Imatinib For Gastrointestinal Stromal Tumors

11/24/21, 4:19 AM Adjuvant and neoadjuvant imatinib for gastrointestinal stromal tumors - UpToDate
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Adjuvant and neoadjuvant imatinib for gastrointestinal

stromal tumors
Authors: Jeffrey Morgan, MD, Chandrajit P Raut, MD, MSc, FACS
Section Editors: Kenneth K Tanabe, MD, Robert Maki, MD, PhD
Deputy Editor: Sonali Shah, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2021. | This topic last updated: Mar 25, 2021.
INTRODUCTION
Stromal or mesenchymal neoplasms affecting the gastrointestinal (GI) tract are divided into two
groups. The most common group is collectively referred to as gastrointestinal stromal tumors
(GISTs). They are most often located in the stomach and proximal small intestine, but can occur
in any portion of the alimentary tract and occasionally in the omentum, mesentery, and
peritoneum. The far less common group is comprised of a spectrum of tumors that are identical
to those that might arise in the soft tissues throughout the rest of the body (ie, lipomas,
liposarcomas, leiomyomas, true leiomyosarcomas, desmoid tumors, schwannomas, and
peripheral nerve sheath tumors). (See "Clinical presentation, histopathology, diagnostic
evaluation, and staging of soft tissue sarcoma".)
Approximately 80 percent of GISTs have mutations in the KIT protooncogene that lead to
constitutive activation of KIT, a receptor tyrosine kinase (RTK). A subset of GISTs lacking KIT gene
mutations harbors activating mutations in a related RTK, platelet-derived growth factor
receptor-alpha (PDGFRA). Approximately 12 percent of GISTs have no mutation in either KIT or
PDGFRA ("wild type" for these two kinase genes), and the majority of these have mutations or
epigenetic silencing of succinate dehydrogenase (SDH) subunits leading to the SDH-deficient
GIST. (See "Clinical presentation, diagnosis, and prognosis of gastrointestinal stromal tumors",
section on 'Pathogenesis'.)
These findings led to the development of effective systemic therapies in the form of small
molecule tyrosine kinase inhibitors (TKIs), of which the prototype is imatinib. These agents block
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signaling via KIT and PDGFRA by binding to the adenosine triphosphate-binding pocket
required for phosphorylation and activation of the receptor. The end result is inhibition of tumor
proliferation. The success of these agents in advanced disease prompted interest in their use in
the preoperative setting as induction therapy for patients with unresectable or borderline
resectable tumors and as adjuvant treatment for patients at high risk of recurrence after
complete resection of a primary GIST tumor. (See "Tyrosine kinase inhibitor therapy for
advanced gastrointestinal stromal tumors".)
This topic review will cover the perioperative use of imatinib for localized GIST tumors. The
epidemiology, classification, molecular pathogenesis, diagnostic work-up, and surgical
treatment of localized GISTs and the use of TKIs in patients with unresectable or metastatic
disease are covered elsewhere. (See "Clinical presentation, diagnosis, and prognosis of
gastrointestinal stromal tumors" and "Local treatment for gastrointestinal stromal tumors,
leiomyomas, and leiomyosarcomas of the gastrointestinal tract" and "Tyrosine kinase inhibitor
therapy for advanced gastrointestinal stromal tumors".)
OVERVIEW OF APPROACH TO THE PATIENT
An approach to management of patients with apparently localized disease is outlined in the

algorithm ( algorithm 1), and general principles are summarized briefly below.
Apparently localized disease
● Surgery versus surveillance – All apparently localized gastrointestinal stromal tumors

(GISTs) ≥2 cm in size should be resected. However, there is no consensus on the
management of smaller tumors, and management must be individualized. Although small
gastric GISTs may be followed endoscopically until they grow or become symptomatic, the
optimal frequency of follow-up and specific risks of this strategy are uncertain. An
algorithmic approach to management of GISTs based upon size and endoscopic
ultrasound (EUS) appearance [1] has been adopted by the National Comprehensive Cancer
Network (NCCN) [2] for gastric GISTs but not those at other sites in the GI tract. We agree
with this approach. When endoscopic assessment is not possible, excision is the standard
approach. (See "Local treatment for gastrointestinal stromal tumors, leiomyomas, and
leiomyosarcomas of the gastrointestinal tract", section on 'GIST and leiomyoma'.)
● Initial surgery versus neoadjuvant imatinib – The goal of surgical treatment is

macroscopically complete resection, if possible. While surgical resection is the treatment of
choice for potentially resectable tumors, initial therapy with imatinib may be preferred if a
tumor is borderline resectable, locally advanced and unresectable but nonmetastatic, or a

potentially resectable primary tumor if a reduction in tumor size would significantly
decrease the morbidity of surgical resection (eg, a GIST arising in the esophagus,
esophagogastric junction, duodenum, or distal rectum). In such cases, a tumor biopsy
should be performed to confirm the diagnosis and establish tumor genotype:
• We do not administer neoadjuvant imatinib to patients who have a platelet-derived

growth factor receptor-alpha (PDGFRA) D842V mutation, or a succinate dehydrogenase
(SDH)-deficient or neurofibromatosis (NF)-related GIST, and instead proceed directly to
surgery. (See 'ACOSOG Z9001' below and "Clinical presentation, diagnosis, and
prognosis of gastrointestinal stromal tumors", section on 'KIT/PDGFRA wild-type
GISTs'.)
• For others, the usual dose of imatinib is 400 mg daily. For the rare patient who is being
considered for neoadjuvant therapy and whose tumor harbors an exon 9 KIT mutation
(the majority of these mutations are in small bowel primaries, which are uncommonly
treated neoadjuvantly), which confers relative resistance to imatinib, an initial dose of
800 mg per day may be preferred, if tolerated.
The optimal duration of neoadjuvant imatinib is not established. In most cases, patients
are treated to "maximal response," usually not exceeding 10 to 12 months. (See
'Duration of therapy' below.)
● Adjuvant imatinib – For patients who undergo initial resection, rather than neoadjuvant
imatinib, the decision to pursue adjuvant imatinib depends on an estimation of the risk of
recurrence, which is typically based upon tumor size, mitotic index, location within the GI
tract, and the presence or absence of tumor rupture (either spontaneously or during
surgery) ( table 1). Regardless of the tool used for risk stratification, we reserve adjuvant
imatinib for those patients who meet criteria for "high-risk" and who have an estimated
risk of recurrence that is >30 to 50 percent. (See 'Estimation of recurrence risk' below.)
We perform molecular analysis on all tumors if adjuvant imatinib is being considered. For
patients with a PDGFRA D842V mutation, or an SDH-deficient or NF-related GIST, we do not
prescribe adjuvant imatinib. For other patients, the usual dose of imatinib for adjuvant
therapy is 400 mg daily. Based upon an analysis of data from the American College of
Surgeons Oncology Group (ACOSOG) Z9001 trial, for patients who harbor an exon 9 KIT
mutation, which confers relative resistance to adjuvant imatinib, a dose of 800 mg per day
may be preferred, if tolerated. (See 'ACOSOG Z9001' below.)
Based upon the results of the Scandinavian Sarcoma Group (SSG) XVIII adjuvant trial,
imatinib treatment for 36 months or longer is preferred over shorter treatment durations.
The optimal duration of adjuvant treatment is not yet established. (See 'SSG XVIII trial'
below.)
For all patients undergoing neoadjuvant imatinib, imatinib should be continued

postoperatively to complete a total of at least three years of imatinib therapy (combined
preoperative and postoperative). Use of preoperative imatinib prohibits accurate
assessment of recurrence risk, based upon analysis of the surgical resection specimen.
(See 'Postoperative management' below.)
Metastatic disease
● Initial imatinib – Most patients with metastatic disease (even potentially resectable
disease) are treated with imatinib rather than initial attempted resection. Patients who
present with metastatic disease should undergo an initial biopsy to confirm the diagnosis
and to establish the tumor genotype. (See "Tyrosine kinase inhibitor therapy for advanced
gastrointestinal stromal tumors".)
● Indications for surgery – There is no consensus as to the indications for surgical

management in patients with metastatic GIST. Surgery may be considered in patients with
potentially resectable metastases who do not develop generalized disease progression
while receiving therapy with a tyrosine kinase inhibitor (TKI) and for the rare patient who
becomes resectable after receiving neoadjuvant imatinib for initially unresectable
metastatic disease at a limited number of sites. (See "Local treatment for gastrointestinal
stromal tumors, leiomyomas, and leiomyosarcomas of the gastrointestinal tract", section
on 'Role of surgery in patients with metastatic disease' and "Tyrosine kinase inhibitor
therapy for advanced gastrointestinal stromal tumors", section on 'Subsequent
management of imatinib-refractory disease'.)
Resection may also benefit selected patients with more advanced disease who are
responding to imatinib or sunitinib (ie, those who have a partial response, stable disease,
or focal progression, and possibly, those with isolated sites of progression). The purpose of
resection in this setting is to delay or prevent the development of resistant clones by
reducing tumor burden. Surgery has little to offer those who experience generalized
disease progression while receiving a TKI, and it should not be attempted.
All patients should resume therapy with a TKI for an indefinite period of time after
resection of metastatic disease.
ADJUVANT THERAPY
Based upon data from the Scandinavian Sarcoma Group (SSG) XVIII trial, we recommend
adjuvant treatment with a tyrosine kinase inhibitor (TKI; imatinib 400 mg daily) for a minimum
of three years in patients who have a completely resected, primary, high-risk gastrointestinal
stromal tumor (GIST). The optimal duration (three years versus longer than three years) is not
yet established. (See 'SSG XVIII trial' below.)
The optimal selection of patients who are at sufficiently high risk for recurrence to warrant
adjuvant imatinib is not established. Several risk stratification tools are available, based upon
tumor size, mitotic rate, location, and in some cases, the presence or absence of tumor rupture
and molecular genotype. However, particularly for tools, such as nomograms, that quantify the
risk of disease recurrence after complete resection as a continuous variable, it is not clear what
cutoff for disease recurrence should be used to select patients for imatinib. Thus, each case
must be approached individually, balancing the estimated likelihood of a disease recurrence
(based upon anatomic site, size, mitotic rate, and presence or absence of tumor rupture (
table 1)) with the risks of therapy. Adjuvant therapy is appropriate for all patients who fall
into a "high-risk" category, regardless of the risk stratification model used. (See 'Estimation of
recurrence risk' below.)
Some centers, including that of the authors, routinely genotype all patients with GIST who are
being considered for adjuvant imatinib. Adjuvant imatinib is not indicated in patients with
succinate dehydrogenase (SDH)-deficient GIST, neurofibromatosis (NF)-related GIST, and
PDGFRA D842V GIST. For patients whose tumors harbor a KIT exon 9 mutation, higher-dose
imatinib (800 rather than 400 mg daily) is a reasonable option, if tolerated, although there are
no prospective data upon which to base a recommendation either for or against this practice.
The standard of care for patients with a primary resectable GIST is surgery, aiming for a
macroscopically complete resection with negative microscopic margins. Complete resection is
possible in the majority of localized GISTs, but only approximately one-half remain recurrence-
free for five or more years with surgery alone. (See "Local treatment for gastrointestinal stromal
tumors, leiomyomas, and leiomyosarcomas of the gastrointestinal tract".)
The success of imatinib in the setting of advanced disease prompted interest in its use in the
adjuvant setting after complete resection of a primary tumor or metastatic disease. Based upon
data from the randomized American College of Surgeons Oncology Group (ACOSOG) Z9000 and
SSG XVIII trials, we recommend adjuvant treatment with imatinib for a minimum of three years
in patients who have a completely resected, primary, higher risk GIST.
Estimation of recurrence risk — Estimation of recurrence risk following resection of a GIST is

of paramount importance when selecting patients who could possibly benefit from adjuvant
imatinib. Several criteria have been proposed, originally to classify the malignant potential of a
GIST. Although the terms "benign" and "malignant" are no longer applied to GIST since all are
considered to have at least some potential to behave in a malignant fashion (either with
unresectable invasive recurrence or with metastatic disease), tumor size, mitotic rate, and site of
tumor origin have gained the greatest acceptance as being predictive of the risk of recurrence
and/or metastases [3]. (See "Clinical presentation, diagnosis, and prognosis of gastrointestinal
stromal tumors", section on 'Risk stratification and prognosis'.)
Risk stratification models, such as the original National Institutes of Health (NIH) consensus
criteria, have been proposed to distinguish prognosis in resected GIST ( table 2) [4]. In the
series of 289 patients used to construct this model, the cumulative five-year disease-specific
survival rates for GISTs classified as risk level I through IV were 100, 96, 67, and 25 percent,
respectively. The prognostic importance of mitotic rate, tumor size, and location was confirmed
in an analysis of the adjuvant imatinib trial ACOSOG Z9001 [5]. (See "Clinical presentation,
diagnosis, and prognosis of gastrointestinal stromal tumors", section on 'Risk stratification and
prognosis' and 'ACOSOG Z9001' below and "Clinical presentation, diagnosis, and prognosis of
gastrointestinal stromal tumors", section on 'Other risk factors'.)
Models such as these do not take into account the location of the primary GIST lesion. In
general, tumors arising from the small bowel, colon, rectum, or mesentery are associated with
less favorable outcomes than those arising from the stomach [6-8]. Other risk prediction models
have taken site of GIST origin into account ( table 3). As an example, largely based upon these
data from the Armed Forces Institute of Pathology (AFIP), which represent the largest published
experience with GISTs diagnosed and treated in the modern era for which long-term clinical
follow-up is available, a tumor, node, metastasis (TNM) staging system for GIST was developed
by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer
Control (UICC) and published in 2010 [9]. The most recent 2017 version is depicted in the table (
table 4) [10]. Although the T and N designations are the same for all disease sites, there are
separate stage groupings for gastric/omental and small
bowel/esophageal/colorectal/mesenteric and peritoneal primaries. Rates of disease progression
for gastric, small bowel, and rectal GISTs, stratified by stage at diagnosis, are presented in the
tables ( table 5 and table 6 and table 7) [6]. (See "Clinical presentation, diagnosis, and
prognosis of gastrointestinal stromal tumors", section on 'Tumor size and mitotic rate'.)
Although not included in the TNM staging system, tumor rupture [11,12] and incomplete
resection are also independent risk factors that negatively impact disease-free survival. A
modification of the NIH consensus criteria for risk stratification has been proposed that
incorporates both site and tumor rupture as prognostic variables [13]. (See "Clinical
presentation, diagnosis, and prognosis of gastrointestinal stromal tumors", section on 'Other
risk factors'.)
As an alternative to the risk classification systems that stratify patients into discrete categories,
others have quantified the risk of disease recurrence after complete resection as a continuous
variable through the use of a GIST tumor nomogram [14]. Different nomograms have been
developed by others [15,16].
The goal of all risk stratification schemes is to identify those patients who are at the highest (or
lowest) risk for recurrence so that management (in particular, the use of adjuvant imatinib) can
be individualized. However, there is no clear consensus from expert groups as to what cutoff
might constitute the lowest "acceptable" level of risk for metastasis or recurrence that would
justify the use of adjuvant imatinib. Furthermore, it is not clear that any one prognostication
tool outperforms the others [11,17]. (See 'Patient selection' below.)
This issue was addressed in an analysis of data from 10 different population-based published
series totaling 2560 patients with completely resected GIST, none of whom received adjuvant
imatinib [11]. Tumors were classified according to the NIH consensus criteria ( table 2) [4], a
modification of the NIH consensus criteria ( table 1) that includes site as well as tumor
rupture [13], and the AFIP criteria ( table 3) [6]. Large tumor size, high mitotic counts, non-
gastric location, presence of rupture, and male sex were all independent adverse prognostic
factors. Most recurrences occurred within the first five years of follow-up, and most patients
were cured by surgery alone (estimated 5-, 10-, and 15-year relapse-free survival [RFS] rates 71,
63, and 60 percent, respectively).
A comparison of the NIH, modified NIH, and AFIP criteria showed that all risk stratification
schemes appropriately predicted RFS and identified high-risk patients. The proposed modified
NIH criteria ( table 1) [13] were best at identifying a single subgroup of patients at high-risk of
recurrence [11]. With all of the different classification schemes, those patients who were
identified as intermediate-risk had a clinical course that was similar to that of the low-risk
group, suggesting that only the high-risk patients would likely benefit from adjuvant therapy.
These investigators also developed a novel risk stratification scheme in which tumor size and
mitotic counts were assessed as continuous non-linear variables; novel prognostic contour
maps were generated based upon these data plus site and tumor rupture. These maps were
better than conventional models at predicting 10-year risk for GIST recurrence and would be
particularly useful for discussing individual risk with patients as they are graphic and easy to
explain.
Whether the results of molecular testing should also be integrated into risk stratification
schemes is unclear. There has been relatively little work to make predictions of risk based on
genotypic subsets of primary resected GIST, although there are data to support the fact that
certain genotypes (such as KIT wild-type GISTs that are SDH-deficient or NF-related, or platelet-
derived growth factor receptor-alpha [PDGFRA] D842V-mutant tumors) are less aggressive with a
lower risk of recurrence or metastasis following primary resection than are other molecular
subtypes [18]. Furthermore, there are no data demonstrating the benefit of adjuvant imatinib in
these subtypes nor basic scientific rationale for antitumor activity. (See 'Impact of molecular
subtypes' below.)
Benefit of imatinib
Phase III trials — At least three phase III trials have evaluated the benefit of adjuvant
imatinib; only two (ACOSOG Z9001 and European Organisation for Research and Treatment of
Cancer [EORTC] 62024) had a no-treatment control arm.
ACOSOG Z9001 — Benefit for imatinib compared with surgery alone was shown in a phase
III, double-blind, multicenter ACOSOG Z9001 trial [19]. In this trial, 713 adults with a completely
resected primary gastrointestinal GIST at least 3 cm in maximal diameter and
immunohistochemically positive for KIT protein were randomly assigned to one year of adjuvant
imatinib (400 mg daily) or placebo. The primary endpoint was RFS.
The trial was stopped early when planned interim analysis disclosed that significantly fewer
patients in the treated group recurred. At a median follow-up of 20 months, 30 patients in the
imatinib group recurred or died versus 70 in the placebo group (8 versus 20 percent). The one-
year RFS rate was 98 versus 83 percent, favoring imatinib, with a hazard ratio (HR) for RFS of
0.35, 95% CI 0.22-0.53 [19]. Once discontinued, adjuvant imatinib appeared to provide one
additional year of protection, after which the rate of recurrence seemed to parallel that of the
control arm.
Subgroup analysis revealed that RFS was significantly longer with imatinib in all risk categories
(based upon size, mitotic rate, and location in the GI tract ( table 3)). As expected, in a later
analysis, the absolute benefit was greatest in those with high-risk disease (relapse rate 47
versus 19 percent for placebo and imatinib, respectively); for moderate-risk disease it was 14
versus 5 percent, respectively [20].
Imatinib was well tolerated by most patients. The drug was discontinued because of adverse
reactions in 16 versus 5 percent of the placebo group. The side effect profile overall was similar
to that observed in other clinical trials of imatinib. There were no significant cardiac toxic
effects. (See "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors"
and "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted

agents, and fluoropyrimidines", section on 'Agents targeting BCR-ABL1'.)
No overall survival (OS) differences have emerged in favor of imatinib in the ACOSOG Z9001
trial. Among the possible reasons are the short duration of follow-up, the limited number of
relapses, and the high degree of efficacy of imatinib in relapsed disease [21]. Furthermore, after
the study was unblinded, all patients randomized to placebo were allowed to crossover to active
treatment, thus obscuring any potential differences in OS between the groups.
Based upon these findings, imatinib was given accelerated approval in the United States in 2008
for adjuvant treatment of completely resected GISTs ≥3 cm in size, without definitive guidance
as to the optimal duration of treatment or which patients are most likely to benefit.
Although imatinib was clearly effective at reducing disease recurrence in this trial, key questions
remain. Two important issues are the value of longer duration imatinib following complete
resection and the definition of subsets of patients who derive the most benefit from adjuvant
imatinib. Patients with GIST of more than 3 cm are a highly heterogeneous population within
which the risk of relapse and death varies considerably. Furthermore, as noted above, the risk of
relapse is affected not only by size, but also by mitotic index, location of the primary site, and
molecular factors. (See 'Estimation of recurrence risk' above.)
Refining the indications for adjuvant treatment remains a big task for future studies.
EORTC 62024 — In another phase III trial (Intergroup EORTC 62024), two years of adjuvant
imatinib therapy improved recurrence free-survival in patients with intermediate- and high-risk
resected GIST and demonstrated a trend towards improved imatinib failure-free survival (IFFS)
in those with high-risk disease [22-24]. Although adjuvant imatinib did not confer an OS
advantage in this study, these data still indirectly support the use of three years of adjuvant
imatinib therapy, as suggested by the results of the SSG XVIII trial. (See 'SSG XVIII trial' below.)
In an open-label multicenter phase III trial, 908 patients with intermediate- or high-risk resected
GIST were randomly assigned to two years of imatinib or observation alone [22,24]. Disease risk
was defined according to the 2002 NIH classification ( table 8). The study also included
patients with R0 and R1 resections (which included tumor rupture) [23]. The primary endpoint
was originally OS, but was subsequently modified to IFFS (ie, the time to start of a new systemic
treatment with or without imatinib, or death from any cause) as a surrogate for OS.
At median follow-up of 9.1 years, compared with observation, imatinib demonstrated the
following results in the entire study population [24]:
● Similar IFFS (5-year IFFS 87 versus 83 percent, 10-year IFFS 75 versus 74 percent, HR 0.87,
95.7% CI 0.65-1.15) and OS (5-year OS 93 versus 92 percent, 10-year OS 80 versus 78
percent, HR 0.88, 95% CI 0.65-1.21).
● Improved RFS (5-year RFS 70 versus 63 percent; 10-year RFS 63 versus 61 percent, HR 0.71,
95% 0.57-0.89).
Among the 526 patients with high-risk disease, compared with observation, adjuvant imatinib
demonstrated a trend towards higher IFFS (10-year IFFS 69 versus 61 percent) and RFS (10-year
RFS 48 versus 43 percent).
SSG XVIII trial — The Scandinavian Sarcoma Group (SSG) XVIII trial compared 36 versus
12 months of adjuvant imatinib (400 mg daily) in 400 patients with high-risk resected GIST [25].
High-risk was defined according to the modified consensus criteria [26] as having at least one of
the following: tumor size >10 cm, mitotic count >10 per 50 high-power fields (HPF), tumor size
>5 cm and mitotic count >5, or tumor rupture. Approximately one-half of the enrolled patients
had gastric primary tumors.
At a median follow-up of 54 months, prolonged treatment was associated with a significant

improvement in RFS, the primary endpoint (five-year RFS 66 versus 48 percent, HR 0.46, 95% CI
0.32-0.65), as well as OS (92 versus 82 percent, HR 0.45, 95% CI 0.22-0.89) [25]. Benefits
persisted in a later report with a longer median follow-up of 119 months; patients assigned to
three years of imatinib continued to have significantly greater RFS at both five years (71 versus
53 percent) and 10 years (53 versus 42 percent) and OS at both five (92 versus 86 percent) and
10 years (79 versus 65 percent) [27]. Extending the duration of treatment to three years reduced
the number of deaths during the first 10 years of follow-up after surgery by approximately 50
percent.
Treatment-related adverse effects were more common with the longer duration of treatment,
including periorbital edema (74 versus 59 percent), diarrhea (54 versus 44 percent), and muscle
cramps (49 versus 31 percent) [25]. However, most were grade 1 or 2; the number of grade 3 or
4 events was similar in both groups. Nevertheless, twice as many patients discontinued imatinib
for reasons other than disease progression in the prolonged therapy group (26 versus 13
percent). Benefits persisted with longer follow-up.
These data established at least 36 months of adjuvant imatinib as a new standard for patients
with high-risk GIST, but questions remain as to whether treatment should be continued for
longer than three years. In both groups, within 6 to 12 months of discontinuing adjuvant
imatinib, rates of disease recurrence were similarly increased [25]. This finding raises questions
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as to whether recurrences are truly being prevented or just delayed. (See 'Optimal duration of
therapy' below.)
Furthermore, factors other than imatinib duration also influence prognosis. A multivariate
analysis of data from the SSG XVIII trial identified four factors other than imatinib duration as
being independently predictive of disease recurrence, including non-gastric location, high
mitotic count, tumor rupture, and large size [12]. Patients with the highest risk scores had a very
high risk of recurrence, despite adjuvant imatinib, and recurrences were frequent both during
adjuvant imatinib and after its completion.
Impact of molecular subtypes — A later exploratory analysis of data from the SSG
XVIII trial also suggests that mutational status influences the benefit from extended duration of
therapy, and that the duration of imatinib might modify the risk of GIST recurrence associated
with some high-risk KIT mutations [28]. Of the 400 enrolled patients, 341 had mutation analysis
for KIT and PDGFRA performed centrally using conventional sequencing, 274 had a KIT mutation,
43 had a PDGFRA mutation, and 24 had tumors that were wild type for these mutations. Patients
with KIT exon 11 deletion or insertion-deletion mutations had better RFS when allocated to
three years of therapy (five-year RFS 71 versus 41 percent), but no significant benefit from three
years of treatment was seen in any other mutational subgroup, likely reflecting primary
resistance to imatinib in these patients. (See 'Molecular subtypes and primary resistance'
below.)
KIT exon 11 deletion mutations, deletions that involved codons 557 and/or 558 (which are
associated with highly aggressive disease), and deletions that led to pTrp557_Lys558del were
associated with poor RFS in the one-year group but not in the three-year group. In addition, in
the subset with KIT exon 11 deletion mutations, tumors with mitotic counts that were higher
than the median had unfavorable RFS with one year of therapy but not in the three-year group.
(See "Clinical presentation, diagnosis, and prognosis of gastrointestinal stromal tumors",
section on 'Other risk factors'.)
Optimal duration of therapy — We recommend adjuvant imatinib for at least three years
after resection of a high-risk GIST. Whether treatment should be continued for longer than
three years is not known. Rates of disease recurrence have been high within 6 to 12 months of
discontinuing adjuvant imatinib for up to three years, and it is possible that imatinib is
maintaining tumor dormancy rather than eradicating microdeposits. Patients with high-risk
tumors might rationally elect to remain on what is for them a well-tolerated medication rather
than be subject to an increased rate of recurrence following discontinuation of the drug.
Preclinical data suggest that imatinib is not curative, inducing cellular quiescence but not death
[29]. As noted above in the SSG XVIII trial, in which patients were randomized to one versus
three years of adjuvant imatinib, rates of disease recurrence were similarly increased in both
groups within 6 to 12 months of discontinuing adjuvant imatinib [25]. Furthermore, although
OS was improved with three years, as compared to one year, of therapy, suggesting an actual
increase in cure, the survival gap became smaller with long-term follow-up [30]. These findings
raise questions as to whether recurrences are truly being prevented or just delayed, or stated a
different way, whether adjuvant imatinib is truly eliminating residual cancer cells and curing a
subset of patients or just stopping them from growing for a period of time [31].
One phase II trial studied five years of adjuvant imatinib in high-risk resected GIST (PERSIST 5);
high-risk disease was defined as a primary GIST of any site ≥2 cm with a mitotic count ≥5 per 50
HPF, or a non-gastric primary GIST ≥5 cm. All patients received imatinib 400 mg daily for five
years or until relapse, progression, or intolerance [32]. Among the 91 enrolled patients, the
median treatment duration was 55.1 months, and only 50 percent of patients completed a full
five years of treatment. The main reasons for stopping treatment early were patient choice and
adverse drug effects. The five-year estimate of RFS was 90 percent, while the OS rate at five
years was 95 percent. One patient recurred and died during adjuvant imatinib; this patient had
an imatinib-insensitive PDGFRA D842V mutation. Six other patients recurred after imatinib
discontinuation. These results suggest that five years of imatinib therapy is effective in
preventing recurrence in patients with sensitive mutations. However, nearly one-half of patients
discontinued study treatment before five years of therapy, and most recurrences occurred after
treatment discontinuation.
With longer-term follow-up, if the same steep recurrence rates after treatment discontinuation
are seen as were observed in the SSG XVIII trial, it will be likely that these patients had
micrometastases that were not eradicated but remained under control for many years through
drug therapy, and that even longer duration imatinib may be needed.
Given the lack of a control arm, the PERSIST-5 trial does not prove that therapy for longer than
three years will be beneficial. A randomized trial of three versus five years of adjuvant imatinib
is currently accruing patients.
Support for longer than three-year duration of therapy for patients with high-risk tumors is also
provided by a retrospective single-institution analysis of 234 patients who underwent complete
(R0) resection and were treated with adjuvant imatinib [33]. For the entire group, long-term
outcomes were significantly improved by longer duration of therapy. Five-year RFS rates for the
one-year, one-to-three-year, three-to-five-year, and more than five-year groups were 52, 72, 73,
and 93 percent, respectively, while the corresponding rates for five-year OS were 44, 82, 84, and
97 percent, respectively. Of the 190 patients who were classified as high risk according to the
2008 NIH risk classification scheme ( table 1), adjuvant treatment was continued for one, one
to three, three to five, and more than five years in 20, 33, 23, and 24 percent of cases,
respectively. The RFS rate of patients receiving imatinib for longer than five years was
significantly better than that of those receiving treatment for less than five years. In contrast,
among the 44 with intermediate-risk disease ( table 1), the differences in RFS for one year,
one to three years, and more than three years of therapy showed improvement, but the
differences were not statistically significant.
Imatinib dosing — The ACOSOG Z9001 trial tested only the 400 mg daily dose in the adjuvant
setting. In randomized trials of patients with advanced metastatic and/or unresectable GIST,
patients whose GIST harbored KIT exon 9 mutations exhibited improved outcomes with 800 mg
daily doses of imatinib compared with the standard 400 mg daily dosing. (See "Tyrosine kinase
inhibitor therapy for advanced gastrointestinal stromal tumors", section on 'Influence of
mutations on response to therapy'.)
Whether doses greater than 400 mg should be used in the adjuvant setting will require
prospective study. Until further information becomes available, some centers, including that of
the authors, routinely genotype all patients with GIST who are being considered for adjuvant
imatinib. The vast majority of the exon 9 mutants come from small bowel GISTs, and we discuss
with such patients the option to take 800 mg of imatinib daily rather than 400 mg daily, if
tolerated.
Patient selection — The optimal selection of patients who are at sufficiently high risk for
recurrence to warrant adjuvant imatinib is not established. Although risk stratification tools are
available based upon tumor size, mitotic rate, location, and in some cases, the presence or
absence of tumor rupture, it is not clear what cutoff for disease recurrence should be used to
select patients for imatinib. Thus, each case must be approached individually, balancing the
estimated likelihood of a disease recurrence (based upon anatomic site, size, mitotic rate, and
mutation type, if available) with the risks of therapy. (See 'Estimation of recurrence risk' above.)
Several risk stratification schema are available ( table 3 and table 1). We recommend
adjuvant therapy to all patients who fall into a "high-risk" category, regardless of the risk
stratification model used.
There is no consensus as to what cutoff for disease recurrence should be used to select patients
for imatinib, and practice is variable. The following information informs this debate:
● In 2008, the US Food and Drug Administration (FDA) granted accelerated approval for
imatinib in the adjuvant setting for completely resected primary GIST ≥3 cm, without
indicating the optimal length of therapy; labeling was updated in January 2012 to include
the significantly prolonged survival seen with three years of therapy as compared with one
year of adjuvant imatinib. However, whether all patients in this broad category have a high
enough risk of recurrence to warrant adjuvant therapy is not established. The European
Medicines Agency (EMA) has extended the licensed indications of imatinib to include
adjuvant treatment of adult patients who are at "significant risk of relapse" after resection
of a KIT-positive GIST but does not define these subsets further.
● The SSG XVIII trial defined high-risk as follows: a ruptured GIST, tumor size >10 cm, mitotic
rate >10 per 50 HPF, or tumor size >5 cm and mitotic count >5 [25]. The risk of recurrence
in these groups is approximately one-third or higher [34-36]. (See 'SSG XVIII trial' above.)
● Consensus-based clinical practice guidelines from the National Comprehensive Cancer

Network (NCCN) [2] suggest adjuvant imatinib for at least 36 months for patients with a
high-risk GIST (tumor >5 cm in size with high mitotic rate [>5 mitoses per 50 HPF] or a risk
of recurrence that is >50 percent after surgery).
● Risk stratification tools are available based upon tumor size, mitotic rate, location, and
tumor rupture, and they all define a "high-risk" subset. The 2012 analysis of Joensuu,
described above, found that all risk classification schema identified a group of patients
with high-risk disease who had a significantly worse RFS than did those with intermediate-
risk of low-risk disease [13]. The proposed modified NIH criteria ( table 1) [13] were best
at identifying a single subgroup of patients at high risk of recurrence. (See 'Estimation of
recurrence risk' above.)
Patients who were identified as intermediate-risk had a clinical course that was similar to
the low-risk group, suggesting that only the high-risk patients would likely benefit from
adjuvant therapy. Although the concept that only high-risk patients derive benefit from
adjuvant imatinib has not been prospectively validated, based upon these data, it would
seem reasonable to offer adjuvant therapy to all patients who fall into a "high-risk"
category, regardless of the risk stratification model used.
Molecular subtypes and primary resistance — We perform molecular analysis on all

tumors if adjuvant imatinib is being considered. There are certain mutations that are associated
with primary resistance to imatinib, and we do not offer adjuvant therapy to individuals who
harbor a KIT mutation-negative tumor with a D842V mutation in the PDGFRA gene, an SDH-
deficient GIST, or an NF-related GIST. This approach is supported by guidelines from the
European Society for Medical Oncology (ESMO) [37]. For individuals whose tumors contain a KIT
exon 9 mutations (which is associated with partial imatinib resistance, which may be overcome
with higher-dose therapy), higher dose imatinib therapy (800 rather than 400 mg daily) may be
preferred, if tolerated ( algorithm 1).
Some molecular features (ie, KIT exon 9 mutations, PDGFRA exon 18 D842V mutations, lack of
detectable KIT or PDGFRA mutations [previously referred to as "wild-type" GISTs, now known
most often to represent the biologically unique SDH-deficient subtype of GIST]) have been
associated with inferior response to imatinib in the setting of advanced disease [5]. (See "Clinical
presentation, diagnosis, and prognosis of gastrointestinal stromal tumors", section on
'KIT/PDGFRA wild-type GISTs' and "Tyrosine kinase inhibitor therapy for advanced
gastrointestinal stromal tumors", section on 'Influence of mutations on response to therapy'.)
At least some data are available to suggest that this primary resistance to imatinib seen with
certain mutations also applies to the adjuvant setting:
● In an analysis of molecular features associated with treatment benefit in the ACOSOG

Z9001 study, described above, adjuvant imatinib was associated with higher RFS in
patients with a KIT exon 11 deletion of any type but not a KIT exon 11 insertion or point
mutation, KIT exon 9 mutation, PDGFRA mutation, or wild-type tumor [5]. (See 'ACOSOG
Z9001' above.)
However, the patient groups were very small, especially those with "KIT/PDGFRA wild-type"
tumors (nine in the placebo, six in the imatinib group) and exon 9 mutations (seven
placebo, four imatinib). Because of these small numbers, the data cannot be considered
definitive, but the therapeutic impact of adjuvant imatinib in these subsets certainly seems
much smaller. As a result, whether patients with KIT exon 9 mutations, PDGFRA exon 18
D842V mutations, or "wild-type" GISTs should be identified prospectively and specifically
counselled not to receive standard-dose adjuvant imatinib is controversial. At several
institutions, including some of the authors', patients with D842V mutations, or SDH-
deficient or NF-related GISTs are not considered for adjuvant imatinib, while a higher
imatinib dose (ie, 800 mg rather than 400 mg daily) may be considered for those with an
exon 9 KIT mutation, based upon data derived from patients with more advanced disease.
(See 'Imatinib dose' below and "Tyrosine kinase inhibitor therapy for advanced
gastrointestinal stromal tumors", section on 'Influence of mutations on response to
therapy'.)
● For patients with a PDGFRA D842V mutation or a KIT/PDGFRA wild-type GIST (usually SDH-
deficient or NF-related GIST), the evidence from the SSG XVIII trial also suggests no benefit
from adjuvant imatinib [25].
● In another report of 95 patients with a KIT/PDGFRA wild-type GIST (84 of which were SDH-
deficient), only 1 of 49 patients treated with imatinib had a partial response [38].
NCCN [2] recommendations do not specifically exclude patients with these or any other
molecular subset from adjuvant therapy with imatinib. However, we discourage the use of
adjuvant imatinib in patients with a PDGFRA D842V mutation or a KIT/PDGFRA wild-type GIST
(often SDH-deficient or NF1-related).
Among patients with a KIT mutation, the type of mutation correlates with tumor response to
imatinib. Based upon an analysis of data from the ACOSOG Z9001 trial, for patients who harbor
an exon 9 KIT mutation, which confers relative resistance to adjuvant imatinib, a dose of
imatinib 800 mg per day may be preferred over the standard dose of 400 mg daily, if tolerated.
NEOADJUVANT THERAPY
There is no consensus as to the indications for neoadjuvant imatinib. For patients with
apparently localized tumors with a KIT or platelet-derived growth factor receptor-alpha (PDGFRA)
D842V mutation or those with wild-type tumors (neither KIT nor PDGFRA mutations), we suggest
initial treatment with imatinib for those with locally advanced, unresectable or borderline
resectable tumors; for potentially resectable primary tumors, if a reduction in tumor size would
significantly decrease the morbidity of surgical resection; and for most patients with a rectal
gastrointestinal stromal tumor (GIST), unless the tumor is small and sphincter-preserving
surgery is possible upfront. If possible, such patients should be enrolled in a clinical trial. For
patients with a PDGFRA D842V mutation or those with wild-type tumors (neither KIT nor PDGFRA
mutations), we do not use neoadjuvant imatinib and, instead, proceed directly to surgery.
Surgery is the only potentially curative option for GISTs. Given the high response rates to
imatinib (and the potential for complete pathologic responses [39]) in the setting of advanced
disease, there are several clinical scenarios in which preoperative (neoadjuvant) imatinib could
be considered. This includes an unresectable or borderline resectable primary tumor, a
potentially resectable tumor that requires extensive organ disruption, a local recurrence of
locally advanced disease, or a limited amount of potentially resectable metastatic disease. In all
cases, the goal of treatment is a reduction in tumor size that may facilitate complete surgical
resection and/or increase the likelihood of organ preservation. (See "Tyrosine kinase inhibitor
therapy for advanced gastrointestinal stromal tumors", section on 'Initial approach based on
mutation status'.)
Role of genotyping — Tumor genotyping should be performed for all patients being

considered for adjuvant or neoadjuvant imatinib. If an exon 9 KIT mutation is identified in a rare
patient being considered for neoadjuvant imatinib, the option of a higher daily dose (800 mg
per day) should be discussed with patients, although there are no prospective data upon which
to base a recommendation either for or against this practice. Most of these patients will have a
small bowel primary tumor and will be referred for upfront surgery rather than neoadjuvant
imatinib. For patients with a PDGFRA D842V mutation or those with wild-type tumors (neither KIT
nor PDGFRA mutations), we do not use neoadjuvant imatinib and, instead, proceed directly to
surgery. If routine genotyping is not practiced, it is wise to check for signs of primary resistance
to neoadjuvant imatinib using computed tomography (CT), positron emission tomography (PET),
or contrast-enhanced ultrasound.
Patients with primary or recurrent localized disease — There is no consensus as to the

indications for neoadjuvant imatinib among patients with apparently localized GIST. We suggest
initial treatment with imatinib for patients with locally advanced, unresectable or borderline
resectable tumors, and for potentially resectable primary tumors if a reduction in tumor size
would significantly decrease the morbidity of surgical resection. We also suggest neoadjuvant
imatinib, rather than initial surgery, for most patients with a localized rectal GIST.
For patients who are bleeding, the approach taken depends on the severity of the bleed. If the
bleeding is brisk and life threatening, the patient needs surgery. However, if the patient is too
frail to survive surgery, treatment with imatinib can itself resolve the bleed. For patients with
low-grade chronic bleeding, neoadjuvant imatinib is even more likely to be helpful.
An important point is that preoperative imatinib prohibits accurate assessment of recurrence

risk based upon analysis of the surgical resection specimen. As a result, for patients undergoing
neoadjuvant imatinib, we continue imatinib postoperatively to complete a total of three years of
imatinib therapy (combined preoperative and postoperative).
Data supporting benefit of neoadjuvant imatinib are available from several case reports and
small retrospective series, most of which include a mix of patients with borderline resectable
and unresectable primary disease, as well as metastatic and locally recurrent disease that is
potentially amenable to gross resection. In addition, a single phase II United States Intergroup
trial of neoadjuvant imatinib has been completed, and preliminary results are available [40];
results are also available from a multi-institutional, Asian phase II trial of neoadjuvant therapy in
large stomach tumors [41].
RTOG 0132/ACRIN 6665 trial — The multicenter Radiation Therapy Oncology Group (RTOG)
0132/American College of Radiology Imaging Network (ACRIN) 6665 trial was a prospective
phase II trial in which 63 patients with KIT-positive GIST, and either a resectable primary ≥5 cm
or resectable recurrent disease received preoperative imatinib 600 mg daily for 8 to 12 weeks
[40]. Following surgery, all patients received at least two additional years of postoperative
imatinib, while those with metastatic disease were treated until disease progression.
Thirty of the 52 analyzable patients had locally advanced primaries, and 22 had locally recurrent
or potentially resectable metastatic disease. Among the patients with localized primary disease,
only two (7 percent) had an objective response to preoperative imatinib (as assessed by CT
scan), but stable disease was achieved in 25 (83 percent). The corresponding values for the
group with metastatic disease were 5 and 91 percent, respectively.
In the latest update, at a median follow-up of 5.1 years, the estimated five-year progression-free
and disease-specific survival rates for patients presenting with localized primary disease were
57 and 77 percent, respectively; the corresponding rates were 30 and 68 percent in those with
recurrent or metastatic disease [42]. (See 'Recommendations of expert groups' below.)
While this trial confirmed the safety of neoadjuvant imatinib, it tested a relatively brief period of
preoperative treatment. The available data suggest that the earliest time to a partial response in
patients treated with neoadjuvant imatinib is 16 weeks [43] and that maximal radiographic
response to imatinib generally occurs after three to nine months of treatment. (See 'Response
assessment' below and "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal
tumors".)
Asian trial in large gastric GIST — A multinational phase II trial enrolled 56 patients with
large (≥10 cm) gastric GIST and administered six to nine months of neoadjuvant imatinib (400
mg daily) [41]. Overall, 53 were evaluable, and 46 completed six or more months of therapy. Of
the patients who received at least six months of neoadjuvant imatinib, the earliest point at
which maximal reduction of tumor size was observed was four weeks in one case (2 percent), 12
weeks in nine cases (20 percent), 24 weeks in 29 cases (63 percent), and 36 weeks in seven cases
(15 percent). The objective response rate by Response Evaluation Criteria In Solid Tumors
(RECIST) was 62 percent, and the complete (R0) resection rate was 91 percent (48 of 53). Of the
48 patients undergoing R0 resection, preservation of at least one-half of the stomach was
achieved in 42. After R0 resection, all patients received imatinib at the same dose as was used
preoperatively for at least one year. At a median follow-up of 32 months, the two-year overall
and progression-free survival rates were 98 and 89 percent, respectively.
Retrospective series — Data from multiple retrospective series also support the benefit of
initial imatinib therapy in patients with locally advanced GISTs [44-50]. The largest experience
consisted of 161 patients who underwent surgery after imatinib; the majority of primary tumors
were in the stomach (55 percent), followed by the rectum (20 percent), duodenum (10 percent),
ileum/jejunum (10 percent), and esophagus (3 percent) [50]. The response to preoperative
imatinib was partial response in 129 (80 percent) and stable disease in 30 (19 percent); only two
patients had disease progression during neoadjuvant therapy. A complete (R0) resection was
possible after a median 40 weeks of imatinib (range 6 to 190). At a median follow-up of 46
months, the five-year disease-specific survival and disease-free survival rates were 95 and 65
percent, respectively. Only 56 percent of patients continued imatinib after resection (for a
median duration of 19 months [range 12 to 76]), and five-year disease-free survival was higher
in this cohort (72 versus 57 percent). During follow-up, there were 37 recurrences, only three of
which were local; the remainder were intraperitoneal dissemination or liver metastases.
Rectal GISTs — Neoadjuvant imatinib might be of particular benefit for rectal GISTs, which
can be large, bulky tumors and require extensive surgery to achieve a surgical complete
resection [51]. The benefits of perioperative imatinib in patients with a rectal GIST can be
illustrated by several retrospective reports [52-56]; two of the largest are described in detail:
● One series included 47 patients with a localized primary rectal GIST treated at a single
center from 1982 to 2016 and stratified by treatment before and after the year 2000, when
imatinib became available [54]. In the imatinib era, 24 of the 30 resected patients had
received perioperative imatinib. Among the 34 high-risk patients (ie, tumor size >5 cm or
mitotic rate >5 per 50 high-power fields [HPF]), rates of organ preservation (92 versus 48
percent) and negative margins (69 versus 29 percent) were higher among the 13 patients
who received neoadjuvant imatinib than among the 21 treated with initial surgery.
Furthermore, high-risk patients who underwent neoadjuvant imatinib had greater five-
year overall survival, disease-specific survival, local relapse-free survival, and distant
relapse-free survival compared with those who had initial surgery (91, 100, 100, and 71
versus 47, 65, 74, and 41 percent, respectively).
● In another report of 32 patients with a rectal GIST, 22 received imatinib prior to surgery for
a median of nine months; complete resection was possible in 17 (77 percent), and the
median disease-free survival had not been reached with a median follow-up duration of 39
months [53]. The 10 patients who underwent initial surgery had smaller tumors (median 6
versus 9.3 cm before treatment) and a similar rate of R0 resection (7 of 10, 70 percent).
Sphincter preservation was achieved in a higher number of those treated with
neoadjuvant therapy, although the difference was not statistically significant (41 versus 30
percent, p = 0.57). Locoregional recurrence developed in 3 of 10 patients treated with
initial surgery (30 percent, versus one patient in the neoadjuvant group, 5 percent), and
distant metastases developed in seven (70 percent, versus two patients in the neoadjuvant
group, 9 percent).
Given these data and the fact that most rectal GISTs have exon 11 KIT mutations (which are
more sensitive to imatinib than are other KIT mutations, such as those affecting exon 9), we
prefer neoadjuvant imatinib, rather than initial surgery, for most patients with a rectal GIST
unless it is small and sphincter-preserving surgery is possible upfront. (See "Local treatment for
gastrointestinal stromal tumors, leiomyomas, and leiomyosarcomas of the gastrointestinal
tract", section on 'Colon and rectum' and "Clinical presentation, diagnosis, and prognosis of
gastrointestinal stromal tumors", section on 'Other risk factors'.)
Imatinib dose — All of the retrospective series and the single prospective trial of neoadjuvant
imatinib utilized a daily dose of imatinib of 400 mg per day, and this is the usual approach.
However, as with adjuvant therapy, if a KIT exon 9 mutation is identified and neoadjuvant
therapy is being considered, dose escalation to 800 mg per day is reasonable and is supported
in the European Society for Medical Oncology (ESMO) guidelines [37]. They also note, however,
that regulatory constraints may limit this practice, which is currently not supported in the
adjuvant setting by controlled trials. (See 'Imatinib dosing' above.)
Other mutations are insensitive to imatinib altogether (eg, PDGFRA exon 18 D842V mutations,
succinate dehydrogenase [SDH]-mutant, neurofibromatosis [NF]-related GIST), and we do not
use neoadjuvant imatinib in these settings. If routine genotyping is not practiced, it is probably
wise to check for an early response to neoadjuvant imatinib using CT, PET, or contrast-enhanced
ultrasound [57]. (See 'Response assessment' below and "Tyrosine kinase inhibitor therapy for
advanced gastrointestinal stromal tumors", section on 'Influence of mutations on response to
therapy'.)
Response assessment — Patients being considered for neoadjuvant treatment of a GIST

should be managed in a center that has a strong multidisciplinary team approach. The usual
schema is to administer imatinib for anywhere from 3 to 12 months, with frequent imaging
studies and periodic reevaluation for surgical intervention.
The best method to assess response of a GIST to tyrosine kinase inhibitors (TKIs) is
controversial. PET scanning using fluorodeoxyglucose (FDG) is highly sensitive for detecting
GIST, as for other types of tumors with a high glucose metabolism. Accumulating data support
the view that very early evidence of tumor response (within days of instituting imatinib [58]) can
be obtained by the use of metabolic imaging as compared with conventional CT scanning. A
clinical scenario where obtaining a baseline and follow-up PET scan might prove useful is a
borderline resectable GIST (or a potentially resectable tumor that requires extensive organ
disruption), in which there is a narrow window for moving to alternative therapy (eg, potentially
function-impairing resection or sunitinib) if imatinib were to be ineffective. This is particularly
important if routine genotyping is not practiced. (See 'Imatinib dose' above and "Tyrosine kinase
inhibitor therapy for advanced gastrointestinal stromal tumors", section on 'Assessing response
to therapy'.)
However, in most cases, periodic cross-sectional imaging using conventional CT scanning is

sufficient to assess response. The following caveats must be kept in mind, however (see
"Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors", section on
'Cross-sectional imaging'):
● Radiographically, GISTs may actually increase in size during early treatment as a

consequence of intratumoral hemorrhage or myxoid degeneration. A decrease in tumor
density as seen on CT (the corollary of decreased FDG uptake on PET, see above) is an
important early clinical marker of antitumor activity. Once tumors become hypodense
(cystic), the size of the lesions may decrease slowly and eventually stabilize.
● Late responses are often seen in patients who initially have stable disease. Maximal
response may take six months or even longer.
● As a result of these issues, response to imatinib is frequently defined as absence of

progression at the time of the first formal disease reevaluation (typically two to three
months after starting therapy) [59]. Clear-cut evidence of progression at this time point is
considered initial (primary) resistance, and a switch to an alternative form of therapy is
indicated.
Duration of therapy — The optimal duration of neoadjuvant TKIs is not established. The

decision as to how long to administer imatinib and when to operate (ie, at first resectability
versus after achieving maximal response) must be individualized. For patients in whom tumor
shrinkage would lessen the complexity of the surgical procedure, imatinib is often administered
for up to 12 months, as long as a continued radiographic response is evident. We usually treat
to "best tumor response" on cross-sectional imaging, trying to limit therapy to no more than 10
to 12 months.
Data on radiologic assessment of response to upfront imatinib come from a retrospective

single-institution review of 20 patients who received neoadjuvant imatinib and then underwent
surgery over a 12-year period [43]. The median duration of neoadjuvant imatinib was 32 weeks.
The best response was a partial response in 16 and stable disease in four. The "best" response
was seen at 28 weeks, irrespective of tumor size or location. Plateau response was seen at 34
weeks, beyond which further treatment was not beneficial.
At least some data suggest that extending neoadjuvant therapy beyond 10 to 12 months
increases the likelihood of a disease recurrence after surgery, at least for primary GISTs [44,60].
Whether longer periods of neoadjuvant treatment are detrimental for patients being treated for
a recurrent/metastatic GIST is unclear [60].
A provocative trial suggests that response rates to very brief periods of neoadjuvant imatinib
(three to seven days), as assessed by FDG-PET and dynamic CT, are as high as 70 percent [61].
However, in this small prospective randomized phase II trial, there was no evidence of histologic
cytoreduction (and, therefore, no potential benefit in terms of reduced tumor bulk) from ≤7
days of neoadjuvant imatinib and no suggestion that intraoperative blood loss was reduced,
even though blood flow to the tumor was reduced, as measured by dynamic CT. Thus, the
clinical benefit of very short periods of neoadjuvant imatinib (termed "nanoneoadjuvant
therapy" [62]) is unproven.
Postoperative management — For patients undergoing neoadjuvant imatinib, we

continue imatinib postoperatively to complete a total of three years of imatinib therapy
(combined preoperative and postoperative).
Mitotic count cannot be reliably assessed on a surgical specimen after neoadjuvant therapy.
Specifically, a low mitotic count in a patient undergoing surgery after neoadjuvant imatinib may
reflect the effect of treatment and not the intrinsic biological behavior of the tumor. Since risk of
recurrence cannot be accurately stratified after neoadjuvant therapy, our practice is to continue
imatinib postoperatively to complete a total of three years of imatinib therapy (preoperative and
postoperative). In these situations, the size of the primary tumor (eg, >15 cm) often is
justification enough for consideration of adjuvant therapy.
Recommendations of expert groups — There is no consensus among expert groups as to the

indications for neoadjuvant therapy [37,63,64]. Some limit this approach to patients with
identifiable high-risk characteristics (size >5 cm, >5 mitoses per 50 HPF, anatomic location
resulting in a potentially morbid resection) [63]. Consensus-based guidelines from the NCCN [2]
recommend initial treatment with imatinib for patients with marginally resectable tumors and
for those who have potentially resectable disease but with the risk of significant morbidity.
Examples might include a GIST arising in the esophagus, esophagogastric junction, duodenum,
or distal rectum [64]. At these sites, preoperative treatment might shrink the tumor and permit
a more conservative local excision to be performed, rather than radical surgery. We agree with
this approach. (See "Local treatment for gastrointestinal stromal tumors, leiomyomas, and
leiomyosarcomas of the gastrointestinal tract", section on 'Neoadjuvant'.)
Patients with metastatic disease — Although therapy with TKIs has become the first-line
treatment for metastatic GIST, subsequent surgical resection may be integrated into therapy for
the following reasons (see "Tyrosine kinase inhibitor therapy for advanced gastrointestinal
stromal tumors"):
● While TKIs control tumor growth in over 80 percent of patients, complete responses are
only rarely achieved, and surgical resection remains the only potentially curative therapy
for GIST.
● Most patients who initially respond to upfront imatinib eventually acquire resistance via
additional mutations in the KIT gene. The median time to progression is approximately two
years. Thereafter, the therapeutic alternatives are limited. Thus, although 95 percent of
salvage surgeries for metastatic GIST fail, resection of residual disease followed by
additional imatinib might delay or prevent the development of resistant clones by
reducing tumor burden, and this may prolong the time to disease progression.
Who benefits from resection — Two trials addressing the question of which patients benefit
from resection after upfront imatinib were begun in Europe and China, but both failed to recruit
quickly enough to meet target accrual. However, the Chinese trial, which accrued only 41 of the
planned 210 patients with recurrent or metastatic GIST who were responding to imatinib and
were randomized to surgery and continued imatinib versus continued imatinib alone, noted
that two-year progression-free survival was higher with surgery (88 versus 58 percent), as was
overall survival (median survival not reached compared with 49 months with imatinib alone).
Subgroup analyses could not be performed because of the limited number of patients.
In the absence of robust, adequately powered controlled trials, some general conclusions can
be drawn from retrospective studies examining disease control following resection for selected
patients with limited metastatic disease:
● In general, resection appears to benefit responding patients (ie, those who have a partial
response, stable disease, or focal progression) but has little to offer those who experience
generalized disease progression while receiving imatinib.
● Resection, even if complete, does not eliminate the need for continued treatment with a
TKI therapy. Progression-free survival is significantly shorter in patients who discontinue
imatinib as compared with those who continue the drug after resection.
This subject, including the data upon which these conclusions are based, is discussed
elsewhere. (See "Local treatment for gastrointestinal stromal tumors, leiomyomas, and
leiomyosarcomas of the gastrointestinal tract", section on 'Role of surgery in patients with

metastatic disease'.)
POSTTREATMENT FOLLOW-UP
There are no evidence-based guidelines on what constitutes appropriate follow-up after

treatment of a gastrointestinal stromal tumor (GIST), and there is no consensus on this issue.
Relapses most often occur to the liver and/or peritoneum; other sites of metastases, including
bone metastases, are rare. Guidelines from the National Comprehensive Cancer Network
(NCCN) [2] suggest the following:
● For a completely resected GIST, history and physical examination every three to six months
for five years, then annually. A computed tomography (CT) scan is recommended every
three to six months for three to five years, then annually.
● For patients with more locally advanced or metastatic disease who are receiving imatinib,
history and physical examination, laboratory studies (complete blood count and
monitoring of phosphate levels), as well as abdominopelvic CT scan are recommended
every three to six months. (See "Tyrosine kinase inhibitor therapy for advanced
gastrointestinal stromal tumors", section on 'Side effects and their management'.)
In contrast, posttreatment follow-up guidelines from the European Society for Medical Oncology
(ESMO) emphasize the value of risk assessment in selecting the frequency and specific
components of follow-up [37].
We stratify our recommendations for posttreatment follow-up according to risk but do not
adhere closely to a specific timetable for patients without high-risk disease. For patients with a
high enough risk to justify adjuvant imatinib, we and others [65] suggest cross-sectional
imaging every six months during adjuvant imatinib, every three to four months during the two
years that follow treatment discontinuation, where the risk of disease recurrence is highest,
then at 6 to 12 month intervals to complete 10 years of follow-up, approximating ESMO
guidelines.
For very low-risk cases, every-other-year scanning seems reasonable. We expect that guidelines
for follow-up will become more specific as more data become available.
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Gastrointestinal stromal
tumors".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics."
The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Soft tissue sarcoma (The Basics)")
SUMMARY AND RECOMMENDATIONS
● Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms
that affect the gastrointestinal tract. Approximately 80 percent have mutations in the KIT
protooncogene that lead to constitutive activation of KIT, a receptor tyrosine kinase (RTK).
A subset of GISTs lacking KIT gene mutations harbors activating mutations in a related
RTK, platelet-derived growth factor receptor-alpha (PDGFRA). Approximately 12 percent of
GISTs have no mutation in either KIT or PDGFRA ("wild type" for these two kinase genes),
and the majority of these have mutations or epigenetic silencing of succinate
dehydrogenase (SDH) subunits, leading to the SDH-deficient GIST. (See 'Introduction'
above.)
● The standard of care for patients with a primary resectable GIST is surgery, aiming for a
macroscopically complete resection with negative microscopic margins. Complete
resection is possible in the majority of localized GISTs, but only approximately one-half
remain recurrence-free for five or more years with surgery alone.
Small molecule tyrosine kinase inhibitors (TKIs), such as imatinib, block signaling via KIT
and PDGFRA, thus halting tumor proliferation. The success of these agents in advanced
disease has prompted interest in perioperative use in patients with earlier stage disease.
An approach to treatment of GISTs, integrating the use of adjuvant (postoperative) and
neoadjuvant (preoperative) imatinib, is provided in the algorithm ( algorithm 1). (See
'Overview of approach to the patient' above.)
● Based upon data from the Scandinavian Sarcoma Group (SSG) XVIII trial, we recommend
adjuvant treatment with a TKI (imatinib 400 mg daily) for a minimum of three years in
patients who have a completely resected primary high-risk GIST (Grade 1A). (See 'SSG XVIII
trial' above.)
Whether treatment should be continued for longer than three years is not known. Rates of
disease recurrence have been high within 6 to 12 months of discontinuing adjuvant
imatinib for up to three years, and it is possible that imatinib is maintaining tumor
dormancy rather than eradicating microdeposits. Patients with high-risk tumors might
rationally elect to remain on what is for them a well-tolerated medication rather than be
subject to an increased rate of recurrence following discontinuation of the drug. (See
'Duration of therapy' above.)
The optimal selection of patients who are at sufficiently high risk for recurrence to warrant
adjuvant imatinib is not established. Several risk stratification tools are available, based
upon tumor size, mitotic rate, location, and in some cases, the presence or absence of
tumor rupture and molecular genotype. However, particularly for tools, such as
nomograms, that quantify the risk of disease recurrence after complete resection as a
continuous variable, it is not clear what cutoff for disease recurrence should be used to
select patients for imatinib. (See 'Estimation of recurrence risk' above.)
Thus, each case must be approached individually, balancing the estimated likelihood of a
disease recurrence (based upon anatomic site, size, mitotic rate, and presence or absence
of tumor rupture ( table 1)) with the risks of therapy. Adjuvant imatinib is appropriate for
all patients who fall into a "high-risk" category, regardless of the risk stratification model
used. (See 'Patient selection' above.)
Many centers, including that of the authors, routinely genotype all patients with GIST who
are being considered for adjuvant imatinib. Adjuvant imatinib is not indicated in patients
with SDH-deficient GIST, neurofibromatosis (NF)-related GIST, and PDGFRA D842V GIST. For
patients whose tumors harbor a KIT exon 9 mutation, higher-dose imatinib (800 rather
than 400 mg daily) is a reasonable option, if tolerated, although there are no prospective
data upon which to base a recommendation either for or against this practice. (See
'Imatinib dosing' above and "Tyrosine kinase inhibitor therapy for advanced
gastrointestinal stromal tumors", section on 'Influence of mutations on response to
therapy'.)
● There is no consensus as to the indications for neoadjuvant imatinib. For patients with
apparently localized tumors with a KIT or PDGFRA mutation other than D842V, we suggest
initial treatment with imatinib for patients with locally advanced unresectable or
borderline resectable tumors; for potentially resectable primary tumors, if a reduction in
tumor size would significantly decrease the morbidity of surgical resection; and for most
patients with a rectal GIST, unless the tumor is small and sphincter-preserving surgery is
possible upfront (Grade 2C). If possible, such patients should be enrolled in a clinical trial.
(See 'Neoadjuvant therapy' above and 'Rectal GISTs' above.)
We initiate imatinib at a dose of 400 mg daily. At the authors' institutions, tumor

genotyping is performed for all patients being considered for neoadjuvant imatinib. If an
exon 9 mutation is identified in a rare patient being considered for neoadjuvant imatinib,
the option of a higher daily dose (800 mg per day) should be discussed with patients,
although there are no prospective data upon which to base a recommendation either for
or against this practice. Most of these patients will have a small bowel primary tumor and
be referred for upfront surgery rather than neoadjuvant imatinib.
For patients with a PDGFRA D842V mutation or those with wild-type tumors (neither KIT nor
PDGFRA mutations), we do not use neoadjuvant imatinib and, instead, proceed directly to
surgery. If routine genotyping is not practiced, it is probably wise to check for an early
response to neoadjuvant imatinib using computed tomography (CT), positron emission
tomography (PET), or contrast-enhanced ultrasound. (See 'Response assessment' above.)
The optimal duration of neoadjuvant TKIs is not established. The decision as to how long
to administer imatinib and when to operate (ie, at first resectability versus after achieving
maximal response) must be individualized and based upon drug tolerance, tumor location
and extent, the results of periodic radiographic assessment, and the urgency of surgical
treatment. In general, we treat to maximal response and try to limit neoadjuvant
treatment to no more than 10 to 12 months. (See 'Duration of therapy' above.)
For patients undergoing neoadjuvant imatinib, we continue imatinib postoperatively to

complete a total of at least three years of imatinib therapy (combined preoperative and
postoperative). (See 'Postoperative management' above.)
● For patients with potentially resectable metastatic GIST who do not have a PDGFRA D842V
mutation or a wild-type GIST, we suggest neoadjuvant imatinib rather than upfront
resection (Grade 2C). The optimal duration of neoadjuvant imatinib is uncertain, and we
individualize this decision based upon drug tolerance, tumor location and extent, and
radiographic assessment during neoadjuvant imatinib.
Selected patients with unresectable metastatic GIST may also be considered for resection.
Aggressive cytoreductive surgery should be offered only to patients whose disease is
stable or responding to TKI therapy, or who have only focal progression. Patients with
extensive disease progression while on TKI therapy gain little benefit from surgery, and it
should not be pursued. (See "Local treatment for gastrointestinal stromal tumors,
leiomyomas, and leiomyosarcomas of the gastrointestinal tract", section on 'Role of
surgery in patients with metastatic disease'.)
Cytoreductive surgery in this setting often requires extensive potentially morbid

procedures, such as gastrectomy, hepatectomy, and pancreatic resection, and should be
carried out in centers of excellence. All patients should resume therapy with a TKI after
resection. (See 'Patients with metastatic disease' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge George Demetri, MD, who
contributed to an earlier version of this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1. Sepe PS, Brugge WR. A guide for the diagnosis and management of gastrointestinal
stromal cell tumors. Nat Rev Gastroenterol Hepatol 2009; 6:363.
2. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncol
ogy. https://www.nccn.org/professionals/physician_gls (Accessed on November 09, 2021).
3. Dematteo RP, Gold JS, Saran L, et al. Tumor mitotic rate, size, and location independently
predict recurrence after resection of primary gastrointestinal stromal tumor (GIST). Cancer
2008; 112:608.
4. Huang HY, Li CF, Huang WW, et al. A modification of NIH consensus criteria to better
distinguish the highly lethal subset of primary localized gastrointestinal stromal tumors: a
subdivision of the original high-risk group on the basis of outcome. Surgery 2007; 141:748.
5. Corless CL, Ballman KV, Antonescu CR, et al. Pathologic and molecular features correlate
with long-term outcome after adjuvant therapy of resected primary GI stromal tumor: the
ACOSOG Z9001 trial. J Clin Oncol 2014; 32:1563.
6. Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at

different sites. Semin Diagn Pathol 2006; 23:70.
7. Miettinen M, Makhlouf H, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the

jejunum and ileum: a clinicopathologic, immunohistochemical, and molecular genetic study
of 906 cases before imatinib with long-term follow-up. Am J Surg Pathol 2006; 30:477.
8. Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the stomach: a
clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with
long-term follow-up. Am J Surg Pathol 2005; 29:52.
9. American Joint Committee on Cancer. American Joint Committee on Cancer Staging Manua
l, 7th ed, Edge SB, Byrd DR, Compton CC, et al (Eds), Springer, New York 2010. p.175.
10. DeMatteo RP, Maki RG, Agulnik M, et al. Gastrointestinal stromal tumor. In: AJCC Cancer Sta
ging Manual, 8th ed, Amin MB (Ed), AJCC, Chicago 2017. p.523. Corrected at 4th printing, 20
18.
11. Joensuu H, Vehtari A, Riihimäki J, et al. Risk of recurrence of gastrointestinal stromal tumour
after surgery: an analysis of pooled population-based cohorts. Lancet Oncol 2012; 13:265.
12. Joensuu H, Eriksson M, Hall KS, et al. Risk factors for gastrointestinal stromal tumor
recurrence in patients treated with adjuvant imatinib. Cancer 2014; 120:2325.
13. Joensuu H. Risk stratification of patients diagnosed with gastrointestinal stromal tumor.
Hum Pathol 2008; 39:1411.
14. Gold JS, Gönen M, Gutiérrez A, et al. Development and validation of a prognostic
nomogram for recurrence-free survival after complete surgical resection of localised
primary gastrointestinal stromal tumour: a retrospective analysis. Lancet Oncol 2009;
10:1045.
15. Bischof DA, Kim Y, Behman R, et al. A nomogram to predict disease-free survival after
surgical resection of GIST. J Gastrointest Surg 2014; 18:2123.
16. Rossi S, Miceli R, Messerini L, et al. Natural history of imatinib-naive GISTs: a retrospective
analysis of 929 cases with long-term follow-up and development of a survival nomogram
based on mitotic index and size as continuous variables. Am J Surg Pathol 2011; 35:1646.
17. Chok AY, Goh BK, Koh YX, et al. Validation of the MSKCC Gastrointestinal Stromal Tumor
Nomogram and Comparison with Other Prognostication Systems: Single-Institution
Experience with 289 Patients. Ann Surg Oncol 2015; 22:3597.
18. Joensuu H, Rutkowski P, Nishida T, et al. KIT and PDGFRA mutations and the risk of GI
stromal tumor recurrence. J Clin Oncol 2015; 33:634.
19. Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection
of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-
controlled trial. Lancet 2009; 373:1097.
20. Blackstein ME. Risk assessment for tumor recurrence after surgical resection of localized pr
imary gastropintestinal stromal tumor (GIST): North America intergroup phase III trial ACO
SOG Z9001 (abstract). Data presented at the 2010 ASCO Gastrointestinal Cancers Symposiu
m, Orlando, FL, January 23, 2010.
21. Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized phase II
trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or
metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 2008; 26:620.
22. Casali PG, Le Cesne A, Poveda Velasco A, et al. Time to Definitive Failure to the First Tyrosine
Kinase Inhibitor in Localized GI Stromal Tumors Treated With Imatinib As an Adjuvant: A
European Organisation for Research and Treatment of Cancer Soft Tissue and Bone
Sarcoma Group Intergroup Randomized Trial in Collaboration With the Australasian Gastro-
Intestinal Trials Group, UNICANCER, French Sarcoma Group, Italian Sarcoma Group, and
Spanish Group for Research on Sarcomas. J Clin Oncol 2015; 33:4276.
23. Gronchi A, Bonvalot S, Poveda Velasco A, et al. Quality of Surgery and Outcome in Localized
Gastrointestinal Stromal Tumors Treated Within an International Intergroup Randomized
Clinical Trial of Adjuvant Imatinib. JAMA Surg 2020; 155:e200397.
24. Casali PG, Le Cesne A, Velasco AP, et al. Final analysis of the randomized trial on imatinib as
an adjuvant in localized gastrointestinal stromal tumors (GIST) from the EORTC Soft Tissue
and Bone Sarcoma Group (STBSG), the Australasian Gastro-Intestinal Trials Group (AGITG),
UNICANCER, French Sarcoma Group (FSG), Italian Sarcoma Group (ISG), and Spanish Group
☆
for Research on Sarcomas (GEIS) . Ann Oncol 2021; 32:533.
25. Joensuu H, Eriksson M, Sundby Hall K, et al. One vs three years of adjuvant imatinib for
operable gastrointestinal stromal tumor: a randomized trial. JAMA 2012; 307:1265.
26. Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a
consensus approach. Int J Surg Pathol 2002; 10:81.
27. Joensuu H, Eriksson M, Sundby Hall K, et al. Survival Outcomes Associated With 3 Years vs 1
Year of Adjuvant Imatinib for Patients With High-Risk Gastrointestinal Stromal Tumors: An
Analysis of a Randomized Clinical Trial After 10-Year Follow-up. JAMA Oncol 2020; 6:1241.
28. Joensuu H, Wardelmann E, Sihto H, et al. Effect of KIT and PDGFRA Mutations on Survival in
Patients With Gastrointestinal Stromal Tumors Treated With Adjuvant Imatinib: An
Exploratory Analysis of a Randomized Clinical Trial. JAMA Oncol 2017; 3:602.
29. Boichuk S, Parry JA, Makielski KR, et al. The DREAM complex mediates GIST cell quiescence
and is a novel therapeutic target to enhance imatinib-induced apoptosis. Cancer Res 2013;
73:5120.
30. Joensuu H, Eriksson M, Sundby Hall K, et al. Adjuvant Imatinib for High-Risk GI Stromal
Tumor: Analysis of a Randomized Trial. J Clin Oncol 2016; 34:244.
31. Blanke CD, DeMatteo RP. Duration of Adjuvant Therapy for Patients With Gastrointestinal
Stromal Tumors: Where Is Goldilocks When We Need Her? JAMA Oncol 2016; 2:721.
32. Raut CP, Espat NJ, Maki RG, et al. Efficacy and Tolerability of 5-Year Adjuvant Imatinib
Treatment for Patients With Resected Intermediate- or High-Risk Primary Gastrointestinal
Stromal Tumor: The PERSIST-5 Clinical Trial. JAMA Oncol 2018; 4:e184060.
33. Lin JX, Chen QF, Zheng CH, et al. Is 3-years duration of adjuvant imatinib mesylate
treatment sufficient for patients with high-risk gastrointestinal stromal tumor? A study
based on long-term follow-up. J Cancer Res Clin Oncol 2017; 143:727.
34. Rutkowski P, Nowecki ZI, Michej W, et al. Risk criteria and prognostic factors for predicting
recurrences after resection of primary gastrointestinal stromal tumor. Ann Surg Oncol
2007; 14:2018.
35. Hohenberger P, Ronellenfitsch U, Oladeji O, et al. Pattern of recurrence in patients with

ruptured primary gastrointestinal stromal tumour. Br J Surg 2010; 97:1854.
36. Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: A
consensus approach. Hum Pathol 2002; 33:459.
37. Casali PG, Abecassis N, Aro HT, et al. Gastrointestinal stromal tumours: ESMO-EURACAN
Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;
29:iv267.
38. Boikos SA, Pappo AS, Killian JK, et al. Molecular Subtypes of KIT/PDGFRA Wild-Type
Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health
Gastrointestinal Stromal Tumor Clinic. JAMA Oncol 2016; 2:922.
39. Chacón M, Roca E, Huertas E, et al. CASE 3. Pathologic complete remission of metastatic
gastrointestinal stromal tumor after imatinib mesylate. J Clin Oncol 2005; 23:1580.
40. Eisenberg BL, Harris J, Blanke CD, et al. Phase II trial of neoadjuvant/adjuvant imatinib
mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal
stromal tumor (GIST): early results of RTOG 0132/ACRIN 6665. J Surg Oncol 2009; 99:42.
41. Kurokawa Y, Yang HK, Cho H, et al. Phase II study of neoadjuvant imatinib in large
gastrointestinal stromal tumours of the stomach. Br J Cancer 2017; 117:25.
42. Wang D, Zhang Q, Blanke CD, et al. Phase II trial of neoadjuvant/adjuvant imatinib mesylate
for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumors:
long-term follow-up results of Radiation Therapy Oncology Group 0132. Ann Surg Oncol
2012; 19:1074.
43. Tirumani SH, Shinagare AB, Jagannathan JP, et al. Radiologic assessment of earliest, best,
and plateau response of gastrointestinal stromal tumors to neoadjuvant imatinib prior to
successful surgical resection. Eur J Surg Oncol 2014; 40:420.
44. Andtbacka RH, Ng CS, Scaife CL, et al. Surgical resection of gastrointestinal stromal tumors
after treatment with imatinib. Ann Surg Oncol 2007; 14:14.
45. Katz D, Segal A, Alberton Y, et al. Neoadjuvant imatinib for unresectable gastrointestinal
stromal tumor. Anticancer Drugs 2004; 15:599.
46. Bonvalot S, Eldweny H, Péchoux CL, et al. Impact of surgery on advanced gastrointestinal
stromal tumors (GIST) in the imatinib era. Ann Surg Oncol 2006; 13:1596.
47. Raut CP, Posner M, Desai J, et al. Surgical management of advanced gastrointestinal
stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J
Clin Oncol 2006; 24:2325.
48. Scaife CL, Hunt KK, Patel SR, et al. Is there a role for surgery in patients with "unresectable"
cKIT+ gastrointestinal stromal tumors treated with imatinib mesylate? Am J Surg 2003;
186:665.
49. Machlenkin S, Pinsk I, Tulchinsky H, et al. The effect of neoadjuvant Imatinib therapy on
outcome and survival after rectal gastrointestinal stromal tumour. Colorectal Dis 2011;
13:1110.
50. Rutkowski P, Gronchi A, Hohenberger P, et al. Neoadjuvant imatinib in locally advanced

gastrointestinal stromal tumors (GIST): the EORTC STBSG experience. Ann Surg Oncol 2013;
20:2937.
51. Gervaz P, Huber O, Morel P. Surgical management of gastrointestinal stromal tumours. Br J

Surg 2009; 96:567.
52. Jakob J, Mussi C, Ronellenfitsch U, et al. Gastrointestinal stromal tumor of the rectum:
results of surgical and multimodality therapy in the era of imatinib. Ann Surg Oncol 2013;
20:586.
53. Tielen R, Verhoef C, van Coevorden F, et al. Surgical management of rectal gastrointestinal
stromal tumors. J Surg Oncol 2013; 107:320.
54. Cavnar MJ, Wang L, Balachandran VP, et al. Rectal Gastrointestinal Stromal Tumor (GIST) in
the Era of Imatinib: Organ Preservation and Improved Oncologic Outcome. Ann Surg Oncol
2017; 24:3972.
55. Wilkinson MJ, Fitzgerald JE, Strauss DC, et al. Surgical treatment of gastrointestinal stromal
tumour of the rectum in the era of imatinib. Br J Surg 2015; 102:965.
56. Hawkins AT, Wells KO, Krishnamurty DM, et al. Preoperative Chemotherapy and Survival for
Large Anorectal Gastrointestinal Stromal Tumors: A National Analysis of 333 Cases. Ann
Surg Oncol 2017; 24:1195.
57. Lassau N, Lamuraglia M, Chami L, et al. Gastrointestinal stromal tumors treated with
imatinib: monitoring response with contrast-enhanced sonography. AJR Am J Roentgenol
2006; 187:1267.
58. Van den Abbeele AD, Gatsonis C, de Vries DJ, et al. ACRIN 6665/RTOG 0132 phase II trial of
neoadjuvant imatinib mesylate for operable malignant gastrointestinal stromal tumor:
monitoring with 18F-FDG PET and correlation with genotype and GLUT4 expression. J Nucl
Med 2012; 53:567.
59. Le Cesne A, Van Glabbeke M, Verweij J, et al. Absence of progression as assessed by

response evaluation criteria in solid tumors predicts survival in advanced GI stromal
tumors treated with imatinib mesylate: the intergroup EORTC-ISG-AGITG phase III trial. J
Clin Oncol 2009; 27:3969.
60. Bednarski BK, Araujo DM, Yi M, et al. Analysis of prognostic factors impacting oncologic
outcomes after neoadjuvant tyrosine kinase inhibitor therapy for gastrointestinal stromal
tumors. Ann Surg Oncol 2014; 21:2499.
61. McAuliffe JC, Hunt KK, Lazar AJ, et al. A randomized, phase II study of preoperative plus
postoperative imatinib in GIST: evidence of rapid radiographic response and temporal
induction of tumor cell apoptosis. Ann Surg Oncol 2009; 16:910.
62. DeMatteo RP. Nanoneoadjuvant therapy of gastrointestinal stromal tumor (GIST). Ann Surg
Oncol 2009; 16:799.
63. von Mehren M, Watson JC. Perioperative tyrosine kinase inhibitors for GIST: standard ... or
an idea that needs further investigation? Oncology (Williston Park) 2009; 23:65.
64. Gronchi A, Raut CP. The combination of surgery and imatinib in GIST: a reality for localized
tumors at high risk, an open issue for metastatic ones. Ann Surg Oncol 2012; 19:1051.
65. Joensuu H, Martin-Broto J, Nishida T, et al. Follow-up strategies for patients with
gastrointestinal stromal tumour treated with or without adjuvant imatinib after surgery.
Eur J Cancer 2015; 51:1611.
Topic 7730 Version 47.0
GRAPHICS
Overview of the approach to treatment of gastrointestinal stromal tumors (GIST)
NF: neurofibromatosis; SDH: succinate dehydrogenase.
* Situations where preoperative (neoadjuvant) imatinib might be considered include a rectal primary site, local
downstaging tumor preoperatively.
¶ Irregular border, cystic spaces, ulceration, echogenic foci, heterogeneity.
Δ Risk stratification based upon mitotic rate, size, tumor site, and presence or absence of tumor rupture.
Graphic 104075 Version 2.0
Modified NIH risk stratification criteria for GIST with rupture included
Mitotic index (per

Risk category Tumor size (cm) Primary tumor site
50 HPFs)
Very low risk <2.0 ≤5 Any
Low risk 2.1 to 5.0 ≤5 Any
Intermediate risk 2.1 to 5.0 >5 Gastric
<5.0 6 to 10 Any
5.1 to 10.0 ≤5 Gastric
High risk Any Any Tumor rupture
>10 cm Any Any
Any >10 Any
>5.0 >5 Any
2.1 to 5.0 >5 Nongastric
5.1 to 10.0 ≤5 Nongastric
NIH: National Institutes of Health; GIST: gastrointestinal stromal tumor; HPF: high power fields.
Reproduced from: Joensuu H. Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum Pathol 2008;
39:1411. Table used with the permission of Elsevier Inc. All rights reserved.
Proposed modification of the original NIH consensus criteria for risk

stratification of GISTs
Risk group Size (cm) Mitotic rate* (per 50 HPF)
Original NIH[1] criteria
Very low risk <2 <5
Low risk 2 to 5 <5
Intermediate risk <5 6 to 10
5 to 10 <5
High risk >5 >5
>10 Any
Any >10
Proposed[2] criteria
Level I ≤5 <5
Level II <5 6 to 10
5 to 10 <5
Level III ≤5 >10
5 to 10 6 to 10
>10 <5
Level IV >5 >10
NIH: National Institutes of Health; GIST: gastrointestinal stromal tumor; HPF: high-power fields.
* Mitotic rate is counted in an area of 5 square millimeters (mm2 ) on the glass slide section. For older
microscopes with traditional field size optics, 50 HPF is equivalent to 5 mm2 . For modern microscopes
with wider 40× lenses/fields, 20 HPF is equivalent to 5 mm2 . If necessary, the field of view should be
measured to determine the actual number of HPF required to cover a 5 mm2 area.[3]
References:
1. Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Int J Surg Path
2002; 10:81.
2. Huang HY, Li CF, Huang WW, et al. A modification of NIH consensus criteria to better distinguish the highly lethal subset of
primary localized gastrointestinal stromal tumors: a subdivision of the original high-risk group on the basis of outcome.
Surgery 2007; 141:748.
3. Rubin BP, Blanke CD, Demetri GD, et al. Protocol for the examination of specimens from patients with gastrointestinal
stromal tumor (GIST): Based on AJCC/UICC TNM, 7th edition, College of American Pathologists (CAP), Washington 2013.
AFIP prognostic model: progression-free survival for gastrointestinal stromal

tumors (GISTs) of the stomach, small intestine, and rectum by mitotic rate and
tumor size*
Percent of patients progression free during long-term follow-up by

Tumor size
primary site
(cm)
Gastric Jejunum/ileum Duodenum Rectum
Mitotic rate¶ (HPF): ≤5/50
≤2 100 100 100 100
2 to 5 98.1 95.7 91.7 91.5
5 to 10 96.4 76 66* 43*
>10 88 48
Mitotic rate¶ (HPF): >5/50
≤2 100Δ 50Δ – 46
2 to 5 84 27 50 48
5 to 10 45 15 14* 29*
>10 14 10
Based on long-term follow-up studies on 1055 gastric, 629 small intestinal, 144 duodenal, and 111 rectal
cancers.
AFIP: Armed Forces Institute of Pathology; HPF: high-power fields.
* Data are combined for tumors >5 cm.
¶ Mitotic rate is counted in an area of 5 square millimeters (mm2 ) on the glass slide section. For older
microscopes with traditional field size optics, 50 HPF is equivalent to 5 mm2 . For modern microscopes
with wider 40× lenses/fields, 20 HPF is equivalent to 5 mm2 . If necessary, the field of view should be
measured to determine the actual number of HPF required to cover a 5 mm2 area.[1]
Δ Small number of cases.
Reference:
1. Rubin BP, Blanke CD, Demetri GD, et al. Protocol for the examination of specimens from patients with gastrointestinal
stromal tumor (GIST): Based on AJCC/UICC TNM, 7th edition, College of American Pathologists (CAP), Washington 2013.

Adapted from: Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn
Pathol 2006; 23:70.
GIST TNM staging AJCC UICC 8th edition
Primary tumor (T)

T category T criteria
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Tumor 2 cm or less
T2 Tumor more than 2 cm but not more than 5 cm
T3 Tumor more than 5 cm but not more than 10 cm
T4 Tumor more than 10 cm in greatest dimension
Regional lymph nodes (N)

N category N criteria
N0 No regional lymph node metastasis or unknown lymph node status
N1 Regional lymph node metastasis
Distant metastasis (M)

M category M criteria
M0 No distant metastasis
M1 Distant metastasis
Mitotic rate
Mitotic rate Definition
Low Five or fewer mitoses per 5 mm2
High Over five mitoses per 5 mm2
Prognostic stage groups
Gastric and omental GIST
When T is... And N is... And M is... And mitotic rate Then the stage
is... group is...
T1 or T2 N0 M0 Low IA
T3 N0 M0 Low IB
T1 N0 M0 High II
T2 N0 M0 High II
T4 N0 M0 Low II
T3 N0 M0 High IIIA
T4 N0 M0 High IIIB
Any T N1 M0 Any rate IV
Any T Any N M1 Any rate IV
Small intestinal, esophageal, colorectal, mesenteric, and peritoneal GIST
When T is... And N is... And M is... And mitotic rate Then the stage
is... group is...
T1 or T2 N0 M0 Low I
T3 N0 M0 Low II
T1 N0 M0 High IIIA
T4 N0 M0 Low IIIA
T2 N0 M0 High IIIB
T3 N0 M0 High IIIB
T4 N0 M0 High IIIB
Any T N1 M0 Any rate IV
Any T Any N M1 Any rate IV
GIST: gastrointestinal stromal tumor; TNM: tumor, node, metastasis; AJCC: American Joint Committee on
Cancer; UICC: Union for International Cancer Control.
Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC
Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing. Corrected at 4th printing, 2018.
2017 AJCC disease progression in small intestinal GISTs
Stage Tumor size (cm) Mitotic rate Observed rate of

progressive disease
Stage IA ≤5 Low 0 to 4%
Stage II >5 to 10 Low 24%
Stage IIIA >10 Low 52%
≤2 High 50%
Stage IIIB >2 to 5 High 73%
>5 to 10 High 85%
>10 High 90%
AJCC: American Joint Committee on Cancer; GISTs: gastrointestinal stromal tumors.
Original figure modified for this publication. Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at
different sites. Semin Diagn Pathol 2006; 23:70. Table used with the permission of Elsevier Inc. All rights reserved.
2017 AJCC disease progression in gastric GISTs

progressive disease
Stage IA ≤5 Low 0 to 2%
Stage IB >5 to 10 Low 3 to 4%
Stage II ≤2 High Insufficient data
>2 to 5 High 16%
>10 Low 12%
Stage IIIA >5 to 10 High 55%
Stage IIIB >10 High 86%
AJCC: American Joint Committee on Cancer; GISTs: gastrointestinal stromal tumors.
Disease progression in rectal GISTs according to AJCC 2017 stage

progressive disease
Stage IA ≤2 cm Low 0%
>2 to 5 Low 8.5%
Stage II >5 to 10 Low NR
Stage IIIA >10 Low 57%
≤2 High 54%
Stage IIIB >2 to 5 High 52%
>5 to 10 High NR
>10 High 71%
GISTs: gastrointestinal stromal tumor; AJCC: American Joint Committee on Cancer; NR: not reported.
Proposed approach for defining risk of aggressive behavior in gastrointestinal

stromal tumors
Size* Mitotic count¶

Very low risk <2 cm <5 per 50 HPF
Low risk 2-5 cm <5 per 50 HPF
Intermediate risk <5 cm 6-10 per 50 HPF
5-10 cm <5 per 50 HPF
High risk >5 cm >5 per 50 HPF
>10 cm Any mitotic rate
Any size >10 per 50 HPF
HPF: high powered fields.
* Size represents the single largest dimension. Admittedly this may vary somewhat before and after
fixation and between observers. There is a general but poorly defined sense that perhaps the size
threshold for aggressive behaviour should be 1 to 2 cm less in the small bowel than elsewhere.
¶ Ideally mitotic count should be standardized according to surface area examined (based on size of high
power fields), but there are no agreed definitions in this regard. Despite inevitable subjectivity in
recognition of mitoses and variability in the area of high power fields, such mitotic counts still prove
useful.
Reproduced with permission from: Fletcher, CD, Berman, JJ, Corless, C, et al. Diagnosis of gastrointestinal stromal tumors: A
consensus approach. Int J Surg Pathol 2002; 10:81. Copyright ©2002 Westminster Publications.
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Imatinib For Gastrointestinal Stromal Tumors

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11/24/21, 4:19 AM Adjuvant and neoadjuvant imatinib for gastrointestinal stromal tumors - UpToDate

Official reprint from UpToDate®

Adjuvant and neoadjuvant imatinib for gastrointestinal

OVERVIEW OF APPROACH TO THE PATIENT

An approach to management of patients with apparently localized disease is outlined in the

Apparently localized disease

● Surgery versus surveillance – All apparently localized gastrointestinal stromal tumors

● Initial surgery versus neoadjuvant imatinib – The goal of surgical treatment is

tumor is borderline resectable, locally advanced and unresectable but nonmetastatic, or a

• We do not administer neoadjuvant imatinib to patients who have a platelet-derived

For all patients undergoing neoadjuvant imatinib, imatinib should be continued

● Indications for surgery – There is no consensus as to the indications for surgical

Estimation of recurrence risk — Estimation of recurrence risk following resection of a GIST is

and "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted

At a median follow-up of 54 months, prolonged treatment was associated with a significant

● Consensus-based clinical practice guidelines from the National Comprehensive Cancer

Molecular subtypes and primary resistance — We perform molecular analysis on all

● In an analysis of molecular features associated with treatment benefit in the ACOSOG

Role of genotyping — Tumor genotyping should be performed for all patients being

Patients with primary or recurrent localized disease — There is no consensus as to the

An important point is that preoperative imatinib prohibits accurate assessment of recurrence

Response assessment — Patients being considered for neoadjuvant treatment of a GIST

However, in most cases, periodic cross-sectional imaging using conventional CT scanning is

● Radiographically, GISTs may actually increase in size during early treatment as a

● As a result of these issues, response to imatinib is frequently defined as absence of

Duration of therapy — The optimal duration of neoadjuvant TKIs is not established. The

Data on radiologic assessment of response to upfront imatinib come from a retrospective

Postoperative management — For patients undergoing neoadjuvant imatinib, we

Recommendations of expert groups — There is no consensus among expert groups as to the

leiomyosarcomas of the gastrointestinal tract", section on 'Role of surgery in patients with

There are no evidence-based guidelines on what constitutes appropriate follow-up after

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

SUMMARY AND RECOMMENDATIONS

We initiate imatinib at a dose of 400 mg daily. At the authors' institutions, tumor

For patients undergoing neoadjuvant imatinib, we continue imatinib postoperatively to

Cytoreductive surgery in this setting often requires extensive potentially morbid

Use of UpToDate is subject to the Subscription and License Agreement.

ACOSOG Z9001 trial. J Clin Oncol 2014; 32:1563.

6. Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at

7. Miettinen M, Makhlouf H, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the

35. Hohenberger P, Ronellenfitsch U, Oladeji O, et al. Pattern of recurrence in patients with

50. Rutkowski P, Gronchi A, Hohenberger P, et al. Neoadjuvant imatinib in locally advanced

51. Gervaz P, Huber O, Morel P. Surgical management of gastrointestinal stromal tumours. Br J

59. Le Cesne A, Van Glabbeke M, Verweij J, et al. Absence of progression as assessed by

Overview of the approach to treatment of gastrointestinal stromal tumors (GIST)

NF: neurofibromatosis; SDH: succinate dehydrogenase.

¶ Irregular border, cystic spaces, ulceration, echogenic foci, heterogeneity.

Graphic 104075 Version 2.0

Mitotic index (per

Low risk 2.1 to 5.0 ≤5 Any

Intermediate risk 2.1 to 5.0 >5 Gastric

5.1 to 10.0 ≤5 Gastric

High risk Any Any Tumor rupture

>10 cm Any Any

Any >10 Any

>5.0 >5 Any

2.1 to 5.0 >5 Nongastric

5.1 to 10.0 ≤5 Nongastric

Graphic 85938 Version 2.0

Proposed modification of the original NIH consensus criteria for risk

Risk group Size (cm) Mitotic rate* (per 50 HPF)

Original NIH[1] criteria