Standard treatment for primary gastrointestinal stromal tumor (GIST) is complete surgical resection, with the aim to obtain negative microscopic margins over the organ of origin [
40]. In some cases, because of the anatomic site or the tumor size, complete resection is either not feasible or possible only through extensive procedures with expected major functional morbidity. Imatinib mesylate is a very active agent for tumor control in advanced and metastatic GIST [
37]. GISTs have a high risk of metastatic relapse. The usual site of recurrence is the liver (65%), the peritoneal surface (50%) and both (20%). GIST's response to conventional chemotherapy is very poor (<10%), while radiotherapy is only used for analgesic purposes or in cases of intra peritoneal hemorrhage [
26]. GISTs may show poor response to chemotherapy, but not to imatinib mesylate, also known as STI571 [
11,
45] which was found to act as a powerful selective inhibitor of tyrosine kinases of PDGFR and of c-kit receptor. Imatinib was initially designed as a PDGFR inhibitor and its efficacy as a tyrosine kinase was assessed in chronic myeloid leukemia [
46]. The use of Imatinib mesylate in recurrent or metastatic, resectable or not GIST in prospective trial has shown response in 50% patients, and in approximately 75-85% patients have at least stable disease. The 2-year survival after Imatinib therapy is approximately 70% and 50% of the patients showed no progression of the disease [
2]. Imatinib interruption after 1 year is associated with a high risk of relapse, even for patients in complete remission [
47]. The treatment should continue until progression, intolerance or patient refusal. The treatment is usually well tolerated, but includes mild to moderate adverse effects such as edema (usually periorbital) [
48], nausea, muscle cramps, diarrhea, headache, dermatitis, fatigue, vitiligo [
49], hypothyroidism [
50], cutaneous pigmentation [
51] and abdominal pain. In patients with large bulky tumors, serious adverse events may include gastrointestinal, intraabdominal hemorrhages [
52], cardiotoxicity [
53] and serosal inflammation [
54]. Other observed effects comprise neutropenia, leukopenia and abnormal liver function [
55]. The ideal dose of Imatinib is not determined, but the current data show no added benefit with doses greater than 400 mg/day. All studies [
44] on the dosage of Imatinib suggest that doses of 400-800 mg/day are safe, efficacious and patients tolerate it well. Imatinib was approved by the FDA for treatment of unresectable and metastatic GISTs on 1 February, 2002. Higher dosage is associated with symptoms of toxicity [
46]. The common side effects of the drug consist of edema, rash, nausea, diarrhea, myalgia, fatigue, headache, and abdominal pain [
56]. Recent study has confirmed that stopping of Imatinib is associated with an increased risk of disease progression but it is not known whether the discontinuation of Imatinib followed by reintroduction when the disease progresses is associated with a reduction in the survival [
57]. Even though, Imatinib is a revolution for the management of GIST, it is not appropriate for all the cases of GIST. Even if it is rare, resistance to Imatinib has been reported [
2,
7,
26]. There are patients, who do not respond to treatment with Imatinib or present an aggravation within 6 months during such treatment. These patients have primary resistance and usually have tumors with KIT exon 9 mutation or a non detectable kinase mutation [
28]. Primary resistance to Imatinib is rare and affects only 15% of patients [
39]. There is, also, another group of patients who has progression of tumor after at least 6 months of measurable response to Imatinib [
55] and we used to say that they have a secondary resistance to Imatinib. Half of the patients, who initially respond, become resistant by 2 years after Imatinib initiation [
57]. The common mechanism of acquired resistance is secondary kit mutation. Resistant lesions appear on imaging studies as a growing nodule in the pre-existing tumor. Primary and secondary resistance to Imatinib is also becoming a major clinical problem in the treatment of this disease. Therefore, new drugs that can be served as alternative therapies in Imatinib-resistant patients with GIST or that can be used in combination with Imatinib are needed [
2]. The first clinical studies demonstrate that Imatinib is the first effective treatment for non resectable or metastatic GIST [
56]. However, long-term results have not been extracted yet, because of the short time of use. It is obvious that further clinical studies must be designed [
58‐
60].