Before the year 2000, there was no known effective therapy for gastrointestinal stromal tumors (GISTs). GIST treatment was developed on the basis of the finding that most GISTs have mutations in KIT and platelet-derived growth factor receptor-alpha (PDGFRA). These findings led to the development of effective systemic therapies in the form of small molecule tyrosine kinase inhibitors (TKIs), of which the prototype is imatinib (IM). It is a small molecule that inhibits intracellular autophosphorylation of tyrosine kinase receptors involved in GIST pathogenesis. After a decade of therapeutic use, IM is proven to be a highly effective targeted agent for the treatment of patients with advanced GIST, with a median overall survival of only approximately 19 months to approximately 5 years (1).

The success of these agents in advanced disease has prompted interest in their use as adjuvant treatment for patients at high risk of recurrence after the complete resection of a primary GIST tumor (2). Patients who received 3 years of IM had longer recurrence-free survival and overall survival times in the clinical trial SSGXVIII than those who received IM for 1 year (3). In the PERSIST-5 clinical trial, none of the patients with resected primary GIST who received 5 years of IM therapy with IM-sensitive mutations experienced disease recurrence during therapy (4). However, the optimal treatment duration remains unknown. We found that there was a tendency for prolonged IM adjuvant therapy in GIST patients with a high risk of recurrence.

In a retrospective study, a significantly shorter time to progression was observed in patients with IM trough levels below 1,100 ng/ml after 1 month of medication (5). A prospective pharmacokinetic study in patients with advanced GIST showed a significant decrease of approximately 30% in IM trough levels after long-term treatment. The authors of this study have called for conducting time-point-specific “trough level–clinical benefit” analyses in the future (6). IM plasma concentration changes over time in patients with advanced GIST. However, no similar research has been conducted on IM adjuvant therapy for patients with GIST. In this context, the primary aim of this long-term study is to assess the changes in IM plasma concentrations in patients with intermediate- or high-risk gastrointestinal stromal tumors. As IM plasma concentration may have changed over time, our secondary aim is to elucidate the factors affecting IM concentration in blood at different time points to formulate better time-specific medication monitoring plans in clinical practice.

This is the first study that focuses on the changes in IM C_min during long-term treatment in patients with adjuvant therapy for GIST. We have shown here that during the first year, IM C_min was highest for the first 3 months and then declined. There were no significant differences in the C_min of IM among patients who took the drug for 1 year, 1 to 3 years, and more than 3 years. We also analyzed the relationships between the clinicopathological characteristics of the patients and IM C_min at different time points. Within the first year of treatment, IM C_min correlated with age, sex, body weight, height, and body surface area. When the medication duration was 12–36 months, IM C_min correlated with the primary site of GIST, surgical procedures, and gene mutations. When the medication duration was over 36 months, IM C_min was significantly higher in patients with primary sites other than the stomach and the corresponding surgical procedures.

For advanced GIST, although IM treatment has proven efficacy, disease progression ultimately occurs because of drug resistance. An altered expression of these transporters may lead to increased clearance of the drug and lower plasma concentrations of IM over time. In a retrospective study, Demetri et al. reported that a significantly shorter time to progression was observed in patients, which showed 1-month IM trough levels below 1,100 ng/ml after 1 month of medication (5). In real-life settings, the concentration of IM significantly influences the duration of tumor control treatment in GIST patients, with a C_min threshold of 760 ng/ml associated with prolonged progression-free survival (10). The reason for the difference in threshold might be that blood sampling was conducted at different times, as Eechoute et al. found a significant decrease of approximately 30% in IM exposure after long-term treatment (6).

To the best of our knowledge, no similar study has been conducted on IM adjuvant therapy. But this is a crucial parameter to monitor IM C_min in populations with intermediate- or high-risk GIST for a long time. This is the first step in determining the C_min threshold value and therapeutic drug monitoring for IM in GIST after complete excision. In this study, during the first year of IM, the plasma trough level was highest for the first 3 months and then declined. During long-term treatment, the IM C_min did not decrease significantly but remained stable or slightly increased after 3 years, but the difference was not statistically significant. This result was consistent with those reported by Eechoute et al. and Yoo et al. in patients with advanced GIST (6, 11).

Exposure to IM during treatment may be influenced by various factors. Pharmacokinetic studies in patients with chronic myeloid leukemia and GIST have found that variables that were significantly influenced or associated with IM C_min included white blood cell count, age, body weight, body surface area, and previous gastrectomy (12–14). Our previous study found that gastrectomy, body weight, body surface area, and sex may impact IM C_min in the Chinese population (9). However, none of the studies focused on patients who received IM adjuvant treatment, and no subgroup analysis was performed by considering the time from the initiation of IM treatment. In this study, patients were grouped according to the duration of IM treatment. Although no statistically significant differences in IM C_min were found for different durations of medication, we were surprised to notice that IM C_min correlated with different clinical characteristics for different durations of medication.

Sex, age, body weight, height, and body surface area were the factors influencing IM C_min within 1 year of taking medicine. IM C_min was higher in females than in males. Some researchers believe that this difference may be attributed to differences in body weight between sexes (13). In addition, our research found that adherence was poorer in male patients than in female patients, which might also be the reason for the lower IM C_min (15). Whether the dose of the drug should be adjusted for body weight, body surface area, or sex remains a controversial issue. First of all, the results of this study need to be verified by using a larger sample size. Moreover, the influence of the above factors on blood concentration was not continuous but existed only at a certain stage of imatinib adjuvant therapy. However, these results could be useful during postoperative follow-up. For example, more attention should be paid to whether obese male patients experience tumor recurrence because of low IM C_min.

When the medication duration was over 12 months, IM C_min was significantly lower both in patients with gastrectomies and in the primary site of the stomach. Although wedge gastric resection was the main type of operation in our study, low IM C_min was also associated with gastrectomy. Because IM tablets dissolved easily and rapidly at pH 5.5 or less (16), the reduced absorption of IM might be caused in part by a lack of gastric acid secretion in patients who had undergone gastric resection.

In addition, after excluding patients with wild-type GIST, IM C_min was found to be much higher in patients with mutation sites other than KIT exon 11 mutation during the medication duration of 12–36 months. KIT exon 11 mutation is the most significant benefit of GIST adjuvant therapy (17, 18), but the blood concentration of patients with KIT exon 11 mutation is not the highest. This suggests that the benefit to these patients might be mainly due to the biological behavior caused by mutation rather than the contribution of high blood IM concentration.

This study has several limitations. First, only 204 patients were included; the results of this study need to be verified by using a larger sample size. Second, there are several other factors influencing IM C_min, but this study does not clarify all of them. Finally, this is a retrospective study, and there is a possibility that selection bias could influence the outcomes, even though strict screening of the enrolled patients was carried out. In future research, we hope to further expand the sample size, undertake a multicenter study, and focus on patient survival.

IM plasma trough levels during long-term treatment of patients with intermediate- or high-risk GIST showed that IM C_min was the highest for the first 3 months and then declined, and the long-term administration of IM showed a relatively stable C_min. The IM C_min correlated with different clinical characteristics at different durations of medication. Our results remind us again that “trough level–clinicopathological characteristics” analyses should be time-point-specific in the future. Prospective studies with larger sample sizes are required to verify the results of this study. There is still a long way to go in adjusting the dosage of IM according to IM C_min and the influencing factors. However, in clinical practice, according to the rules found in this study, we can develop targeted drug monitoring plans for special populations to prevent disease recurrence caused by a low IM C_min.