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]
For more information on some of the conditions listed above, refer to the PDQ summaries on Lymphedema (edema), Gastrointestinal Complications (diarrhea), Nausea and Vomiting, Fatigue (fatigue and anemia), and Pain.
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]
For more information on some of the conditions listed above, refer to the PDQ summary on Nutrition (anorexia).
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.
- Demetri G: Gastrointestinal stromal tumors. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. Vols. 1 & 2. 8th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2008, pp 1204-18.
- Judson I, Demetri G: Advances in the treatment of gastrointestinal stromal tumours. Ann Oncol 18 (Suppl 10): x20-4, 2007.
- Corless CL, Heinrich MC: Molecular pathobiology of gastrointestinal stromal sarcomas. Annu Rev Pathol 3: 557-86, 2008.
- 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.
- 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.
- Edmonson JH, Marks RS, Buckner JC, et al.: Contrast of response to dacarbazine, mitomycin, doxorubicin, and cisplatin (DMAP) plus GM-CSF between patients with advanced malignant gastrointestinal stromal tumors and patients with other advanced leiomyosarcomas. Cancer Invest 20 (5-6): 605-12, 2002.
- Miettinen M, Sobin LH, Lasota J: Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol 29 (1): 52-68, 2005.
- Huguet KL, Rush RM Jr, Tessier DJ, et al.: Laparoscopic gastric gastrointestinal stromal tumor resection: the mayo clinic experience. Arch Surg 143 (6): 587-90; discussion 591, 2008.
- Otani Y, Furukawa T, Yoshida M, et al.: Operative indications for relatively small (2-5 cm) gastrointestinal stromal tumor of the stomach based on analysis of 60 operated cases. Surgery 139 (4): 484-92, 2006.
- Novitsky YW, Kercher KW, Sing RF, et al.: Long-term outcomes of laparoscopic resection of gastric gastrointestinal stromal tumors. Ann Surg 243 (6): 738-45; discussion 745-7, 2006.
- Bonvalot S, Eldweny H, P�choux CL, et al.: Impact of surgery on advanced gastrointestinal stromal tumors (GIST) in the imatinib era. Ann Surg Oncol 13 (12): 1596-603, 2006.
- Plaat BE, Hollema H, Molenaar WM, et al.: Soft tissue leiomyosarcomas and malignant gastrointestinal stromal tumors: differences in clinical outcome and expression of multidrug resistance proteins. J Clin Oncol 18 (18): 3211-20, 2000.
- Blanke CD, Demetri GD, von Mehren M, et al.: Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 26 (4): 620-5, 2008.
- 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.
- 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.
- Verweij J, van Oosterom A, Blay JY, et al.: Imatinib mesylate (STI-571 Glivec, Gleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target. Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study. Eur J Cancer 39 (14): 2006-11, 2003.
- Benjamin RS, Rankin C, Fletcher C, et al.: Phase III dose-randomized study of imatinib mesylate (STI571) for GIST: Intergroup S0033 early results. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-3271, 2003.
- 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.
- Kindblom LG, Meis-Kindblom J, B�mming P, et al.: Incidence, prevalence, phenotype and biologic spectrum of gastrointestinal stromal cell tumors (GIST): a population-based study of 600 cases. [Abstract] Ann Oncol 13 (Suppl 5): A-577O, 157, 2002. Also available online. Last accessed October 14, 2011.
- Gramza AW, Corless CL, Heinrich MC: Resistance to Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumors. Clin Cancer Res 15 (24): 7510-7518, 2009.
- Desai J, Shankar S, Heinrich MC, et al.: Clonal evolution of resistance to imatinib in patients with metastatic gastrointestinal stromal tumors. Clin Cancer Res 13 (18 Pt 1): 5398-405, 2007.
- 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.
- O'Farrell AM, Abrams TJ, Yuen HA, et al.: SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 101 (9): 3597-605, 2003.
- Mendel DB, Laird AD, Xin X, et al.: In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 9 (1): 327-37, 2003.
- Murray LJ, Abrams TJ, Long KR, et al.: SU11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model. Clin Exp Metastasis 20 (8): 757-66, 2003.
- Wagner AJ, Morgan JA, Chugh R, et al.: Inhibition of heat shock protein 90 (Hsp90) with the novel agent IPI-504 in metastatic GIST following failure of tyrosine kinase inhibitors (TKIs) or other sarcomas: clinical results from phase I trial. [Abstract] J Clin Oncol 26 (suppl 15): A-10503, 2008.
- Singer S, Rubin BP, Lux ML, et al.: Prognostic value of KIT mutation type, mitotic activity, and histologic subtype in gastrointestinal stromal tumors. J Clin Oncol 20 (18): 3898-905, 2002.
- Kim TW, Lee H, Kang YK, et al.: Prognostic significance of c-kit mutation in localized gastrointestinal stromal tumors. Clin Cancer Res 10 (9): 3076-81, 2004.
- Andersson J, B�mming P, Meis-Kindblom JM, et al.: Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis. Gastroenterology 130 (6): 1573-81, 2006.
- Antonescu CR: Targeted therapy of cancer: new roles for pathologists in identifying GISTs and other sarcomas. Mod Pathol 21 (Suppl 2): S31-6, 2008.
- Debiec-Rychter M, Dumez H, Judson I, et al.: Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 40 (5): 689-95, 2004.
- Heinrich MC, Corless CL, Demetri GD, et al.: Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21 (23): 4342-9, 2003.
- Heinrich MC, Shoemaker JS, Corless CL, et al.: Correlation of target kinase genotype with clinical activity of imatinib mesylate (IM) in patients with metastatic GI stromal tumors (GISTs) expressing KIT (KIT+). [Abstract] J Clin Oncol 23 (Suppl 16): A-7, 3s, 2005.
- 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.
- 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.
- Wolter P, Stefan C, Decallonne B, et al.: The clinical implications of sunitinib-induced hypothyroidism: a prospective evaluation. Br J Cancer 99 (3): 448-54, 2008.
- Chu TF, Rupnick MA, Kerkela R, et al.: Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 370 (9604): 2011-9, 2007.
- Frye RF, Fitzgerald SM, Lagattuta TF, et al.: Effect of St John's wort on imatinib mesylate pharmacokinetics. Clin Pharmacol Ther 76 (4): 323-9, 2004.
- Dutreix C, Peng B, Mehring G, et al.: Pharmacokinetic interaction between ketoconazole and imatinib mesylate (Glivec) in healthy subjects. Cancer Chemother Pharmacol 54 (4): 290-4, 2004.
- de Groot JW, Zonnenberg BA, Plukker JT, et al.: Imatinib induces hypothyroidism in patients receiving levothyroxine. Clin Pharmacol Ther 78 (4): 433-8, 2005.
- Bolton AE, Peng B, Hubert M, et al.: Effect of rifampicin on the pharmacokinetics of imatinib mesylate (Gleevec, STI571) in healthy subjects. Cancer Chemother Pharmacol 53 (2): 102-6, 2004.
- O'Brien SG, Meinhardt P, Bond E, et al.: Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome p450 3A4 substrate, in patients with chronic myeloid leukaemia. Br J Cancer 89 (10): 1855-9, 2003.