Chapter 24. Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors (GISTs) are rare neoplasms. Although they represent only 0.1–3% of all gastrointestinal (GI) malignancies,1–4 they account for 80% of gastrointestinal mesenchymal neoplasms.5 Approximately 5000–6000 new cases are diagnosed per year in the United States, for an annual incidence of 14.5 per million and prevalence of 129 per million.6 In the last 12 years, the understanding and treatment of GIST has witnessed remarkable advances due to two key developments: (1) the identification of constitutively active signals (oncogenic mutation of the c-kit and platelet-derived growth factor receptor alpha[PDGFRA] gene-encoding receptor tyrosine kinases) and (2) the development of therapeutic agents that suppress tumor growth by specifically targeting and inhibiting this signal (imatinib mesylate, sunitinib malate). These developments in the management of GIST represent a proof of the principle of translational therapeutics in oncology, confirming that specific inhibition of tumor-associated receptor tyrosine kinase activity may be an effective cancer treatment. The advent of effective therapy for GIST has not diminished but rather redefined the role of surgery for this disease. This chapter reviews the biology, treatment, and emerging clinical challenges of these mesenchymal neoplasms.

Historical Background

The term “GIST” was initially coined in 1983 by Mazur and Clark to describe intra-abdominal nonepithelial neoplasms that lacked the ultrastructural features of smooth muscle cells and the immunohistochemical characteristics of Schwann cells.7 GISTs typically exhibit heterogeneous histologic features. They are most commonly composed of long fascicles of spindle cells with pale to eosinophilic cytoplasm and rare nuclear pleomorphism, but may occasionally exhibit epithelioid characteristics, including sheets of round- to oval-shaped cells with abundant eosinophilic cytoplasm and nuclear atypia (Fig. 24-1). Based on their histologic and immunohistochemical features, GISTs are believed to arise from the interstitial cells of Cajal, components of the intestinal autonomic nervous system that serve as intestinal pacemakers.8 Nonetheless, until the late 1990s, there were no objective criteria to classify GISTs. They were frequently misclassified as leiomyomas, leiomyoblastomas, leiomyosarcomas, Schwannomas, gastrointestinal autonomic nerve tumors, or other similar soft tissue histologies.9 Consequently, interpreting clinical results for reports on “GISTs” published before 2000 can be challenging.

Receptor Tyrosine Kinase Mutations

In a landmark publication in 1998, Hirota and colleagues reported two critical findings: (1) near-universal expression of the transmembrane receptor tyrosine kinase KIT in GIST, and (2) presence of gain-of-function mutations in the corresponding c-kit proto-oncogene.10 The KIT receptor is activated by binding its cytokine ligand known as steel factor or stem cell factor.11 KIT plays a critical role in the development and maintenance of components of hematopoiesis, gametogenesis, and intestinal pacemaker cells.12–14 Oncogenic KIT mutations have been identified in neoplasms corresponding to these functions, including mast cell tumors, myelofibrosis, chronic myelogenous leukemia, germ cell tumors, and GIST.12 Mutated KIT remains constitutively active even in the absence of ligand binding and results in both unregulated cell growth and malignant transformation.10

GISTs are now identified by immunohistochemical staining for the CD117 antigen, part of the KIT receptor, in the appropriate histopathologic context (Fig. 24-2). CD117 expression is characteristic of most GISTs but not of other gastrointestinal smooth muscle tumors such as leiomyosarcoma, which are more likely to express high levels of desmin and smooth muscle actin.12–15 Application of CD117 staining as a diagnostic criterion for GIST has altered understanding of the prevalence of this disease (see the following section Epidemiology).

Over 85% of GISTs have activating KIT mutations (Fig. 24-3).12 These mutations commonly occur in exon 11 (in 57–71% of cases), exon 9 (10–18%), exon 13 (1–4%), and exon 17 (1–4%).16–19 Some GISTs may stain strongly for KIT (CD117) by immunohistochemistry (KIT-positive) yet lack KIT mutations,12 while others that do not stain for KIT (KIT-negative) may nevertheless harbor KIT mutations.20 Approximately 35% of neoplasms lacking KIT mutations have activating mutations in a gene encoding a related receptor tyrosine kinase, the PDGFRA.21–23PDGFRA mutations have been identified in exon 12 (1–2% of GISTs), exon 18 (2–6%), and exon 14 (<1%).21,24 Finally, a few GISTs, the so-called wild-type (WT) GISTs, exhibit no detectable KIT or PDGFRA mutations and presumably have alternative pathways for pathogenesis. Recently, additional putative mutations have been identified. A BRAF exon 15 mutation was identified in a small percentage of WT tumors.25 Insulin-like growth factor 1 receptor (IGF-1R) overexpression was documented in some WT GISTs as well.26

Age

The median age at diagnosis of GIST is 60 years (range 40–80 years).2,6 They are equally common in men and women, and there is no racial or ethnic predilection. GIST does occur rarely in children, often as a familial syndrome or as part of Carney's triad (see the following text).27,28 The clinical presentation is typically different in children, who tend to present with multifocal gastric GISTs, harbor WT KIT/PDGFRA genes, and have a higher incidence of lymph node metastases.25

Hereditary GIST

The overwhelming majority of GISTs are sporadic. Nevertheless, 17 kindreds with germline KIT mutations and 3 with a PDFGRA mutation have been reported.29–37 Individuals with GISTs secondary to germline KIT mutations are usually younger than those with sporadic GISTs, manifest multifocal disease at presentation, and only rarely develop metastatic disease.36 The phenotype includes skin hyperpigmentation and diffuse hyperplasia of the intestinal myenteric plexus.38

Approximately 7% of individuals with von Recklinghausen's neurofibromatosis (NF1) have GIST, most commonly in the small intestine.39–41 In addition to their NF1 mutations, these individual express KIT and PDGFRA point mutations in 8 and 6% of GISTs, respectively.42 Conversely, NF1 mutations have not been identified in non-NF1 individuals with sporadic GISTs.43

Gastric GISTs are components of both Carney's triad and Carney-Stratakis syndrome. Fewer than 100 cases of Carney's triad, consisting of gastric GISTs, pulmonary chondromas, and paragangliomas, have been reported.28,44 Approximately 85% occur in women and 80% are diagnosed before the age of 30. Patients with Carney's triad do not have somatic KIT or PDGFRA mutations. The similarly eponymous Carney-Stratakis syndrome describes familial cases expressing the dyad of gastric GIST and paraganglioma.30 Recently, mutations in several succinate dehydrogenase subunits have been reported in Carney-Stratakis syndrome kindreds.45

Incidence

Investigators have attempted to determine the true incidence of GIST using the Surveillance, Epidemiology, and End Results (SEER) database from the National Cancer Institute. However, these data are difficult to interpret because many GISTs were previously misclassified as other GI mesenchymal neoplasms.46 Although a near doubling of the incidence of all GI mesenchymal tumors (over 80% were GIST) has been reported (0.17/100,000 in 1992 to 0.31/100,000 in 2002), this may be due to increased recognition, increased screening, and/or true increased incidence.46 The annual incidence in the United States is estimated to be approximately 5000 new cases per year.47 European population-based studies identified annual incidence rates ranging from 11 to 14.5 cases per million population.6,48

GISTs commonly arise in the stomach (50–70%), small intestine (25–35%), colon and rectum (5–10%), mesentery or omentum (7%), and esophagus (<5%).9,49 Occasionally, GIST may arise in the duodenal ampulla, appendix, gallbladder, and urinary bladder.50–55

GISTs are generally found due to symptoms. In one study, 69% of tumors were symptomatic, 21% were discovered incidentally at surgery, and 10% were discovered at autopsy.6 GISTs are often highly vascular, soft, and friable, and bleeding is a common presenting symptom. They may cause life-threatening hemorrhage by erosion into the bowel lumen. Alternatively, tumor rupture may cause potentially catastrophic intraperitoneal bleeding and/or dissemination by peritoneal seeding. Intestinal obstruction may lead to perforation. Smaller tumors may remain asymptomatic, incidentally detected on radiographic studies, endoscopy, or laparotomy. Between 15 and 47% of patients with GIST have metastatic disease at diagnosis.2,56 Common sites of metastasis include liver, peritoneum, and omentum; lymph node metastases are rare.5 Extra-abdominal metastases (lung, bone, subcutaneous tissues, and brain) are rare, observed in approximately 5% of patients.57

Radiographic Studies

The initial imaging study for a suspected or confirmed GIST is a contrast-enhanced computed tomography (CT) of the abdomen and pelvis.58 Primary GISTs are typically well-circumscribed masses within the walls of hollow viscera (Fig. 24-4). Magnetic resonance imaging (MRI) may help characterize metastatic liver or primary perirectal disease (Fig. 24-5). Although [18F]fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) may help characterize masses ambiguous on CT, monitor response to therapy, and detect emergence of drug-resistant clones, it is not specific for GIST and thus is not recommended for most patients with suspected primary disease.59–61

Endoscopy, Fine-Needle Aspiration, and Biopsy

Endoscopically, a primary GIST may appear as a submucosal lesion, with or without ulceration, present in the upper or lower GI tract. They are often indistinguishable from other GI tumors of smooth muscle origin, such as leiomyomas (Fig. 24-6). Endoscopic ultrasound (EUS) is not necessary to evaluate a confirmed GIST. However, EUS-guided fine-needle aspiration (FNA) may be attempted to establish diagnosis. Nevertheless, EUS-FNA is not consistently diagnostic.62 Additional cytologic morphology, immunohistochemistry, and reverse-transcriptase polymerase chain reaction analysis for KIT mutations may be required to confirm a diagnosis.63

A preoperative biopsy is not routinely necessary for a primary, resectable neoplasm suspicious for GIST. In fact, preoperative biopsy may rupture a suspected GIST and increase the risk of dissemination. However, if the differential diagnosis includes entities such as lymphoma that would be treated differently, if neoadjuvant therapy is under consideration, or if there is metastatic disease, biopsy is appropriate.

While tumors under 1 cm likely have a low risk of recurrence, no tumors can be definitively called benign and most large tumors have malignant potential. The three established prognostic factors are tumor size, mitotic index, and tumor site of origin, with mitotic count the most important (Table 24-1).15,64,65 Individuals with small bowel GISTs have a higher risk of progression than those with gastric GISTs of comparable size and mitotic count.

Additional adverse prognostic factors observed in some but not in all studies include high cellular proliferation index,66 aneuploidy,66,67 telomerase expression,68,69KIT exon 9 mutations,65 and KIT exon 11 deletions involving amino acid W557 and/or K558.70 Point mutations and insertions of KIT exon 11 appear to have a favorable prognosis.65

The ideal margin of resection is unknown. While a macroscopically complete resection with negative or positive microscopic margins (R0 or R1 resection, respectively) is associated with a better prognosis than a macroscopically incomplete resection (R2 resection), there are no data to confirm that a positive microscopic margin (R1 resection) impacts survival.2

Surgery

Technique

Surgery remains the standard of care and only potentially curative therapy for patients with primary, resectable, localized GIST. The goal of the operation should be an R0 resection. Tumor rupture or violation of the tumor capsule during surgery is associated with an increased risk of recurrence.

At laparotomy, the abdomen is thoroughly explored to identify and remove any previously undetected peritoneal metastatic deposits. Although primary GISTs may demonstrate inflammatory adhesions to surrounding organs, they do not generally invade other organs beyond the site of origin despite CT appearance. The extent of surgery is usually a wedge or segmental resection of the involved stomach or bowel without the wide margins necessary for adenocarcinoma. In a series of 140 patients with gastric GISTs, wedge resections were performed in 68%, partial gastrectomies in 28%, and total gastrectomies in only 4%.71 Occasionally, a more extensive resection (total gastrectomy for a large proximal gastric GIST, pancreaticoduodenectomy for a periampullary GIST, or abdominoperineal resection for a low rectal GIST) may be necessary. There are also no data indicating that patients who have an R1 resection require reexcision.47 The value of wide surgical margins is unknown, particularly in the era of the targeted therapies described in the following text. Furthermore, margins may retract after resection, or the pathologist may trim away the staple line (converting a technically negative microscopic margin into a positive one). Therefore, all cases of positive microscopic margins should be carefully reviewed by a multidisciplinary team of surgical oncologists, pathologists, and medical oncologists to assess the need for reexcision. Lymphadenectomy is not required because lymph nodes are rarely involved (in adult patients).

All GISTs 2 cm in size or greater should be resected when possible, as none of these can be considered benign.64 However, the natural history of GISTs under 2 cm in size is unknown, and thus their management is more debatable. Any small GISTs that are symptomatic (eg, hemorrhage from erosion through the mucosa) or increase in size on serial follow-up should be resected.

It is probable that most GISTs under 1 cm in size may be followed (especially gastric GISTs). Two studies have established that subcentimeter gastric GISTs are relatively common, detected in 22.5% of autopsies in adults older than 50 in Germany and in 35% of patients undergoing gastrectomy for gastric cancer in Japan.72,73 Despite their relative frequency, few of these neoplasms appear to become clinically relevant. Until further data are available, the most appropriate management of such small tumors remains uncertain. Although endoscopic resection of small gastric GISTs has been reported, this cannot be recommended.74 Unlike early gastric cancers (mucosal malignancies) amenable to endoscopic mucosal resection, GISTs involve the muscularis propria, so attempts at endoscopic resection risk leaving a positive margin and, due to the depth of the lesion, could result in perforation.

The management of gastric GISTs 1–2 cm in size is even more confusing. On the one hand, the very low risk of recurrence in conjunction with a low mitotic index supports a more conservative, nonoperative approach. On the other hand, an accurate mitotic index cannot be determined by biopsy or FNA. Therefore, observation cannot be recommended based on size alone. Resection (laparoscopic if possible) should be considered, and the risks and benefits of surgery versus observation should be reviewed with the patient.

Little data exist on the natural history of small nongastric GISTs. Given the higher risk of aggressive behavior of small bowel and colon GISTs, any tumor in such locations should be resected irrespective of size.

Laparoscopic or laparoscopy-assisted resection of primary GISTs may be performed following standard oncologic principles (Fig. 24-7). Two early studies confirmed both the safety and feasibility of a laparoscopic approach. Otani et al reported that in a series of 35 gastric GISTs (2–5 cm), resected laparoscopically, no local or distant recurrences were observed for tumors under 4 cm in size with a median follow-up of 53 months.75 Novitsky et al reported a study of 50 patients with gastric GISTs (1.0–8.5 cm) resected laparoscopically or using laparoscopy-assistance, with 92% of patients disease-free with a mean follow-up of 3 years.76

Outcomes

Despite a macroscopically complete resection, as many as 50% of individuals may develop recurrent disease at a median of 24 months.2,77 An R0 or R1 resection is associated with 5-year overall survival (OS) rates of 34–63% whereas R2 resection is associated with 5-year OS rates of as low as 8%.1,2,78–82

Neoadjuvant Therapy for Primary Disease

The identification of two effective, relatively well-tolerated orally available targeted tyrosine kinase inhibitors (TKI)—imatinib mesylate (STI571, Gleevec) and sunitinib malate (SU11248, Sutent)—has revolutionized the treatment of GIST (discussed in a later section). These agents were initially developed for the management of patients with metastatic disease. Imatinib selectively inhibits several tyrosine kinases, including KIT, PDGFRA, and BCR-ABL.18,83–85 Several clinical trials have confirmed that up to 80% of patients with metastatic GIST achieve a complete or partial response or demonstrated stable disease on imatinib.86,87

As demonstrated previously, recurrence rates are high and survival rates are low after an R0/R1 resection. Therefore, the role of neoadjuvant therapy with imatinib combined with resection has been explored in one multi-institutional88 and one single-institution89 prospective trial. For the sake of brevity, only the former is discussed here. The Radiation Therapy Oncology Group (RTOG) 0312 phase II trial is the only multicenter study reported thus far evaluating the use of imatinib as a neoadjuvant agent. Patients with resectable primary or recurrent GIST were treated with 600 mg/d of imatinib for 8–12 weeks prior to surgery (Table 24-2). Nonprogressing patients underwent surgery and were then maintained on adjuvant imatinib for 2 years. An objective response was demonstrated in 90% of patients with primary GIST, and 92% underwent R0/R1 resections. Two-year recurrence-free survival (RFS) was 83%. Although this trial confirmed the safety of imatinib as a neoadjuvant therapy, it is still unclear what the optimal length of preoperative therapy is. Data from trials of advanced GIST have demonstrated that maximal radiographic response to imatinib generally required 6–9 months of treatment.86,90,91 Thus, the optimal preoperative imatinib regimen may be 6 months or more as long as continued radiographic response is observed (Fig. 24-8).

Adjuvant Therapy for Primary Disease

The role of adjuvant therapy with imatinib combined with resection of primary disease was or is being explored in six prospective multi-institutional trials. The trials tested durations of adjuvant imatinib of 12 months (American College of Surgeons Oncology Group Z9000,92 ASOSOG Z9001,93 China Cooperative Group94), 24 months (European Organization for the Research and Treatment of Cancer [EORTC] 62024, Korean trial95), 12 versus 36 months (Scandinavian Sarcoma Group [SSG] XVIII), or 5 years (ongoing phase II multi-institutional trial, CSIT571BUS282) (see Table 24-2).92–94 Data from the only published trial, ACOSOG Z9001, are discussed in detail. In this phase III trial, patients with completely resected primary GISTs at least 3 cm in size were randomized to receive either placebo or imatinib postoperatively for 1 year. The trial was halted early after a planned interim analysis of 644 evaluable patients confirmed that the 1-year RFS was significantly better in the imatinib arm (97 vs 83%, p = .0000014). However, the slopes of the Kaplan-Meier curves representing the two treatment arms, once recurrences were observed, were similar. Thus, adjuvant imatinib may delay recurrence but may not necessarily cure anyone over the short follow-up interval. Furthermore, there was no difference in OS between the two treatment arms. Additional follow-up is necessary to determine if a difference in OS will eventually be observed. Finally, the optimal length of adjuvant therapy is uncertain. The EORTC 62024 and SSG XVIII trials have completed accrual, but data are not yet available. Data from these two trials plus the ongoing CSIT571BUS282 trial will help determine the comparative benefit of 2, 3, or 5 years of imatinib. Perhaps the most important question is whether administration of imatinib after resection of primary disease or after disease recurrence delays time to second-line therapy (imatinib dose escalation or changing to sunitinib). However, with the recent approval of imatinib for adjuvant use by both the Food and Drug Administration in the United States and the European Medicines Agency in Europe, it seems unlikely that any trial will ever be designed to answer this question.

Targeted Therapy

Historically, patients with recurrent GIST have been treated by a combination of the three traditional cancer therapeutic modalities: surgery, intravenous chemotherapy, and radiotherapy. Surgery is effective for patients with resectable disease, but disease may recur in as many as 50% of individuals. Traditional intravenous chemotherapy (including standard sarcoma regimens employing doxorubicin and/or ifosfamide) and radiotherapy have shown little efficacy.1,2,91

To date, two TKIs have been approved for the treatment of metastatic GIST: imatinib mesylate and sunitinib malate. Imatinib is the first-line therapy for advanced (unresectable primary or metastatic) GIST, based on data from international phases I, II, and III trials.60,86,87,90,96 Partial responses (PRs) or stable disease (SD) were noted in nearly 85% of patients with advanced GIST treated with imatinib.60 In the US phase III trial, the median progression-free survival (PFS) and OS with imatinib therapy were 18–20 months and 51–55 months, respectively.86 The starting dose for imatinib is generally 400 mg once daily. In patients who develop progressive disease on 400 mg, dose escalation up to 400 mg twice daily is effective.97–100 However, greater toxicity and more dose reductions are generally required at doses above 400 mg/d. In a meta-analysis of the two large phase III studies, a slight advantage in PFS was noted in patients initially treated with higher-dose imatinib, but that advantage was essentially limited to patients with KIT exon 9 mutations.101

Imatinib should be continued indefinitely. A French randomized imatinib discontinuation study demonstrated that patients with GIST on imatinib who stop imatinib therapy after 1 and 3 years had a much higher rate of disease progression than those who continued on therapy.102,103

If patients continue to progress on higher doses of imatinib or do not tolerate such doses, second-line sunitinib is started. Sunitinib is a multitargeted TKI whose targets include KIT, PDGFR, vascular endothelial growth factor receptor (VEGFR1, VEGFR2, VEGFR3), the ret proto-oncogene receptor (RET), and Fms-like tyrosine kinase-3 receptor (Flt3). A placebo-controlled phase III trial demonstrated significant improvement in time to progression in patients treated with sunitinib compared to those treated with placebo (27.3 vs 6.4 weeks, respectively), as well as PFS and OS.104 Initially dosed as 50 mg daily in a 4-week-on–2-week-off cycle, many oncologists now favor a continuous dose regimen of 37.5 mg daily.105

When sunitinib resistance develops, protocol-based therapies should be considered. Additional TKIs under investigation include sorafenib,106 nilotinib,107 masitinib,108 and vatalanib.109 Novel and potentially attractive targets include heat shock protein-90 (HSP-90)110 and IGF-1R.26

Surgery

Cytoreductive surgery for resectable advanced or metastatic disease is a relatively common practice for disseminated solid tumors originating in the colon, appendix, ovary, and testicle. With the advent of imatinib and sunitinib therapy, a number of investigators have pursued a similar strategy of aggressive cytoreductive surgery in patients with metastatic GIST on TKI therapy. Three observations support such an approach. First, the majority of patients experience durable periods of PR or SD on imatinib, lasting months to years. Second, pathologic complete responses are rare, noted in fewer than 5% of patients.99,100 Third, response to imatinib is not maintained indefinitely; the median time to progression due to the development of secondary resistance to imatinib 18–24 months.86,87 Once drug resistance develops, disease progression may be either limited (progression at one site of tumor, with other tumor deposits showing ongoing response to TKI) or generalized (progression at more than one site).111,112

Several single-institution retrospective studies have documented the PFS and OS rates following extensive cytoreductive surgery in patients with advanced GIST treated with TKI therapy (Table 24-3).111–116

In the experience at Brigham and Women's Hospital/Dana-Farber Cancer Institute (BWH/DFCI), the best results were generally seen in patients whose disease was still responsive to TKI therapy at the time of surgery. The ability to remove all macroscopic disease was greatest in patients demonstrating ongoing response to TKI therapy. After surgery, there was no evidence of any residual disease in 78, 25, and 7% of patients with responsive disease, limited progression, and generalized progression, respectively (p < .0001).112 In contrast, bulky residual disease remained postoperatively in 4, 16, and 43% of patients with responsive disease, limited progression, and generalized progression, respectively.

The series from BWH/DFCI, Memorial Sloan-Kettering Cancer Center, and Istituto Nazionale Tumori each demonstrated that the highest rates of PFS and OS were observed when cytoreductive surgery occurred while the patients were still responding to TKI therapy. PFS rates for patients with ongoing response to TKI therapy (ie, PR or SD at the time of surgery) were 70–96% at 1 year after surgery and 72% at 4 years from the start of imatinib therapy, whereas the 1-year PFS for patients with generalized progression ranged from 0 to 14%.111,112,115 OS rates approached 100% at 1 year after surgery in patients responding to TKI therapy and only 0–60% at 1 year in the setting of generalized progression. Although patients with limited progression had lower rates of PFS than those with responsive disease, the rates of OS were not significantly different; thus the benefits of surgery in this population are unclear.

In the BWH/DFCI series, approximately 40% of patients required liver resections, over 60% underwent peritonectomy and/or omentectomy, and over 60% needed multivisceral resections.112 Radiofrequency ablation may be considered for liver disease. Complication rates ranged from 40 to 60% in the three large series, though the majority were minor.111 Perioperative deaths were rare, usually occurring in the setting of emergency procedures, as reported in the French study.114,116

The goal of such operations is to perform a macroscopically complete (R0 or R1) resection when safely possible. However, the disease may frequently be too extensive to be removed completely, in which case progressing lesions are preferentially removed. Following surgery, these patients should remain on imatinib indefinitely, as failure to resume imatinib results in rapid disease recurrence.

Based on these data, from limited single-institution series, the patients who seemed to derive the most benefit from cytoreductive surgery were the ones still responding to TKI therapy at the time of surgery (PR or SD, Fig. 24-9). Such patients should be considered for surgery on an individual basis. Patients with generalized progression do not appear to derive any benefit from cytoreductive surgery and are best treated nonoperatively. Such patients may nevertheless need urgent surgery for palliative or emergency purposes such as obstruction or hemorrhage (Fig. 24-10). Although cytoreductive surgery is feasible in patients with responsive disease, there is still no evidence that outcomes are superior or even equal to those for patients who continue on TKI therapy without surgery. This question will hopefully be answered in randomized clinical trials under development in the United States and open in Europe and China. Figure 24-11 is a schema for the management of primary and advanced GIST.

The NCCN consensus panel recommended that patients who have had resection of a primary GIST should undergo a history, physical examination, and abdomen/pelvis CT scans with intravenous contrast every 3–6 months during the first 3–5 years and then annually thereafter.47

The principal and only potentially curative treatment for GIST is surgery. However, recurrences are common. In the era prior to the institution of TKI therapy, survival in the setting of recurrent or metastatic disease was poor. Because of its relatively low toxicity and significant efficacy in the treatment of GIST, TKI therapy has dramatically altered the natural history of this disease. The type and dose of TKI administered may soon be guided by mutational analysis. The role of imatinib has been expanded to patients with primary GIST, where it may be used safely as a neoadjuvant agent and improves RFS as an adjuvant agent following complete macroscopic resection. Ongoing studies will address the issues of optimal length and dose of adjuvant and neoadjuvant imatinib therapy, define the subset of candidates most likely to benefit from such therapy, and determine the long-term impact on OS. Cytoreductive surgery may be considered in a subset of patients with advanced disease, but phase III trial data are necessary to determine if surgery adds any PFS or OS benefit over continuing imatinib therapy alone.

Future studies will focus on the integration of surgery with targeted therapy and the development of new agents for drug-resistant GIST.