
chan
ged
durin
g the
cond
uct of
the
trial,
appro
priate
refere

nce
range
s
were
used
to
calcu
late
respo
nse
using
CEA
levels
Tumo
r
respo
nse
using
CEA
was
only
used
for
patie
nts in
who
m the
seru
m
CEA
was
eleva
ted
befor
e
start
of
proto
col
treat
ment.

Resp
onse
and
quali
ty of
life
As
this
trial
was
cond
ucted
in
two
Austr
alian
teach
ing
hospi
tals,
cost
const
raints
dema
nded
that
the
trial
proto
col
be
struct
ured
so

that
follo
w-up
CAT
scans
were
perfo
rmed
only
at
threemont
hly
interv
als,
rather
than
fourweek
ly
interv
als.
This
subst
antial
ly
incre
ased
the
sever
ity of
the
defini
tions
for
respo
nse
for
each
of the
three
criter
ia
whic
h
were;
A
parti
al
resp
onse
(PR)
was
defin
ed as
an
objec
tivel
y
meas
ured
decre
ase
in
tumo
r
size,
meas
ured
for
both
areas
and
volu
mes,
by
50%

or
more
on
two
succe
ssive
CAT
scans
not
less
than
three
mont
hs
apart
and
after
rand
omis
ation
and
befor
e
evide
nce
of
Progr
essiv
e
Dise
ase
in the
liver
and
befor
e any
nonproto
col
treat
ment
had
been
given
.
A
comp
lete
respo
nse
(CR)
was
defin
ed as
the
disap
peara
nce
of all
tumo
r on
two
succe
ssive
CAT
scans
not
less
than
three
mont
hs
apart
and
after
rando
misat
ion
and

befor
e
evide
nce
of
Progr
essiv
e
Disea
se in
the
liver
and
befor
e any
nonproto
col
treat
ment
had
been
given
A
C
E
A
c
o
m
pl
et
e
r
e
s
p
o
n
s
e
(
C
E
A
C
R
)
w
as
d
ef
in
e
d
as
a
d
e
cr
e
as
e
in

seru
m
CEA
into
the
norm
al
rang
e on
any
occa
sion
after
rand
om-

isati
on
but
befor
e
evid
ence
of
Prog
ressi
ve
Dise
ase
and
befor
e
any
nonproto
col
treat
ment
had
been
give
n.
A
CE
A
parti
al
resp
onse
(CE
A
PR)
was
defin
ed as
a
decr
ease
in
seru
m
CEA
by
50%
or
more
, but
not
into
the
norm
al
rang
e, on
any
occa
sion
after
rand
omis
ation
and
befor
e
evid
ence
of
Prog
ressi
ve
Disease
and

befor
e
any
nonproto
col
treat
ment
had
been
give
n.
P
rogre
ssive
disea
se in
the
liver
(PD)
used
the
same
three
objec
tive
meas
ures
that
deter
mine
Resp
onse
to
treat
ment
and
was
defin
ed as
i) an
incre
ase
on
any
occas
ion
in
cross
secti
onal
tumo
r
area,
or
tumo
r
volu
me,
by
25%
or
more
over
the
nadir
as
meas
ured
on
serial
CAT
scans
, or
ii)

the
devel
opme
nt of
new
lesio
ns in
the
liver
or
iii)
an
incre
ase
on
any
occas
ion
in the
seru
m
CEA
by
25%
or
more
over
the
nadir
for
those
patie
nts
with
an
eleva
ted
CEA
at the
time
of
rand
omisatio
n For
patie
nts in
who
m
there
was
an
incre
ase
in
CEA.
this
was
attrib
uted
to
Progr
essiv
e
Dise
ase
in the
liver,
provi
ded
that
there
was
no
evide
nce

of
new
lesio
ns at
any
site
other
than
the
liver.
N
o
chan
ge
(NC)
was
defin
ed as
eithe
r a
decr
ease
in
tumo
r
area,
volu
me
or
CEA
that
is
less
than
that
requi
red
for a
Parti
al
Resp
onse,
or an
incre
ase
that
is
less
than
that
requi
red
for
Prog
ressi
ve
Dise
ase.
N
ot
asse
ssab
le
(NA)
for
any
of
the
resp
onse
criter
ia
was
attrib
uted
to
those

patie
nts
who
had
eithe
r i)
no
follo
w-up
CAT
scan
s due
to
rapid
deter
iorati
on
after
rand
omis
ation
, ii)
had
unm
easur
able
inde
x
lesio
ns
for
esti
mati
ng
cross
secti
onal
tumo
r
areas
, or
iii)
for
the
purp
ose
of
meas
uring
resp
onse
by
CEA
. did
not
have
an
eleva
ted
CEA
at
the
time
of
rand
omis
ation
.
Q
ualit
y of
life
was
recor
ded
at

three
mont
hly
inter
vals
usin
g a
valid
ated
13
point
linea
r
anal
ogue
Self
Asse
ssme
nt
Scal
e
reco
mmen
ded
by
Pnes
tman
and
Bau
m
[19].
Stati
stical
anal
ysis
A
varie
ty of
statis
tical
tech
niqu
es
have
been
used
to
anal
yse
the
outcom
e
data
from
this
stud
y
Outc
ome
criter
ia
were
anal
ysed
on
an
inten
tiontotreat
basis
. The

cond
ition
al
bino
mial
exact
test
(Ric
e
1988
)
was
used
to
com
pare
the
outc
omes
that
are
expr
esse
d as
prop
ortions
in
each
of
the
two
treat
ment
arms
. The
logra
nk
test
was
used
to
com
pare
time
to
even
t
data
in
the
prese
nce
of
cens
ored
obse
rvati
ons.
Mod
ellin
g of
haza
rd
ratio
s
was
perfo
rmed
usin
g the
meth
od of
Cox
and
'time
depe

nden
t'
adap
tatio
n of
Cox
mod
ellin
g
was
perfo
rmed
alon
g the
lines
descr
ibed
by
Harr
ell
and
Lee.
Time
s to
even
t
curv
es
were
const
ructe
d
usin
g the
meth
od of
Kapl
anMeie
r.
Time
s to
even
t
curv
es
from
timedepe
nden
t
anal
yses
were
deriv
ed
from
the
appr
opria
te
Cox
mod
els
as a
posti
che
expl
orato
ry
anal
ysis.
An
expl
orato
ry
Cox
regre

ssion
anal
ysis
was
perfo
rmed
for
patie
nts
survi
ving
eithe
r less
than,
or
more
than.
15
mont
hs.
This
time
perio
d
was
chos
en as
there
was
a
clear
diver
genc
e in
the
survi
val
curv
es
betw
een
patie
nts
treat
ed
with
the
contr
ol or
inves
tigati
onal
treat
ment
arm
at
this
time
and
furth
er
scrut
iny
of
the
data
dem
onstr
ated
that
the
patte
rn of
caus
e of
deat
h
was

diffe
rent
for
patie
nts
dyin
g
eithe
r
befor
e, or
after,
15
mont
hs.
Resp
onse
s
achie
ved
were
com
pare
d
usin
g the
Krus
kalWall
is
test.
Mea
n
Qua
htyofLife
score
s
were
com
pare
d for
each
time
inter
val
betw
een
treat
ment
grou
ps
usin
g
inde
pend
ent
ttests
A
s
expe
rienc
e
prior
to
this
trial
had
show
n
that
the
addit
ion
of

SIRT
to
HAC
was
safe
and
resul
ted
in
high
resp
onse
rates
, the
trial
proto
col
was
origi
nally
desig
ned
and
writt
en to
meas
ure
only
any
incre
ase
in
effic
acy
criter
ia
resul
ting
from
the
addit
ion
of
SIRSphe
res""
.
How
ever,
in
this
repor
t
all /"
valu
es
have
been
deriv
ed
from
twotaile
d
tests
of
signi
fican
ce.
No
interi
m
anal
yses
were
perfo
rmed

on
any
of
the
data

Trea
tmen
t
Surg
ery
Patie
nts in
both
treat
ment
arms
unde
rwen
t
a
lapar
otom
y.
chole
cyste
ctomy
and
insert
ion
of a
perm
anent
hepat
ic
arter
y
cathe
ter
that
was
conn
ected
to a
subc
utane
ous
acces
s
port
by
the
same
surgi
cal
oncol
ogist.
At
lapar
otom
y a
searc
h
was
made
for
extra
hepat
ic
meta

stase
s

1714

and
patie
nts
were
excl
uded
from
the
trial
if
there
were
meta
stase
s
outsi
de
the
liver
and
port
al
lym
ph
node
s
that
coul
d
not
be
com
plete
ly
exci
sed.
The
hepa
tic
arter
y
cath
eter
had
an
inter
nal
diam
eter
of
0.8
mm
as
smal
ler
bore
cath
eters
had
been
sho
wn
to
occa
sion
ally
bloc
k
duri
ng
the
admi
nistr

ation
of
SIRSphe
res*.
Acc
esso
ry
hepa
tic
arter
ies
were
ligat
ed in
orde
r to
ensu
re
that
the
cath
eter
perf
used
the
whol
e
liver
.
Perf
usio
n of
the
whol
e
liver
by
the
cath
eter
was
chec
ked
duri
ng
the
surgi
cal
oper
ation
by
injec
ting
fluor
escei
n
thro
ugh
the
cath
eter
and
obse
rvin
g the
liver
unde
r
ultra
viole
t
light
.

The
cath
eter
was
reposi
tione
d if
need
ed in
orde
r to
ensu
re
perf
usio
n of
the
whol
e
liver
.
Care
was
take
n to
ligat
e the
smal
l
vess
els
pass
ing
back
from
the
hepa
tic
arter
y to
the
duod
enu
m
and
stom
ach
to
prev
ent
SIRSphe
res
from
flow
ing
to
thos
e
orga
ns.
The
ome
ntu
m
was
tack
ed in
betw
een
the
stom
ach

and
liver
to
shiel
d the
stom
ach
from
any
radia
tion
ema
natin
g
from
the
liver

Sele
ctive
inter
nal
radi
atio
n
ther
apy
(SIR
T)
The
first
patie
nt
that
recei
ved
the
com
binat
ion
of
SIR
T
plus
HA
C
had
the
SIRSphe
res*
admi
niste
red
at
the
time
of
the
lapar
oto
my
to
inser
t the
acce
ss
port.
Alth
ough
there
was
no
treat

ment
asso
ciate
d
toxic
ity
in
this
patie
nt,
in
orde
r to
impr
ove
the
logis
tics
of
admi
niste
ring
SIR
T,
all
subs
eque
nt
patie
nts
had
SIRSphe
res
admi
niste
red
after
reco
very
from
surg
ery
and
with
in
four
wee
ks of
the
surgi
cal
proc
edur
e to
inser
t the
hepa
tic
arter
y
acce
ss
port.
SIRSphe
res
were
admi
niste
red
by
inser
ting

a
need
le
into
the
subc
utan
eous
acce
ss
port
and
this
was
conn
ecte
d to
a
cust
omis
ed
SIRSphe
res
deliv
ery
set.
Fifty
micr
ogra
ms
of
Angi
oten
sin2
(Cib
a)
were
injec
ted
into
the
hepa
tic
arter
y
over
a
peri
od
of
thirt
y
seco
nds.
Thir
ty
seco
nds
later
the
SIRSphe
res
was
injec
ted
into
the
hepa
tic
arter
y

thro
ugh
the
acce
ss
port.
This
injec
tion
of
SIRSphe
res*
was
puls
ed
into
the
hepa
tic
arter
y
over
a
peri
od
of
seve
ral
min
utes
to
obtai
n
good
mixi
ng
in
the
hepa
tic
arter
ial
bloo
d
strea
m.
P
atient
s
rand
omis
ed to
recei
ve
SIRT
were
treate
d
with
a
prede
termine
d
quant
ity of
SIRSphe
res
that
was
varie
d
depe

ndin
g on
the
size
of
the
tumo
r.
Patie
nts
with
tumo
r that
was
eithe
r
<25
%,
25%50%
or >
50%
of
the
total
liver
volu
me
were
given
SIRSphe
res
equiv
alent
to
eithe
r
2GB
q.
2.5G
Bq or
3GB
q of
yttriu
m90
activi
ty.
Provi
sion
was
made
for
patie
nts in
who
m the
lungliver
break
throu
gh
scan
indic
ated
that
more
than
10%
of
the
micr
osph
eres
passe
d
thou
gh

the
liver
and
lodge
d in
the
lungs
.
This
requi
red a
reduc
tion
in the
amou
nt of
yttriu
m90
activi
ty to
be
admi
nister
ed by
2%>
for
each
1%
that
the
lungliver
break
throu
gh
perce
ntage
was
great
er
than
10%.
Alth
ough
there
was
the
provi
sion
for
reduc
ing
the
dose
of
SIRSphe
res
if the
lung
break
throu
gh
ratio
was
great
er
then
10%,
no
patie
nt
requi
red
this
reduc
tion.

Patie
nts
were
usual
ly
disch
arged
home
eithe
r the
same
day
or
the
follo
wing
day
after
SIRT
.

Prot
ocol
che
mot
hera
py
Prot
ocol
Che
mot
hera
py is
defi
ned
as
the
admi
nistr
ation
of
FUD
R at
any
dosa
ge
and
admi
niste
red
into
the
hepa
tic
arter
y
port
but
befo
re
any
othe
r
che
mot
hera
py
(i.e.,
nonprot
ocol
che
mot
hera
py)
was

admi
nister
ed.
If
any
nonprot
ocol
che
mot
hera
py
was
admi
niste
red
to
any
patie
nt
after
rand
omis
ation
,
eithe
r via
the
hepa
tic
arter
y
port
or
syst
emic
ally.
then
the
last
date
of
Prot
ocol
Che
mot
hera
py
was
dee
med
to be
the
date
of
the
last
admi
nistr
ation
of
FUD
R
alon
e
thro
ugh
the
hepa
tic
arter
y
port.
A
ll

patie
nts
in
both
treat
ment
arms
recei
ved
12
day
cycl
es of
conti
nuou
s
infu
sion
flox
uridi
ne at
0.3
mg/
kg
of
bod
y
weig
ht/da
y
that
were
repe
ated
at
four
wee
kly
inter
vals.
Prot
ocol
Che
mot
hera
py
was
conti
nued
for
18
cycl
es or
until
there
was
evid
ence
of
eithe
r
tum
or
prog
ressi
on
with
in
the
liver
, the
deve
lop
ment
of
extra
-

hepa
tic
meta
stases
nece
ssita
ting
a
chan
ge to
syst
emic
che
mot
hera
py,
unac
cept
able
toxic
ity.
port
failu
re or
at
the
patie
nt's
requ
est.
The
auth
ors
have
expe
rienc
e
with
this
prot
ocol
of
HA
C
and
cons
ider
it
well
toler
ated.
Non
prot
ocol
treat
men
t
Onc
e
prot
ocol
treat
ment
ceas
ed,
furth
er
canc
er
spec
ific
treat
ment
,

inclu
ding
nonprot
ocol
che
mot
hera
py,
was
allo
wed
to
best
man
age

patie
nt
care.
All
nonproto
col
canc
er
speci
fic
treat
ment
was
recor
ded
in all
patie
nts.
Othe
r
supp
ortiv
e,
but
not
canc
er
speci
fic
treat
ment
was
allo
wed
for
patie
nt
man
age
ment
.
Toxi
city
Toxi
city
was
recor
ded
using
stand
ard
UIC
C
criter
ia

Foll
owup
All
patie
nts
were
follo
wed
at
mont
hly
inter
vals
whil
e on
proto
col
treat
ment
and
not
less
than
three
mont
hly
there
after.
Follo
w-up
was
with
phys
ical
exa
mina
tion
and
serol
ogic
tests
inclu
ding
mont
hly
full
hae
mato
logic
al
scree
n,
liver
funct
ion
tests
and
CEA
and
three
mont
hly
CT
scan
s of
the
abdo
men.

Qua
lity

of
life
Qual
ity
of
life
was
meas
ured
befor
e the
start
of
treat
ment
and
at
three
mont
hly
inter
vals
there
after
usin
g a
valid
ated
IIquest
ion
linea
r
anal
ogue
selfasses
smen
t
quest
ionn
aire.

Res
ults
Pati
ent
and
tum
or
cha
ract
eris
tics
The
trial
rem
aine
d
ope
n
for
pati
ent
entr

y
fro
m
199
1199
7
and
ente
red
74
pati
ents
, of
whi
ch
70
wer
e
elig
ible
for
trial
entr
y
and
wer
e
trea
ted
and
foll
owe
d
acc
ordi
ng
to
trial
prot
oco
l
req
uire
me
nts.
Fou
r
pati
ents
wer
e
dee
me
d
'inel
igib
le'
for
trial
trea
tme
nt,
foll

owup
and
anal
ysis
due
to
the
pres
enc
e of
unc
onfi
rme
d
diss
emi
nate
d
can
cer
at
the
tim
e of
ran
do
mis
atio
n
that
was
sub
seq
uen
tly
con
fir
me
d.
The
se
pati
ents
wer
e
flag
ged
and
out
co
me
anal
yse
s
perf
orm
ed
bot
h
wit
h
and
wit

hou
t
incl
usio
n of
thes
e
four
pati
ents
.
The
re
are
no
sign
ific
ant
diff
ere
nce
s in
any
of
the
out
co
me
resu
lts
if
the
data
is
anal
yse
d
wit
h or
wit
hou
t
the
incl
usio
n of
thes
e
four
pati
ents
.
The
refore
,
the
resu
lts
pres
ente
d
her
e

are
for
elig
ible
pati
ents
onl
y.
At
the
tim
e of
this
anal
ysis
four
pati
ents
rem
ain
aliv
e
(thr
ee
in
the
SIR
T +
HA
C
arm
and
one
in
HA
C
alo
ne
arm
)
and
all
pati
ents
hav
e
bee
n
foll
owe
d
up
for
a
min
imu
m
peri
od
of
3.5
yea
rs
afte

r
ran
do
mis
atio
n.
A
nal
ysis
of
pati
ent
and
tum
or
cha
ract
eris
tics
de
mo
nstra
tes
that
ther
e is
no
sign
ific
ant
diff
ere
nce
in
any
of
thes
e
cha
ract
eris
tics
bet
wee
n
the
two
trea
tme
nt
gro
ups
(Ta
ble
1).
Thi
s
con
fir
ms
the
effe

ctiv
ene
ss
of
the
trial
ran
do
mis
atio
n
pro
cess
.
Sel
ecti
ve
inte
rna
l
rad
iati
on
the
rap
y
Thir
tyfive
of
the
36
pati
ents
rand
omi
sed
into
the
Inve
stigat
iona
l
Ar
m
actu
ally
rece
ived
treat
men
t
with
SIR
T +
HA
C.
One
pati
ent
with

adv
anc
ed
met
asta
ses
dete
riorate
d
rapi
dly
afte
r
trial
entr
y
and
died
befo
re
any
prot
ocol
treat
men
t
coul
d be
start
ed.
All
34
pati
ents
in
the
cont
rol
arm
rece
ived
HA
C.
T
he
thirt
yfive
elig
ible
pati
ents
that
wer
e
trea
ted
wit
h
SIR

T
rece
ive
d a
mea
n of
2.1
56

0.3
24
(SD
)
GB
q of
yttri
um

acti
vity
.
Fiv
e
pati
ents
rece
ive
d
less
and
one

1715

Table I. Patient and tumor characteristics

Number of patients
Mean age (years)
Male/female
Primary Bowel Cancer
Colon/Rectum
Involved lymph nodes
Poorly differentiated
Lead time (days) from resection of bowel
cancer to randomisation: mean/median
Patients treated with prior chemotherapy
for liver metastases
Amount of protocol chemotherapy used
per patient: mean/median (mg)
Number of cycles of Protocol Chemotherapy: mean
Tumor size
<25%
25%-50%
> 50%

90

patient more than the designated protocol amount of yttrium activity, but all six of these patients received within 90% of
90
the 2-3 GBq of yttrium activity re-quired by the protocol. The three ineligible patients in this treatment arm received a
90
mean of 2.276 0.231 GBq of yttrium activity. Some patients experienced discomfort in the upper abdomen after the
implantation of SIR-Spheres but this subsided rapidly either sponta-neously or with analgesia. One patient developed mild
pancreatitis after SIRT + HAC that settled within three days but caused exacerbation of pre-existing diabetes. There were
no other major complications resulting from treatment with SIR-Spheres.

Protocol Chemotherapy
There was no difference in the amount of Protocol Chemotherapy administered to patients in either the
Investigational or Control Arms of the trial when meas-ured by amount of chemotherapy (mean 1863 1735 mg
FUDR vs. 1822 1323 mg FUDR per patient), or number of cycles of chemotherapy (mean 8.7 5.6 vs. 8.0 5.0
cycles per patient).
Non-protocol treatment
Many patients received non-protocol chemotherapy during the course of their illness after cessation of Protocol
Chemotherapy. The main drugs used were systemic chemotherapy with 5-fiurouracil plus Leuco-vorin and Mitomycin-C
given either systemically or
Table 2a. Response measured by tumor area.
Response
HAC (n = 34)
SIRT + HAC (n = 36)
Difference between groups P = 0.01
Table 2b Response measured by tumor volume.
Response

HAC = 34
SIRT + HAC 7 = 36
Difference between groups P = 0.03.
Table 2c. Response measured by CEA.
Response
HACT7 = 3 4

SIRT + HAC/7 = 36
Difference between groups P = 0.004
Tables 2a, 2b and 2c provide response data for patients in both arms of the trial when determined by measurements of tumor areas, volumes and CEA Difference
between treatment groups has been assessed by the Kruskal-Wallis lest for categories CR. PR. NC and PD.
Abbreviations: HAC - hepatic artery chemotherapy; SIRT - selective internal radiation therapy: CR - complete response; PR - partial response; NC - no change;
PD - progressive disease; NA - not assessable.

into the hepatic artery port or FUDR given off-protocol into the hepatic artery port. If any non-protocol chemotherapy was added in any patient while the hepatic artery FUDR was continued, then the FUDR was considered to be
non-protocol chemotherapy from that date.
The total amount of the each of the three most commonly used non-protocol chemotherapy drugs was higher for the
patients in the Control Arm. In the case of 5-fluorouracil, patients on the Control Arm received approximately 36% more,
and for FUDR, 59% more in the period following cessation of protocol treatment. The fact that patients in the Control Arm
received more non-protocol chemotherapy than patients in the Inves-tigational Arm indicates that the improved outcome
benefits observed for patients receiving the combination treatment cannot be attributed to greater quantities of non-protocol
chemotherapy.
Response
Response measured by the three criteria are shown in the following Tables 2a, 2b and 2c.
One patient in each arm had their disease reduced to such an extent that they were subsequently deemed surgically
resectable and underwent surgical excision of the metastases. The patient treated with SIRT + HAC

1716

Chemo
SIRT

Figure I. Time to first disease progression in the liver measured tumour area

0.6

0.4
0.2

24

has since remained disease free for eight years and the patient treated with HAC alone subsequently developed

recurrent cancer in the liver and lungs.

10

by

When response is assessed by changes in cross-sectional tumor areas, more than twice as many patients receiving SIRT
achieve either a Complete or Partial Response and this difference is highly significant (18% vs. 44% P = 0.01). When measured
by changes in tumor volume a similar difference is evident (24% vs. 50% P 0.03). Responses measured by changes in CEA
strongly support the findings of changes in tumor areas and volumes and confirm that significantly more patients treated with
SIRT + HAC will respond compared with HAC alone (47% vs. 72% P = 0.004). By all measures of response (volumes, areas and
CEA) more patients in the HAC alone arm had Progressive Disease as their best
response to treatment.

Number at Risk
Chemo

34

SIRT

36

Figure 2 Time to first disease progression in the liver measured by lumoui volume.

SIR-Spheres + HAC
-HAC
as
p = 0 18 (logrank test)
0.6

0.4

n?

12
months since randomisation

Adjusted tor Protocol strata, 2-tailed test

SIR-Spheres + HAC: mean 23.5 months, median 17 months HAC: mean 18.4 months, median 15.9 months
Hazard Ratio = 1.41, 95% confidence interval 0.86-2.34,p = 0.18

Figun'S. Survival: Kaplan-Meier.

Progressive disease (PD) in the liver is an objective measure of cancer progression that indicates the current treatment is no
longer effective. As both treatment regimens in this trial are delivered directly into the hepatic arterial circulation, they only have
potential to affect tumor within the liver and have virtually no affect on cancer at other sites. Time to progressive disease in the
liver is measured as the time from randomisation to the time at which PD was recorded. For patients in whom there was no
objective measure of PD as defined above, then PD is defined as the date of death. For patients in whom there was no objective
evidence of PD and who are still alive, then the date of last follow-up has been used.
Figures 1 and 2 provide time to progressive disease in the liver using cross-sectional tumor areas and tumor volumes as
measures of disease progression.
Survival
Survival is defined as the time from randomisation to death or last follow up if still alive. Table 3 and Figures 3 and 4 present
comparisons of survival between the two treatment groups.
The Kaplan-Meier analysis shows a non-significant trend towards increased survival for patients treated with SIRT + HAC,
compared with those receiving HAC alone. The hazard ratios suggest that patients

receiving HAC alone have approximately a 40% higher death rate than for patients receiving SIRT + HAC. A test for
proportional hazards did not show any evidence of departure from the proportionality assumption. An exploratory Cox regression
analysis suggests that pa-tients treated with the combination of SIRT + HAC who survive more than 15 months experience a
survival advantage compared with those treated with HAC alone. This survival advantage is not evident for patients surviving
less than 15 months. The period of 15 months was chosen for this analysis as there was a divergence of survival curves at this
time and subsequent investigation showed that there was a markedly different pattern for the cause of death for patients surviving
either less than, or more than, 15 months.
Cause of death
Sixty-five of the seventy patients have died and four remain alive (three patients in the investigational arm and one patient in the
control arm). One patient treated with SIR-Spheres is considered permanently cured and has been disease free for more than eight
years, while the other three patients all have existing disease that will eventually prove fatal.
At the time of randomisation all patients had meta-static cancer that was limited to the liver and draining portal lymph nodes.
Many patients subsequently devel-oped extra-hepatic dissemination of their cancer, which either was, or contributed to, the cause
of death. There-fore, all patients that died were considered to have died from i) progression of the liver metastases if there was no
evidence of extra-hepatic metastases at the time of death or ii) dying from disseminated cancer if extra-hepatic metastases had
developed at the time of death.
As both SIRT and HAC are both regional treatments only, the ability to control progression of the liver metastases could only
translate into a survival benefit for those patients that did not rapidly develop and die of disseminated extra-hepatic disease.
Therefore, the cause of death has been analysed for patients dying before and after 15 months from randomisation.
Twice as many patients that received HAC alone died of progression of the liver metastases as the sole cause of death (53%
vs. 27%). The risk of death from progression of the liver metastases was 3.1 times higher (95% con-fidence interval (95% CI):
1.1-8.8, P - 0.03) for patients receiving HAC only compared to those treated with the combination of SIRT + HAC. The
reasonable interpre-tation of this finding is that patients that do not rapidly develop extra-hepatic disease are more likely to
benefit from the greater control of the liver metastases resulting from treatment with the combination of SIRT + HAC.
Toxicity

The main toxicity events that occurred were changes in liver function tests. There were more grade 1 and 2 toxicity events in
patients receiving SIRT + HAC for
1717
Table 4. Grade 3-4 toxicity experienced during protocol treatment.
Parameter
Hb

Bilirubin
AST

Alk Phos
Nausea/vomiting
Diarrhoea
No. grade 3 & 4 events

assessments of liver function tests (300 vs. 207 events) and nausea and diarrhoea (16 vs. 11 events). However, there was no
difference in the rate of any grade 3 and 4 toxicity events between the two treatment arms (23 events in each arm). The profile of
grade 3-4 toxicity events is detailed in Table 4. Grades 1 and 2 changes in liver function tests are of minor importance in the
clinical setting of patients with liver metastases and are frequently abnormal as a result of the liver tumor itself. It can be
concluded that the addition of SIRT to HAC does not significantly increase any major toxicity that is clinically relevant.

Quality of life (QOL)

Of the 11 measures used in this assessment, only sexual interest/ability deteriorated over the 18 month period during which
protocol treatment was administered. For all of the other measures used, the trend was towards improvement in the QOL scores
over the first 18 months for both treatment groups. After this period there was often some deterioration in QOL scores, but this
was usually related to recurrence of disease and/or associated with other treatment. Both treatment regimens tended to improve
and not deteriorate quality of life. There was no significant difference between the treatment groups for any of the measures
indicating that there is no major adverse impact on QOL of life resulting from the addi-tion of SIRT to HAC.

Discussion
Systemic chemotherapy is widely used to treat patients with disseminated colorectal cancer, including those with liver
metastases. The combination of 5-fluororacil and leucovorin has been the most common chemotherapy regimen in this setting
during the past decade. Although a small percentage of patients will respond to treatment with this chemotherapy regimen, the
survival advantage is minimal [20]. More recently other systemic agents have shown promise when used either alone or in combination with 5FU/LV. In a recent randomised trial involving 683 patients with metastatic colorectal cancer, the combination of
5FU/LV combined with irinotecan

1718
was shown to result in a greater response, increased progression free survival and increase in survival when compared to 5FU/LV
alone [5]. Other new drug combi-nations such as oxaliplatin have also shown promise for treatment of this patient group [7]
Continuous hepatic artery chemotherapy (HAC) using either floxuridine of 5-FU has been used for several decades for
treatment of liver metastases and has been shown to result in a higher response rate than for systemic chemotherapy [21]. Biliary
sclerosis has been reported as a problem with continuous high dose floxur-idine given as a hepatic artery infusion, but may be
overcome by using 5-fiuorouracil rather than floxuridine as the infused drug, and this may be achieved while maintaining the
high response rate [22].
Two recently published meta-analyses compared pa - tient outcomes for HAC and systemic chemotherapy. These analyses
showed HAC resulted in a higher re-sponse rate than systemic chemotherapy and suggested a small survival advantage as well.
There is doubt how-ever whether this minor improvement can be justified as the administration of HAC requires the surgical
implantation of an access port [8, 23].
External beam radiotherapy is rarely used to treat liver cancer, as the radiation doses that can be used are limited by the
tolerance of the normal liver tissue. The technique of embolising radioactive microspheres into the arterial circulation of the liver
was first reported several decades ago, but was abandoned because of poor targeting characteristics of the particles and leach-ing
of the radionuclide from the microsphere matrix. Solid glass microspheres were then developed in an attempt to overcome the
problem of leaching. However, the reports on the use of glass microspheres conclude that they are associated with a low response
rate in both primary and metastatic liver cancer. In the combined experience of six published studies using solid glass
microspheres and involving 66 patients, an objective response of less than 10% was obtained [24-28]. Solid glass microspheres
have also been reported as deposit-ing in other organs outside the liver such as the duode-num and stomach, thereby causing
significant radiation damage to those organs. In one report there was also a poor correlation between the radiation dose delivered
to the liver by glass microspheres and the nuclear scans that are used to determine radiation dose to various organs [14].
SIR-Spheres were developed with physical charac-teristics to optimise targeting of tumors and ensure that leaching of the
radionuclide does not occur. The re-search group at the Cancer Research Institute Inc. has extensively investigated the parameters
necessary for targeting microspheres in order to deliver high radiation doses to liver tumors. Investigations have included the
physiological mechanisms of tumor targeting [32, 34], microsphere characteristics [30], tissue tolerance to mi-crosphere
irradiation [36], radiation dosimetry [34, 35] and enhanced tumor targeting with vasoactive drugs [10, 36-38]. This has allowed
resurgence of interest in

the use of SIRT for the treatment of advanced liver cancer. SIR-Spheres have now been used in several clinical trials for
treating patients with both primary and metastatic liver cancer.
We have previously reported our experience in treat-ing patients with liver metastases from large bowel adenocarcinoma with
either SIR-Spheres alone or in combination with hepatic artery chemotherapy. In 16 patients treated with SIR-Spheres alone
the CEA fell in all patients and the majority experienced a reduction in tumor volume [11]. In a further phase II trial involv-ing 71
patients with advanced colorectal liver metasta-ses, SIR-Spheres were combined with hepatic artery chemotherapy with higher
tumor regression rates that have been reported using chemotherapy alone with more than 85% of patients demonstrating at least
some level of tumor regression on serial CAT scans at three months after treatment [12]. Others have also reported high response
rates for this group of patients treated with SIR-Spheres in combination with chemotherapy [13]. Similarly, high response rates
have also been reported using SIR-Spheres to treat patients with advanced primary liver cancer [14].
As a result of this experience, this randomised trial was undertaken to assess any increase in outcome criteria that measure
treatment effect for patients with advanced liver metastases, over and above that achieved by HAC. HAC was chosen as the
control arm in this trial as it has been shown until now to have the highest response rates and to improve survival in this patient
group.
The results of this randomised study conclude that the addition of a single injection of SIR-Spheres to hepatic artery
chemotherapy more than doubles the tumor response rate and significantly increases the time to disease progression. Survival
appears to be improved to a lessor extent for those patients that do not die from extra-hepatic metastases within 15 months of
starting treatment. This enhanced survival for patients who are treated with SIRT and do not rapidly develop extra-hepatic disease
mirrors the experience of Stubbs et al. [39].
The response rates and survival for patients treated with SIR-Spheres reported here are consistent with the results from other
studies using the SIRT technique. As with other reports using SIR-Spheres, we did not observe any increase in severe treatmentrelated toxicity and conclude that treatment with SIRT in experienced hands is generally a safe procedure.
The response rate for patients treated with HAC alone appears low in comparison with previously re-ported studies. However,
as previously detailed, follow-up CT scans were only performed at three monthly intervals due to cost constraints in the
Australian Public Health system. Therefore, in order to qualify as a partial or complete response, a response has to be observed
firstly at not less than three months after starting treat-ment with a confirmatory response at not less than three months later.
Furthermore, the survival rate for patients treated with HAC alone in this trial is almost identical

to that reported in the meta-analysis for similar patients treated with HAC [8].
As patients with liver metastases usually have few or no symptoms and a comparatively good quality of life, the addition of
SIR-Spheres might be expected to com-promise quality of life. No decrease in quality of life was observed which is in accord
with the lack of serious toxicity and treatment-related complications.
In summary, this randomised trial has demonstrated that adding a single injection of SIR-Spheres to a stand-ard regimen of
hepatic artery chemotherapy signifi-cantly increases treatment effectiveness when measured by tumor response and time to
disease progression and suggests an increase in survival for patients surviving more than 15 months. Treatment with SIRSpheres does not compromise quality of life or add significant toxicity.
As newer drugs such as irinotecan, oxaliplatin and capecitabine have recently become available for treating metastatic
colorectal cancer, further trials are underway to evaluate the effect of combining these drug combina-tions with SIR-Spheres.

References
1. Silverberg E, Borig C. SequiresT. Cancer Statistics CA 1991; 41: 19-36.
2. Gilbert J, JelTery I, Evans M et al. Sites of recurrent tumor after curative colorectal surgery. Implications for adjuvant therapy. Br JSurg 1984; 71: 203-5.
3. Advanced Colorectal Cancer Meta-analysis Project. Modulation of fluorouracil in patients with advanced colorectal cancer: Evi-dence in terms of response
rate. J Clin Oncol 1992; 10: 896-903.
4. Poon MA, O'Connell MJ, Moertel C et al. Biochemical modula-tion of fluorouracil: Evidence of significant improvement of survival and quality of life in
patients with advanced colorectal carcinoma. J Clin Oncol 1989; 7: 1407-18.
5. Saltz L, Cox J, Blanke C et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 2000; 343: 905-14.
6. Pitot H,Wender D, O'Connell M et al. Phase II trial of irinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol 1997: 15: 2910-9.
7. Martoni A, Mini E, Pinto C et al. Oxaliplatin and protracted continuous 5-fluorouracil infusion in patients with pre-treated advanced colorectal carcinoma
Ann Oncol 2001; 12 (4): 519-24.
8. Meta-analysis group in cancer. Reappraisal of hepatic arterial infusion in the treatment of non-resectable liver metastases from colorectal cancer J Natl
Cancer Inst 1996: 88: 252-82
9 Archer S, Gray BN The vascularisation of small liver metastases. Br J Surg 1989, 76; 545-548.
10. Burton MA, Gray BN, Colletti A. Effect of Angiotensin-2 on blood flow in the transplanted sheep squamous cell carcinoma. Eur J Cancer Clin Oncol 1988;
24 (8): 1373-6.
11. Gray B, Anderson J, Burton M et al. Regression of liver metas-tases following treatment with yttrium90 microspheres. Aust NZ J Surgery 1992; 62: 105-10.
12 Gray B, Van Hazel G, Buck M et al. Treatment of colorectal liver metastases with SIR-Spheres plus Chemotherapy. Gl Cancer 2000; 3 (4): 249-57.
13. Stubbs R, Cannan R, Mitchell A et al Selective internal radia-tion therapy (SIRT) with yttrium microspheres for liver tumors. Hepato-gastroenterology
1998, Suppl II, LXXVI1 (Abstr).

1719
14. Lau W, Ho S, Leung Tet al Selective internal radiation therapy for non-resectable hepatocellular carcinoma with intra-arterial infusion of yttnum90
microspheres. hit J Radiat Oncol Biol Phys 1998:40:583-92.
15. Ho S. Lau W, Leung T et al. Partition model for estimating radiation doses from yttnum-90 microspheres in treating hepatic tumors. Eur J Nuclear Med
1996; 23; 947-952.
16. Ettinger D, Leitchner P Siegelman S et al. Computed tomography assisted volumetric analysis of primary liver tumor as a measure of response to therapy.
Am J Clin Oncol 1985: 8: 413-8.
17. Preketes A, King J. Capelehorn J et al. CEA reduction after cryotherapy for liver metastases from colon cancer predicts sur-vival. Aust NZ J Surg 1994; 64:
612-614.
18. Allen-Mersh T. Kemeny N. Niedzwiecki D et al. Significance of a fall in serum CEA concentration in patients treated with cylo-toxic chemotherapy for
disseminated colorectal cancer. Gut 1987: 28 (12). 1625-9.
19. Pnestman T. Baum M. Evaluation of quality of life in patients receiving treatment for advanced breast cancer. Lancet 1976; I: 899-901.
20 Machover D. A comprehensive review of 5-fluorouracil and leuco-vorin in patients with metaslatic colorectal carcinoma. Cancer 1997; 80: 1179-87.
21. Vauthey J, Marsh W, Cendan J et al. Arterial therapy for hepatic colorectal metastases. Br J Surg 1996; 83. 447-55
22. Sugihara K. Continuous hepatic arterial infusion of 5-fluoroura-cil for unresectable colorectal liver metastases: A phase II study. Surgery 1995, 117. 624-8.
23 Harmantas A, Rotstein L. Langer B. Regional vs. systemic chemotherapy in the treatment of colorectal carcinoma meta-static to the liver. Cancer 1996: 78:
1639-45.
24. Shepherd F, Rotstein L, Houle S et al. A phase 1 dose escalation trial of yttrium-90 microspheres in the treatment of primary hepatocellular carcinoma.
Cancer 1992. 70: 2250-4.
25. Anderson J, Goldberg J. Bessent R el al. Glass yttrium-90 micro-spheres for patients with colorectal liver metastases. Radiother Oncol 1992. 25. 137-9.
26. Herba M, Illescas F, Thirlwell M et al. Hepatic malignancies: Improved treatment with intra-arterial y-90. Radiology 1988, 169:311-4.
27. Andrews J.Walher S. Ackerman R et al Hepatic radioemboliza-tion with yttrium-90 containing glass microspheres: Preliminary results and clinical followup. J Nucl Med 1994; 35- 1637-44.
28. Houle S.YipT, Shepherd Fet al. Hepatocellular carcinoma: Pilot trial of treatment with Y-90 microspheres. Radiology 1989: 172: 857-60.
29. Stribley KV. Gray BN. Chmiel R el al. Internal radiotherapy for hepatic metastases. The homogeneity of hepatic arterial blood flow. Surg Res 1982; 33: 1724.
30. Stribley KV, Gray BN. Chmiel R et al. Internal radiolheiapy for hepatic metastases; The blood supply of hepatic metaslases. Surg Res 1982; 33, 25-32
31. Chamberlain M. Gray BN, Heggie JCPet al Hepatic metastases: A physiological approach to treatment. Br J Surg 1983: 70: 596-598.
32.
33
34
35.

Meade V, Burton M. Gray B el al. The distribution of different sized microspheres in experimental hepatic tumors. Eur J Clin Oncol 1987; 23: 37-41.
Gray BN. Matz L, Burton MA el al. Tolerance of the liver to Yttrium-90 irradiation. Int J Radiat Oncol Biol Phys 1990; 18: 619-23
Fox RA, Klemp PFB. Egan G et al. Dose distribution following selective internal radiation therapy. Int J Radiat Oncol Biol Phys 1991:21:463-7.
Yorke E. Jackson A, Fox R et al. Can current models explain the lack of liver complications in Y-90 microsphere therapy? Clinical Cancer Res 1999; 5:
3024-30 (Suppl).
36. Burton MA. Kelleher DK. Codde JP. Gray BN. Alteration of experimental liver tumor blood flow. I. Effects of phenylephrine and vasopressin. Cancer J
1990: 3: 346-50.

1720
37. Burton MA, Gray BN. Redistribution of blood flow in exper- Received 21 February 2001; accepted 21 June 2001. imental
hepatic tumors with Nor-Adrenaline and Propanalol Br
J Cancer 1987; 56: 585-8.
Correspondence to
38. Burton M, Gray B. Self G et al. Manipulation of experimental rat
B.N. Gray, MD
and rabbit liver tumor blood flow with angiotensin-2. Cancer Res
Cancer Research Institute Inc
1985, 45: 5390-4.
PO Box 405
39. Stubbs R, Cannan R. Mitchell A. Selective internal radiation Victoria Park therapy (SIRT)
with yttrium90 microspheres for extensive colo- WA 6979, Australia
rectal liver metastases. Hepato-Gastroenterology 2001; 48: 333-7.
E-mail bgray@sirtex.com