4 Discussion
Correlation between imatinib Cssmin and clinical efficacy has been confirmed in many studies. Demetri et al. considered 1100 ng/mL as the threshold for clinical effect in patients with unresectable or metastatic GIST.18 Rapid disease progression and low survival benefit have been observed without Cssmin reaching the concentration threshold. Another European multicenter study showed that imatinib Cssmingreater than 760 ng/mL can prolong the progression free survival (PFS) of patients diagnosed with GIST.23 Therefore, explicit threshold value is a prerequisite for TDM to enhance clinical response, efficacy and safety of imatinib. However, the relationship between imatinib Cssmin and prognosis of patients receiving adjuvant imatinib therapy and preoperative imatinib neoadjuvant therapy is unclear. In our research, the Cssmin of 16 patients with imatinib adjuvant therapy and 9 patients with neoadjuvant therapy were determined by this developed UPLC-MS/MS method, and the characteristics of the Cssmin of the above patients were preliminarily explored.
The recommended dosage of imatinib for adjuvant treatment or neoadjuvant treatment is 400 mg/d. In this research, the average Cssmin of imatinib with neoadjuvant treatment at the dosage of 400 mg/d was 1858.7 ng/mL, and that of adjuvant treatment was 1741.0 ng/mL. Statistical analysis indicated that the Cssmin of imatinib with neoadjuvant treatment was not obvious different from that with adjuvant treatment, which revealed that the Cssmin may not be affected by tumor load. For 18 patients given 400 mg/d imatinib, the median of Cssmintend to be higher in female than male patients (1998 ng/mL vs 1468 ng/mL, p<0.05). Wu et al. also found a significant decrease of approximately 19% in the mean Cssmin of male patients compared to the female. It can be suspected that the Cssmin of imatinib may be related to gender.24 Meanwhile, imatinib Cssminwas found to be obviously related with gender in a Korean study (p=0.010).25 For efficacy, Lv et al. has indicated that male gender proved to be a negative indicator of survival with the 5-year overall survival (OS) for male and female was 83.37% and 87.68%, respectively.26 Since imatinib is a substrate of P-glycoprotein (P-gp) efflux transporter, the reason for this result may be the difference of this efflux transporter activity in different gender groups.27,28 Due to the higher activity of P-gp in male patients than the female, more imatinib could be transported from the intracellular to the extracellular, thereby decreasing imatinib concentration in intracellular and reducing clinical efficacy.
Of the 9 patients who received imatinib neoadjuvant treatment, 7 patients mainly had large tumor diameter initially showed in CT, and the other 2 patients were treated before surgery because of the special tumor location and the difficulty of complete resection. The duration of preoperative imatinib neoadjuvant treatment was 5-13 months. The primary tumor of 6 patients were shrinking, that of 2 patients had no significant change, but that of 1 patient was growing. This may be related to unclear initial genotype or secondary mutation during preoperative neoadjuvant treatment. Several studies on imatinib dosage and clinical efficacy show that imatinib is most sensitive to GIST with c-kit exon 11 mutation and also has good efficacy for those with PDGFRA exon 18 non-D842V mutation, while the dosage of imatinib is required to increase for GIST with c-kit exon 9 mutation to achieve considerable clinical efficacy.29-32 In neoadjuvant treatment group, 1 patient with tumor growth and 1 patient without tumor changing were not tested for gene. The other 7 patients were tested as c-kit 11 gene mutation. Similarly, 1 GIST patients with adjuvant treatment was tested as c-kit 9 gene mutation. After surgical operation given at a dosage of 400 mg/d for 15 months, the dosage increased to 600 mg/d as a result of tumor progression. Therefore, for GIST with indications for neoadjuvant and adjuvant treatment, identification of genotype is important for adjusting drug dosage to improve clinical efficacy.
Imatinib is generally well tolerated, with a low risk of adverse reactions and the occurrence of adverse reactions and severity are often related to the dosage of imatinib.33 The most common adverse effects include mild to moderate edema, nausea and vomiting, diarrhea, muscle cramps, and rash, while the incidence of myelosuppression and elevated transaminase levels is low.17 In the imatinib neoadjuvant treatment group, the adverse reactions after imatinib treatment were mainly leukopenia, anemia, periorbital edema, and skin. Only one patient had grade 4 leukopenia requiring drug control. In the imatinib adjuvant treatment group, the adverse reactions were mainly nausea and vomiting, anemia, limb edema, limb edema and skin. No obvious grade 4 and 5 adverse reactions were found. Previous study has showed that the incidence of adverse reactions is positively correlated with the level of imatinib Cssmin.34,18 There was no obvious relationship between adverse reactions and imatinib Cssmin in this study due to limited sample size of GIST patients. However, the determination of Cssmin in Chinese patients using imatinib can effectively reduce the risk of adverse reactions. Fever and neutropenia was caused by high levels of imatinib Cssmin (4722 ng/mL) and not be tolerated in one patient with neoadjuvant treatment. The drug needs to be discontinued, and the dosage will be reduced to 200 mg/d after appropriate treatment. As a result, the Cssmin dropped to 1640 ng/mL without related adverse reactions. After 11 months of targeted therapy, relevant imaging examination showed tumor shrinking.
Among 25 patients in this study, the Cssmin of 20 patients was higher than 1100 ng/mL. For neoadjuvant treatment group, the Cssmin was from 1083 to 4722 ng/mL, and that of 78% patients was within 1100 ng/mL and 2000 ng/mL after receiving 400mg/d imatinib. Meanwhile, tumor shrinking was found in 67% patients to complete resection. For adjuvant treatment group, the Cssmin was in the range of 584 ng/mL and 2692 ng/mL, and that of 75% patients ranged from 1100ng/mL to 2692 ng/mL with the dosage of 200, 300, 400 and 600 ng/mL. During the follow-up, 44% of the patients did not adjust the dosage of imatinib between 4 months and 14 months. It is assumed that the Cssmin threshold of 1100ng/mL is applicable to most GIST patients in our study. It is impossible to determine the explicit Cssmin threshold of imatinib with adjuvant treatment and neoadjuvant treatment by reason of the limited small number of patients. The sample size can be expanded to further to explore the characteristics of imatinib Cssmin in special populations.