Management of Localized Disease
Complete surgical resection with negative
margins is the recommended
treatment for localized GISTs. Extended
anatomic
resection and lymphadenectomy are not
required. Resection
of even locally advanced tumors is
associated with improved
survival.199 The 5-year survival rate for all
patients with GISTs
ranges from 20% to 44%, and the 5-year
survival rate for
patients with completely excised early-
stage tumors is up to
75%.199 An analysis of 200 patients by
DeMatteo and colleagues
found a disease-specific survival rate of
54% for patients with
grossly complete resection of primary GIST,
and the median
survival duration for patients with
metastatic disease was only
20 months.57
As for other soft tissue sarcomas, tumor
size has consistently
been identified as an important prognostic
factor for
GIST. Mitotic activity has also been
identified as an important
prognostic factor and is generally
categorized as fewer than
5, 5 to 10, or more than 10 mitoses per
high-power field. The
National Institutes of Health200 and the
Armed Forces Institute
of Pathology196 have proposed prognostic
criteria for risk
stratification of surgically treated,
localized primary GIST.
Both groups take into account tumor size
and mitotic count; the
Armed Forces Institute of Pathology also
includes tumor site as
a prognostic variable. Accurate risk
stratification is essential for
selecting patients most likely to benefit
from adjuvant treatment.
Management of Locally Advanced
or
Metastatic Disease
Treatment with imatinib mesylate (Gleevec,
ST1571), a selective
inhibitor of the KIT protein tyrosine
kinase, has resulted in
impressive clinical responses in a large
percentage of patients
with unresectable or metastatic GISTs. On
the basis of the initial
results in a single patient with metastatic
GIST, the EORTC Soft
Tissue and Bone Sarcoma Group initiated a
phase I study to
test the safety and efficacy of imatinib. 201
In that study, 53% of
patients with GISTs had confirmed partial
responses; investigators
concluded that imatinib is safe and
effective against this
disease.201 A multicenter, international
trial of imatinib for GIST
was begun in July 2000 at four treatment
centers: Dana-Farber
Cancer Institute, Oregon Health Sciences
University, Fox Chase
Cancer Center, and University Hospital of
Helsinki, Finland.202
A total of 147 patients with unresectable
or metastatic GISTs
were randomized to 400 or 600 mg of
imatinib daily for up to
24 months. Objective response was
demonstrated in 79 patients
(54%); all had partial responses, and there
was no significant
difference in response rate between
imatinib doses.203 Fourteen
percent of patients experienced disease
progression. The toxicity
profile was acceptable; the predominant
effects were gastrointestinal
effects (diarrhea, nausea), periorbital
edema, muscle
cramps, and fatigue. However, 21% of
patients experienced
serious (grade 3 or 4) adverse events,
including gastrointestinal
bleeding in 5% of patients, most likely
related to the rapid tumor
response of mural lesions.
A phase III randomized Intergroup trial was
simultaneously
performed to assess the clinical activity
of imatinib at
two dose levels for patients with
unresectable or metastatic
GIST expressing the c-Kit tyrosine kinase.204
From December
15, 2000, through September 1, 2001, 746
patients were
accrued and randomized to low-dose (400
mg/d) or high-dose
(800 mg/d) imatinib. The primary endpoint
of the trial was survival.
Preliminary toxicity data from 325 patients
revealed a
23% incidence of grade 3 or 4 adverse
events, including nausea
and vomiting, gastrointestinal bleeding,
abdominal pain, edema,
fatigue, and rash.
In February 2002, the U.S. Food and Drug
Administration
approved imatinib for treatment of GIST
based on the results of
these promising clinical trials. Both the
Intergroup trial mentioned
in the preceding paragraph and a separate
phase III trial
compared the efficacy of low-dose (400
mg/d) and high-dose
(800 mg/d) imatinib in patients with
metastatic or unresectable
GISTs.205,206 Both studies showed equivalent
response rates and
overall survival for the two doses but
increased toxicity for the
800-mg/d dose. Current recommendations
include consideration
of dose escalation to 800 mg/d for patients
who experience disease
progression at a dose of 400 mg/d and for
patients with
advanced GIST and KIT exon 9 mutations.1,207
The optimal duration of imatinib treatment,
the duration
of benefit from imatinib, and the long-term
toxicity of imatinib have not been
established. When feasible, imatinib should
be
continued in the absence of disease
progression. A randomized
trial reported worse median progression-
free survival in patients
who stopped imatinib after 1 year than in
patients who continued
beyond 1 year (progression-free survival of
6 months vs.
18 months).208 Less than 4% of patients with
GISTs have experienced
serious adverse events with imatinib. Mild
gastrointestinal
toxicity is the most frequently reported
adverse event, but
gastrointestinal tract hemorrhage,
presumably from rapid tumor
necrosis, has also been reported. Thus, all
patients with GISTs
treated on clinical protocols should be
evaluated and followed
by a team of medical professionals that
includes a surgeon.
Many patients with GIST develop resistance
to imatinib.
Primary resistance is defined as clinical
progression that develops
during the first 6 months of treatment and
is most commonly
seen in patients with KIT exon 9 mutation,
PDGFRA exon 18
mutation, or no mutations.209 Secondary
resistance is defined as
progression that develops more than 6
months after the start of
treatment in a patient with an initial
response.210 Imatinib resistance
should be managed by either dose escalation
or transition
to treatment with sunitinib.1
In 2006, sunitinib malate (SU11248, Sutent,
Pfizer)
emerged as an alternative systemic
treatment for patients unable
to tolerate imatinib and patients with
imatinib-refractory GIST.
Sunitinib is a tyrosine kinase inhibitor
that targets multiple
kinases, including the vascular endothelial
growth factor receptors,
PDGFRA, KIT, and FLt3. Sunitinib has both
antiangiogenic
and antiproliferative activity. In a phase
III randomized
placebo-controlled trial, sunitinib was
associated with a significant
improvement in median time to progression
(27.3 weeks
vs. 6.4 weeks with placebo) in patients
with imatinib-resistant
GIST.131 In addition, sunitinib therapy was
well tolerated; diarrhea,
fatigue, and nausea were the most common
adverse effects.
Sunitinib has also been associated with
hand-foot skin reaction,
hypertension, cardiotoxicity, and
hypothyroidism.211-213 In 2006,
sunitinib was approved by the U.S. Food and
Drug Administration
for treatment of patients with resistance
or intolerance to
imatinib.
Other tyrosine kinase inhibitors are in
development, many
of which target more than one family of
protein kinases.214
Among these are sorafenib, dasatinib, and
nilotinib, which
are actively being investigated for the
treatment of imatinib-resistant
GIST.215 Everolimus (RAD001) and protein
kinase C
are being investigated as agents that may
maximize the extent
and duration of response to imatinib by
blocking potential pathways
of resistance.
Multidisciplinary Treatment
Although imatinib has improved survival of
patients with
advanced GIST, most patients with advanced
GIST are not
cured with imatinib. Some patients develop
secondary resistance
to imatinib with one or more sites of
disease progression after
6 months of clinical response (Fig. 36-10A
[before imatinib],
Fig. 36-10B [after imatinib]). The
mechanisms of imatinib
resistance are currently being
investigated. Surgery has been
shown to be beneficial for selected
patients with isolated disease
progression during imatinib therapy. 216-219
Surgical resection of
residual metastatic disease responding to
imatinib-sensitive
GIST has also been shown to result in
progression-free survival
in 70% to 96% of patients with imatinib- or
sunitinib-sensitive
GISTs.218-220 The optimal timing of surgery in
relation to imatinib
therapy for patients with metastatic
disease remains to be determined. It is not
possible to compare outcomes for patients
treated with kinase inhibitors alone and
patients treated with
kinase inhibitors plus surgical resection
outside the context of
randomized trials given the heterogeneity
of patients and biases
associated with selection of patients for
surgical resection.
Postoperative Imatinib
Given the promising results of imatinib
therapy for metastatic
and locally advanced GIST, the next step
was to study the
efficacy of imatinib as adjuvant
(postoperative) treatment in
patients with surgically resectable
disease, particularly those
at high risk for recurrence because of
large tumor size or high
mitotic count. The ACOSOG first evaluated
the efficacy of 1
year of postoperative imatinib in a single-
arm phase II trial with
106 patients with high-risk GIST and
compared the results with
historical controls. Adjuvant treatment
with imatinib for GIST
patients was then examined in two key
trials. In the ACOSOG
randomized, double-blind, phase III Z9001
study,207 treatment
with 12 months of imatinib was compared
with placebo, following
complete resection of a primary GIST >3 cm.
Primary
and secondary endpoints were recurrence-
free survival (RFS)
and overall survival (OS), respectively.
Results showed a significant benefit in RFS,
but not OS, with 12 months of imatinib.
Based on these results, imatinib for the
adjuvant treatment
of adult patients following resection of
KIT-positive GIST was
approved by the U.S. Food and Drug
Administration in 2008
and by the European Medical Agency (EMA) in
2009.
A more recent study conducted by the
Scandinavian Sarcoma
Group (SSG) and the Sarcoma Group of the
Arbeitsgemeinschaft
Internistische Onkologie (AIO; SSGXVIII/AIO
trial) compared 12 versus 36 months of
adjuvant imatinib 400
mg/d in patients with GIST at high risk of
recurrence (defined
as a GIST tumor diameter >10 cm, or mitotic
count >10 per
50 high-powered fields, or tumor diameter
>5 cm and mitotic
count >5 per 50 high-power fields, or tumor
rupture).208 Results
showed that both RFS and OS significantly
improved with 36
months of imatinib: the 5-year RFS rates
for patients receiving
36 versus 12 months of imatinib were 65.6%
versus 47.9%,
respectively, and the 5-year OS rates were
92% versus 81.7%,
respectively.
The NCCN and the European Society of
Medical Oncology
now recommend that imatinib be considered
for patients
at intermediate or high risk of recurrence
after resection and
that at least 36 months of adjuvant
imatinib be considered for
patients at high risk of recurrence. 221
Further, both the Food and
Drug Administration and EMA updated the
label, extending the
duration of adjuvant therapy to at least 36
months in patients at
high risk of recurrence.
Another study, sponsored by the EORTC
(EORTC-
62024), compared imatinib for 24 months
versus no treatment.
209 Results will be soon communicated.
Whether longer treatment durations may be
of further
benefit is still an open question, which
will be addressed by
future studies. However, paralleling what
is commonly done
in the metastatic setting, many
investigators believe that even
adjuvant imatinib should become a chronic
therapy. While
moving toward more prolonged adjuvant
treatment durations,
it is all the more essential to identify
the appropriate patients to
treat to avoid the burden of adverse events
or increased financial
liability for patients who will not derive
therapeutic benefit
from imatinib. Risk stratification based on
patients’ risk of
recurrence is a key component to optimizing
adjuvant treatment.
The most practical stratification scheme to
use for making a
decision for adjuvant therapy is the
modified National Institutes
of Health consensus criteria.222 High-risk
GIST patients,
whose tumor harbors a sensitive genotype,
should be treated by
adjuvant imatinib, because they have a poor
prognosis. On the
contrary, neither low-risk nor
intermediate-risk GIST patients
need adjuvant therapy, even if their tumor
carries a sensitive
genotype. In fact, evidence has been
provided that the outcome
of these patients with intermediate- or
low-risk GIST is good.
When using other risk stratification
schemes, such as the Armed
Forces Institute of Pathology table,
Memorial Sloan-Kettering
Cancer Center nomogram, or the heat
map,197,223,224 there is a
consensus to treat all patients having 30%
or higher risk of
recurrence, if their tumor carries a
sensitive genotype. There is
also a consensus not to treat patients
having 10% or less risk of
recurrence, even if their tumor carries a
sensitive genotype. All
patients having a risk between 10% and 30%
should be evaluated
on a case-by-case basis, and
advantages/disadvantages of
treatment should be made clear and
discussed with the patient.
Whenever a decision for adjuvant therapy is
made, treatment
duration of at least 36 months should be
considered independently
from the risk.
Beside the risk of recurrence, the other
important factor
to consider is the tumor genotype. In other
words, as found in
both the metastatic and adjuvant settings,
GIST tumors with
KIT exon 11 and PDGFRA non-D842V mutations
are sensitive
to imatinib. Patients with these mutations
are suitable for
adjuvant imatinib if the risk determined by
stratification tools
is significant. Patients with KIT exon 9
mutations should also
be treated; a higher dose (800 mg/d) may be
more appropriate
but remains to be studied clinically.
Patients with PDGFRA
D842V–mutated tumors should not be treated
with adjuvant
imatinib, nor should patients with KIT and
PDGFRA wildtype
tumors associated with neurofibromatosis
type 1 or the
pediatric GIST/Carney-Stratakis syndromes,
whatever the risk.
Patients with sporadic wild-type GIST could
be treated on an
individual basis.
Preoperative Imatinib
Patients with marginally resectable GIST or
at significant risk
for operative morbidity should be
considered for preoperative
imatinib with close monitoring. Since the
optimal duration of
preoperative therapy is unknown, imatinib
should be continued
until maximal response is achieved or until
there is evidence
of progression.225 Preoperative imatinib can
be stopped immediately
before surgery and resumed when oral
medications are
restarted.
Preoperative imatinib in patients with
primary GIST or
resectable metastatic GIST has been
evaluated in the context
of two randomized phase II studies. The
Radiation Treatment
Oncology Group (RTOG 0132/ACRIN 6665)
evaluated the
efficacy of preoperative imatinib (600
mg/d) for 8 to 10 weeks
before surgery and 24 months after surgery
in patients with primary
(n = 30) or potentially resectable recurrent
or metastatic
(n = 22) tumors.226 Primarily stable disease
was noted during
imatinib treatment, and the 2-year
progression-free survival rates
were 83% for primary GIST and 77% for
recurrent or metastatic
GIST.227 In another study, 19 patients
undergoing surgical resection
at a single institution were randomized to
preoperative imatinib
(600 mg/d) for 3, 5, or 7 days followed by
surgical resection
and postoperative imatinib for 24 months.
The response rate
assessed using FDG-PET was 69%, and the
median disease-free
survival time following treatment with
surgery and imatinib was
46 months.228
Similar results were observed in a
prospective series of
patients treated at a major institution. 229
All these studies show that neoadjuvant
treatment is feasible,
but to maximize the benefit of preoperative
therapy, the
following factors need to be considered.
First, the patient should
in principle have a favorable mutational
status; otherwise, the
treatment would be in vane, allowing the
tumor to continue
growing. Fortunately. the majority of GISTs
will respond, but
it should not be forgotten that, especially
in gastric location, the
amount of insensitive mutations in the
localized setting is less
uncommon than what has been previously
reported.230 However,
we do not absolutely need to know the
mutational status
in advance, but should be aware that
mutation is an issue. Alternatively,
if mutation status is not determined prior
to treatment,
we may also check response very early,
either by CT, PET,
or contrast-enhanced ultrasound. If a
radiographic response is
detected within a month, then the mutation
status is likely favorable,
and the treatment could be continued
without necessarily
pursuing mutation testing. If not, then
mutation status should be
investigated before continuing the
treatment.