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.