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Ati
m
I
TAXOL
DOSE
INTENSIFICATION
AND
ITS
CLINICAL
IMPLICATIONS
Gisele
Sarosy,
MD,
and
Eddie
Reed,
MD
Bethesda,
Maryland
Taxol
is
the
most
exciting
new
anticancer
agent
developed
in
the
past
two
decades.
Of
great
interest
is
its
level
of
activity
in
ovarian
cancer,
as
well
as
substantial
activity
in
breast
cancer,
nonsmall-cell
lung
cancer,
melanoma,
and
other
malignancies.
Recent
studies
suggest
that
when
taxol
is
administered
in
a
fashion
to
increase
milligram
dosage
per
unit
time
(mg/
m2/week),
the
response
rate
in
patients
with
ovarian
cancer
is
markedly
increased.
This
article
reviews
studies
that
suggest
taxol
dose
intensity
is
important
in
the
treatment
of
pa-
tients
with
ovarian
cancer.
(J
NatI
Med
Assoc.
1
993;85:427-431.)
Key
words
*
taxol
*
ovarian
cancer
*
dose
intensity
Taxol
is
a
diterpene
compound
isolated
from
the
bark
of
the
Northwestern
yew
tree
Taxus
brevifolia.
I
In
1971,
taxol
was
evaluated
in
the
National
Cancer
Institute's
(NCI)
new
drug
screening
program
and
found
to
have
activity
against
a
variety
of
malignant
cell
lines
in
vitro.2
Based on
this
observation,
laboratory
studies
were
instituted
to
define
the
mechanism
of
action
of
this
new
agent.
Preclinical
evaluation
showed
that
the
mechanism
of
action
of
taxol
was
distinct
from
that
of
any
previously
described
anticancer
agent."
2
Taxol
promotes
assembly
of
intracellular
microtubules,
which
subsequently
dis-
rupts
cellular
function.
This
is
in
contrast
to
vinca
alkaloids
such
as
colchicine,
vincristine,
and
vinblastine,
which
inhibit
microtubular
aggregation.
However,
a
mechanism
of
resistance
to
taxol
is
the
multidrug-resistant
membrane
glycoprotein,
which
has
From
the
Medical
Ovarian
Cancer
Section,
Medicine
Branch,
National
Cancer
Institute,
Bethesda,
Maryland.
Requests
for
reprints
should
be
addressed
to
Dr
Gisele
Sarosy,
Medical
Ovarian
Cancer
Section,
Medicine
Branch,
National
Cancer
Institute,
Bldg
10,
Rm
12N226,
Bethesda,
MD
20892.
been
associated
with
in
vitro
and
clinical
resistance
to
various
natural
products.2
Recently,
public
attention
has
been
drawn
to
taxol
because
of
two
seemingly
disparate
factors.
The
first
is
the
encouraging
activity
observed
following
treatment
with
taxol
in
cancer
of
the
ovary,3
malignant
mela-
noma,4-6
breast
cancer,7
nonsmall-cell
lung
cancer,89
and
in
other
cancers
that
have
failed
to
respond
or
have
recurred
following
standard
cherotherapy.l°ll
The
second
is
the
environmental
impact
of
harvesting
enough
yew
trees
to
provide
a
sufficient
supply
of
taxol
to
treat
such
patients.
Debates
regarding
the
relative
importance
of
patient
care
versus
environmental
preser-
vation
continues.
Discussions
are
currently
underway
between
the
US
government
and
the
private
sector
to
resolve
these
differences.
DOCUMENTATION
OF
CLINICAL
ACTIVITY
Although
responses
were
reported
in
phase
I
trials
in
several
malignancies,
the
most
exciting
activity
was
observed
in
carcinoma
of
the
ovary
of
epithelial
histology.3
Initial
clinical
studies
demonstrated
sub-
stantial
activity
in
ovarian
carcinoma,3
malignant
melanoma,4
nonsmall-cell
lung
cancer,12
and
in
some
types
of leukemia."
l
Investigators
at
the
Johns
Hopkins
University
Medical
Center
showed
that
taxol
has
activity
in
ovarian
cancer
patients
who
are
clinically
sensitive
or
resistant
to
platinum-based
chemotherapy.3
At
the
same
time
that
impressive
clinical
activity
of
taxol
was
noted,
substantial
side
effects
were
observed
following
the
administration
of
taxol.
Although
these
side
effects
are
well
documented,
it
is
unclear
whether
they
are
directly
attributable
to
the
drug
taxol
or
to
the
vehicle
in
which
taxol
is
dissolved."
2
The
taxol
vehicle,
cremophor
EL,
has
been
used
to
formulate
other
drugs
that
are
difficult
to
solubilize.
The
cremophor
vehicle
has
been
shown
to
cause
many
of
the
allergic
reactions
currently
associated
with
taxol.
Several
life-threatening
toxicities
have
been
reported
JOURNAL
OF
THE
NATIONAL
MEDICAL
ASSOCIATION,
VOL.
85,
NO.
6
427
TAXOL
following
administration
of
taxol.
Taxol
is
associated
with
acute
anaphylactic
reactions
in
a
small
percentage
(<5%)
of
patients.",2
Current
treatment
guidelines
include
premedication
with
dexamethasone
and
HI
and
H2
blockers
such
as
cimetadine
and
diphenhydramine
hydrochloride.
Taxol
administration
is
associated
with
life-threatening
cardiac
toxicities
that
may
include
myocardial
infarction,
ventricular
tachycardia,
and
second-degree
heart
block.13
In
many
patients,
the
cardiac
rhythm
will
be
slowed
such
that
sinus
bradycar-
dia
will
range
between
40
and
50
beats/minute.'4
Hematologic
toxicities
are
common
with
taxol,
particularly
at
high
dose.
Taxol
appears
to
be
preferen-
tially
toxic
to
the
leukocyte
compartment
of
the
bone
marrow
with
relative
sparing
of
platelets
and
red
cells.3
However,
peripheral
thrombocytopenia
below
50000
cells/cu
mm,
and
the
need
for
intermittent
red
blood
cell
transfusions
are
common
with
this
agent.'5
Neurologic
toxicities
have
been
dose-limiting
in
several
clinical
studies
of
taxol.101416
These
findings
are
most
commonly
observed
in
patients
who
have
received
doses
3250
mg/M2
per
dose.
Generally,
this
is
manifested
as
a
peripheral
neuropathy
with
a
stocking-
and-glove
distribution
that
is
clinically
similar
to
cisplatin-related
peripheral
neuropathy.
Nerve
conduc-
tion
studies
have
demonstrated
reductions
in
sensory
amplitude
potentials
of
patients
studied,
with
sparing
of
the
motor
amplitude
potential.'4
DEMONSTRATION
OF
ACTIVITY
IN
OVARIAN
CANCER
The
first
demonstration
of
substantial
activity
in
advanced-stage
ovarian
cancer
was
reported
by
McGuire
et
al.3
In
a
study
of
the
administration
of
taxol
in
doses
ranging
from
110
to
over
200
mg/m2
every
3
weeks,
taxol
induced
objective
responses
in
both
patients
who
had
not
responded
to
initial
therapy
and
those
who
had
not
responded
to
and
then
recurred
after
initial
platinum-based
therapy.
Taxol
appeared
to
be
active
in
cisplatin-sensitive
and
cisplatin-resistant
dis-
ease,
with
some
patients
experiencing
complete
remis-
sion
that
lasted
for
a
number
of
months
after
the
cessation
of
taxol
therapy.
A
group
at
Albert
Einstein
University
attempted
to
conduct
a
study
of
high-dose
taxol
(250
mg/m2
per
cycle),
without
colony-stimulating
factor
support,
in
a
similar
cohort
of
patients
with
ovarian
cancer.'7
In
this
study,
mucositis
and
myelosuppression
were
com-
monly
observed,
as
well
as
episodes
of
peripheral
nephropathy.
This
resulted
in
a
large
percentage
of
patients
experiencing
either
dose
reductions
or
dose
delays
during
the
course
of
treatment.
The
objective
response
rate
reported
in
this
study
was
21%
compared
with
the
32%
objective
response
rate
reported
by
the
Johns
Hopkins
group.3
The
Gynecologic
Oncology
Cooperative
Study
Group
(GOG)
conducted
a
multi-institution
study
to
examine
the
taxol
dose
of
175
mg/m2,
administered
every
3
weeks
to
a
similar
cohort
of
patients
without
colony-stimulating
factor
support.'8
Although
the
tox-
icities
that
were
observed have
not
been
reported
in
detail,
a
preliminary
report
indicated
that
the
objective
response
rate
to
taxol
at
this
dose
was
36%.
With
the
GOG
report,
three
different
studies
had
demonstrated
substantial
activity
for
taxol
in
advanced-stage
recur-
rent
ovarian
cancer,
both
in
platinum-resistant
and
platinum-sensitive
subsets
of
patients.
As
a
result,
the
Medicine
Branch
of
the
NCI
sought
to
determine
if
taxol
dose
intensification
would
be
possible,
and,
if
so,
whether
that
would
translate
into
an
improved
response
rate
in
ovarian
cancer.
TAXOL
DOSE
INTENSIFICATION
The
first
study
undertaken
by
the
Medicine
Branch
of
the
NCI
examined
taxol
dose
intensification
with
granulocyte
colony-stimulating
factor
(G-CSF)
sup-
port.
In
this
phase
I
study,
15
patients
were
treated
with
increasing
doses
of
taxol
to
determine
the
maximally
tolerated
taxol
dose
when
drug-related
hematologic
toxicity
is
ameliorated.14
This
study
showed
that
patients
tolerated
250
mg/M2
of
taxol
administered
as
a
24-hour
intravenous
infusion
every
3
weeks,
when
followed
by
a
G-CSF
dose
of
10
,ug/kg/day.
Granulo-
cyte
colony-stimulating
factor
was
administered
daily
through
the
granulocyte
nadir.
At
a
dose
of
300
mg/m2/day,
the
dose-limiting
toxicity
was
peripheral
neuropathy
similar
to
that
observed
by
the
investigators
at
Albert
Einstein.
'7
This
stocking-and-glove
peripheral
neuropathy
was
primarily
manifested
as
a
propriocep-
tive
disorder.
Patients
experiencing
this
toxicity
were
frequently
unable
to
recognize
objects
by
touch
alone
and
experienced
difficulty
ambulating
without
the
use
of
visual
cues.
This
severe
neurologic
toxicity
was
brief,
resolving
within
several
days
or
weeks
after
the
onset
of
symptoms.
A
milder
form
of
neurotoxicity
also
was
seen.
This
consisted
of
numbness
and
tingling
in
the
fingers
and
toes,
and
persisted
in
some
patients
for
several
months
after
the
cessation
of
taxol
therapy.
Since
all
patients
had
previously
been
treated
with
cisplatin
or
carboplatin,
it
is
unclear
whether
platinum
compounds
predispose
to
this
taxol-related
toxicity.
428
JOURNAL
OF
THE
NATIONAL
MEDICAL
ASSOCIATION,
VOL.
85,
NO.
6
TAXOL
Without
bone
marrow
support,
taxol-induced
myelo-
suppression
is
dose-limiting,
primarily
manifested
as
leukopenia.3
With
standard
doses
of
taxol,
leukopenia
can
be
expected
to
last
4
to
5
days
in
most
patients.
With
G-CSF
support,
taxol
at
high
doses
is
associated
with
modest
myelosuppression,
with
leukopenia
and
thrombocytopenia
lasting
for
an
average
of
1
day
in
most
patients.
Further,
current
data
suggest
that
bone
marrow
toxicity
is
not
cumulative
with
the
taxol-G-
CSF
combination.
When
G-CSF
is
used,
patient
age
appears
to
have
no
impact
on
the
hematologic
toxicity
profile.
19
A
phase
II
study
of
taxol
was
conducted
at
the
maximal
tolerated
dose
defined
in
the
phase
I
study.20
Thirty-eight
patients
with
recurrent
or
refractory
ovar-
ian
cancer
were
evaluated
for
response
following
treatment
with
250
mg/m2.
Response
to
taxol
was
determined
by
changes
in
disease
status
as
measured
from
computed
tomography
scans
of
the
abdomen
or
at
peritoneoscopy.
Although
serum
CA125
levels
were
followed
in
patients
in
whom
the
CA125
had
been
initially
elevated,
a
change
in
CA125
levels
was
never
accepted
as
the
sole
criterion
for
defining
an
objective
response.
The
patients
were
deemed
to
have
an
objective
response
to
therapy
only
if
there
was
>50%
reduction
in
the
sums
of
the
products
of
the
longest
perpendicular
diameters
of
all
measurable
lesions
that
lasted
at
least
1
month.
Of
38
patients,
19
experienced
objective
responses,
with
another
four
experiencing
minor
responses
(a
reduction
in
tumor
of
<50%).
Of
the
19
objective
responders,
four
had
complete
radiographic
resolution
of
their
disease.
Fifteen
individuals
did
not
respond
to
therapy.
If
one
pools
data
from
the
three
prior
taxol
studies
discussed
above,
there
were
33
responders
in
a
total
of
110
patients
studied,
for
an
objective
response
rate
of
30%.
Thus,
the
50%
response
rate
seen
in
this
phase
II
study
of
taxol
with
G-CSF
was
more
than
a
60%
improvement
over
previous
studies.
The
ability
to
dose
intensify
taxol
appeared
to
be
related
in
part
to
flexible
G-CSF
dosing.
Flexible
G-CSF
dosing
is
extremely
important
in
maintaining
taxol
dose
intensity.21
In
47
patients
treated,
4
of
the
first
5
had
recurrent
episodes
of
fever
and
neutropenia
when
G-CSF
dose
was
kept
constant
during
subsequent
cycles
of
therapy
at
a
dose
of
10
,ug/kg/day.
Among
the
remaining
42
patients,
taxol
dose
reductions
were
avoided
in
38%
of
patients
by
increasing
the
G-CSF
dose
to
20
pug/kg/day.
In
these
patients,
recurrent
episodes
of
life-threatening
febrile
neutropenia
were
rarely
seen.
One
should
consider
reducing
the
G-CSF
60
50
a
Z
40-
0
c-
30-
Z
20
w
10
0
NCI
GM
J.H.
A.E.
INSTITUTION
CONDUCTING
STUDY
Figure.
Disease
response
rates
are
compared
for
the
four
studies
of
taxol
in
recurrent
adenocarcinoma
of
the
ovary.
(AE
=
Albert
Ein-
stein
University,
JH=Johns
Hopkins
Univer-
sity,
GOG
=
Gynecologic
Oncology
Coopera-
tive
Study
Group,
and
NCI
=
Medicine
Branch
of
the
National
Cancer
Institute.)
The
NCI
study
had
the
highest
target
dose
intensity
and
the
highest
disease
response
rate.
The
administered
dose
intensity
in
the
NCI
study
was
higher
than
the
target
response
rate
for
any
of
the
other
three
studies.
dose
for
bone
pain
that
is
not
readily
responsive
to
acetaminophen
or
diphenhydramine.
In
the
phase
II
study,
the
first
response
in
patients
who
experienced
febrile
neutropenia
was
to
increase
the
G-CSF
dose
from
10
,ug/kg/day
to
20
,ug/kg/day.
This
increase
in
G-CSF
dose
was
associated
with
a
reduction
in
the
expected
incidence
of
febrile
neutropenia
and
in
the
preservation
of
taxol
dose
intensity.
The
Figure
compares
the
Medicine
Branch
Phase
II
study
with
studies
performed
by
the
Albert
Einstein
group,
the
Johns
Hopkins
group,
and
the
GOG.
Detailed
data
on
dose
intensification
has
yet
to
be
reported
from
these
three
studies.
In
the
Medicine
Branch
study,
target
dose
intensity
was
83.3
mg/m2/wk,
and
this
was
the
median
administered
dose
intensity
in
this
cohort.
The
mean
administered
dose
intensity
was
79
mg/m2/wk.
In
each
of
the
three
prior
studies,
the
target
dose
intensity
was
substantially
less
than
the
83.3
mg/m2/wk
of
the
Medicine
Branch
study,
and
it
is
probable
that
neither
of
the
three
previous
groups
were
able
to
administer
100%
of
their
target
dose
intensity.
OTHER
DISEASE
SITES
Taxol
has
been
evaluated
in
only
a
few
disease
sites
because
of
its
limited
supply.
Initial
phase
II
studies
were
undertaken
in
sites
in
which
responses
were
JOURNAL
OF
THE
NATIONAL
MEDICAL
ASSOCIATION,
VOL.
85,
NO.
6
429
TAXOL
TABLE
1.
SUMMARY
OF
THE
FOUR
STUDIES
OF
TAXOL
USE
IN
RECURRENT
OVARIAN
CANCER
Institution
Projected
(Target)
Taxol
Dose
Intensity
Disease
Response
Medicine
Branch,
National
Cancer
250
mg/m2/every
3
weeks
(83.8
mg/m2/wk)
50%
Institute20
Gynecologic
Oncology
Cooperative
175
mg/m2/every
3
weeks
(58.3
mg/m2wk)
36%
Study
Group18
Johns
Hopkins
University3
1
10-210
mglm2/3
weeks
(37-70
mg/m2/wk)
32%
Albert
Einstein
University17
250
mg/m2/every
3-4
weeks
(62-83
mg/m2wk)*
21%
*Manv
dose
reductions
were
made.
TABLE
2.
MALIGNANT
DISEASES
IN
WHICH
TAXOL
DOSE
INTENSITY
IS
BEING
(OR
HAS
BEEN)
STUDIED,
WITH
OR
WITHOUT
OTHER
AGENTS
Disease
Type
Taxol
Dose
Other
Agents
Breast
cancer
250
CIV
Dl None7
125-160
CIV
Doxorubicin
60
Dl
mg/M2
CIV
D2,
D3
G-CSF22
160-180
CIV
Doxorubicin
45-75
over
72
hrs
mg/M2
CIV
over
72
hrs
G-CSF23
Nonsmall-cell
250
CIV
Dl
None8
lung
cancer
200
CIV
Dl
None9
Melanoma
200-250
CIV
None5
Dl
250
CIV
Dl
None6
observed
in
phase
I
studies,
and
some
of
the
more
common
malignancies.
The
published
data
are
summa-
rized
in
Table
2.
Perhaps
the
most
exciting
results
to
date
have
been
observed
in
phase
II
studies
in
breast
cancer
and
nonsmall-cell
lung
cancer.
Investigators
at
MD
Anderson
treated
25
patients
with
recurrent
breast
carcinoma
with
taxol
200
to
250
mg/in2
without
G-CSF
support.
Complete
responses
were
observed
in
three,
and
partial
responses
were
observed
in
11
(56%
objective
response
rate).
Hematologic
toxicity
was
dose-limiting,
and
most
patients
required
a
reduction
in
the
dose
of
taxol.
The
nonhematologic
toxicities
observed
were
similar
to
that
previously
reported
following
taxol
administration.7
Based
on
this
encour-
aging
report,
several
studies
have
attempted
to
combine
taxol
with
doxorubicin,
the
most
active
single
agent
in
patients
with
metastatic
and
recurrent
disease.
Two
phase
I
studies
of
taxol
and
doxorubicin
have
been
undertaken.
In
the
phase
I
study
at
MD
Anderson,
patients
received
taxol
as
a
24-hour
continuous
intrave-
nous
infusion
on
day
one;
on
days
two
and
three,
patients
received
doxorubicin
60
mg/mi2
intravenously.
The
initial
dose
level
of
taxol
was
125
mg/m2.
Granulocyte
colony-stimulating
factor
5
,ug/kg
was
given
from
day
four
to
day
nineteen.
Only
seven
patients
were
treated.
At
the
first
dose
level,
all
four
patients
experienced
either
dose-limiting
stomatitis
or
febrile
neutropenia.
Among
these
seven
patients,
three
objective
responses
were
observed.22
In
a
study
undertaken
by
the
NCI
Medicine
Branch,
15
patients
were
treated
with
taxol
160
to
180
mg/mi2
and
doxorubicin
45
to
75
mg/m2,
given
concurrently
as
a
72-hour
continuous
intravenous
infusion,
followed
by
G-CSF
10
,ug/kg/day.
At
the
highest
dose
level,
gastrointestinal
toxicity
was
dose-limiting
in
all
pa-
tients
treated.
Objective
responses
were
observed
in
five
patients.23
Work
is
ongoing
to
determine
the
optimal
dose
and
schedule
of
these
two
active
agents
in
breast
cancer
and
the
role
of
this
combination
in
patients
with
metastatic
disease.
Taxol
also
has
generated
a
great
deal
of
interest
in
the
treatment
of
patients
with
nonsmall-cell
lung
cancer.
Based
on
responses
observed
during
phase
I
studies
in
patients
with
nonsmall-cell
lung
cancer,12'24
two
phase
II
studies
were
undertaken,
which
did
not
use
G-CSF.
An
Eastern
Cooperative
Onocology
Group8
study
demonstrated
five
partial
responses
among
24
evaluable
patients
treated
with
taxol
250
mg/M2,
and
investigators
at
MD
Anderson9
reported
six
objective
responses
among
25
evaluable
patients
treated
with
taxol
200
mg/m2.
These
response
rates
are
comparable
to
the
activity
of
standard
chemotherapeutic
agents
used
to
treat
this
disease.
Further
studies
will
explore
the
optimal
dose
and
schedule
of
taxol,
and
the
agents
with
which
it
should
be
combined.
Investigators
at
Albert
Einstein
University
reported
that
several
patients
with
melanoma
in
their
phase
I
study
responded
to
therapy
with
taxol.4
Two
phase
II
studies
were
undertaken
based
on
this
observation,
in
which
an
objective
response
rate
of
12%
to
14%
was
reported.5'6
Additional
studies
in
patients
with
ad-
vanced
melanoma
exploring
taxol-based
combinations
are
anticipated
when
there
is
increased
drug
supply.
Evaluation
in
other
disease
sites
has
been
limited.
A
study
of
taxol
250
mg/m2
in
renal
cell
cancer
430
JOURNAL
OF
THE
NATIONAL
MEDICAL
ASSOCIATION,
VOL.
85,
NO.
6
TAXOL
demonstrated
no
responses
among
14
patients.25
Stud-
ies
in
other
disease
sites
have
not
yet
been
reported.
SUMMARY
Based
on
currently
available
data,
there
are
four
studies
that
have
investigated
the
level
of
activity
of
taxol
in
advanced-stage
recurrent
epithelial
carcinoma
of
the
ovary.
Of
those
four
studies,
the
association
of
high-dose
intensity
with
high
rates
of
disease
response
appears
to
be
a
direct
one,
suggesting
that
dose
intensity
may
be
an
important
factor
for
taxol
drug
administra-
tion.
However,
these
data
should
not
be
accepted
as
proof
of
this
hypothesis.
The
NCI
is
sponsoring
a
multi-institution
prospective
randomized
trial
to
assess
the
role
of
taxol
dose
intensity
in
this
disease.
Until
Medicine
Branch
data
are
confirmed
in
such
a
prospective
trial,
the
presumption
that
taxol
dose
intensity
is
better
than
taxol
at
standard
doses
remains
an
hypothesis.
Acknowledgments
The
authors
thank
Mrs
Joan
Effriom
for
her
careful
handling
of
the
manuscript,
and
Drs
Robert
Wittes
and
Bruce
Chabner
of
the
National
Cancer
Institute
for
their
careful
review
of
the
manuscript
and
helpful
comments.
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NO.
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