The primary treatment of patients with metastatic or recurrent gastrointestinal stromal tumors (GIST) involves medical therapy with a tyrosine kinase inhibitor (TKI); in select cases, surgical therapy may be added. Patients with metastatic or recurrent tumors that do not respond to these measures may be candidates for clinical trials.
- Therapy with imatinib is standard for patients with metastatic or recurrent disease. The initial dose may range from 400 mg to 600 mg daily, except for patients with tumors containing KIT exon 9 mutations, who may receive 800 mg daily. Response is evaluated with computed tomography (CT), magnetic resonance imaging (MRI), or 18 fluoro-deoxyglucose-positron emission tomography (18 FDG-PET).[2,3,4,5,6] Treatment is usually continued indefinitely in the absence of disease progression or unacceptable toxicity.[3,7]
In a phase III randomized trial involving 746 patients with advanced incurable GIST (CLB-80004), higher dose treatment with 800 mg imatinib daily did not show any advantage over lower-dose treatment with 400 mg imatinib daily as primary systemic therapy; no statistically significant differences in objective response rates, progression-free survival (PFS), or overall survival (OS) were observed.[Levels of evidence: 1iiA; 1iiDiii; and 1iiDiv].
However, in a phase II randomized trial examining dose selection in 946 patients with advanced GIST (EORTC-62005 [NCT00685828I]), pretreatment samples of GIST from 377 patients were analyzed for KIT gene mutations; those patients whose tumors expressed an exon 9 KIT mutation and were treated with a daily dose of 800 mg of imatinib (vs. 400 mg) experienced a significantly superior PFS (P = .0013) with a reduction of relative risk of 61%.[Level of evidence: 1iiDiii]
In the event of progression of tumors without KIT exon 9 mutations on lower dose imatinib (i.e., 400 mg -600 mg daily), the imatinib dose may be increased to 800 mg daily (in split doses). Alternatively, in the management of imatinib resistance, the patient may be switched directly to sunitinib from low-dose imatinib.
- In case of tumor progression or intolerance to imatinib, the second-line standard therapy consists of sunitinib administered at a dose of 50 mg daily in a 4-weeks-on/2-weeks-off regimen. Alternatively, a regimen consisting of a daily dose of 37.5 mg may be used. As with imatinib therapy, the response to therapy with sunitinib is evaluated with CT, MRI, or 18 FDG-PET, and treatment is usually continued indefinitely in the absence of disease progression or unacceptable toxicity.[2,3,11]
In a randomized controlled trial involving 312 patients with imatinib-resistant GIST, median time to tumor progression was more than four times as long with sunitinib (27.3 weeks, 95% CI 16.0-32.1) than with placebo treatment (6.4 weeks, 95% confidence interval (CI), 4.4-10.0; hazard ratio (HR) = 0.33; 95% CI, 0.23-0.47; P < .0001) on the basis of radiologic assessment. Overall survival was similarly better for sunitinib-treated patients (HR for death = 0.49; 95% CI, 0.29-0.83).[Level of evidence: 1iA]
It has been suggested that patients with limited disease progression continue on imatinib or sunitinib at a dose that can be tolerated. For patients with large bulky tumors who are receiving imatinib, there may be a 5% risk of tumor hemorrhage unassociated with thrombocytopenia;[12,13] accordingly, patients with large, high-risk tumors are monitored very closely for evidence of a decline in hemoglobin levels during the first 4 to 8 weeks of imatinib therapy. All patients on TKI therapy are closely monitored for tumor response and side effects, which may require dose reductions, interruptions, or cessation of TKI therapy in cases of persistent, excessive toxicity. In addition, dose modification of the TKI or substitution with medications that do not affect CYP450 3A4 levels may be necessary for patients taking drugs that affect CYP450 3A4 levels.
- Surgery may be added to medical therapy for selected patients with GIST in an effort to delay or prevent recurrence, although the benefit of this therapeutic approach in metastatic GIST has yet to be proven in a randomized clinical trial.
In a retrospective study involving 69 consecutive patients who underwent surgery for unresectable primary or metastatic GIST while receiving kinase inhibitors, patients with stable disease or limited progression were found to have prolonged survival after debulking procedures. In this group of GIST patients, no evidence of disease was found in 78%, 25%, and 7% of patients with stable disease, limited progression, and generalized progression, respectively, after surgery; the 12-month PFS was 80%, 33%, and 0% for patients with stable disease, limited progression, and generalized progression, whereas the 12-month OS was 95%, 86%, and 0% for the same patient subsets.[Levels of evidence: 3iiDii and 3iiA] The authors of this study concluded that surgery for patients with generalized progression be limited to a palliative role.
Overall, the indications for surgery in the management of metastatic or recurrent GIST include the following:
- For stable disease (i.e. disease that is stable or shrinking on TKI therapy when gross resection is possible).
- For limited disease progression (i.e., isolated tumor deposits that are progressing on TKI therapy after initial response [indicating delayed drug resistance], while other sites of disease remain stable).
- For oncologic emergencies including hemorrhage, perforation, obstruction, or abscess.
The first two indications (1 and 2) identify subsets of patients with advanced disease that are selected for relative disease stability. Therefore, the favorable outcomes that have been noted in case series may be principally the result of selection bias rather than true benefit from surgery. Because the median time to the development of secondary resistance to imatinib has been found to be about 2 years, it has been suggested that surgery for metastatic or recurrent disease in patients on imatinib/sunitinib be performed before 2 years. Most experts would recommend considering surgery after 6 to 12 months of disease stability with TKI therapy. Drug therapy may be continued after surgery. Patients with generalized disease progression are managed medically and may be enrolled in clinical trials.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with gastrointestinal stromal tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
- Debiec-Rychter M, Sciot R, Le Cesne A, et al.: KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42 (8): 1093-103, 2006.
- Demetri GD: Gastrointestinal stromal tumor. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1060-73.
- Demetri GD, Benjamin RS, Blanke CD, et al.: NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)--update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 5 (Suppl 2): S1-29; quiz S30, 2007.
- Blanke CD, von Mehren M, Joensuu H, et al.: Evaluation of the safety and efficacy of an oral molecularly-targeted therapy, STI157, in patients (pts) with unresectable or metastatic gastrointestinal stromal tumors (GISTs) expressing c-kit (CD117). [Abstract] Proceedings of the American Society of Clinical Oncology 20: A-1, 1a, 2001.
- van Oosterom AT, Judson I, Verweij J, et al.: Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 358 (9291): 1421-3, 2001.
- Choi H, Charnsangavej C, Faria SC, et al.: Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol 25 (13): 1753-9, 2007.
- Blay JY, Le Cesne A, Ray-Coquard I, et al.: Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group. J Clin Oncol 25 (9): 1107-13, 2007.
- Blanke CD, Rankin C, Demetri GD, et al.: 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. J Clin Oncol 26 (4): 626-32, 2008.
- Rutkowski P, Nowecki Z, Nyckowski P, et al.: Surgical treatment of patients with initially inoperable and/or metastatic gastrointestinal stromal tumors (GIST) during therapy with imatinib mesylate. J Surg Oncol 93 (4): 304-11, 2006.
- Demetri GD, van Oosterom AT, Garrett CR, et al.: Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 368 (9544): 1329-38, 2006.
- Prior JO, Montemurro M, Orcurto MV, et al.: Early prediction of response to sunitinib after imatinib failure by 18F-fluorodeoxyglucose positron emission tomography in patients with gastrointestinal stromal tumor. J Clin Oncol 27 (3): 439-45, 2009.
- Demetri GD, von Mehren M, Blanke CD, et al.: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347 (7): 472-80, 2002.
- Dagher R, Cohen M, Williams G, et al.: Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin Cancer Res 8 (10): 3034-8, 2002.
- Raut CP, Posner M, Desai J, et al.: Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J Clin Oncol 24 (15): 2325-31, 2006.
- Verweij J, Casali PG, Zalcberg J, et al.: Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 364 (9440): 1127-34, 2004.