Imatinib Plasma Monitoring-Guided Dose Modification for Managing Imatinib-Related Toxicities in Gastrointestinal Stromal Tumor Patients
A 67-yr-old Asian man who presented with intermittent melena and significant weight loss was diagnosed with small bowel GIST with multiple liver metastases and peritoneal seeding on May 25, 2010. He underwent jejunal resection and anastomosis with palliative intent. The excised jejunal GIST measured 7 × 5 × 5 cm and had a c-KIT exon 9 mutation (1,510-1,515 duplication). After surgery, the patient was treated with 400 mg/day imatinib. He had no concomitant medications or co-morbid diseases.\nTwo months later, the patient developed grade 3 edema, grade 3 ascites, and grade 2 vomiting, with chest radiography revealing layering of a moderate amount of pleural fluid. Because the patient had peritoneal seeding, it was hard to determine whether his ascites and pleural effusion were due to imatinib toxicity or the progression of GIST. Although the follow-up abdomino-pelvic computed tomography (CT) scan showed that the patient's liver metastases had not changed significantly, disease progression was suspected, which prompted a cessation in imatinib treatment and a commencement of sunitinib treatment. The patient was transferred to our hospital for a second opinion after he had been taking sunitinib for approximately 2 months. A thorough review of his previous serial CT scans showed no definitive evidence of disease progression whilst he was on imatinib treatment. We therefore decided to resume 400 mg/day imatinib and use 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT for accurate assessment of response to imatinib treatment.\nOne month after the patient restarted imatinib, a PET/CT scan revealed a significant decrease in maximum standardized uptake value from 4.2 to 2.9 in one of his liver metastases (), suggesting the tumor was responding to imatinib. However, the patient required paracentesis once weekly to control his ascites, and he complained of peripheral edema and dyspnea. Because imatinib blood level testing revealed that the patient had very high imatinib trough plasma exposure, 4,120 ng/mL and 4,600 ng/mL on two different days (), we decreased his dose to 300 mg/day, which resulted in a steady-state imatinib plasma trough concentration of 3,220 ng/mL (). However, the patient still had grade 2 edema, ascites, and dyspnea on exertion due to pleural effusion. As his imatinib trough plasma exposure was sufficiently high to achieve an adequate tumor response (), we further reduced his dose to 200 mg/day. At this dose, his fluid retention, including ascites, edema, and pleural effusion, was greatly improved, and he had no difficulties in daily life; in addition, his liver metastases remained stable ().\nFive months later, the patient expressed concerns that 200 mg/day of imatinib may be insufficient to control his tumor, as studies have shown that GIST patients with the c-KIT exon 9 mutation may benefit from higher than normal exposure to imatinib (, , ). We therefore increased his dose to 300 mg/day. He was able to tolerate ascites and dyspnea with the use of regular diuretics but had some limitation of activities. Follow-up CT scans to date showed the patient's disease remained stable ().