Table 6. Relationship Between Tyrosine Kinase Genotype and Response to Imatinib Therapya continued...
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
The most common toxicities associated with imatinib therapy, all of which may improve with prolonged treatment, include the following:[5,16,17,34,35]
(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).
(Refer to the anorexia section in the PDQ summary on Nutrition in Cancer Care for more information on some of the conditions listed above.)
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.[4,38,39,40,41,42] 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.
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