Treatment Option Overview
The management of patients with gastrointestinal stromal tumors (GIST) is a multidisciplinary effort involving close collaboration between pathologists, medical oncologists, surgeons, and imaging experts.
Treatment may involve surgery and/or the use of tyrosine kinase inhibitors (TKI) depending on the extent of disease and tumor sensitivity to TKI. Although recurrence is common for patients with high-risk tumors (see Table1), complete resection of localized tumors may be associated with long-term disease-free survival (DFS).[Level of evidence: 3iiiDii] Standard chemotherapy is not used because of the insensitivity of GIST to chemotherapeutic agents.[3-6] Radiation therapy rarely has a role in the management of patients with GIST; it may occasionally be used for pain control in patients with limited, bulky hepatic metastases or with a single, large metastatic lesion fixed to the abdominal or pelvic wall.[Level of evidence: 2Div] Whether tumors 2 cm or smaller with a mitotic index of 5 or less per 50 high-power fields require surgery is controversial. Such tumors appear to have low rates of progression and metastasis, but the absolute rates are not known with precision. Endoscopic surveillance is an option.Surgical Therapy
Surgery is typically the initial therapy for the following types of patients:
- Those with primary GIST who do not have evidence of metastasis.
- Those with tumors that are technically resectable if the risks of morbidity are acceptable.
In the surgical treatment of GIST, the goal is complete gross resection with an intact pseudocapsule and negative microscopic margins. Because lymph node metastasis is rare with GIST, lymphadenectomy of clinically uninvolved nodes is not necessary.
Although a prospective, randomized trial studying the role of laparoscopic surgery in the management of GIST has not been performed, several studies, listed below, indicate a role for this surgical approach with gastric tumors:
- In one retrospective study involving 33 patients with gastric tumors ranging in size from 0.5 cm to 10.5.cm, all gross tumors could be successfully removed by laparoscopic surgery, with short hospitalizations and low morbidity. There were no recurrences observed with a mean follow-up of 13 months.[Level of evidence: 3iiDii]
- In another retrospective study involving 60 patients, laparoscopic or laparoscopy-assisted resections of GIST measuring 2 cm to 5 cm were associated with a 5-year DFS of 100% for very low-risk groups and low-risk groups versus a 5-year DFS of 89.9% for intermediate-risk groups and high-risk groups; no local or distant recurrences were observed for tumors smaller than 4 cm in size.[Level of evidence: 3iiDi]
- In another study involving 50 consecutive patients undergoing laparoscopic or laparoendoscopic resection of gastric GIST (mean tumor size = 4.4 cm) who were identified in a prospectively collected database, 46 (92%) patients were found to be disease free at a mean follow-up of 36 months.[Level of evidence: 3iiDi]
Neoadjuvant imatinib therapy can be used for patients with large tumors or difficult-to-access small GIST that are considered marginally resectable. In addition, patients with primary localized GIST deemed unresectable are often treated with imatinib.[4,11]Chemotherapy
Before the advent of molecularly targeted therapy with TKI, efforts to treat GIST with conventional cytotoxic chemotherapy were essentially futile. The extreme resistance of GIST to chemotherapy may be caused, in part, by the increased expression of P-glycoprotein, the product of the MDR-1 (multidrug resistance-1) gene, and MRP1 (multidrug resistance protein-1), which are cellular efflux pumps that may prevent chemotherapeutic agents from reaching therapeutic intracellular concentrations in GIST cells.[1,12] There is universal agreement that standard chemotherapy has no role in the primary therapy of GIST.[4-6]Tyrosine Kinase Inhibitor Therapy
TKIs have revolutionized the management of GIST. The TKI imatinib mesylate is used as the first-line treatment for unresectable, metastatic, or recurrent GIST. Although complete responses are rare, a large majority of patients with metastatic or inoperable GIST have either a partial response or disease stabilization after starting imatinib. Median survival rates have gone from less than 2 years to more than 5 years since the advent of imatinib therapy.
Therapy with neoadjuvant imatinib to reduce the tumor volume may be used for patients with very large primary GIST that cannot be removed without the risk of unacceptable morbidity. Additional therapy with adjuvant imatinib is being studied to determine whether imatinib reduces recurrence, which is common after resection of primary GIST.
Because disease progression has been reported to follow the cessation of imatinib therapy, patients with unresectable or metastatic disease are often treated with a TKI indefinitely, as long as the disease does not progress and patient tolerance permits.[1,14] In a multicenter trial in which 58 patients with advanced GIST who had disease stability after at least 1 year of imatinib therapy were randomly assigned to continue (n = 26) or to discontinue (n = 32) imatinib (with reinstitution for progression), 8 and 26 patients progressed at a median of 18 and 6.1 months, respectively (P < .0001). However, 24 of the 26 patients in the latter group responded again to reinstitution of imatinib.[Level of evidence: 1iiDiii] There were no differences in overall survival (OS), development of imatinib resistance, or quality of life between the two groups.[Level of evidence: 1iiA and 1iiC]Drug dose and schedule
A patient with unresectable or metastatic GIST may be treated with an initial dose of 400 mg imatinib mesylate daily, with therapeutic effects monitored by 18fluoro-deoxyglucose-positron emission tomography (18FDG-PET) or computed tomography; dose escalation to 400 mg twice a day may be appropriate for patients with progressive disease, although it is unlikely to help patients who progress within 2 months of initiation of imatinib therapy.[4,15-17] An initial dose of 800 mg daily may be appropriate for patients with GIST harboring KIT exon 9 mutations. Resistance to imatinib may be primary with rapid progression of disease despite an increase in the imatinib dose, although this appears to occur in fewer than 20% of patients; some investigators have speculated that GIST with primary resistance to imatinib have mutations in other oncogenic signaling pathways that do not involve KIT.[1,19,20]
The majority of patients treated with imatinib ultimately experience disease progression after an initial response because of the development of delayed imatinib resistance. In most cases, delayed resistance is associated with secondary mutations in a separate portion of the KIT-coding sequence.[20,21]
The oral TKI sunitinib malate is generally given to patients with unresectable disease who progress on higher-dose imatinib, although individuals with localized progression may be candidates for resection. Less specific than imatinib, sunitinib inhibits vascular endothelial growth factor receptors (VEGFR 1-3), Fms-like tyrosine kinase-3 (FLT3), colony-stimulating factor 1 receptor (CSF-1R), and RET as well as KIT and PDGFR and displays antiangiogenic activity.[23-25] A number of other targeted therapeutics for the treatment of GIST are in development, including a variety of other kinase inhibitors, heat-shock protein 90 (Hsp90) inhibitors such as IPI-504, the mTOR inhibitor RAD001, and histone deacetylase inhibitors.[3,26]
Treatment with imatinib or sunitinib may be continued for as long as the patient appears to be deriving clinical benefit or has disease stability.Response to kinase inhibitors
KIT- and PDGFRA-mutational analysis may be of help in predicting responses to kinase inhibitors for patients with unresectable, metastatic, or recurrent GIST who are undergoing therapy with selective TKIs.[18,27-30] However, the data are preliminary and mutational analysis for treatment decisions is not routine. There is currently no evidence that basing treatment decisions on mutational analysis improves OS. Four trials involving 768 patients and imatinib doses ranging from 400 mg to 800 mg per day have correlated tumor genotypes and complete and partial objective responses (see Table 6). For these 768 genotyped GIST, the objective response for KIT exon 11 mutant, KIT exon 9 mutant, and wild-type (no KIT or PDGFRA mutation) GIST were 71%, 38%, and 28% (weighted averages), respectively; rates of primary resistance to imatinib therapy were 5%, 16%, and 23%, respectively.Table 6. Relationship Between Tyrosine Kinase Genotype and Response to Imatinib Therapya
|European Phase I/IIb Trial, % (n) ||B-2222 Phase IIc Trial, % (n) ||European/Australasian Phase IIId Trial, % (n) ||North American CLB-80004 Phase IIIe Trial, % (n) |
|Study participants||(N = 37)||(N = 127)||(N= 377)||(N = 324)|
|KIT exon 11||83 (24)||83g (85)||70g (248)||67g (211)|
|KIT exon 9||25 (4)||48 (23)||35 (58)||40 (25)|
|Wild-type||33 (6)||0 (9)||25 (52)||39 (33)|
|KIT exon 11||4||5||3||NR|
|KIT exon 9||0||17||17||NR|
|N = number in sample, number of observations; NR = not reported.|
|aAnnual review of pathology by ANNUAL REVIEWS, INC. Reproduced with permission of ANNUAL REVIEWS, INC., in the format Internet posting via Copyright Clearance Center.|
|b[Level of evidence: 1iiA, 1iiDii, 1iiDiv (Phase 1) and 2A; 2Div (Phase II)]|
|c[Level of evidence: 1iiDiv]|
|d[Level of evidence: 1iiA and 1iiDiii]|
|e[Level of evidence: 1iiDiv]|
|fDefined as complete or partial response by Southwest Oncology Group (SWOG) criteria for B-2222 or RECIST (Response Evaluation Criteria in Solid Tumors) for all other trials; excludes nonevaluable patients.|
|gStatistically significant difference compared with KIT 9 and wild-type (no KIT or PDGFRA mutation) groups.|
Kinase genotype appears to correlate with progression-free survival (PFS) and OS. The median time to tumor progression (TTP) for patients whose GIST harbors a KIT exon 11 mutation has been reported to be more than 1 year longer than the median TTP for patients whose tumors have KIT exon 9 or wild-type kinase genotypes; a similar OS benefit has been reported for patients with KIT exon 11 mutations versus the other common genotype subsets. In a subset analysis of the European/Australasian phase III trial, it was found that the PFS of GIST patients with KIT exon 9 mutations was significantly better when patients were treated with 800 mg of imatinib per day as compared with 400 mg per day (P = .0013), with a reduction of relative risk of 61%.[Level of evidence: 1iiDiii] Accordingly, routine tumor typing and imatinib dose selection based on the presence or absence of a KIT exon 9 mutation is recommended by some but not all GIST experts.[3,4]Drug side effects and other considerations
- Fluid retention (especially periorbital edema or peripheral edema; occasionally pleural effusion or ascites).
- Nausea (may be diminished if taken with food).
- Muscle cramps.
- Abdominal pain.
- Mild (macrocytic) anemia.
(Refer to the PDQ summaries on Lymphedema [edema], Gastrointestinal Complications [diarrhea], Nausea and Vomiting, Fatigue [fatigue and anemia], and Pain for more information on some of the conditions listed above.)
Treatment with sunitinib may be considered for patients with life-threatening side effects from imatinib that cannot be managed by maximum supportive care. Common side effects associated with sunitinib therapy include the following:[22,36]
- Nausea and vomiting.
- Abdominal pain.
- Skin or hair discoloration.
- Hypothyroidism (thyroid function monitoring with TSH is generally recommended to detect subclinical hypothyroidism).
Less frequent toxicities include bleeding, fever, and hand-foot syndrome.
Therapy with sunitinib also may be cardiotoxic. In a retrospective study of a phase I/II trial studying the efficacy of sunitinib in treating imatinib-resistant, metastatic GIST, 8% of 75 patients who received repeating cycles of sunitinib experienced congestive heart failure while 47% developed hypertension (>150 per 100 mm Hg); reductions in left ventricular ejection fraction were at least 10% in 28% of patients.[Level of evidence: 3iiB]
A number of other drugs and certain fruit juices (e.g., grapefruit, pomegranate) may alter plasma levels of imatinib or sunitinib by inducing or inhibiting cytochrome P450 isoenzyme 3A4 (CYP450 3A4), the primary enzyme involved in the metabolism of these TKIs.[4,38-42] For patients taking drugs that affect CYP450 3A4 levels, dose modification of the TKI or substitution with medications that do not affect CYP450 3A4 may be necessary.References
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