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Adjuvant and neoadjuvant imatinib for gastrointestinal stromal tumors
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Adjuvant and neoadjuvant imatinib for gastrointestinal stromal tumors
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Jul 06, 2016.

INTRODUCTION — Stromal or mesenchymal neoplasms affecting the gastrointestinal (GI) tract are divided into two groups. The most common group is collectively referred to as GI 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 SDH subunits leading to the SDH-deficient GIST. (See "Epidemiology, classification, clinical presentation, prognostic features, and diagnostic work-up of gastrointestinal mesenchymal neoplasms including GIST", section on 'Classification and molecular 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 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 "Epidemiology, classification, clinical presentation, prognostic features, and diagnostic work-up of gastrointestinal mesenchymal neoplasms including GIST" 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) 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 an SDH-deficient or neurofibromatosis (NF)-related GIST, and instead proceed directly to surgery. (See 'ACOSOG Z9001' below and "Epidemiology, classification, clinical presentation, prognostic features, and diagnostic work-up of gastrointestinal mesenchymal neoplasms including GIST", section on 'SDH subunit mutations and epimutant tumors'.)

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 durations of treatment. (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 'Management of imatinib-refractory or intolerant patients'.)

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 — The standard of care for patients with a primary resectable gastrointestinal stromal tumor (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 Scandinavian Sarcoma Group (SSG) XVII 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 [2]. (See "Epidemiology, classification, clinical presentation, prognostic features, and diagnostic work-up of gastrointestinal mesenchymal neoplasms including GIST", section on 'Prognostic determinants'.)

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) [3]. 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 [4]. (See "Epidemiology, classification, clinical presentation, prognostic features, and diagnostic work-up of gastrointestinal mesenchymal neoplasms including GIST", section on 'Prognostic determinants' and "Epidemiology, classification, clinical presentation, prognostic features, and diagnostic work-up of gastrointestinal mesenchymal neoplasms including GIST", section on 'Significance of tumor genotype and kinase mutation status' and 'ACOSOG Z9001' below.)

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 [5-7]. 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 TNM (tumor-node-metastasis) staging system for GIST was developed by the American Joint Committee on Cancer (AJCC) and International Union Against Cancer (UICC), and published in the 2010 seventh edition of the cancer staging manual (table 4) [8]. The T and N designations are similar for all disease sites, but there are separate stage groupings for gastric/omental and for small bowel/esophageal/colorectal/mesenteric primaries. Rates of disease progression for gastric and small bowel GISTs, stratified by stage at diagnosis, are presented in the tables (table 5 and table 6). (See "Epidemiology, classification, clinical presentation, prognostic features, and diagnostic work-up of gastrointestinal mesenchymal neoplasms including GIST", section on 'Tumor size, mitotic rate, and location'.)

Although not included in the TNM staging system, tumor rupture [9,10] 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 [11]. (See "Epidemiology, classification, clinical presentation, prognostic features, and diagnostic work-up of gastrointestinal mesenchymal neoplasms including GIST", section on 'Tumor rupture'.)

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 though the use of a GIST tumor nomogram [12]. Different nomograms have been developed by others [13,14].

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 [9,15]. (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 [9]. Tumors were classified according to the NIH consensus criteria (table 2) [3], a modification of the NIH consensus criteria (table 1) that includes site as well as tumor rupture [11], and the AFIP criteria (table 3) [5]. 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) [11] were best at identifying a single subgroup of patients at high-risk of recurrence [9]. 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 neurofibromatosis (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 [16]. Furthermore, there are no data demonstrating the benefit of adjuvant imatinib in these subtypes nor basic scientific rationale for antitumor activity. (See 'Molecular subtypes' below.)

Benefit of imatinib

Phase II trials — In the phase II US Intergroup trial ACOSOG Z9000, 107 patients with a completely resected GIST ≥10 cm in size, ruptured, hemorrhaging, or multifocal GIST (<5 sites total) all received 400 mg imatinib daily for one year [17]. RFS was the primary endpoint. At a median follow-up of 7.7 years, the one-, two-, and three-year overall survival rates were 99, 97, and 83 percent, respectively, and the corresponding rates of RFS were 96, 60, and 40 percent, respectively.

A single-arm phase II five-year adjuvant imatinib trial, PERSIST5, has completed accrual; data will not be available for several years.

Phase III trials — At least three phase III trials have evaluated the benefit of adjuvant imatinib; only two (ACOSOG Z9001 and EORTC 62024) had a no-treatment control arm.

ACOSOG Z9001 — Benefit for imatinib compared with surgery alone was shown in a subsequent phase III, double-blind, multicenter ACOSOG Z9001 trial [18]. 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 [18]. 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 [19].

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 nonanthracycline cancer chemotherapy agents", section on 'Imatinib'.)

No overall survival 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 [20]. Furthermore, after the study was unblinded, all patients randomized to placebo were allowed to crossover to active treatment, thus obscuring any potential differences in overall survival 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 [21,22]. 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.

Molecular subtypes — 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 [4]. (See "Epidemiology, classification, clinical presentation, prognostic features, and diagnostic work-up of gastrointestinal mesenchymal neoplasms including GIST", section on 'SDH subunit mutations and epimutant tumors' and "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors", section on 'Influence of mutations on response to therapy'.)

Few data are available with regard to the adjuvant setting. In an analysis of molecular features associated with treatment benefit in the ACOSOG Z9001 study, 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 [4]. 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'.)

Although routine genotype testing (mutational profiling) of any individual patient's GIST continues not to be performed widely, particularly in the United States, in our view, mutational profiling is important for patients being considered for adjuvant (or neoadjuvant) therapy with a tyrosine kinase inhibitor (TKI), so that the most accurate prognostic information and the most informed care decisions can be made based upon the specific mutations that are associated with different molecular subtypes. (See "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors", section on 'Influence of mutations on response to therapy'.)

EORTC 62024 — The Intergroup EORTC 62024 trial randomly assigned 908 patients with intermediate- or high-risk GIST (according to the 2002 NIH classification (table 7), and including tumor rupture or intraoperative tumor spillage) to two years of imatinib or observation alone. The primary endpoint was originally overall survival, but the protocol was modified in 2009 to change the primary endpoint to imatinib-free survival (IFS, the time to death or starting a TKI other than imatinib); the accrual target was subsequently also increased. At a median follow-up of 4.7 years, five-year IFS was 87 percent in the imatinib arm compared with 84 percent in the control arm (HR 0.79, 98.5% CI 0.50-1.25), three-year RFS was 84 versus 66 percent, and five-year overall survival was 100 versus 99 percent [23]. Even among the 528 patients with high-risk GIST according to the 2002 NIH classification (table 7) as determined by central pathology review, there was only a trend toward better IFS that favored adjuvant imatinib (five-year IFS 79 versus 73 percent, p = 0.087). Similarly, when risk was stratified according to modified NIH risk stratification criteria to include primary tumor site (table 1), the difference in IFS between the treated and control groups was still not statistically significant.

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 [24]. High-risk was defined according to the modified consensus criteria [25] as having at least one of the following: tumor size >10 cm, mitotic count >10/50 high-power fields (HPF), tumor size >5 cm with mitotic rate >5/HPF, 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 overall survival (92 versus 82 percent, HR 0.45, 85% CI 0.22-0.89) [24]. Benefits persisted in a later report with a longer median follow-up of 90 months; patients assigned to three years of imatinib continued to have significantly greater RFS (71 versus 52 percent) and overall survival (92 versus 85 percent) [26].

Treatment-related adverse effects were more common with longer treatment, including periorbital edema (74 versus 59 percent), diarrhea (54 versus 44 percent), and muscle cramps (49 versus 31 percent) [24]. 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 [24]. This finding raises questions 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 [10]. 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.

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 EMA (European Medicines Agency) 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 >10/50 HPF, or tumor size >5 cm and >5 mitoses/HPF [24]. The risk of recurrence in these groups is approximately one-third or higher [27-29]. (See 'SSG XVIII trial' above.)

Consensus-based clinical practice guidelines from the National Comprehensive Cancer Network (NCCN) 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/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 [11]. The proposed modified NIH criteria (table 1) [11] 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. 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).

Resistance to treatment with imatinib can be divided into two types, primary and secondary. Approximately 10 percent of patients with GIST have primary resistance, and most of these tumors lack mutations in the KIT gene. The implications of specific mutations on decisions about therapy for advanced disease are discussed elsewhere. (See "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 to benefit from adjuvant imatinib is unconvincing [4,24], and treatment of this group remains controversial [30]. In one 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 [31].

NCCN 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.

Optimal duration of therapy — We recommend adjuvant imatinib for at least three years after resection of a high-risk GIST. However, whether treatment should be continued for longer than three years (or even lifelong) is not known. Preclinical data suggest that imatinib is not curative, inducing cellular quiescence but not death [32]. 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 [24]. Furthermore, although overall survival 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 [26]. 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 [33].

At least one trial studying five years of adjuvant imatinib in high-risk resected GIST (PERSIST 5) has completed accrual, but follow-up is too short for preliminary results to be informative [34]. With long-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 longer duration (perhaps lifelong) imatinib may be needed [33].

NEOADJUVANT THERAPY — Surgery is the only potentially curative option for gastrointestinal stromal tumors (GISTs). Given the high response rates to imatinib (and the potential for complete pathologic responses [35]) 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 'Efficacy of imatinib'.)

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 platelet-derived growth factor receptor-alpha (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 [36].

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 [36]. 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 [37]. (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 [38] 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".)

Retrospective series — Data from multiple retrospective series also support the benefit of initial imatinib therapy in patients with locally advanced GISTs [39-45]. 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) [45]. 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 [46]. The benefits of perioperative imatinib in patients with rectal GIST can be illustrated by the following reports:

In a series of 39 patients with rectal GIST, 21 received preoperative and/or postoperative imatinib [47]. Patients who received preoperative imatinib had a significantly higher rate of tumor excision with a negative surgical margin. Five patients developed a local recurrence, all of whom had undergone local tumor excision with positive margins, without preoperative imatinib. In addition, five patients developed distant metastases, all of whom had tumor surgery without receiving perioperative imatinib.

In another report of 32 patients, 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 [48]. 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. (See "Epidemiology, classification, clinical presentation, prognostic features, and diagnostic work-up of gastrointestinal mesenchymal neoplasms including GIST", section on 'Significance of tumor genotype and kinase mutation status'.)

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 recommended in the European Society for Medical Oncology (ESMO) guidelines [49]. (See 'Imatinib dosing' above.)

Other mutations are insensitive to imatinib altogether (eg, PDGFRA exon 18 D842V mutations, SDH-mutant, 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 [50]. (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-PET) 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 [51]) 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 'Conventional CT scans'):

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) [52]. 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 [38]. 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 34 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 [39,53]. Whether longer periods of neoadjuvant treatment are detrimental for patients being treated for a recurrent/metastatic GIST is unclear [53].

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 [54]. 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" [55]) 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 [49,56,57]. Some limit this approach to patients with identifiable high-risk characteristics (size >5 cm, >5 mitoses/50 HPF, anatomic location resulting in a potentially morbid resection) [56]. Consensus-based guidelines from the NCCN 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 [57]. 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 in China, but both failed to recruit quickly enough to meet target accrual. In the absence of controlled trials, some general conclusions can be drawn from single-institution 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) 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 [49]:

For high-risk tumors (based upon mitotic count, tumor size, and tumor site), routine follow-up with CT or magnetic resonance imaging (MRI) every three to six months for three years during adjuvant therapy, with tighter clinical follow-up due to the need to manage the side effects of adjuvant therapy. On cessation of adjuvant imatinib, routine follow-up with imaging every three months for two years, then every six months until five years from stopping adjuvant imatinib, then annually for an additional five years.

For low-risk tumors, the usefulness of routine follow-up is not known; if selected, this is carried out with CT or MRI every 6 to 12 months for five years.

For very low-risk GISTs, routine follow-up is probably not warranted, though the risk of recurrence is not nil.

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 [58] 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.

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SUMMARY AND RECOMMENDATIONS

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms that affect the Gl 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 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.)

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. We recommend adjuvant therapy to all patients who fall into a "high-risk" category, regardless of the risk stratification model used (Grade 1B). (See 'Patient selection' above.)

Some centers, including that of the authors, routinely genotype all patients with GIST who are being considered for adjuvant imatinib. We generally discourage the use of adjuvant imatinib in patients with SDH-deficient GIST, 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, 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 an apparently localized rectal GIST (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 would like to acknowledge George Demetri, MD, who contributed to an earlier version of this topic review.

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