2 MATERIALS
From 2019 to 2020, the patients with
histologically confirmed GIST in Sichuan University Gastrointestinal
Surgery Center in Chengdu, China, actively participated in this study.
Inclusion criteria are as follows: (1) ≥18year-olds with hepatic and
renal functions, adequate hematological, histologically proven GIST; (2)
Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2; (3)
The duration of imatinib adjuvant therapy at least 29days. The study
protocol was approved by the medical ethics review boards and performed
following the Declaration of Helsinki. All patients provided written
informed consent before registration. This trial was registered with the
Chinese Clinical Trial Registry and the registration number was
ChiCTR1900020854
(http://www.chictr.org.cn.).
Patients underwent follow-up with enhanced computed tomography or
magnetic resonance imaging scans every 6 months for the first 2 years,
every 1 year for the next 5 years in the process of imatinib adjuvant
therapy. Hematological and non-hematological adverse events were
documented and graded in light of CTCAE (Common Terminology Criteria for
Adverse Events Version 5.0) v5.0. Moreover, patient medical records were
reviewed retrospectively.22
Clinical data of patients with GIST, who had been treated with various
doses of imatinib (200–600 mg/day) for at least 29 days were collected
between December 2019 and November 2020. Within 24±2 h after the last
dosage of imatinib, blood samples (at least 3 mL) were collected into
heparinized tubes, centrifuged at 3,000 rpm for 10 min at room
temperature, and stored at −80°C until analysis. Cminwas measured by a validated liquid chromatography-tandem mass
spectrometry (LC-MS/MS) method,
specific methods have been previously reported.23 All
samples were detected in the Laboratory of Clinical Pharmacology, West
China Hospital of Sichuan University (Chengdu, China). In addition, to
evaluate the correlations between imatinib Cmin and
different dosages, the patients were divided into four groups according
to the imatinib Cmin quartiles. The lower quartile (Q1)
included the 25% of patients with the lowest imatinib
Cmin; Q2 and Q3 indicated the 25 % below and above the
median concentration, respectively; Q4 included the 25% of patients
with the highest imatinib Cmin.
Statistical analysis
Pearson χ2 or Fisher’s exact test was used for the
comparison of categorical variables, while the Wilcoxon rank-sum test
was used for ordinal and continuous variables. Recurrence-free survival
(RFS) was the primary endpoint of this study, which was defined as the
time from the date of the first dose of imatinib to the date of the
first documented tumor recurrence assessed by radiographic imaging or
mortality resulting from any cause. Patients who were alive and without
the disease-specific recurrence were censored at the last follow-up.
We calculated the inverse probability of treatment weighting (IPTW)
method using the propensity scores for eliminating the effects of
confounding and selection bias by creating a pseudo-sample with the
method as reported previously. 24,25 To estimate the
IP weights, we calculated each patient’s probability of imatinib dosage
adjustment via application of multivariate logistic regression model,
with dosage adjustment of imatinib as the outcome and BSA, age, gender,
risk stratification, mutation status, primary tumor site, and imatinib
trough concentration (Cmin) as covariates. The IP
weights were then calculated based on each patient’s estimated
probability of whether dose reduction of imatinib, given their actual
regimen of imatinib therapy.
To study the effect of dosage of imatinib adjustment on RFS of resected
GISTs, weighted Cox proportional hazard regression models were
estimated. Hazard ratios (HRs) along with their 95% confidence
intervals (CI) were reported. RFS was calculated by the Kaplan–Meier
method and compared by log-rank test. Cox proportional hazard model was
used to assess the prognostic factors for the IPTW-matched patients.
All statistical analyses were
performed by using RStudio
(https://www.rstudio.com/) in
the text of R, version 4.1.2 (R Core Team 2021, Vienna, Austria)
(https://www.r-project.org/).
All tests were two-sided, P-values less than .05 were considered
statistically significant.