Question: Could we begin with
a brief overview of
the issue of
drug-resistant GIST?
Dr. Blanke: As the most
effective drug
therapy for GIST
available to date,
Gleevec®
(Gleevec) has
completely changed
the way GIST
patients are managed
and has brought them
an unprecedented
degree of hope. But
we do not believe at
this time that it
cures the disease,
and we are seeing
cases of primary
resistance—that is,
people who do not
benefit from
Gleevec from the
outset. The number
of these cases is
extremely small—5%
to 15%.
A secondary
population will
either respond to
the drug or have
complete
stabilization of
their disease, and
then later
demonstrate
resistance, in the
form of tumor
growth. Renewed
disease activity in
Gleevec-treated
patients, when it
occurs, is commonly
seen after about 15
to 18 months of
therapy, but of
course it can appear
at any time. It is
important to monitor
GIST patients
carefully for
disease recurrence.
We at OHSU, and
other experts
throughout the
United States,
recommend seeing a
GIST patient every 3
months; obtaining a
CT scan every 3
months; and
performing blood
tests, mainly for
toxicity.
Question: When you see a
resistant patient,
what do you do next?
Dr. Blanke: First, it is
important to make
sure that what you
are seeing truly is
disease progression
A massive lesion may
become very necrotic
and liquefied, and
it can actually be
larger if a CT scan
is obtained at 8
weeks after the
start of Gleevec
treatment. But this
finding can
represent cellular
death, not growth of
cells or
proliferation. To
confirm progression,
a PET scan might be
helpful. If the
patient’s CT
findings worsen but
the PET scan shows
improvement, then
the patient’s GIST
is not progressing.
On the other hand,
if both the CT and
PET scans show
worsening, then
progression probably
is occurring.
Second, there are
different patterns
of progression in
GIST. Some people’s
tumors basically
progress
everywhere—all the
lesions become
larger. The initial
line of attack in
that setting is an
increase in the
Gleevec dose if the
patient is not
already receiving
high-dose therapy
and the escalation
is tolerable. In
other cases, the
overwhelming
proportion of
disease sites remain
under control with
Gleevec—that is,
90%to 95% of the
tumors continue to
shrink or cease to
grow—but one area on
the CT scan
enlarges. If a
patient has what we
consider to be one
bad clone, the
physician should
probably think very
strongly about
whether there is any
potential for
surgical eradication
of that clone,
either by surgical
resection or
radiofrequency
ablation.
Question: Would you say, then,
that the current
options for the
Gleevec-treated
patient with GIST
progression are dose
escalation, Sutent and/or
excision of growing
lesions?
Dr. Blanke: Yes, and the next
step should be
referral for an
experimental trial.
Question: Is there any role
for discontinuation
of Gleevec?
Dr. Blanke: No. This is an
incredibly important
point and very
different from what
we do in other
malignancies. There
is a large quantity
of anecdotal data
now indicating that
even in cases of
GIST progression,
stopping Gleevec
causes the disease
to progress faster.
Patients may sicken
and die within a
couple of weeks.
Basically, unless
patients are minutes
from death or they
are tolerating
Gleevec very
poorly, experts in
the United States
recommend continuing
the drug
indefinitely. I
would be very
reluctant to
discontinue the
drug.
Question: Dosing is another
frequently discussed
issue.
At what dosage
should Gleevec
therapy be started?
Dr. Blanke: The
dosing question
stems from 2
studies. There is a
US phase III trial
and a European phase
III trial that have
yielded slightly
different findings.
The US trial, for
which a preliminary
analysis is
available, compared
400 and 800 mg of
Gleevec daily for
the treatment of
GIST and found no
difference in
response,
progression, or
survival. The
European trial found
a minimal advantage
with respect to
progression for the
800-mg dose. The
data are still
preliminary. In my
opinion, the
evidence does not
yet prove that the
800-mg daily dose is
better. US
physicians strongly
advocate starting
patients at 400 mg/d
and then escalating
the dose if the
disease progresses.
Some European
authorities do
advocate a higher
starting dose.
Question: Suppose the patient
is started on
Gleevec therapy at
400 mg/d, but the
response seems to be
suboptimal. Should
dose escalation be
considered?
Dr. Blanke: It depends on the
therapeutic goal. If
the physician thinks
that with shrinkage
the disease might
ultimately become
resectable, then
dose escalation
could well be a
reasonable step. If
there is massive
widespread disease,
it can be difficult
to balance the risk
of toxicity against
the possible benefit
of escalation. I
have used this
approach for
selected patients
who wanted to
proceed more
aggressively with
their treatment.
Question: What final thoughts
would you want to
share with the broad
community of your
colleagues in
oncology?
Dr. Blanke: GIST remains
relatively rare in
the community, and
it is a disease in
which treatment
experience is
particularly
valuable. Most of
the international
experts are very
friendly about
receiving telephone
calls or e-mail
messages requesting
advice. I would
encourage physicians
who are caring for
GIST patients to
contact the research
centers if they have
any type of
question.
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UPDATE: On January 26, 2006,
Sutent® was
approved for patients in the
United States. We asked Dr.
Blanke several questions
about this new option for
GIST patients.
Question: What is Sutent and how does
its approval change the
options for
Gleevec-resistant GIST?
Dr. Blanke: Sutent is a oral drug which
inhibits several targets
potentially important in
GIST growth. It is the only
drug approved after Gleevec
failure. The difficulty will
be knowing when to integrate
Sutent into the treatment
paradigm.
Question: For Gleevec-resistant GIST,
should dose-escalation of
Gleevec precede therapy with
Sutent?
Dr. Blanke: If a patient is on less than
800 milligrams per day, and
is tolerating the drug;
absolutely. The American and
European large-scale studies
both showed a substantial
proportion of patients will
benefit from that simple
intervention.
Question: For
Gleevec-resistant patients;
which should be considered
first, Sutent or a clinical
trial?
Dr. Blanke: This is a difficult question
to answer. Sutent has a
proven track record, helping
some, but not all patients.
One important question would
be whether taking Sutent
disqualifies the patient
from the trial. If so, the
trial would have to come
first.
Question: Are there some groups of
patients that should
consider a clinical trial
prior to Sutent?
Dr. Blanke: See above. I would not use
genetic testing currently to
make that decision-the
numbers of patients in each
genetic group are too small
to make a firm decision. On
the B2222 Gleevec study,
none of the wild-type
patients had a remission.
That was not true in the
much larger US study.
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