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From www.bloodjournal.org by guest on February 11, 2015. For personal use only.
“Concentration
x Time”
Methotrexate
Via a
Subcutaneous
Reservoir:
A Less Toxic
Regimen
for Intraventricular
Chemotherapy
of Central
Nervous
System
Neoplasms
By W. Archie
with
John
Neurotoxicity
Bleyer,
the assistance
David
L. Zeigler,
associated
G. Poplack,
of Edward
Arthur
with
S. Levine,
drug
in the
as with
the
study
19
kemia
were
of
cerebrospinal
fluid
cumulative
dosage.
total
patients
with
single
injections
a low-dose
of 1 rng
There
were
no
tween
the
two
N
of
“concentration
T) schedule
every
12
significant
the
improve
T) regimen
(C x
brospinal
regimens.
reservoir
1 SD)
66
of
number
remission.
cumulative
metho-
41
m
±
mg/sq
in
in
ten
(p
suggest
intrathecal
central
and
the
mg/sq
12
These
the
C
and
dosage
equally
methotrexate
ef-
nervous
has
administered
been
and
system)4
In
a “concentration
concentrations
in
observa-
x T
of central
nervous
antifolate
were
of
T group
0.05).
in the treatment
leukemia.
we devised
methotrexate
courses
<
x
in
neurotoxic
of methotrexate
in the
C
that
is less
fective
system
the
patients
with
an
at-
x time”
in the cere-
than conventional
dosage
randomized
to receive
via a
low-dose
C
x
T
therapy
or
single
the first 19 patients
were treated,
a significantly
was noted
in the C x T group
and is described
report.
in this
MATERIALS
Nineteen
1973
the
durations
was
group
tions
less total
leukemia
either
of
schedule
therapy,
peak
injections
of 12 mg/sq
m. After
lower
incidence
of neurotoxicity
induction,
the
patients
rn/dose
with
delivered
meningeal
dose
seven
the
drug
mean
eight
amount
intrathecal
that reduced
fluid and that
Patients
with
subcutaneous
total
of the
to
(±
x
associated
with
The
bein
of remission
or
3 days.
groups
concentrations
tempt
hr for
differences
treatment
correlated
(C
K. Ommaya
of relapses,
an
of either
rn/dose
or
x time”
EUROTOXICITY
elevated
leucourses
via
consisting
12 mg/sq
M. Simon,
G. Leventhal,
theC x Tgroup
and 173 ± 64mg/sq
m in
the 12 mg/sq
m/dose
group (p < 0.005).
Neurologic
toxicity
occurred
in one of the
In our
methotrexate
reservoir
Ayub
trexate
as well
to receive
intraventricular
Ornmaya
to
of
meningeal
randomized
Richard
Brigid
and
rate
intrathecal
methotrexate
therapy
has been shown
correlate
with elevated
concentrations
the
and
S. Henderson,
children
and
Front
with
December
the
National
31,
Pediatric
Cancer
acute
1975.
Orthopedic
Hospital
Submitted
March
The
Oncology
institute.
Branch
/977;
were
and
Md..
Center,
accepted
METHODS
leukemia
results
Bethesda,
and Medical
2/.
AND
lymphocytic
were
analyzed
Biostatistic.s
and
the
Section,
Division
and the University
December
/3,
entered
into
study
as of September
of
between
1, 1976.
Dis’ision
of
Cancer
Hematology/Oncology.
of Washington,
Seattle,
August
Meningeal
1,
leu-
Treatment,
Children’s
Wash.
1977.
Supported
hi’ USPHS
Grant
CA -16525
front
the National
Cancer
institute,
an American
Cancer
Society
Junior
Faculty
Clinical
Fellowship
A ward,
and a Phar,naceutical
Manufacturers
Associati()n Foundation
Faculty Des’elopment
A ward in Clinical
Pharmacology
(Dr. B/ever).
Presented
in part at the Twelfth
Annual
Meeting
of the American
Society
of Clinical
Oncology.
Toronto,
Ontario,
Address
cal Center,
1978
Blood,
Vol.
for
Mat’,
reprint
1976.
requests:
P.O. Box C-537/,
by Grune
& Stratton.
51.
No.
5 (May),
W.
Seattle,
Inc.
1978
A rchie
B/ever,
M.D.,
Children’s
Orthopedic
Hospital
and Medi-
Wash.
ISSN
98/05.
0006 -4971/78/5/05-0004
.cO/.00/0
835
From www.bloodjournal.org by guest on February 11, 2015. For personal use only.
BLEYER
836
El
Al.
C M MYI
RE SE P v C P
djcIon
Consoldalon
-e4.----
-e4Mantenance--*
6 weeks)
-
--
;
(
1:rAiw_
2 years)
.
_
q. mon.
--;-------------“ii(Iii)
I
I
kemia
was
analysis
diagnosed
I
ingql2h
M
12mg/rn2
I
i..
consent
obtained.
above
ventricle.
the
The
regimens
Elliott’s
until
remission
This
was
induced
at
ministered
monthI
for
T therapy.
I mg.
in
I ml
vided
a
relatively
in lumbar
after
the
dose
was
A
then
elevated,
reservoir
randomized
the
were
(2.5
tip
involved
a maximum
as defined
cm
of the
to
below.
cannula
design.
cytocentrifuge
consecutive
required.
lumbar
After
standard
the
Study
and
two
in the
via
1.
elevated
diameter,
receive
“course”
of
C
at
x
12-hr
If the
(Fig.
parental
burr-hole
frontal
horn
reservoir
2 sk
2).
A
indesign)
of
one
for
three
whichever
occurred
T therapy
consisted
lumbar
T
courses
courses
methotrexate,
of
the
right
two
treat-
This
commenced
(consolidation
of
of
six
schedule
injections
sas
5
fluid
sample
repeated
l0
sample
was
every
therapy).
ad-
not
7
a
.
E
‘
Hours
methotrexate.
because
and
2 x
was
obtained
5 (±2)
x
days
until
10
Maintenance
‘0
level within 48 hr after injection
(unpublished
data
of the
authors). #{149},
actual values
in
one
patient.
and
injections
of
selected
x
so
after
12 mg/sq
m intraventricularly
(dashed
line).
Horizontal
dotted
line, approximation
of the
therapeutically
effective
methotrexate
concentration.1#{176} Approximately
95%
of patients
treated
with
12 mg/sq
m fell below
this
in
weekI
immediately
single
2mg/rn2
Fig.
2.
Mean
cerebrospinal
fluid (CSF)
methotrexate
concentrations
during
intraventricular
C x T therapy
(solid
line)
and
m,
tsice
earlier.
cerebrospinal
in the
repeated
consisted
between
were
12 mg/sq
were
therapy
therapy
concentration
x
of
Injections
Consolidation
concentration
methotrexate
C
injections
IS mg.
intervals.
methotrexate
fluid
of
Maintenance
relapse,
B solution
singlc
dose
intervals.
accordingly.
every
was
not
sith
then
regimen
constant
dose.
count
sas
cytoccntrifugation
Ommaya
2 yr or until
Elliott’s
adjusted
cell
count
was
seekly
cerebrospinal
first
white
cell
forehead
with
doses
six
fluid
white
on
Fig.
I):
B solution,
comprised
x
right
en/dose.
6 ml
an
patient
(Fig.
/2 nzg/.sq
If the
lymphoblasts
was
inserted
lateral
,
cerebrospinal
cells.
demonstrating
formcd
induction,
the
leukemia
6
-------------
-- -
when
revealed
punctures
(_
I
q mon.
-
ment
I
MTX
.---
was
I
3mg-rn2
--
it proM
l0_6
12 hr
l0
M.
the
remission
therapy
con-
From www.bloodjournal.org by guest on February 11, 2015. For personal use only.
“C
x I”
sisted
INTRAVENTRICULAR
ofC
x T courses
Ventricular
sampling
protocol:
The
was
pumped
the
chamber
patient
xas
iodine
dried,
3”,,
the
The
iodine
Central
cells
on
fluid.
If the
containing
CNS
system
(CNS)
and
hite
cell
radiotherapy
Tso
tpes
while
of
cerebrospinal
fluid
a methotrexate
by signs
or
symptoms
of
rather
than
brain
disease
Nine
patients
Tso
died
from
brain
onl
those
sas
2 4 days.5
reservoir
The
chamber
drug
and
the
to
which
was
in-
needle
was
povidoneof leukemia
cytocentrifugation
ventricular
fluid
cells
in the
and
of
every
cerebrospinal
ctocentrifugate
specimens
the
patients
meninges.
considered
received
occurring
leukemia
during
12 mg/sq
For
during
clinical
m/dose
purposes
of
paresis,
and
CNS
group,
statistical
remission
were
of Duttera
et al.6
remission
did
not
analysis
focal
methotrexate
CNS
criteria
after
primarily
intraventricular
to the
fever,
hours
characterized
seizures,
to
a delayed
within
sas
obtundation,
according
and
meningismus.
occurring
attributable
reactions
lost
syndrome
headache.
Encephalopathy
classified
in the
acute
h
pressure
dementia,
ssLemic
both
and
(i.e.,
the
b
None
an
characterized
reactions
reactions
patients,
analssis
for
neurotoxic
ofprogressive
of the
examinations
on
consecutive
intracranial
dysfunction:
itself,
ofthese
After
disappearance
leukemia
of relapse.
recogniicd,
was
increased
persisting
of neurotoxic
thisstud.
censored
and
In evaluating
to the
Severit
to
se-
solution.
the
determined
monthly
diagnosis
sere
syndrome
pleoctosis,
deficits.
as the
as
of
over
six times.
defined
recurrence
skin
swabbed
6 ml).
bandage
pumped
chamber
The
then
was
B solution,
follossing
reservoir
fluid.
into
earlier.
the
study.
toxic
and
skin
(maximum
fluid.
elevated,
the
site
adhesive
again
performed
the
neurotoxicity
acute
injection
neurologic
cluded.
on this
for
povidone-iodine
Elliott’s
was
as the
not
required
drug-induced
The
was
then
10’,,
a spot
was
induction
defined
count
xere
with
and
to
reservoir
reservoir
the
occurred
according
The
removed
with
whichever
and
through
was
cerebrospinal
were
was
and
flushed
remission
position
inserted
reservoir
lumbar
Relapse
lymphoblasts
encephalopathy.
covered
The
examinations
fluid.
total
then
was
applied.
ventricular
lumbar
sas
decubitus
drapes.
to be injected
needle
conducted
sponge,
was
relapse,
were
of ventricular
sterile
needle
of the
site
lateral
mixing
a dry
to that
been
reservoir
left
with
scalp-vein
equal
(‘ytocentrifuge
3 mo
in the
isolated
for 2 yr or until
the
adequate
hexachlorophene,
had
both
analsis.
and
injection
nervous
from
placed
tubing
ointment
injection
to insure
of fluid
slosly.
removed.
monthly
via
a 25-gauge
a volume
jected
administered
shaved
with
837
and
was
six times
quentially
and
METHOTREXATE
and
have
in-
while
on
postmortem
these
patients
were
at the time of death.
to follos-up)
RESULTS
Paiietits
Nine
patients
received
m/dose.
12 mg/sq
methotrexate
dosage
ment
alyses)
logic
prior
level
in these
fell
were
with
respect
x T methotrexate
C
x T patients
outside
patients
groups
was
the
to the
(as
who
and
12-hr
lumbar
range
of
to 1 .5 and
0.75
determined
following
by
parameters:
of leukemic
cells
prior CNS therapy,
of patients
therapy
the
desired
adjusted
comparable
relapse,
number
CNS leukemia,
number
C
In two
subsequently
ten
2)
5 (±
mg
while
with
t
sex,
fluid
test
The
in CNS
treat-
x2
and
concurrent
CNS
C x T
M.
12 hr.
Student’s
age,
treated
l0
x
every
in the cerebrospinal
the type of prior
died
were
cerebrospinal
an-
hemato-
fluid
at diagnosis,
therapy
and the
remission.
(Table
1).
Efficaei’
All patients
or autopsy
186, and
days
(Fig.
achieved
evidence
240 days
meningeal
3). Of those patients
mission
duration
(35689)
days
was
for
remission
for CNS relapse
was
and in three
12 mg/sq
the
345
12 mg/sq
except
remaining
(67Il78)
rn/dose
one
C
x T patient.
Clinical
found
in three
C x T patients
rn/dose
patients
at 87, 192,
in remission,
days
group.
for
the
There
C
were
the
median
x
T
no
group
significant
at
and
157,
639
(range)
and
re324
differ-
From www.bloodjournal.org by guest on February 11, 2015. For personal use only.
838
BLEYER
1.
Table
Dab
Patients
rison of C x T and
Compa
12 mg/sq
Compared
C x 1
entered
Prognostic
m /Dose
El
AL.
Patients
12 mg/sq
rn/Dose
9
10
9 (5-20)
10 (5-19)
p
*
-
factors
Age
(yr)t
Male
patients
relapse
NS
6
7
NS
2
3
NS
Patients
with
concurrent
hematologic
Patients
with
prior
CNS
leukemia
5
5
NS
Patients
with
prior
CNS
therapy
7
9
NS
Patients
with
prior
intrathecal
methotrexate
5
7
NS
Patients
with
prior
intrathecal
cytosine
4
4
NS
prior
cranial
5
7
NS
arabinoside
Patients
with
Cerebrospinol
fluid
x ray,
blast
2400
R
cells at diagnosis
(/pl)t
129(2-1800)
111
(2-2500)
NS
Efficacy
Remission
inductions
Clinical
CNS
Meningeal
relapses
leukemia
During
NS
1
NS
1/3
methotrexate
remission
Total
10
2
at autopsy/autopsies
performed
Cumulative
8
(mg/sq
2/4
NS
dosage
induction
(mg/sq
8 ± 3
m)t
m)t
66
22
41
±
173
±
11
<0.005
±
64
<0.005
Toxicity
Patients
with
neurotoxicity
Complications
2
or
unpaired
tMedians
are
The
NS,
means
±
(±
two
groups
(Table
<0.05
NS
in the
In the
relapse
rate,
the
duration
of remission,
or
I).
1 SD)
cumulative
methotrexate
±
12 mg/sq
doses ( 24 mg/sq
dosage
was
64 mg/sq
m for the
amount
of methotrexate
induction
was 8 (6-12)
mg in the
mg/sq
m/dose
group
(p < 0.05).
remission
in the C x T group
did
more
1?
not significant.
for the C x T group
and 173
(p < 0.005).
The mean
(range)
trexate).
7
1
1 SD.
the
on study
mean
1
in parentheses).
between
the time
to reservoir
I test;
(ranges
tValues
ences
related
C
x T group
and
Five (63#{176},))of the
so after one course
rn/dose
group
half
66
±
12 mg/sq
required
41 mg/sq
m
m/dose
group
for remission
22 (12-36)
mg in the 12
eight
patients
achieving
of therapy
(6 mg metho-
of the
patients
required
two
or
m methotrexate).
Toxicity
Neurologic
toxicity
during
C x T group
and in seven
(p < 0.05).
The one patient
tained
a single
tenance
course.
rn/dose
pathy,
group,
and one
described
below.
grand
mal
Of the
two
had
remission
of ten patients
in
in the C x T group
seizure
seven
occurred
6 days
patients
after
with
in one
the
was
completing
neurotoxic
had the acute
toxic
syndrome,
both.
The five encephalopathic
of eight
12 mg/sq
a 12-yr-old
her
reactions
third
patients
in the
m/dose
group
girl who
susC x T mainin the
12 mg/sq
four
developed
encephaloreactions
in this group
are
From www.bloodjournal.org by guest on February 11, 2015. For personal use only.
“C
x T”
INTRAVENTRICULAR
METHOTREXATE
839
CxT
60
c
0-
-0
5,)
2mg/rn2
40
‘
METI-IOTREXATE
5:
E
c
0
CNS
Remission,
Alive
S
CNS
Remission,
Dead
20
CNS
Relapse,
0
‘
Fig. 3.
Case
,
‘
200
Life table
rn/dose.
analysis
,
400
CNS
of CNS
,
,
remission
with
,
‘
600
Remission
Duration
,
800
(Days)
C x T therapy
and
,
000
200
in patients
treated
with
1
This
The
7-yr-old
girl
dementia
elsewhere.7
Case
2
At the
end
nerves.
of methotrexate
In this
boy
of his
of
the
for meningeal
beginning
of
9-yr-old
boy
improvement
with
folate
in
and
6 mo
after
methotrexate.
developed
his
onset
and
status
of
patient
dementia
neurologic
citrovorum
the
This
therapy.
has
been
palsies
despite
of
re-
cranial
discontinuation
factor.
dementia
life.
lesions
began
Areas
of
in the
centrum
during
white
consolidation
matter
and
necrosis
ovale
and
were
progressed
observed
periventricular
gradually
at
tissues.
autopsy,
There
over
sith
was
the
a con-
no
evidence
leukemia.
4
Severe
intracranial
Cerebrospinal
showed
brospinal
hypertension
fluid
tomogram
fluid
intracranial
began
examination,
no
were
brain
abnormalities
withdrasn
after
other
from
the
scan,
the
third
consolidation
radionuclide
than
diftuse
reservoir
once
dose
cisternogram,
cerebral
or
tss
edema.
ice
daily
in this
and
to
12-yr-old
boy.
computerized
Thirty
to
help
reduce
fifty
axial
ml
the
of cereincreased
pressure.
5
This 5-yr-old boy was
Subsequent
Two
threatening,
reaction
The
this
no
treatment
l5-r-old
9 mo
centration
Case
was
dementia
discontinuation
consolidation
There
and
after
3
ensuing
Case
progressive
subsided
of CNS
cervical
Case
developed
slowly
ported
and
Autopsy
‘
0
12 mg/sq
Clinical
Relapse,
V CNS
injections
of
the
unable
were
to salk for
given
neurotoxic
reactions
one was severe,
in the C x T group
neurotoxic
and
at half
7 days
dosage.
in the
three
were
was judged
nontoxic
after
The
patients
one
gait
of
his
monthly
abnormality
12 mg/sq
moderate,
to be mild.
were
did
maintenance
not
rn/dose
and
also
one
compared
injections.
recur.
group
was
mild.
were
life
The
one
separately
for
From www.bloodjournal.org by guest on February 11, 2015. For personal use only.
840
BIEYER
factors
that
to entry
may
onto
have
this
predisposed
study
had
the acute
toxic
syndrome
and
also no significant
diflerences
total
amounts
this
to
been
of intrathecal
neurotoxicity.
administered
Cranial
to four
to five of the
between
the
rnethotrexate
ET
irradiation
of the
AL.
prior
six patients
with
ten nontoxic
patients.
There
toxic
and nontoxic
patients
were
in the
administered
prior
to
treatment
in
two
on
study.
Complications
related
(Table
I). One
and a 12 mg/sq
to
the
reservoir
were
C x T patient
sustained
rn/dose
patient
developed
the reservoir.
The latter
occurred
in association
and head trauma
and probably
was unrelated
at that
there
was
time
were
no evidence
continued
without
epidermidis
hematorna
on
with severe
to the presence
This study
was closed
to patient
entry
on
apparent
that
the incidence
of neurotoxicity
single
injections
of 12 mg/sq
rn/dose
than
study
encountered
a Staphylococcus
a subdural
patients
meningitis
the side
of
thrombocytopenia
ofthe
reservoir.
January
1, 1976, when
it became
was
significantly
greater
with
in the C x T group.
Patients
on
therapy
modification
provided
that
of encephalopathy.
DISCUSSION
Design
leukemia
mated
ofthe
C x T regimen
cells.
The
cell
and
1 day,
at 3 days
for blast
cells
trexate
l07
residing
M.’#{176}
Six
injections
reduction
in the
(from
time
of
total
12 to
in part
and
CNS.9
the
1 mg
amount
6 mg)
The
minimal
Our
to encompass
experience
thus
12 hr
tive against
established
requires
significantly
methotrexate
used
neurotoxic,
treated
thus
for the
ing
in the
number
reservoir
of
by
objective
may be accomplished
and leaving
the second
dose
then
self-administered
study
by the
the
more
toxic, and this arm of
schedule
involved
single
until
remission
monthly
thereafter
this
for
therapy
metho5
x
concentration
dose
reaction,
is that
cell
indicates
a single
it requires
We
are
that
12 hr later
dosage
the randomization
intraventricular
induction,
weekly
for 2 yr (maintenance
was
injections
for
6 wk
therapy).
mg),
to
two
It is also
the
doses
the first
chamber.
therapy.
It
the total
significantly
one
less
patients
hospital
possibility
with
of halvinjection.
dose out of the reserThe second
dose
is
by pumping
schedule
it is as effec-
dose
two-thirds
seizure,
in nine
more
visits to the
exploring
by flushing
in the reservoir
l8
thought
antifolate
cycle.
regimen.
administering
patient
treatment
72 to
fluid rnethotrexate
level
prolongation
of cytocidal
of the
conventional
a single
(from
leukemia
as conventional
reducing
by one-half
to
injections.
injections
extracellular
provides
C x T schedule
conventional
This
voir
In this
S phase
meningeal
less drug,
esti-
be longer
is approximately
required
consolidation
the
with
only
one toxic
far. One disadvantage
additional
the
with
been
may
of 12 mg/sq
m provides
this level for less
advantages
of this C x T regimen
include
a
for
the
far
cytocidal
of human
have
intervals
in vitro,
every
elimination
of the high peak
cerebrospinal
be one of the causes
of neurotoxicity,
and
concentrations
cytokinetics
duration
these
studies
given
the
S-phase
of methotrexate
and
on
although
from
a single
injection
The theoretical
).
based
respectively,8
estimated
for 72 hr. whereas
than 32 hr (Fig.
1
course
cycle
in the
concentration,
was
the
was
discontinued.
of 12 mg/sq
(consolidation
reservoir.
excessively
neuro-
The
more
toxic
m twice
weekly
therapy),
and
From www.bloodjournal.org by guest on February 11, 2015. For personal use only.
“C x I”
The
INTRAVENTRICULAR
only
published
frequency
dren,
was
study
that
of
15 of whom
moderate
intralumbar
differed
therapy
between
did
not
intralumbar
receive
CNS
severe
signs
and
of
equally
schedules
were
neurotoxic
than
reactions
suggests
that
the
neurotoxicity.
Less
frequent
injections,
probably
however,
for clinical
comparison.
Although
the biochemical
brain
remains
unknown,
the
nor
factors
known
trations
than
nontoxic
toxic
consistent
with
also
reservoir
be a safe
the
and
and
regarded
The
however.
We
insertion
of
need
the
for
nondominant
hemisphere,
strictly
technique
sterile
surgery
mg/sq
(2
neurotoxicity
was
the
approach
the
compared
an
lumbar
that
Only
observaantifolate
the
Ommaya
1 patient
hospitalization)
and
must
of’ the
the
25-gauge
costs
be
of intraoperative
into
neuro-
related
to the reservoir.
the reservoir
to lumbar
expertise
use of the
and
et al.
definitely
preferred
use
groups,
groups
in
concen-
group,
of
obin
similar
methotrexate
3
also
trial
on the
patient
methotrexate
modality.
3 days
m used
of methotrexate
predispose
the
analysis
neurosurgical
a frontal
and
that
6.25
treatment
on
complication
unanimously
for sampling
This study showed
modifications
may
another
controlled
of Shapiro
recommend
cannula,
(e.g.,
effect
may
therapeutic
of the
doses
same
conclusion
optimal
specifically’
the
the
when
most
later
in maintenance
have contributed
to the
ventricular
findings
effcctivc
19 in this study
had a significant
Our patients
and their
families
punctures
neurotoxic
That
intraventricular
higher
within
previous
supports
more
or
vomit-
was
interrupted
it appeared
that
puncture.
also
The
17 chil-
These
require
adverse
irradiation
with
had
main-
in
well as in toxic
versus
nontoxic
patient
differences
between
the two treatment
patients
our
noted
It cannot
account
for the
frequency
of prior
radiotherapy
patients
levels.4
This study
ceptable.
the
to be correlated
In general,
can
or lower
basis for
prior
cranial
encephalopathy.’
study
in that the
toxicity.
tion
somewhat
by lumbar
less neurotoxic.
and ideally
would
two treatment
groups
as
were there
any significant
other
or
given
studied
Nausea,
were
severe.
Therapy
comparisons,
occurred
during
consolidation
frequency
of administration
may
by others#{176}12), are
jeopardize
efficiacy,
to methotrexate
served
in this
when
same
15, 4 developed
therapy.
irritation
similar
dosage
the
et al.i2
maintenance
meningeal
were graded
Based
on thcsc
intraventricularly
Of
Sullivan
the
m to 31 chil-
m every
8 wk, in 26 children.
that
there
was
no consolidation
dren,
and in all but two symptoms
or discontinued
in 4 children.
given
at
given
15 mg/sq
therapies.
toxicity.
12 mg/sq
however,
in
induction
local
methotrexate
administered
other
6 had
methotrexate,
from
ours,
and
841
et al,6 who
and
remission
headache,
of
Duttera
neurotoxicity
tenance
schedule
ing,
METHOTREXATE
as ac-
emphasized,
fluoroscopy
lateral
for
ventricle
scalp-vein
in
needles
the
and
a
injection.
to a regimen
of 12 mg/sq
rn/dose,
I mg
of
methotrexate
every 12 hr for six doses
is equally
effective
and
neurotoxic.
We believe
that this concentration
x time approach
significantly’
less
should
be con-
tinued
and
leukemia.
than
for
that
Three
patients
publication.
single
injections
it is worthy
have
Two
of
of study
in CNS
neoplasms
had CNS
relapse
since
this
of the three
relapses
occurred
12 mg/sq
m, one
at 612
days
after
other
manuscript
in patients
entry
on
men
ingeal
was submitted
treated
with
study
and
the
From www.bloodjournal.org by guest on February 11, 2015. For personal use only.
BLEYER
842
other
at 944
chemotherapy.
entry
and
tricular
days
The
after
third
396 days
starting
relapse
after
chemotherapy
(180
occurred
stopping
was
days
after
stopping)
in a C x T patient
maintenance
discontinued
therapy.
tional
sions
intraventricular
1444 days
Maintenance
at 2 yr as scheduled
tients,
one C x T patient
and one 12 mg/sq
remission
282 and 324 days,
respectively,
after
neurotoxicity
has been observed.
discussed
in the manuscript.
El
AL.
after
intraven-
in two
other
pa-
rn/dose
patient
who
continue
in
termination
of therapy.
No addi-
These
events
do
not
alter
the
conclu-
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1978 51: 835-842
"Concentration x time" methotrexate via a subcutaneous reservoir: a less
toxic regimen for intraventricular chemotherapy of central nervous system
neoplasms
WA Bleyer, DG Poplack and RM Simon
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