Gastrointestinal (GI) stromal tumor (GIST) is the most common mesenchymal tumor of the GI tract, constituting 80% of all GI mesenchymal tumors and approximately 20% of all small bowel malignancies, excluding lymphomas. This article provides a summary of recent randomized clinical trials of these tumors.
Gastrointestinal (GI) stromal tumor (GIST) is recognized as the most common mesenchymal tumor of the GI tract. It constitutes 80% of all GI mesenchymal tumors and approximately 20% of all small bowel malignancies, excluding lymphomas. It is believed that there are up to 5000 new cases of GIST diagnosed each year in the United States. GIST first gained recognition as a distinct tumor type in the 1980s, before which it was considered a type of leiomyomatous tumor. Further research has demonstrated that approximately 90% of GISTs contain an activating KIT (CD117) mutation, while 5% carry a mutation in platelet-derived growth factor receptor alpha (PDGFRα). Accordingly, the treatment of GIST has changed radically with the evolution of targeted therapies in oncology. Six prospective, randomized controlled trials have been published on the treatment of this disease during the brief period since its molecular and pathologic characterization.
Surgery and radiation
There are no data from randomized controlled trials regarding the surgical management of GIST. By consensus, surgical resection with negative microscopic margins remains the primary treatment and is the only modality that appears to offer a significant chance of cure. Aggressive surgical therapy to debulk progressive, nonlocalized disease or to resect metastatic disease is advocated in select circumstances, but these approaches have not been evaluated in prospective, controlled studies.
Similarly, no randomized controlled trials have been published on the use of radiation therapy for GIST. In fact, retrospective data are sparse. Current applications for this treatment modality remain limited.
Chemotherapy and metastatic disease
In general, traditional chemotherapeutic agents, including doxorubicin, alone or with gemcitabine, or ifosfamide with etoposide or temozolomide, have not been efficacious in treating patients with GIST. The application of imatinib mesylate in the treatment of GIST reflects a major advance in the treatment of solid tumors with specific, therapeutic, molecular targeting. Imatinib, a product of rational drug development, demonstrates inhibitory activity against BCR-ABL, PDGFRα, and KIT kinases. By binding to the adenosine triphosphate (ATP)-binding pocket of these proteins, imatinib blocks the transfer of a phosphate group to the substrate molecule and leads to inhibition of KIT or PDGFRα signal transduction. Given these effects, and regardless of the KIT or PDGFRα mutation status, imatinib has become the first-line medical treatment for metastatic, unresectable, or recurrent GIST. Surgery alone for metastatic disease often has limited value. The initial starting dose of imatinib is 400 mg/d administered orally, although some studies have compared this starting dose with an 800 mg/d dose. The data from these randomized trials will be discussed later, but 400 mg/d remain the standard initial therapy in most patients. The task of characterizing tumor mutation status (KIT/PDGFRα), assessing disease progression, and integrating surgery and targeted therapy has led to the necessity for a multidisciplinary approach to treating patients with GIST. A team including radiologists, pathologists, medical oncologists, and surgeons is required for successful care of these patients.
All of the currently available randomized controlled trials in the treatment of GIST address the use of targeted biologic agents, primarily in advanced (surgically unresectable or metastatic) disease but more recently in the adjuvant setting as well. Although initially advanced for use in chronic myelogenous leukemia, the dramatic benefits of imatinib mesylate for treating GIST were demonstrated by Demetri and colleagues with an initial case report in 2001 followed by report of their phase 2 trial in 2002. This latter study demonstrated unprecedented early improvements in progression-free survival (PFS) and overall survival in patients treated with either 400 mg/d or 600 mg/d of imatinib. A subsequent long-term follow-up study demonstrated a median survival of 57 months in patients for whom a 20-month median survival traditionally would have been estimated.
Subsequent studies of imatinib in GIST have addressed some of the questions regarding dosing and duration of therapy. Verweij and colleagues, reporting in 2004 for the European Organization for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group, the Italian Sarcoma Group (ISG), and the Australasian Gastrointestinal Trials Group (AGITG), demonstrated a small but statistically significant improvement in progression-free survival among patients receiving 800 mg/d of imatinib over those receiving 400 mg/d. A concurrent study of similar design published by Blanke and colleagues (SWOG S0033), however, failed to demonstrate significant improvements in the higher-dose group. Nevertheless, some clinical benefit, in the form of delayed progression of disease, was identified in both trials among patients who crossed over to high-dose therapy after progressing on conventional-dose imatinib. In 2007, Van Glabbeke and colleagues presented results of the MetaGIST analysis, which combined 1640 patients from the SWOG S0033 and the EORTC-ISG-AGITG phase 3 trials. This meta-analysis affirmed a small but statistically significant improvement in PFS in the higher-dose arm (800 mg/d), although no difference in overall survival was demonstrated. In particular, patients with exon 9 KIT mutations demonstrated worse PFS, which may have been improved somewhat by higher-dose imatinib. Because the original trials were not stratified for mutation location, however, the results of this post-hoc subgroup analysis require further validation.
As for the question of therapy duration, Blay and colleagues, reporting for the French Sarcoma Group in 2007, clearly demonstrated the risks of interrupting imatinib therapy after 1 year. Eighty-one percent of patients with stable or responsive disease who interrupted imatinib therapy demonstrated prompt disease progression. In summary, these results suggest that initiating therapy with conventional-dose imatinib is appropriate for most patients with surgically unresectable disease, and interruption in therapy should be avoided in patients with responsive or stable disease.
For patients whose disease progresses on imatinib or who are unable to tolerate the drug, Demetri and colleagues demonstrated the viability of sunitinib as a second-line treatment. Although the response rates in this group are not nearly as dramatic as with first-line imatinib, sunitinib clearly offers improvement in PFS over no treatment.
Finally, DeMatteo and colleagues, reporting for the American College of Surgeons Oncology Group, published in 2009 the results of the first randomized controlled trial addressing the role of imatinib in the adjuvant setting. Early results from this trial demonstrated that imatinib 400 mg/d, administered for 1 year after complete resection of localized, primary GIST, provided a 15% absolute reduction in recurrence events compared with placebo at 1 year. Reductions in risk of recurrence were observed among all subgroups as stratified by tumor size. The impact on overall survival will require longer follow-up to establish but is not different at this time.
At the time of this writing, no randomized trials evaluating the neoadjuvant use of imatinib have been reported, although phase 2 data support its safety. In the absence of randomized data, retrospective data would suggest that patients can be treated in a neoadjuvant setting to improve resectability or reduce the extent of the operation.
Ongoing trials
Several active and recently closed trials should help answer important questions regarding the optimal use of imatinib in adjuvant or neoadjuvant settings. The Scandinavian Sarcoma Group has completed enrollment and is currently in the data collection phase on a randomized, controlled trial evaluating adjuvant therapy with imatinib (400 mg/d) administered as a short (12 months) versus long (36 months) course of treatment, following complete gross resection of GIST at high risk for recurrence. Recurrence-free survival is the primary endpoint. The EORTC recently closed their trial (protocol 62024) comparing 2 years of adjuvant therapy with imatinib versus observation alone in patients undergoing complete resection of localized primary GIST. Because overall survival is the primary endpoint, results are not expected for about 9 years. Additionally, the EORTC is accruing subjects for a phase 3 randomized study (protocol 62063) evaluating resection of residual disease in patients with metastatic GIST responding to imatinib.
Level Ia evidence: randomized clinical trials in GIST
1. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors.
Demetri GD, von Mehren M, Blanke CD, et al. N Engl J Med 2002 Aug 15; 347(7):472–80.
Hypothesis : Imatinib, evaluated at two different dose regimens, improves PFS in patients with unresectable or metastatic GIST beyond historical expectations.
| # Patients Randomized | Study Groups | Stratification | Significance Demonstrated | % Change Identified in Trial |
|---|---|---|---|---|
| 147 | 400 mg imatinib daily n = 73 600 mg imatinib daily n = 74 | None | No difference in PFS | P = not significant |
Published abstract : BACKGROUND: Constitutive activation of KIT receptor tyrosine kinase is critical in the pathogenesis of GISTs. Imatinib mesylate, a selective tyrosine kinase inhibitor, has been shown in preclinical models and preliminary clinical studies to have activity against such tumors. METHODS: The authors conducted an open-label, randomized, multicenter trial to evaluate the activity of imatinib in patients with advanced gastrointestinal stromal tumor. They assessed antitumor response and the safety and tolerability of the drug. Pharmacokinetics were assessed in a subgroup of patients. RESULTS: One-hundred forty-seven patients were randomly assigned to receive 400 mg or 600 mg of imatinib daily. Overall, 79 patients (53.7%) had a partial response; 41 patients (27.9%) had stable disease, and for technical reasons, response could not be evaluated in 7 patients (4.8%). No patient had a complete response to the treatment. The median duration of response had not been reached after a median follow-up of 24 weeks after the onset of response. Early resistance to imatinib was noted in 20 patients (13.6%). Therapy was tolerated well, although mild-to-moderate edema, diarrhea, and fatigue were common. GI or intra-abdominal hemorrhage occurred in approximately 5% of patients. There were no significant differences in toxic effects or response between the two doses. Imatinib was absorbed well, with pharmacokinetics similar to those reported in patients with chronic myeloid leukemia. CONCLUSIONS: Imatinib induced a sustained objective response in more than half of patients with an advanced unresectable or metastatic GIST. Inhibition of the KIT signal transduction pathway is a promising treatment for advanced GISTS that resist conventional chemotherapy. (Copyright [2002] Massachusetts Medical Society. All rights reserved.)
Editor’s summary and comments : In this seminal, multicenter, phase 2 study, Demetri and colleagues demonstrated the unprecedented efficacy of imatinib in unresectable or metastatic KIT-positive GIST. Beginning as a proof-of-concept study, promising early results prompted expanded enrollment. Following a 6-month follow-up of the first 100 patients, interim analysis demonstrated no difference in PFS but illustrated a dramatic response over historical expectations. The study was closed as enrollment into a phase 3trial was initiated. Of the 147 patients enrolled, 120 patients (81.6%) demonstrated either disease regression or stabilization. Although differences in efficacy were not observed between the two administered doses, the vast improvements in overall survival and PFS seen in both arms over historical controls established the benefits of imatinib in advanced GIST. In a subsequent follow-up study, the investigators demonstrated the sustained benefit of imatinib administered at either dose. With longer follow-up, objective radiological responses, as determined by Response Evaluation Criteria In Solid Tumors (RECIST) criteria, increased from 54% to 68%. More importantly, survival was shown to be independent of the extent of response, such that patients with partial responses or with stable disease experienced similar survival benefits. This may reflect the inadequacy of RECIST criteria in categorizing responses to molecular therapy. More specifically, changes in tumor density do not always correlate with alterations in tumor size ( Fig. 1 ).
2. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033.
Blanke CD, Rankin C, Demetri GD, et al. J Clin Oncol 2008 Feb 1;26(4):626–32.
Hypothesis : High-dose imatinib (400 mg twice daily) achieves better PFS and overall survival than conventional-dose imatinib (400 mg once daily).
| # Patients Randomized | Study Groups | Stratification | Significance Demonstrated | % Change Identified in Trial |
|---|---|---|---|---|
| 746 | Imatinib 400 mg daily n = 345 Imatinib 400 mg twice daily n = 349 | By Zubrod performance status (0–2 versus 3) and by disease status (measurable versus unmeasurable) | No significant differences in PFS or overall survival | P = not significant |
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