INTRODUCTION — Stromal or mesenchymal neoplasms affecting the gastrointestinal (GI) tract are divided into two groups. The most common group consists of neoplasms that are 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).
The pathologic characterization of GIST as a unique form of GI sarcoma was first described in 1983, and it was later demonstrated that mutational activation of one of two proto-oncogenes, KIT or platelet-derived growth factor receptor-alpha (PDGFRA), stimulated the growth of the cancer cells. These mutations represent the molecular hallmark of GISTs. (See "Epidemiology, classification, clinical presentation, prognostic features, and diagnostic work-up of gastrointestinal mesenchymal neoplasms including GIST".)
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 effectiveness of these agents can be illustrated by the fact that following the introduction of imatinib, the median survival of patients with advanced GIST increased from approximately 20 to 60 months [1]. (See "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors".)
The success of these agents in advanced disease prompted interest in their perioperative use. This includes both preoperative or induction therapy for patients with unresectable or borderline resectable tumors, and adjuvant treatment for patients at high risk of recurrence after complete resection of a primary GIST tumor.
This topic review will cover the perioperative use of imatinib for localized GIST tumors. The epidemiology, classification, molecular pathogenesis, diagnostic workup, 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".)
ADJUVANT THERAPY — 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 about one-half remain recurrence-free for five or more years. (See "Local treatment for gastrointestinal stromal tumors, leiomyomas, and leiomyosarcomas of the gastrointestinal tract".)
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 malignant potential, 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 NIH consensus criteria, have been proposed to distinguish prognosis in resected GIST (table 1) [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. (See "Epidemiology, classification, clinical presentation, prognostic features, and diagnostic work-up of gastrointestinal mesenchymal neoplasms including GIST", section on 'Prognostic determinants'.)
Models such as these do not take into account the location of the GIST. In general, tumors arising from the small bowel, colon, rectum, or mesentery are associated with less favorable outcomes than those arising from the stomach [4-6].
Largely based upon data from the Armed Forces Institute of Pathology, 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 7th edition of the cancer staging manual (table 2) [7]. 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 3 and table 4). (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 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 [8]. (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 nomogram [9].
The goal of risk stratification schemes is to identify those patients who are at the highest 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 level or cutoff of recurrence risk would justify the use of adjuvant imatinib. (See 'Summary and recommendations of expert groups' below.)
Benefit of imatinib — 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 [10-13].
Phase II trials — In the phase II US Intergroup trial, American College of Surgeons Oncology Group (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 [11]. Recurrence-free survival (RFS) was the primary endpoint. In a preliminary report, at a median follow-up of four years, the one-, two-, and three-year overall survival rates were 99, 97, and 97 percent, respectively, and the corresponding rates of relapse-free survival (RFS) were 94, 73, and 61 percent.
Phase III trials
ACOSOG Z9001 — Benefit for imatinib compared to surgery alone was shown in a subsequent phase III, double-blind multicenter ACOSOG Z9001 trial [12]. 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 for RFS of 0.35, 95% CI 0.22 to 0.53 [12].
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 5). 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 [14].
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 [1]. 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 US 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 [15,16]. 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.
Although not included in the study, the results may be relevant to the 4 percent of patients with GISTs that lack KIT overexpression, but have mutations in KIT or PDGFRA, and can respond to imatinib [1]. On the other hand, patients who lack detectable KIT or PDGFRA mutations or who have specific mutations that are known to be insensitive to imatinib (eg, PDGFRA exon 18 D842V) may not benefit. Whether such patients should be identified prospectively and specifically excluded from receiving adjuvant imatinib is unclear. Routine molecular testing of individual GISTs to define genotype is not performed widely. (See "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors", section on 'Influence of mutations on response to therapy'.)
SSG XVIII trial — The Scandinavian Sarcoma Group (SSG) XVIII trial compared 36 versus 12 months of imatinib (400 mg daily) in 400 patients with high-risk resected GIST [17]. High-risk was defined according to the modified consensus criteria [18] 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. About 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 to 0.65) as well as overall survival (92 versus 82 percent, HR 0.45, 85% CI 0.22 to 0.89). 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). 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).
These data establish 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. This finding raises questions as to whether recurrences are truly being prevented or just delayed.
Other completed trials — In addition to the ACOSOG Z9001 trial and the SSG XVIII trial, both of which had RFS as the primary endpoint, the Intergroup EORTC 62024 trial, a randomization between two years of imatinib and observation alone, has been completed and is awaiting data maturation. Overall survival is the primary end point. A single-arm phase II five-year adjuvant imatinib trial, PERSIST5, has also completed accrual; data will not be available for several years.
Imatinib dosing — The ACOSOG Z9001 trial tested only the 400 mg daily dose in the adjuvant setting. In randomized trials, patients with advanced GIST and KIT exon 9 mutations do better with 800 mg daily doses. (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 ours, routinely genotype patients with lower gastrointestinal GISTs who are starting adjuvant imatinib. The vast majority of the exon 9 mutants come from small bowel GISTs, and we encourage patients who have these mutations to take 600 to 800 mg of imatinib daily rather than 400 mg daily, if tolerated. However, this practice is not widespread.
Summary and recommendations of expert groups — Data from the SSGXVIII trial provide compelling evidence that at least three years of adjuvant imatinib therapy is both safe and effective in reducing GIST recurrence and that it improves overall survival as well. Whether longer duration of therapy than three years will provide additional benefit and the optimal selection of patients for adjuvant therapy remains unclear.
In 2008, the FDA granted accelerated approved 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 to 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.
Although risk stratification tools are available, based upon tumor size, mitotic rate, location, and in some cases, the presence of absence of tumor rupture, there is no consensus as to what cutoff for disease recurrence should be used to select patients for imatinib, and practice is variable. Each case must be approached individually, balancing the estimated likelihood of a disease recurrence based upon size, mitotic rate and tumor location (and mutation type, when available) with the risks of three years of adjuvant imatinib. The SSGXVIII trial defined high-risk as follows: a ruptured GIST, tumor size >10 cm, mitotic rate >10/50 hpf, or tumor size >5cm and >5 mitoses/hpf [17]. The risk of recurrence in these groups is approximately one-third or higher [19-21].
Existing clinical practice guidelines from the National Comprehensive Cancer Network (NCCN) suggest adjuvant imatinib for at least 36 months for patients with 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). The European Society of Medical Oncology (ESMO) [22] does not give a strong recommendation for the use of adjuvant imatinib, stating that its use can be “proposed as an option for those patients with a substantial risk of relapse for shared decision-making”; however, these recommendations were written prior to the publication of results from the SSGXVIII trial, which established a survival benefit from the use of three as compared to one year of adjuvant imatinib.
NEOADJUVANT THERAPY — Surgery is the only potentially curative option for GIST. Given the high response rates to imatinib (and potential for complete pathologic responses [23]) in the setting of advanced disease, there are several clinical scenarios in which neoadjuvant treatment 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'.)
Benefit — There are no randomized trials addressing the benefit of neoadjuvant imatinib. Since 2003, several case reports and small retrospective series have been published, 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 [24-30]. A single phase II US Intergroup trial of neoadjuvant imatinib has been completed, and preliminary results are available [31].
RTOG 0132/ACRIN 6665 trial — The multicenter RTOG (Radiation Therapy Oncology Group) 0132/ACRIN (American College of Radiology Imaging Network) 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 [31]. 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 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 preliminary update at a median follow-up of 5.1 years (presented at the 2011 meeting of the American Society of Clinical Oncology [ASCO]), 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 77 percent in those with recurrent or metastatic disease [32]. These data support the view that longer postoperative treatment with imatinib in patients with high-risk disease should be considered, although the optimal duration is not established. (See 'Summary and recommendations of expert groups' above.)
While this trial confirmed the safety of neoadjuvant imatinib, it tested a relatively brief period of preoperative treatment. The available data from patients treated for advanced disease suggest that maximal radiographic response to imatinib generally occurs after three to nine months of treatment. (See "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors".)
Retrospective series — Data from retrospective series also support the benefit of initial imatinib therapy [25-28,30,33]. The largest experience consisted of 46 patients who underwent surgery after imatinib, 11 with a locally advanced primary tumor, and 35 with recurrent or metastatic disease [25]. All 11 patients who were treated for a locally advanced primary tumor (median 12 months of imatinib prior to resection, with one complete and eight partial responses as assessed by CT) successfully underwent complete surgical resection. There was one complete pathologic response. At a median follow-up of 19.7 months postresection, all 11 remained alive, ten recurrence-free.
There were 11 partial responses among the 35 patients treated for recurrent/metastatic disease, and 11 patients were able to undergo a compete resection, two with pathologic complete response. Patients with an objective partial response to imatinib (by CT) were significantly more likely to undergo a complete resection (91 versus 4 percent of those whose best response was progressive disease). All eleven of the completely resected patients remained alive at a median follow-up of 30.7 months, but six recurred at a median of 15 months, despite continued imatinib.
Response assessment — The best method to assess response of a GIST to TKIs is controversial. PET scanning using fluorodeoxyglucose (FDG-PET) is highly sensitive for detecting tumors with a high glucose metabolism. Accumulating data support the view that very early evidence of tumor response (within days of instituting imatinib [34]) can be obtained through the use of metabolic imaging as compared to 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, resection or sunitinib) if imatinib is ineffective. (See "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors", section on 'Assessing response to therapy'.)
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 [35]. 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" [36]) is unproven.
Summary and recommendations of expert groups — Although randomized trials proving benefit are not available, data from retrospective series and an early report of a prospective multicenter phase II trial suggest that initial (neoadjuvant) therapy with imatinib can reduce tumor bulk, and permit later resection of initially unresectable or borderline resectable disease.
There is no consensus as to the indications for neoadjuvant therapy. Some suggest that the use of neoadjuvant imatinib, especially for primary tumors, should be restricted to clinical trials [37], while others 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) [38]. 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 [39]. We agree with this approach.
These patients should be managed in a center that has a strong multidisciplinary team approach. The usual schema is give imatinib for anywhere from 3 to 12 months, with frequent imaging studies, and periodic reevaluation for surgical intervention. 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.
A daily dose of 400 mg per day is the usual approach, although if a KIT exon 9 mutation is identified, dose escalation to 800 mg per day is reasonable, and is recommended in ESMO guidelines [15]. However, routine genotyping of GISTs is not widely practiced. (See "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors", section on 'Influence of mutations on response to therapy'.)
For patients who have a good response to neoadjuvant imatinib, continuation of treatment after resection for at least one year is recommended. (See 'Adjuvant therapy' above.)
Patients with metastatic disease — Although therapy with TKIs has become the first-line treatment for metastatic GIST, 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 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.
Single institution retrospective studies document long-term disease control following resection for selected patients with limited metastatic disease. In the absence of controlled trials, some general conclusions can be drawn from the published experience of several groups:
- 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 to 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 GIST, and there is no consensus on this issue. Guidelines from the National Comprehensive Cancer Network (NCCN) suggest the following [40]:
- For a completely resected GIST tumor, history and physical examination every three to six months for five years, then annually. A 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 as well as abdominopelvic CT scan are recommended every three to six months.
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.)
SUMMARY AND RECOMMENDATIONS
- Gastrointestinal stromal tumors (GISTs) are common mesenchymal neoplasms that affect the Gl tract.
- 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 has activating mutations in a related RTK, platelet-derived growth factor receptor-alpha (PDGFRA). (See 'Introduction' above.)
- Small molecule tyrosine kinase inhibitors 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.
- We recommend adjuvant treatment with a tyrosine kinase inhibitor (imatinib 400 mg daily) for a minimum of three years rather than one year 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. 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. (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 mutation type, if available) with the risks of therapy (table 5) [4]. In the SSGXVIII trial, high-risk GISTs were defined as >10 cm, or mitotic count >10/50 high-power fields (HPF), or >5 cm with a mitotic rate >5/HPF, or a ruptured tumor.
If a known KIT exon 9 mutation is identified, higher dose imatinib may be considered, but 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'.) - For patients with nonmetastatic but locally advanced unresectable GIST, potentially resectable primary tumors but with the risk of significant morbidity, or potentially resectable metastatic GISTs, we suggest initial treatment with imatinib followed by attempted resection as long as there is no evidence of generalized progression (Grade 2B). If possible, such patients should be enrolled on a clinical trial. (See 'Neoadjuvant therapy' above.)
The optimal duration of neoadjuvant imatinib is uncertain, and we individualize this decision based upon drug tolerance, tumor location and extent, and the urgency of surgical treatment. - For patients with potentially resectable metastatic disease, aggressive cytoreductive surgery should be offered only to patients whose disease is stable or responding to TK inhibitor therapy, or who have only focal progression (Grade 1B). Patients with extensive disease progression while on TK inhibitor therapy gain little benefit from surgery, and it is not recommended. (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, pancreatic resection, and should be carried out in centers of excellence. All patients should resume therapy with a TK inhibitor after resection. (See 'Patients with metastatic disease' above.)
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