Trends and Outcomes for Patients Receiving Neoadjuvant Therapy for Stage I-III Gastric Gastrointestinal Stromal Tumors

Abstract

Background:

The use of neoadjuvant therapy is not well characterized across the entire spectrum of localized gastrointestinal stromal tumors (GISTs). We aim to identify treatment trends for the utilization of neoadjuvant therapy and survival outcomes for patients who underwent surgery for gastric GISTs.

Methods:

The National Cancer Database (NCDB) was queried to identify patients with stage I-III gastric GISTs from 2006-2020 who underwent curative-intent surgery following neoadjuvant (NAT) systemic therapy or up-front surgery (UFS). Cohort demographics and cancer characteristics were compared via ANOVA, generalized linear models, and Chi-Squared analysis. Treatment trends were assessed via linear regression. Cox proportional hazards models and Kaplan-Meier curves were propensity-score matched 3:1.

Results:

From 2006-2020, 1504 patients (8.1%) received NAT followed by surgery and 17,150 (91.9%) received up-front surgery with curative intent. Cohort analysis revealed that patients that underwent NAT had higher grade tumors (p=0.031), larger tumors (12.0 cm vs 6.4 cm; p<0.001), and had higher clinical staging (p<0.01). Linear regression indicated that the use of NAT became more common each year (0.88%,p<0.05) and was administered for longer durations prior to surgery (increase in 5.5 days per year, SE=0.9, p<0.05). Despite being used for larger and higher-grade tumors, patients who underwent NAT had similar outcomes compared to those who underwent UFS (UFS: HR=0.86, 95%CI=0.76-1.01, p=0.07).

Conclusion:

Our results demonstrate that the use of NAT has been increasing over time and is used for more advanced gastric GISTs. Although used for higher-risk tumors, the use of NAT for gastric GISTs leads to similar outcomes compared to patients who undergo upfront surgery.

Graphical Abstract

Introduction:

Gastrointestinal stromal tumors (GISTs) are rare neoplasms of the gastrointestinal tract that have an annual incidence of approximately 1.2 people for every 10000 individuals.^1-3 The majority (56%) of GISTs are located in the stomach.⁴ Although many GISTs are found incidentally and are asymptomatic¹, patients with GISTs can occasionally have associated GI symptoms, such as vomiting, abdominal pain, distention, and bleeding.^5,6

The primary treatment for GISTs is surgical resection, via either a minimally invasive or open approach⁷, according to National Comprehensive Cancer Network (NCCN) guidelines⁸, of which the ultimate objective is to achieve a complete R0 resection.⁶ However, in instances when upfront surgical resection may lead to increased morbidity, such as in locally advanced tumors with multivisceral involvement, imatinib, a tyrosine kinase inhibitor, is recommended in the neoadjuvant setting.⁶ One of the earliest studies assessing neoadjuvant therapy, specifically imatinib, use in patients with locally advanced GISTs demonstrated that 66% of patients were able to safely undergo an R0 resection following preoperative therapy.⁹ Bednardski et al. further described prognostic factors with the utilization of neoadjuvant treatment, such as length of neoadjuvant treatment and use in the setting of multivisceral GIST involvement, both which were associated with worse overall survival (OS).¹⁰ Furthermore, a recent study using a large national database comparing up-front surgery with neoadjuvant imatinib and demonstrated improved outcomes for patients treated with neoadjuvant therapy in the setting of localized, gastric GISTs.¹¹ Given the current landscape and the evolution of its use, it is important to clarify the trends in practice as well as the most favorable setting within which neoadjuvant treatment should be utilized.

Although improved outcomes following neoadjuvant therapy have been demonstrated in select populations, a comparison of neoadjuvant therapy and up-front surgery has not been conducted on a large scale for the entire spectrum of non-metastatic gastric GISTs. The objectives of this study are to identify demographic and cancer characteristics associated with neoadjuvant use, analyze neoadjuvant treatment trends over time, and characterize its use in the context of tumor presentation.

Methods:

Inclusion and Exclusion Criteria

Considering that this study used deidentified patient data, this study was determined to be exempt from review by the Institutional Review Board.

In this retrospective cohort study, we used the National Cancer Database (NCDB) to identify patients diagnosed with gastric GISTs who underwent surgical resection from 2004 to 2020. The NCDB is a cancer registry that is managed by the American College of Surgeons’ Commission on Cancer (CoC) and the American Cancer Society for CoC-accredited hospitals, resulting in one of the largest and most informational databases in the world.^12,13 Patients were included in the study if they had gastric GISTs (based on “HISTOLOGY” code “8936”), were at least 18 years old, and underwent definitive surgical resection during their treatment course. Patients who received palliative treatment or had evidence of metastatic disease (clinical staging classified as M1 or a positive Collaborative Staging Metastasis status) were excluded. Any patients with GISTs outside of the gastric region were excluded from analysis.

Patients were then defined as having been treated with either neoadjuvant systemic therapy (NAT) or up-front surgery (UFS). NAT is defined as any systemic therapy given prior to curative-intent resection. Patients in the NAT group could have received NAT alone or NAT with adjuvant therapy following resection whereas, patients in the UFS cohort either underwent UFS alone or UFS followed by adjuvant therapy. Patients were excluded if they received systemic therapy if the date of systemic therapy did not suggest it was prior to curative intent resection.

Independent Variables

The following variables were examined across the entire cohort. Demographics included age at diagnosis, sex (male or female), race (Asian, Black, Native American, Pacific Islander, Other, and White), ethnicity (hispanic/non-hispanic origin), insurance type, urban/rural status (urban, rural, metro), facility type, geographic location, travel distance (miles), education level in area of residence, median income in area of residence, and year of diagnosis. Unknown classifications were included in the demographics analysis. Tumor and patient characteristics included location of the primary site, tumor grade, how the tumor was diagnosed, tumor size, node status, overall stage group, and Charleson-Deyo score. Charleson-Deyo score was utilized for both its availability and its prognostic evidence in the setting of gastric cancer.¹⁴

Outcomes

Multiple outcomes were assessed during data analysis. We analyzed NAT and UFS utilization trends from 2006 to 2020 in both absolute and proportional terms. Additionally, secondary outcomes included multivisceral resections performed, average tumor size, and average time to surgical resection between the two cohorts. Finally, we also determined overall survival between the two cohorts using propensity-score matched Kaplan Meier curves.

Statistical Analysis

Baseline demographics as well as tumor and patient characteristics were compared between patients in the NAT and UFS cohorts using analysis of variance (ANOVA) tests for continuous variables and chi-squared tests for categorical variables. Linear regression analyzed trends in NAT and UFS from 2006-2020. We also utilized linear regression to identify changes in tumor size in each cohort and across both cohorts to determine if neoadjuvant treatment was being used for progressively larger tumors due to recommendations for its use in gastric GISTs.¹⁶ Average length to definitive surgery from diagnosis was followed yearly using linear regression.

Prior to survival analysis, cohorts were compared using least absolute shrinkage and selection operator (LASSO) analysis to identify potential covariates. These covariates (age, sex, ethnicity, Charleson-Deyo score, year of diagnosis, node status at surgery, tumor size, and surgery type) were used to 3:1 propensity-score match prior to all survival analyses performed. We applied propensity-score weights to all survival models. Kaplan-Meier curves and Cox Proportional Hazards models were used to assess differences in overall survival between cohorts. Statistical significance was set at p < 0.05. All statistical analyses were performed with R-4.4.1.

Results:

Group Characteristics

Overall, there were 18,654 patients across included in the study, with 1504 patients (8.1%) undergoing NAT and 17,150 patients (91.9%) undergoing UFS. Patients treated with NAT were younger (62.8 years vs 64.7 years, p<0.001), included more males (50.1% vs 47.5%, p=0.049), were more often Black or Asian, were most likely to be privately insured (p < 0.05), were more often treated at academic centers, and had to travel further for definitive surgery (53.9 mi vs 23.9 mi, p<0.001).

In addition, there were differences in cancer characteristics between these cohorts. Of note, patients that underwent NAT had higher tumor grade at diagnosis, larger pathologic tumor size (12.0 cm vs 6.4 cm; p<0.05), higher clinical stage (p<0.05), and a larger percentage of patients that ultimately underwent multivisceral resections (14.1% to 4.2%; p < 0.05). Table 1 and Table 2 highlight the key demographics and cancer characteristics of the cohorts, respectively.

Table 1.

Demographics info for the NAT and UFS cohorts. P-value < 0.05 indicate differences between the two cohorts based on indicated variable.

Variable	NAT	UFS	P-Value
Number of Patients (%)	1504 (8.1)	17150 (91.9)
Age			<0.001
Mean (SD)	62.75 (12.18)	64.66 (12.56)
Sex			0.049
Male (%)	754 (50.1)	8138 (47.5)
Race (%)			<0.001
Asian	114 ( 7.7)	825 ( 4.9)
Black	425 (28.6)	4112 (24.2)
Native American	2 ( 0.1)	35 ( 0.2)
Other	20 ( 1.3)	193 ( 1.1)
Pacific Islander	17 ( 1.1)	57 ( 0.3)
White	906 (61.1)	11778 (69.3)
Ethnicity			0.372
Spanish/Hispanic (%)	99 ( 6.7)	1008 ( 6.1)
Insurance Status (%)			<0.001
Medicaid	120 ( 8.1)	942 ( 5.6)
Medicare	653 (44.0)	8479 (50.2)
Not Insured	41 ( 2.8)	498 ( 2.9)
Other Government	22 ( 1.5)	206 ( 1.2)
Private Insurance	648 (43.7)	6762 (40.0)
Population Status (%)			0.621
Metro	1272 (87.9)	14629 (88.0)
Rural	16 ( 1.1)	231 ( 1.4)
Urban	159 (11.0)	1766 (10.6)
Facility Type (%)			<0.001
Academic/Research Program	821 (56.6)	6724 (40.6)
Community Cancer Program	45 ( 3.1)	835 ( 5.0)
Comprehensive Community Cancer Program	328 (22.6)	5743 (34.7)
Integrated Network Cancer Program	256 (17.7)	3253 (19.6)
Facility Location (%)			<0.001
East North Central	219 (15.1)	2930 (17.7)
East South Central	94 ( 6.5)	1202 ( 7.3)
Middle Atlantic	205 (14.1)	2719 (16.4)
Mountain	51 ( 3.5)	560 ( 3.4)
New England	68 ( 4.7)	957 ( 5.8)
Pacific	235 (16.2)	1900 (11.5)
South Atlantic	381 (26.3)	3930 (23.7)
West North Central	92 ( 6.3)	1104 ( 6.7)
West South Central	105 ( 7.2)	1253 ( 7.6)
Travel distance (mi)			<0.001
Mean (SD)	53.89 (212.00)	29.93 (102.72)
% with No High School Degree for Area of Residence			0.468
<5.0%	301 (22.7)	3193 (21.1)
15.3%	295 (22.2)	3272 (21.6)
5.0-9.0%	366 (27.6)	4294 (28.4)
9.1-15.2%	366 (27.6)	4358 (28.8)
Median Income by Area of Residence (%)			0.031
$46277-57856	242 (18.3)	3142 (20.8)
$57857-74062	299 (22.6)	3610 (23.9)
$74063+	539 (40.7)	5609 (37.2)
<$46277	244 (18.4)	2727 (18.1)

Table 2.

Tumor and patient characteristics for the NAT and UFS cohorts. P-value < 0.05 indicate differences between the two cohorts based on indicated variable.

Variable	NAT	UFS	P-Value
Number of Patients (%)	1504 (8.1)	17150 (91.9)
Primary Site			<0.001
Body	134 ( 8.9)	1716 (10.0)
Cardia, NOS	134 ( 8.9)	886 ( 5.2)
Fundus	219 (14.6)	2660 (15.5)
Gastric Antrum	68 ( 4.5)	1283 ( 7.5)
Greater Curvature, NOS	238 (15.8)	2294 (13.4)
Lesser Curvature, NOS	181 (12.0)	2043 (11.9)
NOS	425 (28.3)	5075 (29.6)
Overlapping Lesion	100 ( 6.6)	1140 ( 6.6)
Pylorus	5 ( 0.3)	53 ( 0.3)
Grade			0.031
Moderately Differentiated	77 (23.4)	1730 (26.0)
Poorly Differentiated	33 (10.0)	441 ( 6.6)
Undifferentiated	28 ( 8.5)	423 ( 6.4)
Well Differentiated	191 (58.1)	4057 (61.0)
Diagnostic Confirmation			<0.001
Direct Visualization	0 ( 0.0)	1 ( 0.0)
Imaging Techniques	1 ( 0.1)	3 ( 0.0)
Positive Cytology	68 ( 4.5)	125 ( 0.7)
Positive Histology	1432 (95.3)	17012 (99.2)
Positive Microscopic Confirmation, NOS	1 ( 0.1)	2 ( 0.0)
Tumor Size (mm)			<0.001
Mean (SD)	12.0 (11.0)	6.4 (8.5)
Node Status
Positive (%)	911 (61.6)	13307 (78.9)	<0.001
Stage			<0.001
1	500 (42.3)	9823 (71.7)
2	305 (25.8)	1834 (13.4)
3	250 (21.2)	1763 (12.9)
Multivisceral Status			<0.001
Not Multivisceral	1292 (85.9)	16434 (95.8)
Charleson-Deyo Comorbidity Score			<0.001
0	1129 (75.1)	11951 (69.7)
1	262 (17.4)	3579 (20.9)
2	69 ( 4.6)	1056 ( 6.2)
3+	44 ( 2.9)	564 ( 3.3)

Utilization Analysis

Next, we sought to understand trends in treatment of gastric GISTs over time. In general, the number of GIST patients undergoing curative-intent surgery in either cohort has increased over time. The rate of increase has been greater in patients undergoing UFS compared with patients undergoing surgery after NAT. Table 3 provides absolute counts by year for patients who underwent UFS and NAT and demonstrates significant differences between usage by cohort. While there has been an increased number of patients who underwent NAT (12 cases per year), there has been an even greater increase in the number of patients that underwent UFS (62 cases per year; p<0.05, Figure 1a). However, when evaluating the proportion of total patients that underwent NAT compared to prior to surgery, this has increased by 0.88% per year (p<0.05, Figure 1b).

Table 3.

Distribution by year for NAT and UFS usage.

Variable	NAT	UFS	P-Value
Number of Patients (%)	1504 (8.1)	17150 (91.9)
Year of Diagnosis			<0.001
2006	25 ( 1.7)	492 ( 2.9)
2007	38 ( 2.5)	591 ( 3.4)
2008	40 ( 2.7)	622 ( 3.6)
2009	57 ( 3.8)	702 ( 4.1)
2010	67 ( 4.5)	1057 ( 6.2)
2011	56 ( 3.7)	1114 ( 6.5)
2012	72 ( 4.8)	1260 ( 7.3)
2013	94 ( 6.2)	1305 ( 7.6)
2014	97 ( 6.4)	1271 ( 7.4)
2015	119 ( 7.9)	1298 ( 7.6)
2016	138 ( 9.2)	1477 ( 8.6)
2017	137 ( 9.1)	1604 ( 9.4)
2018	200 (13.3)	1579 ( 9.2)
2019	210 (14.0)	1582 ( 9.2)
2020	154 (10.2)	1196 ( 7.0)

Fig. 1.

a.) Utilization analysis for patients that underwent neoadjuvant therapy (NAT; blue line) and patients who underwent up-front surgery (UFS; red line). Total counts are increasing more rapidly for UFS with 62 cases per year than NAT with 12 cases per year (p<0.05). b.) Proportional utilization of treatment sequence by year. Generalized logistic regression indicates that up-front surgery is becoming less common overall by 0.88% per year (p<0.05).

Tumor Size Trends

We next evaluated trends in primary tumor size resected in patients undergoing curative-intent surgery in our cohort. We found an overall decrease in pathologic tumor size in patients over the study period with a decrease in 1.8 mm per year (p < 0.05). Moreover, the average tumor size from 2006-2009 was larger than the average tumor size from 2010-2020 (82.1mm vs. 62.0 mm, p=0.02). Figure 2a depicts changes in tumor size over time.

Fig. 2.

a.) Trends in overall tumor size by year in the setting of GISTs. In general, tumor size has dropped from 2006-2020 (p<0.05) by a rate of −1.92 mm per year. However, average tumor size in 2006-2010 was higher than average tumor size from 2010-2020 (Mean Difference = − 21.5 mm, p<0.05), which possibly suggests some therapeutic or diagnostic change resulted in this difference. b.) Trends in overall tumor size by year for each treatment sequence in the setting of GISTs. Tumor size for NAT is larger than tumor size for UFS (120.3 to 63.6, p<0.05). Average tumor size has not changed for NAT, but it has decreased for UFS by year (−2.6 mm per year, SE = 0.4 mm; p<0.05

We then evaluated pathologic tumor size with respect to the type of treatment received. On average, tumor size was larger for patients who underwent NAT compared to UFS (12.0 cm vs 6.4 cm, p<0.05) Over time, pathologic tumor size has not changed for patients undergoing surgery after NAT (−0.04 mm/yr, p = 0.97). In contrast, pathologic tumor size for patients who underwent UFS decreased by 2.6 mm per year (mm; p < 0.05; Figure 2b).

Multivisceral Treatment Trends

Given the broad use of NAT in patients with multivisceral involvement, we sought to evaluate trends in patients requiring multivisceral surgical resections. We found that for the entire cohort, multivisceral resections increased from 2006-2020 by a rate of 2.8 cases per year (p <0.05; Figure 3a). There was no difference in rate of increase in multivisceral resections when comparing patients who underwent NAT prior to surgery or those who underwent UFS (UFS = −0.69 cases per year, p = 0.19; Figure 3b).

Figure 3.

a.) Total count of multivisceral resections by year from 2006-2020. The number of cases is increasing by 2.8 cases per year (SE = 0.54 cases; p < 0.05). b.) Total count of multivisceral resections by year for each treatment sequence. NAT utilization for multivisceral resections is becoming more commonplace (1.74 cases/year, SE = 0.37 cases, p<0.05). Utilization of UFS is increasing as well (1.05, SE = 0.37, p < 0.05). There is no difference in trends between groups (UFS = −0.69 cases per year, SE = 0.52, p = 0.19).

Time to Definitive Surgery

Given the increase in the proportion of patients undergoing NAT for gastric GISTs over time, we next sought to understand how treatment patterns changed with respect to timing of surgery from diagnosis. We first compared time to definitive surgery for patients that underwent NAT versus UFS, which, as expected, demonstrated greater time to surgery for patients who underwent NAT (223.8 days vs 27.3 days, p<0.001). For patients who underwent UFS, the mean time to definitive surgery increased by 1.3 days per year over the study period (SE = 0.09, p < 0.05), while for those who underwent NAT, the mean time to definitive surgery increased by 5.5 days per year from 176.6 to 233.8 over the study period (, p < 0.05). Figure 4 depicts the length in days from diagnosis to definitive surgery for both cohorts.

Fig. 4.

Average time to definitive surgery by year when comparing treatment sequences. Length of time to definitive surgery is 5.5 days per year (SE = 0.9, p < 0.05) for NAT and 1.3 days per year (SE = 0.09, p < 0.05) for UFS. NAT time to definitive surgery is longer than UFS (p < 0.05).

Survival Analysis

Next, we evaluated survival outcomes for patients in the study cohort. When comparing overall survival for patients who underwent NAT followed by surgery compared to patients who underwent we found that there was no difference in survival with a univariate Cox Proportional Hazards Model (UFS: HR=0.96, 95%CI=0.85-1.1, p=0.54). Given differences in clinical and patient factors in each cohort with respect to treatment sequence, we next performed propensity-score matching to better compare survival outcomes based on known prognostic risk factors. The propensity-matched Cox proportional hazards model also demonstrated no difference between NAT and UFS after controlling for differences between cohorts (HR = 0.86, 95%CI=0.76-1.01, p=0.07, Figure 5). Taken together, the use of NAT did not improve overall survival for patients in this study cohort.

Fig. 5.

Propensity-Matched Kaplan-Meier Curve of overall survival for each treatment sequence in the setting of GISTs. The curve indicates that there is no difference in overall survival between the groups with UFS having an HR of 0.86 (95%CI=0.76-1.01, p=0.07).

Discussion

Although adjuvant imatinib use is well-characterized in this patient population^5,6,15, the use of neoadjuvant therapy, specifically imatinib, has not been adequately studied in a real-world population of patients. Given the evolution of neoadjuvant treatment over time in this disease, our retrospective cohort analysis aims to compare utilization trends, patient characteristics, and survival outcomes between those who received neoadjuvant therapy and up-front surgery for patients with gastric GISTs. Our results indicate that patients who received NAT presented with more advanced disease with higher Clinical Stage, larger pathologic tumor size, higher tumor grade, and the need for a larger proportion of multivisceral resections.

We also found that the use of NAT is becoming more prevalent over time and that tumor size has decreased over the last 15 years, matching recent reports assessing neoadjuvant imatinib utilization and its impacts on GISTs.^1,9,11,16-20 Furthermore, multivisceral resections were performed more frequently, but without a difference in the rate of increase in patients who underwent NAT versus UFS. These results may suggest that neoadjuvant therapies, specifically imatinib, have improved the ability to perform surgery on prognostically-worse and more complex tumors that may have been unresectable in years prior to the introduction of neoadjuvant treatment.¹¹

We also identified a sudden drop in tumor size resected after 2009. It is difficult to identify the causal factor for this. However, it is important to note that trials utilizing neoadjuvant imatinib for GISTs began in the 2000s, with initial reports from these trials published in 2009, which is the year before we see the drop-off in tumor size^21-23 NCCN guidelines first suggested the use of neoadjuvant imatinib in 2007²⁴, potentially highlighting an important role in these.^6,21,22 As such, this may suggest that neoadjuvant therapy, specifically imatinib, may have played a role in the decreased size of tumor at curative surgery, but more analysis needs to be completed to identify if this is the true driver of this finding.

When evaluating the length of NAT prior to surgery, we found that over time, there has been an increase in time from diagnosis to definitive surgery, suggesting a greater familiarity with trends in response to treatment. Current guidelines indicate that neoadjuvant therapy should be given to help downstage tumors and achieve R0 resection, with a recommended treatment time of 6-12 months.^1,25,26 In comparison, our study found that the average length to definitive surgery is over 6 months, which is likely caused by its role in reducing tumor size and downstaging tumors to increase the probability of R0 resection. Further, the growing length in treatment time can also be explained by the greater complexity of these tumors seen in the patients receiving NAT as compared to UFS. ¹⁹ As such, these results are in line with the current recommendations and indicate that physicians have developed a better understanding of the proper utilization of neoadjuvant therapy in improving patient prognoses.²¹ .

Although neoadjuvant therapy is used for more severe GISTs, we found no difference in survival outcomes for univariate and propensity-matched models. In the literature, the impact of neoadjuvant imatinib, has unclear effects on overall survival. Using the same database as this study, Janczewski et al. found no difference in overall survival on propensity-matched models, but they did note that NAT did have better survival when adjusting for other possible confounders.¹¹ Kelly et al. established similar findings in which there was no difference in survival between neoadjuvant imatinib and adjuvant imatinib following surgery.¹⁷ Considering these findings, our results are in line with the current understanding on the impact that neoadjuvant imatinib has on survival.²⁷ However, given that prospective data is limited on this subject, clinical trials should be designed to address this question for specific subpopulations of patients to more accurately establish its impact on overall survival and disease specific survival. Interestingly, we also found that survival in the neoadjuvant cohort was similar to up-front surgery without accounting for prognostic factors, which seems to suggest that our results may not be properly balancing for the most important confounders. Further, neoadjuvant therapy may play a role in mitigating the recurrence rate for GISTs, so the utilization of neoadjuvant imatinib could be applied to less severe cases to achieve this effect and improve patient outcomes.^19,20 Therefore, future research may need to identify better prognostic indicators and if neoadjuvant imatinib use in this population should be maintained for improved operability and lower rates of recurrence.

The observed association between neoadjuvant therapy and OS in gastric GISTs may be influenced by several factors outside of the treatment and tumor characteristics. Academic centers, which tend to have higher surgical volumes and more specialized multidisciplinary teams, are more likely to employ neoadjuvant therapies, likely due to higher rates of complex cases being seen.^28,29 This finding is in line with our own findings as we see that neoadjuvant therapy is more commonly seen in academic programs, compared to its UFS counterpart. High surgical volume has been linked to better survival outcomes in sarcomas and other complex cancers, potentially enhancing the apparent benefit of NAT when performed at these centers.²⁹ Conversely, multiple studies, including our own, have established that NAT is more frequently used in cases with larger tumor size and multivisceral involvement—factors that are inherently associated with poorer prognosis.^11,26,30,31 Therefore, the improved survival seen with NAT could reflect the complex interplay between care at high-volume centers and selection bias towards more aggressive disease biology. Additionally, differences in institutional practice patterns, patient selection, and treatment protocols across centers may further contribute to these findings.²⁹ Understanding the relationship between these factors in the setting of gastric GISTs is crucial for interpreting the true impact of NAT and guiding future treatment.

In general, treatment patterns for patients who present with GISTs have recently become increasingly established in the literature. Using the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) registries, Alvarez et al. and Khan et al. illustrate that incidence for gastric GISTs has increased over time^32,33, which fall in line with our results. These trends may be due to better diagnostic capability^34,35 or that the tumor is becoming more common in the US population. However, the results of the current study uniquely show that more multivisceral resections are being performed each year, suggesting that with the increase utilization and familiarity with this disease and the utilization of NAT, patients with more advanced tumors are more likely to undergo definitive curative-intent surgery.

It is important to recognize certain limitations with this study. Although the NCDB dataset is often utilized due to its accuracy and size¹¹, it should be noted that there was likely measurement and reporting bias due to improper variable classification or missing values.^12,13 Additionally, the NCDB dataset is missing variables that may affect prognosis, such as pattern of recurrence, therapy type, and molecular data that may demonstrate if certain patients would benefit more from targeted therapy.³⁶ An important detail we were unable to assess was the presence of certain mutations, such as those within the c-kit exon, that may provide key diagnostic and prognostic value for this study. While the database did provide information on time from diagnosis to surgery and to the start of treatment, the dataset did not provide information on exact dosing, changes in dosing, or pauses in therapy as well. Finally, our study’s statistical analysis has some limitations as it only provides information on the types of patients receiving NAT, the tumor characteristics, and how it impacts overall survival. It does not, however, draw definitive conclusions on how neoadjuvant therapy can be best utilized for these patients. Besides these limitations, the dataset and associated analysis provides key information into the overall impact that neoadjuvant therapy has on survival compared to up-front surgery. Future studies should determine the benefit of neoadjuvant therapy in the setting of locally advanced GISTs by considering the impact it has on tumor size, downstaging tumors, and helping to achieve R0 resection.

Conclusion

Our study examines current trends in locally advanced gastric GISTs, highlighting differences between patients receiving neoadjuvant therapy (NAT) and those undergoing upfront surgery (UFS) using the National Cancer Database. We show that NAT is increasingly utilized for more severe tumors and for longer durations, yet it achieves comparable outcomes to UFS despite worse prognostic factors. These results support the growing role of neoadjuvant imatinib in clinical practice, emphasizing its benefits in reducing tumor size and improving the likelihood of complete resection. Considering the lack of evidence with neoadjuvant therapy in improving survival in gastric GISTs, future studies need to assess the impact of neoadjuvant therapy on recurrence and identify the prognostic factors that influence survival in this subtype of GISTs.