1 Introduction
Gastrointestinal stromal tumor (GIST) is a relatively rare tumor, but it is the most common stromal tumor of the gastrointestinal tract with complicated biological manifestations. It can occur anywhere from the esophagus to the rectum.1 The development of this tumor is related to increased tyrosine kinase activity caused by multiple genetic mutations, such as mast/stem cell growth factor receptor kinase (c-Kit) and platelet-derived growth factor (PDGF).2 GIST is not sensitive to conventional chemotherapy with its efficacy less than 5%.3Meanwhile, the efficacy of radiotherapy has not been clinically proven.4 Even with complete surgical resection of the primary tumor, a high recurrence rate, higher than 50% within 2 years, still is observed.5
Imatinib mesylate is one of orally small molecule tyrosine kinase inhibitors.6 BCR-ABL fusion protein and the tyrosine kinases for PDGF and c-Kit can be selectively inhibited by this drug.7,8 Therefore, imatinib was developed as first-line standard therapy in patients with unresectable, metastatic, or recurrent GIST.9 Adjuvant imatinib therapy has dramatically reduced relapse rate, mortality and prolonged the overall survival rates of patients with GISTs.10,11 However, there are still some GIST patients with large tumors or tumor located in special areas, such as esophagogastric junction, duodenum, rectum), which may cause difficulties in surgical resection or require combined multiple organ resection, and even lead to permanent lifestyle changes of patients.12 For such patients, preoperative imatinib neoadjuvant therapy can effectively shrink the tumor, strive for the opportunity of complete resection, protect the surrounding organs, and reduce the difficulty of surgery.13
Despite the apparent clinical activity of imatinib, there is a high drug resistance rate in patients with GIST treated with imatinib, and 10% to 15% of patients have primary drug resistance to imatinib. Patients with effective imatinib therapy in the past may also have secondary drug resistance after imatinib treatment.14,15 Meanwhile, patients taking standard doses of imatinib have significantly different response. Adverse reactions included diarrhea, edema, muscle cramps still be observed as the dosage of 400 mg/d imatinib is generally withstood for the bulk of patients.16 Clinical efficacy has been shown to be related to trough plasma levels (Cssmin) in patients with chronic myelogenous leukemia (CML) in chronic phase or advanced unresectable GIST.17,18 Thus it is necessary to implement TDM under imatinib treatment. The threshold of 1100 ng/mL has been perceived to be an important indicator of higher response rates for advanced unresectable GIST by some prospective clinical trials.18,19 In China, 1100 ng/mL is used as the recommended threshold for imatinib Cssmin for metastatic recurrence/unresectable GIST patients by Chinese Society of Clinical Oncology.20 However, there are few studies on the threshold of imatinib Cssmin for adjuvant imatinib treatment following by complete turmor resection and neoadjuvant treatment. Consider individual differences of GIST patients with advanced unresectable GIST and adjuvant treatment or preoperative imatinib neoadjuvant treatment, whether imatinib imatinib Cssmin threshold of 1100 ng/mL can be used to guide adjuvant imatinib therapy or preoperative imatinib neoadjuvant therapy remains to be discussed.
Xia et al. studied the profile of Cssmin of imatinib at different doses. A broad ranges of the Cssmin (421-7493 ng/mL, 1103-3775 ng/mL, 2303-5017 ng/mL) were observed in patients given 400, 600 and 800 mg/d imatinib, respectively.17 The high variability in imatinib Cssmin manifests that Cssmin may be affected by a variety of factors, such as mainly resulted from genetic, demographic, and environmental factors. In addition, some of adverse reactions have been proven dose-related.14 Considering TDM of imatinib in clinic has not been fully promoted in China, it is necessary and urgent to investigate related factors of imatinib Cssmin in Chinese GIST patients to improve therapeutic effect.
The aim of this study was to develop an UPLC-MS/MS method for analysis of imatinib Cssmin in human plasma. Then it was applied for routine TDM in GIST patients with adjuvant imatinib therapy and preoperative imatinib neoadjuvant therapy.