Management of Resectable GIST

SYNOPSIS

Gastrointestinal stromal tumor (GIST) is a rare neoplasm that has recently become an intense focus of scientific investigation, as it serves as a model for the molecular therapy for cancer. Although surgery remains the principle treatment of primary localized GIST, imatinib mesylate, a selective inhibitor of KIT protein, achieves dramatic responses in metastatic GIST. Multimodality therapy integrating surgery and molecular therapy has shown promise. In this review, we will summarize the epidemiology, clinicopathologic features, natural history, and clinical management of GIST.

BACKGROUND

The literature on gastrointestinal stromal tumors (GISTs) has expanded exponentially, demonstrating how medical advancement in the understanding of a disease can revolutionize its diagnosis and treatment. In the past, these tumors were classified as leiomyomas, leiomyosarcomas or leiomyoblastomas. Only recently it has become evident that GIST is a separate entity and the most common sarcoma of the gastrointestinal (GI) tract.^{1, 2}

GIST is a mesenchymal tumor that mainly arises from the alimentary tract but can also develop in the omentum and mesentry. The term GIST was first coined in 1983 by Mazur and Clark to describe GI non-epithelial neoplasms that lacked immunohistochemical features of Schwann cells, and did not encompass ultrastructural characteristics of smooth muscle cells.¹ GIST continued to be rarely diagnosed until late 1990s, when they became a focus of intense investigation. In 1998, Hirota et al.³ reported that majority of GIST harbored gain-of-function mutations in the KIT (also called CD117) proto-oncogene, a hallmark of GIST.

The KIT gene encodes the KIT protein, which serves as the transmembrane receptor for the cytokine known as stem cell factor (SCF). The intracytoplasmic portion of KIT functions as a tyrosine kinase.⁴ Subsequent reports have found KIT mutations in up to 85% of GISTs, while another 3% to 5% GISTs harbor platelet derived growth factor receptor α(PDGFRα) mutations.^5–7 PDGFRα also exhibits tyrosine kinase function.

In 2001, Joensuu et al.⁸ discovered imatinib mesylate (Gleevec; Novartis Pharmaceuticals, Basel Switzerland) to be highly effective against chemotherapy-resistant GIST. Imatinib is a molecular inhibitor of the KIT and PDGFRα proteins. The dramatic response achieved in a solid tumor with targeted agent imatinib has made GIST a paradigm for the use of new molecular agents. Over 80% of patients benefit from tyrosine kinase inhibitor therapy and median survival from the diagnosis of metastatic GIST is now nearly 5 years. ^{9, 10}

EPIDEMIOLOGY

GISTs demonstrate a fairly equal distribution between men and woman, although some literature suggests that GIST has a slight male predominance.¹⁰ The precise incidence of GIST in the US is difficult to quantify, because of its recent identification as a separate entity. Surveillance, Epidemiology, and End Results (SEER) program of National Cancer Institute’s (NCI) report in 1995 indicated 500–600 new cases of GIST were diagnosed in the US annually.¹¹ Recent guidelines published by National Comprehensive Cancer Network (NCCN) estimate the incidence of GIST in the US to be near 5000.^{12, 13} Furthermore, based on a recent study from Sweden, the estimated annual incidence of GIST in the US would similarly be 4,000–5,000.¹⁴ As clinicians become more acquainted with the molecular, histological, and clinical features of this disease, we will gain a better understanding of the true incidence and prevalence of GIST. Although GIST has been documented in patients of all ages, most of the people affected by GIST are between 40–80 years old at the time of diagnosis, with the median age of 60 years.¹⁰

The majority of GISTs are sporadic. However, there are a few case reports of familial germline mutations in the KIT proto-oncogene, and one family carried a PDGFRα mutation.^{15, 16} Additionally, GIST has been diagnosed in hereditary syndromes such as Neurofibromatosis¹⁷ and Carney’s traid¹⁸, a rare entity that predominantly occurs in young women and is associated with gastric GIST, paraganglioma, and pulmonary chondroma. However, only 25% of the patients manifest the complete triad. Approximately 60% of GISTs occur in the stomach, 30% in the small intestine, 5% in the rectum, and 5% in the esophagus^{10, 19} Rarely, GIST may develop outside of the alimentary tract in locations such as the mesentery, omentum, pancreas, or other retroperitoneal structures.²⁰ While GIST is the most common mesenchymal tumor in the GI tract, leiomyomas predominate in the esophagus.²¹

As mentioned previously, although GIST predominates in adults over 40 years of age, it can also occur children and younger adults, with unique clincopathologic distinctions. Children are more likely to present with multifocal gastric tumors, harbor epitheloid histology, contain wild-type KIT/PDGFRα genome, and possess a higher rate of lymph node (LN) metastasis.²² In young adult patients, GISTs can either present as the pediatric- or adult-type tumors. The unique gene expression profile of GIST in the pediatric and young adult population is currently an intensive area of investigation, to gain a finer understanding of the complex pathophysiology of the disease.

HISTOPATHOLOGY

The histopathologic diagnosis of GIST has had significant advancement over the last several years, mainly as a result of the recent progress in the understanding of molecular pathogenesis of GIST. Demonstrating characteristics of smooth muscle cells under microscopy, these unique tumors were initially characterized as leiomyomas when exhibiting benign features and leiomyosarcoma when displaying malignant characteristics.^{23, 24} Advances in medicine and technology led to identification of cellular features in GISTs, which were consistent with neural elements.²⁵ Soon, it was found that majority of GISTs express CD117 or KIT, a transmembrane growth-factor receptor with tyrosine kinase activity³, and arise from a KIT-positive interstitial cell of Cajal (ICC), the pacemaker cell of the GI tract.²⁶ Normally, KIT is found in its inactive confirmation. However, when bound by its ligand, KIT activates various other kinases including MAP kinase, STAT5, RAS, JAK2, and PI3 kinase leading to cellular proliferation, differentiation, and adhesion.²⁷ Although up to 85% of GISTs express the KIT mutation, another 3–5% possess a PDGFRα mutation, while 10–15% of the cases contain the wild-type forms of these proto-oncogenes, yet overexpress KIT.^5–7 Activating KIT mutations, similar to those described in GISTs, have been reported recently in a subset of acral and mucosal malignant melanomas.²⁸

Histologically, GISTs can be characterized as spindle cell type (70%), epithelioid type (20%), or a rare mixed type where both features are present.²⁹ Spindle-cell GISTs appear as uniform fusiform cells in intersecting fascicles or whorls. Epithelioid GISTs typically appears as rounded cells in a nested pattern. GISTs usually have scant stroma and uniform cytology with fibrillary eosinophilic cytoplasm and nuclei containing fine chromatin and inconspicuous nucleoli (Fig. 1).³⁰

FIGURE 1.

KIT (CD117) staining in gastrointestinal stromal tumor. The left panel shows hematoxylin and eosin staining, and the right panel demonstrates KIT immunohistochemistry of the same tumor. Diffuse, high-level KIT staining is typical. Magnification 40× (courtesy of Dr. Cristina Antonescu, Department of Pathology, Memorial Sloan-Kettering Cancer Center). From DeMatteo, Ann Surg Oncol 2002; 9:831 with permission.⁵⁹

While expressing KIT (CD117), GISTs may be positive for CD34 (60–70%), smooth-muscle actin (SMA; 30–40%), and approximately 5% stain positive for S-100 protein.³¹ GISTs rarely express desmin, but when desmin is found, it is invariably focal, with only small numbers of immunopositive cells. The diagnosis of KIT-negative GIST can present difficulty and depends on tissue morphology as well as genotyping the tumor for a KIT or PDGFRα mutation, as some tumors negative for KIT by immunohistochemistry have mutations in either of the proto-oncogenes. ^{32, 33}

Unlike other GI malignancies, the behavior of GIST is difficult to predict based on histopathology alone. The best indicator of malignancy is the confirmation of metastatic disease. The three most important characteristics that have shown some ability to predict how GISTs will behave are size, mitotic rate and location of tumor.³⁴ Tumors with low mitotic counts (<5 per 50 HPF) and diameters <2 cm generally exhibit benign behavior, while diameters >10 cm and high mitotic counts (>5 per 50 HPF) are associated with malignant behavior. Tumors located in the stomach have a more favorable outcome. Importantly, neither small size nor low mitotic rate excludes the potential for malignant behavior.^{35, 36}

MOLECULAR GENETICS

The KIT proto-oncogene is found on chromosome 4q11-q12 and controls KIT expression. KIT is expressed by ICC, which are the pacemaker cells of the alimentary tract and believed to give rise to GISTs. Additionally, KIT is also found in hematopoietic cells, mast cells, and germ cells. The natural ligand for KIT has several names including KIT ligand , SCF, steel factor, and mast cell growth factor. KIT is involved in many cellular functions, including differentiation, cell growth, and survival. Binding of KIT to its ligand leads to dimerization and autophosphorlyation of KIT, which initiates a cascade of intracellular signaling leading to adhesion, differentiation, proliferation, and tumorgenesis. In GIST, a gain-of-function mutation in KIT leads to constitutive activation of KIT and its tyrosine kinase function.³ In a transgenic mouse model, KIT mutation has been shown to be sufficient in inducing GIST formation.³⁷ A number of other malignancies including mastocytosis,³⁸ germ cell tumors,³⁹ acute myelogenous leukemia,⁴⁰ and neuroblastoma⁴¹ have also been shown to express activating KIT mutations.

KIT mutation can occur in up to 85% of GISTs and is nearly always somatic.⁵ A variety of mutations have been detected in GIST. The most common sites involve KIT exon 11 (70% of GISTs), whereas an exon 9 mutation occurs in approximately 10% of the cases. Mutations of exon 13 or 17 are rarely found.^{5, 6, 42} Approximately 3–5% of GISTs harbor mutations in exons 12, 14 and 18 of PDGFRα proto-oncogene.⁴³ Interestingly, about 10–15% of the patients with GISTs do not possess a detectable mutation in either of the two proto-oncogenes. At the level of the chromosomes, there have been other abnormalities confirmed in the development of GIST, such as early loss of 14p and 22q, which may suggest that chromosomal derangement may represent another mechanism for cancer progression.⁴⁴ Approximately 3% of GISTs are found in the pediatric population.²²

PRESENTATION & DIAGNOSIS

Although almost 70% of patients that harbor GIST suffer from vague symptoms, the diagnosis is often made only after laparotomy for other pathology and detailed pathologic examination. Due to the scarcity of this tumor, the disease is rarely suspected prior to the time of surgery. Preoperative diagnosis of GIST requires a high degree of suspicion and certain key radiologic findings may hint towards the elusive diagnosis.⁴⁵

The most common presenting symptoms of GISTs are GI bleeding, abdominal discomfort, and abdominal mass. These all likely result from the fact that GISTs are fast-growing tumors that quickly outgrow their blood supply. As a result, they develop a necrotic center (evident on radiologic imaging), which can fistulize to an enteric lumen and result in GI bleeding. Rarely, GISTs can rupture into the abdominal cavity and cause massive intraperitoneal hemorrhage. Since GISTs tend to displace adjacent organs rather than invade them, they may become quite large before causing symptoms such as nausea, emesis, bloating, early satiety, increased abdominal girth or a palpable mass, which are all non-specific. As with other neoplasms that arise in certain locations, GISTs can cause dysphagia when found in the esophagus or gastroesophageal junction, obstructive jaundice when periamupulary in location, or instussusception with obstruction in the small bowel.^{45, 46} A recent population based study demonstrated that approximately 70% of GISTs induce symptoms, while 20% do not cause any symptoms, and 10% are detected at time of autopsy. The median tumor size for these categories was 8.9 cm, 2.7 cm, and 3.4 cm, respectively.¹⁴

GISTs are most frequently diagnosed during workup for other pathology. Depending on their location, they may be identified as masses on EGD, colonoscopy, computed tomography (CT) or magnetic resonance imaging (MRI). The most useful radiologic study for the diagnosis of GISTs is the CT scan. Contrast enhanced CT can evaluate the primary tumor as well as the liver and peritoneum, which are the most common sites metastatic disease. Lymph node metastases are extremely rare. Metastases in the lungs and other extra-abdominal locations are usually observed only in advanced cases. A primary tumor is typically a well-circumscribed and often highly vascular mass closely associated with the stomach or small intestine. GISTs may appear heterogeneous due to central necrosis or intratumoral hemorrhage. On CT, GISTs usually appear as hyperdense, enhancing masses. Unfortunately, neither CT nor MRI can accurately predict whether the tumor has invaded adjacent structures. Fluorodeoxyglucose positron emission tomography (¹⁸FDG-PET) has shown to be sensitive in identifying metabolic activity within these tumors but it is not specific enough for the diagnosis of GIST. However, PET is useful at present in determining the clinical response to molecular treatment of GISTs (Fig. 2).⁴⁵

FIGURE 2.

¹⁸FDG-PET scan showing response of metastatic GIST to imatinib mesylate. The patient presented with synchronous primary disease in the small bowel and metastatic disease in the liver. The scan on the left was obtained at presentation, and the scan on the right was obtained after 3 weeks of therapy. In the interval, there has been a decrease in size and ¹⁸FDG uptake in both the small bowel and liver tumors consistent with a good response to imatinib. The SUV of the liver metastases, shown with the open arrow, went from SUV 10.6 to 4.6, whereas the SUV of the primary tumor, shown with the closed arrow, went from 11 to 4.3. The patient eventually went on to complete surgical resection. From Gold and DeMatteo, Ann Surg 2006; 244:176 with permission.⁴⁵

Endoscopy may lead to diagnosis of gastric or colorectal GIST. On endoscopic evaluation, GIST appears as a submucosal mass. Endoscopic ultrasound can be useful to confirm that a tumor originates from the bowel wall and not the mucosa. As GIST rarely initially metastasize to the chest, a chest radiography is appropriate to assess the thorax. Bone scan should be ordered only to work-up specific symptoms. Percutaneous biopsy should rarely be used to confirm the diagnosis of a resectable GIST, as they can precipitate tumor rupture and lead to tumor dissemination or hemorrhage. Additionally, it may be extremely challenging to diagnose GIST from a percutaneous biopsy (FNA or core needle) if necrotic or hemorrhagic tissue is sampled. Percutaneous biopsy is indicated if the results will change the management. For instance, if another diagnosis is entertained, such as a lymphoma, then the patient may not benefit from surgical resection. A biopsy may also be helpful in cases where the mass is marginally resectable and neoadjuvant molecular treatment is desirable.

GISTs manifest a spectrum of clinical behavior. It is difficult to predict whether any particular GIST will recur after complete resection. Several variables have been identified to predict the clinical behavior of GIST. Tumor size, mitotic index and tumor location are the three most important prognostic variables for GIST.^{19, 47} In a recent multivariate analysis from MSKCC,³⁴ each of these variables was found to independently predict recurrence-free survival after excision of primary, localized GIST (Fig. 3). The effect of mitotic rate was the most dramatic with hazard ratio (HR) of 14.6 for patients with ≥5 mitoses/50 HPF (Fig. 3C). Patients with tumors located in small bowel (Fig. 3A) and tumors ≥10 cm in size (Fig. 3B) were also more likely to recur, with HR of 3.3 and 2.5, respectively. Patients with tumor size <5 cm or tumor located in the stomach had more favorable outcomes. Upon univariate analysis, patients with KIT exon 9 mutations or KIT exon 11 deletions involving amino acid W557 and/or K558 had a higher rate of recurrence (Fig. 3D). Point mutations and insertions of KIT exon 11 had a favorable prognosis.

FIGURE 3.

(A) Recurrence-free survival in 127 patients with completely resected localized gastrointestinal stromal tumor (GIST) based on tumor location, (B) tumor size, (C) mitotic rate, (D) and the type of mutation. From DeMatteo, Cancer 2008; 112:608 with permission.

In addition to tumor size, mitotic rate, and location, several other variables have been investigated in their ability to predict recurrence.⁴⁷ While complete gross resection has been associated with improved outcome,⁴⁸ so far we have not found that microscopically positive margins impact survival (Fig. 4).¹⁰ Tumor rupture either before or during resection has been correlated with poor outcome and often leads to peritoneal metastasis (Table 1).⁴⁹ Cellular proliferation estimated by Ki67 immunohistochemistry has been shown to be an independent prognostic factor.⁵⁰ Diffuse mucosal invasion is a rare finding and associated with an aggressive disease course.⁵¹ Aneuploidy is a marker of malignancy,^{50, 52, 53} and several studies have suggested telomerase expression as a poor prognostic factor.^{49, 54} KIT immunoreactivity or staining pattern and CD34 expression do not appear to be independent prognostic factors for survival.⁴³

FIGURE 4.

Disease-specific survival by margin status in patients with primary disease who underwent complete resection (n = 80). From DeMatteo, Ann Surg 2000; 231:51 with permission.¹⁰

TABLE 1.

NA.

Prognostic Factors for GIST
Tumor size
Mitotic rate
Location of primary tumor
Completeness of resection
Tumor rupture
Cellular proliferation index (Ki67)
Diffuse mucosal invasion
Aneuploidy
Telomerase expression
Extent of disease

Even despite these established prognostic factors, predicting clinical behavior of a GIST in a particular patient remains a challenge. It is now accepted that all GISTs can exhibit malignant potential and none, except perhaps <1 cm tumors, can be labeled as definitely benign.⁴⁵ Therefore, most pathologists classify GISTs as having very low, low, intermediate, or high risk for malignancy.⁵⁴ There are general guidelines established to group GISTs into one of these risk categories (Table 2).^{4, 29, 35, 47} Tumors greater than 5–10 cm in size and containing >5 mitoses per 50 HPFs are considered high risk for malignancy. It should be made clear, however, that even GISTs with low mitotic index (<5 mitoses per 50 HPFs) may possess malignant potential.⁵⁵ Between 10% and 25% of patients present with metastatic disease.⁵⁶

TABLE 2.

Assessment of the risk of recurrence in respectable GIST. Adapted from Fletcher et al., 2002.²⁹

Risk category	Size	Mitotic count
Very low risk	<2 cm	<5/50 HPF
Low risk	2–5 cm	<5/50 HPF
Intermediate risk	<5 cm 5–10 cm	6–10/50 HPF <5/50 HPF
High risk	>10 cm any size >5 cm	Any mitotic rate >10/50 HPF >5/50 HPF

HPF, high power field.

Historically, patients who underwent complete surgical resection had a local recurrence rate of approximately 50%, with median time to recurrence of 24 months.^{10, 57} Recurrence tends to involve the peritoneal surface, the liver or both. We found liver to be involved in 63% of the 80 patients who underwent complete resection of their primary tumor, and it was the only site of recurrence in 44% of the recurrences.¹⁰ Similarly, a study from MDACC showed that nearly 40% of patients had recurrence confined to the peritoneum.⁵⁷ There may be a benefit to resecting recurrent isolated local or metastatic disease in highly selected patients when all gross tumor can be removed,⁵⁸ as the typical pattern of disease at the time of death is overwhelming intraperitoneal or intrahepatic tumor burden.

TREATMENT

Primary Disease

For patients with primary localized GIST, surgical resection remains the only chance for cure.⁵⁹ It typically carries little morbidity for tumors less than 10 cm that are confined to the stomach or small intestine. Resection can usually be accomplished with wedge resection of the stomach or a segmental resection of the small bowel. Extensive surgery is rarely required. Every effort should be spent to obtain gross negative margins, but wide margins have not been associated with better prognosis (Fig. 4),¹⁰ as GIST does not exhibit an intramural spreading behavior. Since GISTs rarely metastasize to lymph nodes, formal lymphadenectomy is not necessary unless locoregional lymph nodes are enlarged. When adherence to adjacent organs is identified, an en bloc resection is favored. An incomplete resection should only be carried out as a palliative therapy for bleeding, pain, or symptoms secondary to mass effect. Complete gross resection is possible in 85% of patients with primary, localized disease. Nevertheless, historically, at least 50% of patients developed tumor recurrence and 5-year survival was approximately 50% (Fig. 5).^{10, 49}

FIGURE 5.

Disease-specific survival in patients with primary disease who underwent complete resection (n = 80). From DeMatteo, Ann Surg 2000; 231:51 with permission.¹⁰

Conventional chemotherapy for the treatment of GIST has a dismal response rate of approximately 5%. ^60–63 Radiotherapy is also of limited value, owing to the location of the tumors and the limit this places on the doses that can be employed.⁴³ Treatments such as hepatic artery embolization and debulking surgery followed by intraperitoneal chemotherapy have also been investigated but with discouraging results.⁶⁴

The development of imatinib mesylate has revolutionized the treatment of GISTs. Imatinib is a selective inhibitor of specific tyrosine kinases, including KIT, PDGFRα, ARG, c-FMS, ABL, and BCR-ABL.⁶⁵ Imatinib was initially developed as a PDGFRα inhibitor. Its first use as a therapeutic agent was for the treatment of chronic myeloid leukemia (CML), in which a BCR-ABL fusion protein leads to an unregulated tyrosine kinase activity.⁶⁶ Imatinib has been shown to induce a complete response in nearly all patients in the chronic phase of CML.

In 2001, Joensuu et al. published their experience with the treatment of metastatic GIST in a single patient with imatinib.⁸ The results were dramatic as seen on serial MRI and PET imaging. This landmark case report prompted several clinical trials, and it is now apparent that up to 80% of patients with metastatic GIST achieve partial response or remain with stable disease while on imatinib.³⁰ Imatinib is usually well tolerated, and the side effect profile includes edema, rash, diarrhea, nausea, abdominal pain, and fatigue.

The use of adjuvant imatinib after complete resection of primary GIST was evaluated in a Phase II trail lead by the American College of Surgeons Oncology Group (ACOSOG), and sponsored by the Cancer Therapy Evaluation Program (CTEP) and Novartis. The study aimed to answer whether adjuvant imatinib at a dose of 400 mg/day for 12 months after complete resection of the primary tumor in high-risk patients can lead to decreased recurrence rates and improved 3-year survival. High risk was defined as a tumor size >10 cm, intraperitoneal tumor rupture or hemorrhage, or multifocal (>5) tumors. There were 107 evaluable patients enrolled between September 2001 and September 2003. Imatinib was initiated at a median of 59 (range 25–84) days after operation. The median age was 58 years (range 19–79). The median tumor size was 13 cm (range 3–42) and 50% of tumors originated from the stomach while 42% arose in the small intestine. At a median follow-up of 4 years, the 1, 2, and 3 year overall survival rates were 99, 97, and 97%, respectively. The 1, 2, and 3 year recurrence-free survival rates were 94, 73, and 61%, respectively. The data from this trial have shown that imatinib is well tolerated in the adjuvant setting, prolongs recurrence-free survival, and is associated with improved overall survival when compared with historical controls.⁶⁷ There were no CTC Grade 4 or Grade 5 toxicities reported, 18% of patients had Grade 3 adverse events, and 83% of the patients completed the 12 months of imatinib therapy.⁶⁸ Additionally, a randomized, double-blinded Phase III ACOSOG intergroup trial in which patients received imatinib (400 mg/day) or placebo for 1 year after undergoing complete resection of their primary GIST (≥3 cm tumor size) has just been completed. Accrual to the trial was halted due to a recommendation of the ACOSOG External Data Monitoring Committee based on the results of a planned interim analysis of 644 evaluable patients. Median follow-up time in recurrence-free patients was 1.2 years. 21% of the expected events had occurred. Patients assigned to the imatinib arm had a 1 year recurrence-free survival of 97% while those assigned to the placebo arm had a 1 year recurrence-free survival of 83%, with a hazard ratio of 0.325 (95% CI 0.198–0.534), and a nominal unadjusted log-rank p-value of 0.0000014. No difference in overall survival between the two treatment arms was noted. However, measuring overall survival is immature at the time of this publication. Patients will continue to be followed per protocol, for up to 10 years. These original results support the role of imatinib in the adjuvant setting.⁶⁹ A Phase II neoadjuvant trial for primary GIST led by the Radiation Therapy Oncology Group (RTOG) has also met accrual, and will define the role of imatinib in a preoperative setting. Neoadjuvant imatinib is particularly attractive for patient population with large or poorly localized tumors that would otherwise require extensive surgery or sacrifice large amount of normal tissue. Neoadjuvant therapy may convert the resection of a rectal GIST from an abdominoperineal resection to a low anterior resection. It should be mentioned that positive KIT staining on immunohistochemistry is an inclusion criteria for all these trials.

As there is now effective treatment for recurrent or metastatic GIST, the NCCN recommends CT scans of the abdomen and pelvis with IV contrast every 3–6 months during the first 3–5 postoperative years and yearly thereafter.¹³

Recurrent and Metastatic Disease

In patients for whom curative surgery is not feasible, or who develop recurrent metastatic disease, imatinib is now the first line treatment.^{9, 70} In fact, the majority of patients will present with tumor recurrence despite undergoing complete resection of their primary tumor.¹⁰ The median time to recurrence is reported to range from 18–24 months. At the time of recurrence, approximately two-thirds of the patients have liver involvement and half present with peritoneal disease.¹⁰ Extra-abdominal metastasis to lung or bone may develop as the disease progresses.

Surgery alone has limited efficacy in recurrent or metastatic GIST. Excision of peritoneal disease is usually followed by subsequent recurrence. Liver metastases are usually multifocal, but approximately 26% of the patients are still candidates for resection.⁶³ However, essentially all of the patients develop recurrent disease after hepatic resection.

The gold standard for treatment of recurrent metastatic GIST is now imatinib, with few exceptions. Patients who have primary GIST with synchronous, low volume metastatic disease may be considered for surgical resection first, especially if they are symptomatic. Imatinib is reported to produce a partial tumor response in 45% of patients and stable disease in approximately 30%. Remarkably, the 2-year survival of patients with metastatic disease is now reported to be approximately 70%.^{9, 70, 71} By contrast, before the introduction of imatinib, the median survival after surgical resection of recurrent GIST was only 15 months.⁷⁰

Since imatinib rarely induces a complete response and median time to progression with imatinib therapy is less than 24 months, a multimodal approach utilizing surgical resection in conjunction with imatinib therapy to treat recurrent metastatic GIST is highly desirable. In a recent study from our institution,⁵⁸ forty patients with metastatic GIST were treated with tyrosine kinase inhibitors for a median of 15 months prior to surgical resection. After surgery, 20 patients who had responsive disease based on preoperative serial radiologic imaging had a 2-year progression free survival of 61% and 2-year overall survival of 100% (Fig. 6). In contrast, 13 patients that experience focal resistance of their disease progressed at a median of 12 months postoperatively, with a 2-year overall survival of 36%. There were 7 patients with multifocal resistant disease and they progressed postoperatively at a median of 3 months and experienced a 1-year overall survival of 36%. Based on these results, selected patients with metastatic GIST who have responsive disease or focal resistance to imatinib may benefit from resection. In contrast, in patients with metastatic GIST and multifocal resistance, surgery is generally not indicated.⁵⁸ Similar results were observed by Gronchi et al. in a study employing 38 patients with advanced GIST that underwent surgery following a variable period of imatinib therapy.⁷² Additionally, Raut et al. published their series of 69 patients with advanced GIST who underwent surgery and concluded that patients with advanced GIST exhibiting stable disease or minimal progression on kinase inhibitor therapy have prolonged overall survival after debulking procedures. Surgery has little to offer in patients with generalized progression of disease while on therapy.⁷³

FIGURE 6.

(A) Timeline of treatment and outcome for 40 patients with metastatic GIST treated with molecular therapy and then surgery. Each patient is represented by a horizontal bar. The patients are grouped by their response at the time of surgery to tyrosine kinase inhibitor (TKI) therapy. The time period from the start of TKI therapy to surgery is shown by the black boxes. All patients were operated upon at time zero. After surgery, patients had either no gross residual disease (white boxes) or gross residual disease (gray boxes). Postoperative progression is shown by the striped boxes. A plus sign designates the patients who were alive at last follow-up; the other patients have died of disease. (B) Progression free and overall survival after resection of metastatic GIST. From DeMatteo, Ann Surg 2007; 245:347 with permission.⁵⁸

We propose that the risk of developing imatinib resistance is proportional to the amount of residual viable GIST. Therefore, once maximal response to imatinib occurs (generally after 2–6 months of therapy), we evaluate patients for complete resection. Imatinib therapy is continued postoperatively to delay or prevent subsequent disease recurrence, although the optional duration of therapy is unknown.³¹ A recent study showed that an increase in the rate of progressive disease when imatinib was interrupted.⁷⁴

The success of imatinib in treating patients with GIST is defined by lack of disease progression, rather than shrinkage of existing tumors.⁷⁵ When metabolic and anatomic imaging is combined, GISTs that respond to molecular therapy may be stable in size but demonstrate areas of necrosis. When using these criteria, 12% of patients with GIST who are treated with imatinib demonstrate primary resistance, defined as progression within the first 6 months of imatinib treatment.⁷⁵ Clinical studies have demonstrated that the location of mutations in the pathogenic kinase is an important factor in both treatment response and development of resistance to imatinib.⁷⁶ Patients who experience primary resistance usually express both wild-type KIT and PDGFRα, or contain mutations in exon 9 of KIT or a PDGFRα with a D842V mutation.^{43, 77}

Secondary or late resistance therefore occurs in patients who have initially demonstrated stabilization of their disease for at least 6 months. Unfortunately, most patients who initially demonstrate a clinical response to imatinib will subsequently develop (secondary) resistance, as a result of selection for additional point mutations in the KIT kinase domains.⁷⁸ Usually, most resistant GISTs with secondary mutation had primary mutations in exon 11. The second site mutations are mainly substitutions involving exons 13, 14, and 17 of KIT, corresponding to the kinase domain. Recent studies suggest that patients with primary KIT mutations in exon 13 K642E and in exon 14 T670I have acquired resistance to imatinib.⁷⁸

There is general agreement that multifocal resistance to imatinib should be treated with another targeted agent such as sunitinib (Pfizer, New York, NY), which has activity against KIT and PDGFRα, as well as the vascular endothelial cell growth factor (VEGF) and fms-related tyrosine kinase 3 (Flt3) receptors. Sunitinib may also have activity in GIST harboring secondary KIT mutations.⁷⁹ In 48 patients who were treated with sunitinib after disease progression with imatinib therapy, there were 20 patients with stable disease and 6 who achieved a partial response. Increasing the imatinib dose from 400 to 800 mg/day may overcome or balance the effects of drug resistance to imatinib and increase progression free time. However, the success of this strategy appears to be limited, except in tumors with primary mutations in KIT exon 9. For other GISTs, the dose of imatinib required to overcome drug resistance or delay progression is prohibitively high. A number of other agents are in clinical trials, as different agents interact with alternate moieties on the KIT protein, and resistance to one agent may not preclude a therapeutic benefit from another. Further understanding of the mechanisms of resistance to imatinib may allow for the delay or prevention of this phenomenon, in addition to utilizing additional targeted therapies.⁷⁸ A proposed algorithm for treatment of primary and recurrent metastatic GIST is outlined (Fig. 7), and has been revised as the patiently awaited results of Phase II and III ACOSOG trials are now out, and Phase II RTOG trial finindings will be published in the near future.

FIGURE 7.

Algorithm for the treatment of GIST. From Gold and DeMatteo, Ann Surg 2006; 244:176 with permission.⁴⁵

SUMMARY

Imatinib treatment for GIST has become paradigm of oncogene treatment of solid tumors. As a consequence, the treatment of GIST has evolved rapidly, with dramatic changes in clinical practice. Nevertheless, time has shown the limitations of treating GIST with this single agent alone, as resistance to tyrosine kinase inhibitors is an emerging clinical dilemma. Surgical resection still remains the only chance for cure, however, recent studies have begun to delineate effective ways to integrate surgery and targeted therapy or reduce recurrence after resection of primary disease and to prolong survival in metastatic disease. The lessons learned in GIST along with ongoing and future investigations will be extremely relevant to the potential use of molecular therapy for other cancers.