The clinical efficacy and pathological assessment of neoadjuvant imatinib treatment in patients with primary gastrointestinal stromal tumors

Introduction

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor in the gastrointestinal tract, with a yearly incidence of 10–15 per 1,000,000 persons (1,2). The tumor is most commonly located in the stomach (50–60%), followed by the small intestine (30–40%), colon and rectum (5%), esophagus (<5%), and extra-gastrointestinal tract (<5%) (3). GIST is insensitive to conventional chemotherapy, and surgical resection is considered the mainstay of treatment for localized disease. The therapeutic role of imatinib in the metastatic and adjuvant settings has been well established (4,5), as approximately 80% of GISTs harbor gain-of-function mutations in KIT (3).

Neoadjuvant treatment refers to therapy that is administered before surgery to improve the likelihood of radical resection by decreasing tumor vascularity and size (6). The effectiveness of imatinib in the treatment of metastatic GISTs has prompted clinical research into the use of neoadjuvant treatment for large-sized tumors and those located in anatomically challenging sites. Several studies have reported on the efficacy and safety of neoadjuvant imatinib treatment (NAT) in GIST (7,8); however, the role of this strategy still needs to be further elucidated. Moreover, research on the pathological regression and long-term prognosis of patients who received NAT is limited. The superiority of NAT compared to upfront resection followed by adjuvant imatinib (UR + AT) treatment is also unclear due to the absence of randomized controlled clinical trials.

This retrospective study aimed to investigate the effectiveness of NAT for localized GISTs with a tumor size larger than 5.0 cm. It also aimed to evaluate pathological regression following NAT, and explore the independent prognostic factors affecting the long-term survival of these patients. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-538/rc).

Methods

Patient selection

NAT is recommended for patients with large-sized tumors or tumors located in anatomically challenging sites. The treatment is expected to minimize the extent of surgery, increase the R0 resection rate, reduce the risk of tumor rupture, and preserve the function of the important organs. The suggested duration of NAT is 6–12 months until the maximal response has been achieved according to the clinical recommendations (6). This study reviewed the clinical data of patients who received NAT followed by surgical resection for primary GISTs at The First Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou), China between January 2007 and December 2022. No sample size calculation was performed due to the retrospective nature of this study. Endoscopic or percutaneous biopsies were conducted to diagnose the GISTs before imatinib treatment. The pathological diagnosis relied on a combination of histopathological evaluation and immunohistochemistry staining for CD117 and/or DOG-1. Data on patients’ gender, age, clinical symptoms, radiological results, pathological characteristics, and post-operative treatment were retrospectively collected. Paraffin-embedded tissue samples were examined for somatic mutations in KIT (exons 9, 11, 13, and 17) and PDGFRA (exons 12, 14, and 18) by polymerase chain reaction amplification, and Sanger sequencing. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of The First Affiliated Hospital, Zhejiang University School of Medicine (No. 2023-0805), and the requirement of informed consent was waived due to the retrospective nature of this study.

Patients were included in this study if they met the following inclusion criteria: (I) 18 to 80 years; (II) a definitive pathological diagnosis of primary GIST; (III) a tumor size greater than 5.0 cm; (IV) an Eastern Cooperative Oncology Group (ECOG) performance status score 2 or less; and (V) receipt of surgery after imatinib treatment. Patients with metastatic/recurrent GISTs or any other malignant tumors were excluded from the study, as were those with a history of preoperative chemotherapy, other targeted therapy or radiotherapy.

Pathological evaluation

The pathological regression of surgical specimens was retrospectively evaluated according to a standardized protocol by an experienced pathologist (9), and the mitotic count was also calculated. After effective treatment, tumors usually show a significant decrease in cell density and extensive interstitial collagenization microscopically, which may be accompanied by varying levels of hemosiderin deposition, inflammatory cell infiltration, and a histiocytic response (9,10). Thus, we proposed five classifications of pathological regression: Grade 0 [complete response (CR), no residual tumor cells]; Grade 1 (high response, ≤10% residual tumor cells); Grade 2 (median response, >10–50% residual tumor cells); Grade 3 (low response, >50–90% residual tumor cells); and Grade 4 (minor response, >90% residual tumor cells).

Follow-up

During NAT, all the patients were followed-up every 1–3 months. Post-operatively, the patients were followed-up every 3–6 months for 1–2 years, every 6–12 months for 3–5 years, and then annually after 5 years. The follow-up included a combination of laboratory tests, radiographic imaging [computed tomography (CT) or magnetic resonance imaging (MRI)], or gastrointestinal endoscopy if necessary.

Statistical analysis

The descriptive statistics are expressed as the frequency with the percentage for the categorical variables, and the median with the range for the continuous variables. The Shapiro-Wilk normality test was used to explore the normality of distribution for the continuous variables. The t-test was used to compare the continuous variables with a normal distribution. For variables with a non-normal distribution, a Wilcoxon test or Mann-Whitney test was used. Progression-free survival (PFS) was defined as the time from the diagnosis of GIST until the occurrence of one of the following events: local progression, post-operative recurrence, distant metastasis, or death (regardless of the cause). Overall survival (OS) was defined as the time from the diagnosis of GIST to death of any cause. Patients who were alive and free of tumor recurrence in September 2023 were censored from the PFS analysis. The survival curves were analyzed using the Kaplan-Meier method, and differences were compared using the log-rank test. A Cox proportional hazard model was used to determine the independent prognosis factors for PFS, and the variables significantly associated with prognosis in the univariate analysis (P<0.20) were included in the multivariate analysis (11). A correlation analysis between pathological regression and tumor change was conducted using the Kendall test. All the results were two-sided, and a P value <0.05 was considered statistically significant. All the statistical analyses were performed with SPSS version 26.0 for Windows (IBM, Armonk, New York, USA).

Results

The data of 113 patients who were diagnosed with primary GISTs and received NAT were retrospectively reviewed (Figure 1), Ultimately, the data of 80 patients were analyzed in the study. Of the 80 patients, 54 (67.5%) were men and 26 (32.5%) were women. The median age of the patients was 60 (range, 39–75) years. Common symptoms included abdominal pain (n=16, 20.0%), melena (n=15, 18.8%), and difficult defecation (n=13, 16.3%). However, 20 (25.0%) patients presented without any symptoms at diagnosis. Of the 80 included patients, 46 (57.5%) underwent endoscopic or endoscopic ultrasonography (EUS) biopsy, and 34 (42.5%) underwent percutaneous biopsy. The most common primary tumor site was the stomach (n=46, 57.5%), followed by the rectum (n=17, 21.3%), small intestine (n=8, 10.0%), duodenum (n=7, 8.8%), and other sites (n=2, 2.5%). All the clinical data are shown in Table 1.

Figure 1 Study flow chart of patients who received neoadjuvant imatinib treatment for primary GISTs. GISTs, gastrointestinal stromal tumors.

Of the patients, 78 received an initial dose of 400 mg of imatinib daily, while 2 patients with KIT exon 9 mutations received 600 mg daily. The radiological response evaluation during neoadjuvant treatment was performed every 1–3 months using CT and/or MRI. All patients underwent surgical tumor resection, and the median duration of NAT was 7.0 (range, 0.4–23) months. The median tumor size before treatment was 9.4 (range, 5.4–27.0) cm, which decreased to 6.2 (range, 2.9–18.0) cm after imatinib treatment, representing a statistically significant decrease of 34.0% (P<0.001). A decreased tumor size was observed in 74 (92.5%) patients, while 2 (2.5%) patients showed no change in tumor size, and 4 (5.0%) patients showed an increase in tumor size (Figure 2).

Figure 2 Waterfall plot showing the mutations of all patients with the percentage of tumor reduction by imatinib treatment.

The tumors of 77 (96.2%) patients were evaluated using the Choi criteria; 3 (3.8%) patients with missing Hounsfield unit (HU) data from CT scans could not be evaluated. A partial response (PR) was observed in 74 (92.5%) patients, stable disease (SD) in 2 (2.5%) patients, and progressive disease (PD) in 1 (1.3%) patient. Of all the patients, 58 (72.5%) had mutations, including KIT exon 11 mutations (n=47, 58.8%), KIT exon 9 mutations (n=2, 2.5%), PDGFRA D842V mutations (n=2, 2.5%), and wild-type mutations (n=7, 8.8%). Of the 47 patients with KIT exon 11 mutations, the tumor size decreased in 44 patients, showed no change in 1 patient (N564_Y578del), and increased in 2 patients (V559D, E554_K558del). Of the 2 patients with PDGFRA 18 mutations (D842V), as confirmed by post-operative tumor specimens, the tumor size showed no change in 1 patient, but decreased by 60.2% in the other patient.

Of the GIST patients, 79 (98.8%) patients received R0 resection, and only 1 (1.2%) received R1 resection. One patient with an exon 9 mutation underwent surgery after sunitinib treatment due to imatinib resistance. Further, 14 (17.5%) patients underwent multi-visceral resection, and 17 (21.3%) patients underwent laparoscopic surgery after the effective imatinib treatment.

Twenty-one (26.3%) patients suffered from post-operative complications, but only 2 (2.5%) patients had Clavien-Dindo grade III complications (one of whom had anastomotic stenosis, and the other of whom had a rectourethral fistula). There were no deaths within 90 days of surgery.

In relation to the pathological examination results, 1 (1.3%) patient had lymph node metastasis from GIST. In terms of pathological regression, 23 (28.7%) patients were classified as grade 1, 24 (30.0%) as grade 2, 17 (21.3%) as grade 3, and 12 (15.0%) as grade 4. None of the patients achieved a pathological CR.

Pathological regression was found to be significantly associated with a decrease in tumor size (Kendall-test P=0.008, Figure 3) and density (Kendall-test P<0.001, Figure 3). After surgery, 71 (88.8%) patients continued imatinib treatment, only 39 (48.8%) of whom had stopped the treatment at the last follow-up (September 2023). One (1.3%) patient who underwent pancreaticoduodenectomy after sunitinib treatment received regorafenib treatment post-operatively.

Figure 3 Pathological regression was correlated with a decrease in tumor size (A) and density (B), but not with long-term prognosis (C). A patient who received surgery after sunitinib was not included in the survival analysis. HU, Hounsfield unit.

The median follow-up time of the study was 69 (range, 11–193) months. At the last follow-up, 17 (21.3%) patients had experienced post-operative tumor recurrence. The most common site of recurrence was the peritoneum (N=9), followed by the liver (N=5). Of these 17 patients, 5 died from GIST. The estimated 5-year PFS and OS rates were 86.4% and 95.4%, respectively (Figure 4). According to the Kaplan–Meier analysis, pre-neoadjuvant tumor size (log-rank, P=0.043), tumor rupture (log-rank, P=0.01), tumor location (log-rank, P=0.08), post-operative imatinib treatment (log-rank, P=0.08), and mitotic count (log-rank, P=0.10) were associated with long-term prognosis (Figure 5). Patients who received long-term (≥5 years) post-operative imatinib treatment had a better prognosis than those who received short-term (<5 years) post-operative imatinib treatment or refused post-operative treatment (Figure 5F). Pathological regression was not associated with long-term prognosis (log-rank P=0.61, Figure 3). After adjusting for the above variables in the Cox proportional hazard model, pre-neoadjuvant tumor size [hazard ratio (HR) =5.263, 95% confidence interval (CI): 1.552–17.849, P=0.008], tumor location (HR =3.522, 95% CI: 1.161–10.683, P=0.03), mitotic count (HR =3.647, 95% CI: 1.070–12.428, P=0.04), and post-operative imatinib treatment (HR =0.124, 95% CI: 0.027–0.571, P=0.007) were identified as independent prognostic factors (Table 2).

Figure 4 Survival analysis of progression-free survival (A) and overall survival (B) for all patients. The estimated 5-year PFS and OS rates were 86.4% and 95.4%, respectively. OS, overall survival; PFS, progression-free survival.

Figure 5 Survival analysis of progression-free survival for patients with different characteristics. (A) Pre-neoadjuvant tumor size (log-rank test P=0.043); (B) post-neoadjuvant tumor size (log-rank test P=0.27); (C) tumor location (log-rank test P=0.08); (D) tumor rupture (log-rank test P=0.01); (E) mitotic counts (log-rank test P=0.10); (F) different duration of post-operative imatinib treatment (log-rank test P=0.08). A patient who received surgery after sunitinib was not included in the survival analysis. HPF, high-power field.

Discussion

This study included 80 patients with large-sized (>5.0 cm) primary GISTs who received NAT. Tumor shrinkage was observed in 92.5% of the patients, and the R0 resection rate reached 98.8%. With a median follow-up time of 69 months, the estimated 5-year PFS and OS rates were 86.4% and 95.4%, respectively. The results of present study provide further evidence that NAT is effective for most GIST patients.

The purpose of surgical treatment for primary GIST is R0 resection. NAT can theoretically improve the R0 resection rate of large or inoperable tumors by reducing the tumor size. Previous studies have reported R0 resection rates of 80–100% after effective NAT (7,12-14). The high R0 resection rate in the present study may be attributed to the sufficient duration of the preoperative imatinib treatment and the sensitive mutations. The median duration of the preoperative imatinib treatment in the present study was 7.0 (range, 0.4–23) months, which accords with the recommendations of several clinical guidelines (6,15,16). Besides the improved R0 resection rates, tumor shrinkage induced by NAT can lead to less extensive surgical procedures. GISTs are known to be very fragile, especially in locally advanced tumors, which are associated with a high risk of tumor rupture. Thus, laparotomy is considered the standard treatment for large GISTs. Recently, several studies have shown that laparoscopic resection results in similar long-term outcomes and low morbidity in small-sized gastric GISTs (17-19), supporting its use as an acceptable approach. In the present study, 11 of 36 (30.6%) gastric GIST patients underwent laparoscopic resection with low surgical complications, followed by effective NAT. While the use of laparoscopic resection is increasing in NAT settings, randomized controlled trials need to be conducted to determine whether it is superior to laparotomy.

Approximately 70–90% of GISTs have gain-of-function mutations of KIT or PDGFRA, resulting in the ligand-independent activation of kinases, which is considered the main driver of GIST development (4). Imatinib is recommended as the first-line treatment for metastatic GISTs and as an adjuvant for locally advanced GISTs; however, the diverse mutational status of GISTs is associated with different drug sensitivities (3). In the present study, 43 of 47 (93.6%) patients with KIT exon 11 mutations showed tumor size reduction, which reflects previous reports (20,21). However, the two patients with KIT exon 9 mutations did not display a satisfactory effect despite receiving a high dose (600 mg/d) of imatinib, one of whom showed PD on the radiological findings and received a pancreaticoduodenectomy. Surprisingly, one patient with a PDGFR (D842V) mutation responded well to imatinib with a 60.2% size reduction after NAT. These results are in line with those of three other recent studies examining the use of imatinib treatment in locally advanced GISTs (13,21,22). Thus, imatinib NAT may still be appropriate for patients with PDGFR (D842V) mutations if primary surgery could cause severe morbidity and avapritinib cannot be administered for any reason (21). The heterogeneity of the treatment response in patients with similar mutations should be further investigated. Further, mutation analyses should be conducted before NAT to individualize the treatment approach.

The long-term effects of imatinib NAT on OS remain unclear. Several single-arm studies have reported 5-year OS rates ranging from 77% to 93.8% (8,15,21). The variability in the survival analyses maybe related to differences in patient recruitment and imatinib treatment duration. The estimated 5-year OS rate in our study was 95.4%, which is similar to that reported in previous studies. Our study also found that pre-treatment tumor size, tumor location, and mitotic count were prognostic factors for poor PFS, while post-operative imatinib treatment was a favorable prognostic factor. Three of the four patients with tumor rupture experienced tumor recurrence in the present study, but it was not identified as a prognostic factor in the Cox model. This result may be due to the small sample size of the study; and the potential role of post-operative imatinib treatment in eliminating micro-metastases should still be considered.

Overall, the patients who received NAT appeared to have a favorable prognosis compared to those who received UR without adjuvant therapy. To date, only a few studies had compared NAT and UR + AT. After matching for adjuvant imatinib duration, Wong et al. found no significant survival difference between patients treated with NAT and those treated with UR + AT (23). Similarly, Ling et al. found no significant OS difference between patients treated with NAT and those treated with UR + AT across GISTs from all sites, but their subgroup analysis showed that NAT was associated with better outcomes in patients with non-gastric GISTs (15). Thus, further randomized controlled trials need to be conducted to verify the role of NAT for locally advanced GISTs, and the mutational status of patients should also be considered.

The evaluation of the therapeutic response after NAT is primarily based on radiological examinations, while pathological regression is rarely reported. This study retrospectively reviewed the tissue sections of surgical specimens, and pathological regression was classified into five grades. Notably, none of the patients achieved a CR. Pathological regression was found to be significantly associated with radiological changes in the tumor, including reductions in size and density, indicating the reliability of the evaluation, but it was not associated with long-term prognosis. Notably, post-operative imatinib treatment might improve the prognosis of locally advanced GIST patients, which might mask the predictive effect of pathological regression. Despite the lack of statistical significance, pathological regression provides important information after NAT, as it represents an in vivo test of the imatinib treatment and may serve as a stratification criterion for tailored post-operative treatment in future studies.

The present study had several limitations. First, as a single-arm retrospective study, selection bias was inevitable. Second, the patients who received NAT in this study were intermediate or high risk, and the absence of a group of control patients who received UR + AT represents a limitation. Third, mutation status data were only available for 58 (72.5%) of the patients; most of the missing data originated from the earlier years of the study. Further, the mutation analysis was conducted less frequently before NAT (n=36, 45.0%), and the association between NAT and mutation status could not be further analyzed in our study.

Conclusions

NAT is effective for most GIST patients with a tumor size larger than 5.0 cm and sensitive mutations, and the long-term survival of such patients is favorable. Pre-neoadjuvant tumor size, tumor location, mitotic count, and post-operative imatinib treatment were identified as prognostic factors in GIST patients who received NAT. The pathological response to NAT proposed in the present study was significantly correlated with a decrease in both tumor size and tumor density, but it was not associated with prognosis. Future randomized controlled trials need to be conducted to verify the above issues.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-538/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-538/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-538/prf

Funding: This work was supported by The Heathcote-Zedin Oncology Therapeutic Research Fund Project (Y-zai2021/ms-0133) and The National Natural Science Foundation of China Programs (82001695).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-538/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of The First Affiliated Hospital, Zhejiang University School of Medicine (No. 2023-0805), and the informed consent was exempted because of the retrospective nature of this study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: L. Huleatt)