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.