Abstract
Surgical resection with negative margins of non-metastatic gastric GISTs is considered the main therapeutic option in GISTs treatment. Neoadjuvant therapy with imatinib is associated with higher response rates in advanced GISTs. We reported 34 patients with non-metastatic gastric GISTs who underwent partial gastrectomy at the Oncology Center, Mansoura University, Egypt, after receiving a daily dose of 400 mg of imatinib as a neoadjuvant treatment in the period between October 2012 and January 2021. Twenty-two cases underwent open partial gastrectomy, and twelve cases had a laparoscopic partial gastrectomy. The median tumor size at diagnosis was 13.5 cm (range 9–26 cm) and the duration of neoadjuvant therapy was 10.91 months (range 4–12 months). Thirty-three patients had a partial response, while one patient showed progression of the disease on neoadjuvant treatment. Adjuvant therapy was conducted in 29 (85.3%) cases. Complications of neoadjuvant treatment were reported in seven cases in the form of gastritis, bleeding per rectum, fatigue, thrombocytopenia, neutropenia, and edema lower limbs. The disease-free survival (DFS) in this study was 34.53 months, and the overall survival (OS) was 37 months. Recurrence developed in two cases, gastric and peritoneal recurrence (25 and 48 months from the initial diagnosis, respectively). We have concluded that neoadjuvant treatment with imatinib for non-metastatic gastric GISTs is a safe and effective method for tumor downsizing and devitalization to allow minimally invasive and/or organ sparing surgery. Moreover, it decreases the risk of intraoperative tumor rupture and relapse, thus improving the oncological outcome of such tumors.
Keywords: Gastric GISTs, Neoadjuvant treatment, Partial gastrectomy
Introduction
Gastrointestinal stromal tumors (GISTs) are rare cancers with an average incidence of 1.5 per 100,000 inhabitants. Moreover, GISTs are considered the most common gastrointestinal mesenchymal tumors [1]. GISTs originate from interstitial cells of Cajal that are present in between the muscle layers of the bowel wall and are responsible for controlling its peristalsis. The stomach is the most common location of these cells in the gastrointestinal tract (60%), followed by the small bowel (20–30%) [2]. These cells are sometimes located outside the digestive tract.
The molecular mechanisms of GISTs were not fully understood before 2000 when the effective treatment for unresectable and metastatic GISTs was unknown. The identification of CD117 (KIT transmembrane receptor tyrosine kinase) made it easy to understand the nature of this specific disease [3]. About 80% of GISTs have KIT gene mutations that activate the KIT receptors. Imatinib (a tyrosine kinase inhibitor) is a targeted therapy that is being used in the treatment of chronic myeloid leukemia. It was found to be effective and has a marvelous impact on patients with GISTs [4]. Clinical trials have been performed to confirm the therapeutic value of imatinib in GISTs patients with metastatic or unresectable disease, and these patients had improvement in their oncological outcomes.
Surgical resection is the main line of treatment for gastric GISTs without distant metastasis, and complete resection with clear safety margins remains the only therapeutic modality in its treatment [5]. Approximately half of the patients with GISTs develop tumor recurrence. Many factors affect tumor recurrence such as the tumor size, location in the gastrointestinal tract, intraoperative tumor rupture, and proliferative activity. Frequently, local, peritoneal, or visceral recurrence in the liver renders the disease unresectable, despite the use of concurrent receptor tyrosine kinase inhibitors (RTKI) in treatment [6].
Recently, the recurrence rate was proved to be strongly related to the tumor size even after complete resection of large tumors [7]. Advanced GISTs were found to have a high response rate to neoadjuvant imatinib. Neoadjuvant therapy is utilized to allow more conservative surgeries, avoid tumor rupture, and reduce peri-operative morbidities. Furthermore, the shrinkage of tumors treated with imatinib allows less invasive resections, especially for gastric GISTs located at the proximal and distal part of the stomach, and permits minimally invasive surgery for large-sized gastric GISTs [5]. This study aims to analyze the role and the efficacy of neoadjuvant imatinib for gastric GIST patients admitted to the Oncology Center, Mansoura University, Egypt, with the assessment of its surgical and oncological outcomes.
Patients and Methods
We recently reported 34 patients with non-metastatic gastric GISTs who underwent partial gastrectomy at the Department of Surgical Oncology, Oncology Center, Mansoura University, Egypt, after receiving a neoadjuvant therapy with imatinib in the period between October 2012 and January 2021. This study was done after receiving the approval of the Institutional Research Board (IRB) of the Faculty of Medicine, Mansoura University, with a code number R.21.02.1229.
Patients included in this study were with non-metastatic gastric GISTs more than 5 cm, especially in the gastroesophageal junction, pylorus, and locally advanced tumors that needed combined resection. We excluded patients who were not fit for anesthesia, patients undergoing emergency surgery, and patients refusing to receive neoadjuvant therapy. All the patients have signed informed consent before enrollment in this study. The baseline characteristics of the patients such as age, sex, body mass index (BMI), and American Society of Anesthesiologists (ASA) score were collected. The clinicopathological variables of the tumors were collected including tumor size before the start of neoadjuvant treatment, tumor location in the stomach, the morphological subtypes, immunohistochemical staining, and the mitotic index counted per HPF (high-power field). The National Institute of Health (NIH) risk management program was used for tumor risk assessment. Operative outcomes were collected including the surgical approach either open or minimally invasive surgery, operative duration, blood loss, and intraoperative complications. The postoperative outcomes including the length of hospital stay, the time of initiation of oral intake, and the complications according to Clavien-Dindo classification were reported. We also reported relevant dates such as the date of operation, recurrence, death, or follow-up.
All the patients in this study received neoadjuvant imatinib for a maximum duration of 12 months. The modification of Response Evaluation Criteria for Solid Tumors (RECIST [8]) was used for tumor response assessment to the neoadjuvant treatment. Computed tomography (CT) measurements were used to assess the tumor response to neoadjuvant therapy. According to RECIST categories, progressive disease (PD) means ≥ 20% increase in tumor size, stable disease (SD) is < 20% increase to < 30% decrease in tumor size, partial response (PR) ≥ 30% decrease in tumor size, and complete response (CR) which is the complete disappearance of the lesion.
Statistical Analysis
Data were analyzed using Statistical Package for Scientific Studies (SPSS) v.26 for macOS v11.4. The means ± standard deviation (SD) methods were used for numerical data expression. Comparison between groups was done using the Chi-square test and the independent samples t-test. The disease-free survival (DFS) was estimated by the Kaplan–Meier method.
Results
Thirty-four patients with non-metastatic gastric GISTs received neoadjuvant treatment with imatinib and underwent partial gastrectomy. The patients’ demographics are shown in Table 1. The mean age of the patients was 54.65 years, and the mean BMI was 32.79 kg/m2. Most of the patients had ASA score I. Ten patients had comorbidities (three with diabetes, three had hypertension, two were hepatic, and two combined). The commonest presentation in our study was dyspepsia (67.6%), while bleeding was noticed in only 26.5% of the patients. The tumors had a median size at the time of diagnosis of 13.5 cm (range 9–26 cm). The neoadjuvant imatinib was used for 10.91 months (range 4–12 months). According to RECIST criteria of tumor response to neoadjuvant treatment, 33 patients had partial response while only one patient had progressive disease. Complications of neoadjuvant treatment were noted in 7 cases in the form of gastritis, bleeding per rectum, fatigue, thrombocytopenia, neutropenia, and edema in lower limbs. All patients in this study received 400 mg of a daily dose of imatinib except for one case with a progressive disease and thrombocytopenia who received 600 mg/day.
Table 1.
Baseline characteristics of the patients
| Patients, n = 34 (%) | |
|---|---|
| BMI, kg/m2 (mean ± SD) | 32.79 ± 5.989 |
| Age, years (mean ± SD) | 54.65 ± 14.163 |
| ASA score | |
| I | 32 (94.1%) |
| II | 2 (5.9%) |
| Gender | |
| Male | 15 (44.1%) |
| Female | 19 (55.9%) |
| Comorbidities | |
| None | 24 (70.6%) |
| Diabetes | 3 (8.8%) |
| Hypertension | 3 (8.8%) |
| Hepatic | 2 (5.9%) |
| Combined | 2 (5.9%) |
| Complaint | |
| Asymptomatic (incidental) | 2 (5.9%) |
| Dyspepsia | 23 (67.6%) |
| Bleeding | 9 (26.5%) |
| Tumor size at diagnosis (cm) | |
| (mean ± SD) | 14.02 ± 3.45 |
| (median, range) | 13.5 (9–26) |
| Patients received neoadjuvant treatment | 34 (100%) |
| Neoadjuvant treatment duration (months; mean ± SD) | 10.91 ± 2.094 |
| Complications of neoadjuvant therapy | |
| None | 27 (79.4%) |
| Bleeding per rectum | 1 (2.9%) |
| Gastritis | 1 (2.9%) |
| Fatigue | 1 (2.9%) |
| Thrombocytopenia | 1 (2.9%) |
| Neutropenia | 1 (2.9%) |
| Edema lower limbs | 2 (5.9%) |
| RECIST categories of tumor response | |
| Progressive disease (PD) | 1 (2.9%) |
| Stable disease (SD) | 0 (0%) |
| Partial response (PR) | 33 (97.1%) |
| Complete response (CR) | 0 (0%) |
BMI body mass index, ASA American Society of Anesthesiology, RECIST response criteria for solid tumors
The tumors were commonly located in the greater curvature in 41.2% of the cases (Table 2). Twenty-two cases underwent open partial gastrectomy, and twelve cases had a laparoscopic partial gastrectomy. A single patient required additional splenectomy due to infiltration of the splenic hilum. The mean operative duration was 152.5 min, and the estimated blood loss (EBL) was 151.47 ml. Intraoperative blood transfusion was needed in only one case that underwent open partial gastrectomy and there was no case with intraoperative tumor rupture.
Table 2.
The surgical outcomes of the patients
| Total n = 34 (%) |
Open partial gastrectomy n = 22 (%) |
Laparoscopic partial gastrectomy n = 12 (%) |
p | |
|---|---|---|---|---|
| Tumor site | 0.754 | |||
| Cardia | 9 (26.5%) | 5 (22.73%) | 4 (33.33%) | |
| Lesser curvature | 9 (26.5%) | 7 (31.81%) | 2 (16.67%) | |
| Greater curvature | 14 (41.2%) | 9 (40.91%) | 5 (41.67%) | |
| Antrum | 2 (5.9%) | 1 (4.55%) | 1 (8.33%) | |
| Operation time (min; mean ± SD) | 152.5 ± 56.034 | 150.91 ± 59.435 | 155.42 ± 51.587 | 0.827 |
| EBL (ml; mean ± SD) | 151.47 ± 60.309 | 157.27 ± 61.581 | 140.83 ± 59.001 | 0.456 |
| Blood transfusion | 1 (2.9%) | 1 (4.55%) | 0 (0%) | 0.453 |
| Operative complications | 0 (0%) | 0 (0%) | 0 (0%) | |
| Intraoperative tumor rupture | 0 (0%) | 0 (0%) | 0 (0%) | |
| POP complications (CD classification) | 0.909 | |||
| CD I | 30 (88.2%) | 19 (86.36%) | 11(91.67%) | |
| CD II | 3 (8.8%) | 2 (9.09%) | 1 (8.33%) | |
| Ambulation (days; mean ± SD) | 1 ± 0.83 | 1.50 ± 0.512 | 0.00 ± 0.00 | < 0.005 |
| Oral intake (days; mean ± SD) | 2.21 ± 1.30 | 2.95 ± 0.999 | 0.83 ± 0.389 | < 0.005 |
| ICU stay (days; mean ± SD) | 0.03 ± 0.171 | 0.05 ± 0.213 | 0.00 ± 0.00 | 0.469 |
| Hospital stay (days; mean ± SD) | 5 ± 1.97 | 6.05 ± 1.588 | 3.08 ± 0.793 | < 0.005 |
| 30-day mortality | 1 (2.9%) | 1 (4.55%) | 0 (0%) | 0.453 |
EBL estimated blood loss, POP postoperative, CD Clavien Dindo
Regarding the postoperative outcomes, three patients had CD (Clavien and Dindo) grade II morbidities. We had one case with 30-day mortality due to pneumonia. One patient had to stay in the ICU for 1 day. The patients were ambulant on postoperative day 1 (POD 1). The oral intake was started in POD 2 and the hospital stay had a mean duration of 5 days. There was a significant difference between the open and laparoscopic partial gastrectomy regarding ambulation, oral intake, and hospital stay (p < 0.005).
Most of the cases had large tumors (range 5–10 cm, n = 27 cases). Spindle-shaped GISTs were the common morphological subtype in 70.6% of the cases. A low mitotic index was noticed in 30 cases. Tumor necrosis was found in only two cases (5.9%), immunohistochemical markers such as CD117 was positive in 91.2%, CD34 was positive in 97.1%, and DOG1 was positive in 100%. Most cases (47.1%) had an intermediate risk tumor according to the National Institute of Health (NIH) risk stratification (Table 3).
Table 3.
Histopathological characteristics of the tumors resected
| Patients, n = 34 (%) | |
|---|---|
| Tumor morphology | |
| Spindle | 24 (70.6%) |
| Epithelioid | 9 (26.5%) |
| Mixed | 1 (2.9%) |
| Tumor size | |
| < 2 cm | 0 (0%) |
| 2–5 cm | 6 (17.6%) |
| 5–10 cm | 27 (79.4%) |
| > 10 cm | 1 (2.9%) |
| Mitotic index per 50 HPF | |
| Low (< 5/5 mm) | 30 (88.2%) |
| High (> 5/5 mm) | 4 (11.8%) |
| Necrosis | |
| No | 32 (94.1%) |
| Yes | 2 (5.9%) |
| CD117 | |
| Negative | 3 (8.8%) |
| Positive | 31 (91.2%) |
| CD34 | |
| Negative | 1 (2.9%) |
| Positive | 33 (97.1%) |
| DOG1 | |
| Positive | 30 (100%) |
| NIH risk | |
| Very low | 0 (0%) |
| Low | 9 (26.5%) |
| Intermediate | 16 (47.1%) |
| High | 9 (26.5%) |
NIH National Institute of Health, HPF high power field
The patients were followed up within 37 months (Table 4), and adjuvant therapy was conducted in 29 cases (85.3%). The adjuvant treatment was conducted in a mean period of 18.21 months. The disease-free survival (DFS) was 34.53 months (Fig. 1) and the overall survival (OS) was 37 months. Recurrence developed in two cases: gastric and peritoneal recurrence (25 and 48 months from the initial diagnosis, respectively).
Table 4.
The follow-up data of the patients who had neoadjuvant therapy for non-metastatic gastric GISTs
| Patients, n = 34 (%) | |
|---|---|
| Adjuvant imatinib | |
| No | 5 (14.7%) |
| Yes | 29 (85.3%) |
| Duration of adjuvant therapy (months; mean ± SD) | 18.21 ± 12.497 |
| The overall survival (months; mean ± SD) | 37 ± 23.25 |
| The disease-free survival (months; mean ± SD) | 34.53 ± 20.18 |
| Recurrence | |
|
No Yes |
32 (94.1%) 2 (5.9%) |
Fig. 1.
Kaplan–Meier curve of the disease-free survival for patients who had neoadjuvant therapy for non-metastatic gastric GISTs
Discussion
The role of neoadjuvant therapy with imatinib for GISTs is an evolving area of research. The NCCN (National Comprehensive Cancer Network) and the ESMO (European Society for Medical Oncology) guidelines have considered complete surgical resection of GISTs as the main line of treatment [6, 9]. Moreover, these guidelines have recommended neoadjuvant treatment with cases of locally advanced GISTs to avoid multiorgan resection or morbidities that may be associated with extensive surgical resection.
The American US guidelines described rectal GISTs as a desirable model for neoadjuvant therapy. The aim was to achieve sphincter-preserving surgery to have an adequate functional outcome. Trans-anal resection of rectal GISTs without opening the peritoneum decreases the risk of tumor spillage in the peritoneum, thus reducing the rate of peritoneal metastasis [10]. Many case series have conducted local excision of rectal GISTs with sphincter preservation after preoperative therapy [11].
Gastric GISTs, located in the cardia or the pylorus, can be resected without the need for esophagogastric junction resection or distal gastrectomy. Moreover, wedge resection of duodenal GISTs has replaced Whipple’s operation [12]. Partial gastrectomy with organ preservation for gastric GISTs affects the adjuvant imatinib therapy. Recent studies evaluated the blood levels of imatinib in patients who received adjuvant treatment and found lower imatinib levels in patients who had total gastrectomy than those with a history of partial gastrectomy [13]. Therefore, the extent of gastrectomy for gastric GISTs affects the adjuvant therapy and tumor response. The preoperative imatinib therapy in patients with gastric GISTs will lead to higher levels of adjuvant imatinib by limiting the extent of gastrectomy. Thus, the overall prognosis of patients with gastric GISTs after neoadjuvant therapy will be improved [14].
Many cohort studies co-related tumor recurrence and tumor rupture as its incidence may be up to 100% after intraoperative tumor rupture [15]. Adjuvant RTKI therapy may decrease the incidence of tumor recurrence after its rupture, but it cannot prevent the incidence of gastric or intraperitoneal recurrence. The disseminated intraperitoneal disease has a worse prognosis compared to liver metastasis [16]. Neoadjuvant therapy improves the surgical handling of the large-sized GISTs, downsizes them and causes their devitalization, and subsequently prevents intraoperative rupture. In the current study, we did not report any case with intraoperative tumor rupture.
Twelve cases in the current study underwent minimally invasive surgery and twenty-two cases had conventional open surgery. The neoadjuvant therapy and its effect on the tumor shrinkage and its devascularization made the use of the laparoscopy in the gastric GISTs resection more feasible with the easier handling of the downsized tumor, decreased the risk of intraperitoneal bleeding, and allowed easier delivery of the specimen without rupture or contamination. Laparoscopic gastric surgery for gastric GISTs had less postoperative morbidity and better cosmetic outcome and we had a significant difference between open and laparoscopic approaches regarding ambulation, oral intake, and hospital stay (p < 0.005).
The tumor size at the time of diagnosis was 13.5 cm (range 9–26 cm), comparable to another study with a median tumor size of 12 cm (range 10–23 cm) [17]. The duration of neoadjuvant treatment in the current study ranged from 4 to 12 months. There is a controversy regarding the optimal duration of neoadjuvant treatment. Guidelines recommend the continuation of neoadjuvant imatinib until a maximal response is reached. The maximal response is defined as the absence of any improvement within two successive computed tomography (CT) scans [18]. However, NCCN guidelines described the duration of maximal response after neoadjuvant therapy as 6 months or more [5]. Other studies of neoadjuvant therapy in rectal GISTs have reported 3–19 months as an optimal duration for tumor response [19, 20]. Another study concluded that 4 months is a minimum therapy duration to achieve treatment response and 12 months is a maximum duration to avoid tumor progression after initial response [9]. Complications of neoadjuvant therapy in the current study included gastritis, bleeding per rectum, fatigue, thrombocytopenia, neutropenia, and edema lower limbs. There was no report of treatment-related mortality. Treatment was postponed in cases with hematological toxicity till improvement of these side effects. Complications reported in other studies included facial edema (72%), rash (45%), neutropenia (8%), and cerebral ischemia in one patient, and no cases of mortality from treatment. Neoadjuvant treatment was discontinued in seven cases in these studies [17].
We did not wait for a maximal response in every case to perform surgery. The multidisciplinary team reviewed all cases with every follow-up CT scan of the abdomen and decided to perform either surgery or to continue with neoadjuvant therapy. According to RECIST categories of tumor response, 97.1% of cases in this study achieved a partial response. Phase II RTOG 0132 study has described the minimal duration of neoadjuvant treatment as ranging between 8 and 12 weeks with a 7% response rate [21]. Other studies with longer preoperative duration of treatment (range 6–12 months) have exceeded 50% response rates. A cohort study of the EORTC 62005 trial reported a response rate of up to 80% with a minimal optimal duration of 9 months to achieve a partial response [22]. The tumor response in the current study was assessed through CT scans with measurement of the longest cross-sectional tumor dimensions after 1st month of neoadjuvant therapy and tumor viability by evaluating its blood supply and density through the development of tumor necrosis, cystic or myxoid degeneration. CT is a sensitive and specific method to assess the GIST tumor response to imatinib as the decrease in tumor size of > 10% or its density of > 15% had a sensitivity of 97% and a specificity of 100% in detecting patients with good response [23]. No gene sequencing was done in this study. Imatinib is the most effective in 80% of all GIST tumors, those with exon 11 and 9 KIT gene mutations and those tumors that have non-D842V PDGFRA mutations [24]. About 15% of GISTs are imatinib-resistant, those with KIT gene mutations in exons 13, 14, and 17; tumors associated with D842V PDGFR mutations; and in GISTs with BRAF-mutation. Imatinib shows some activity in succinate dehydrogenase–deficient GISTs [25].
All cases in this study had R0 resection with a mean operative time of 152.5 min, with no report of tumor rupture or intraoperative complications. All cases underwent partial gastrectomy and combined gastrectomy, and splenectomy was done in only one case. In another study, the operative time was 150.5 min, with partial gastrectomy in 84%, proximal gastrectomy in 10%, and total gastrectomy in 6% of cases. It also reported combined resections in the form of splenectomy in 9 cases, distal pancreatectomy in 3 cases, transverse colectomy in 2 cases, and liver resection in 2 cases [17].
Adjuvant therapy was given to 29 cases (85.3%). It is conducted in tumors with high-risk features and those with sensitive mutations to imatinib. The published trials of neoadjuvant therapy did not report whether either to omit the adjuvant treatment after preoperative imatinib therapy or not. NCCN and ESMO guidelines have recommended adjuvant therapy with imatinib for 3 years in patients with significant risks of tumor recurrence [5, 6].
We followed up with the patients within a mean period of 37 months, and disease-free survival was 34.53 months. Recurrence has developed in 2 cases (5.9%), within 25 and 48 months from initial diagnosis. Patients with high‐risk GISTs experience recurrence within the first 5 years postoperative, even after complete surgical resection with free margins [26]. Therefore, adjuvant therapy is recommended in these patients to improve their oncological outcomes.
Conclusion
Surgery is the main line of therapy for gastric GISTs. Preoperative treatment with imatinib is indicated for tumor devitalization and downsizing to allow minimal invasive resection and organ sparing surgery. Moreover, tumor downsizing prevents the intraoperative tumor rupture and its subsequent relapse. The less extent of gastric resection is associated with high adjuvant RTKI drug uptake. Therefore, partial gastrectomy for gastric GISTs after neoadjuvant therapy may improve the response to adjuvant imatinib.
Acknowledgements
The authors are grateful to their patients and colleagues at the Oncology Center, Mansoura University.
Authors’ Contributions
All authors contributed to the study’s conception and design. Material preparation, data collection, and analysis were performed by Amr Abouzid. The first draft of the manuscript was written by Amr Abouzid and all authors commented on previous versions of the manuscript. All authors read and approved the final version of the manuscript.
Data Availability
The datasets generated and analyzed during the current study are not publicly available and are available from the corresponding author on reasonable request.
Declarations
Ethics Approval and Consent to Participate
Approval was obtained from the Institutional Research Board (IRB) of the Faculty of Medicine, Mansoura University, code R.21.02.1229. Written informed consent was obtained from all the patients included in this study.
Consent for Publication
Not applicable.
Competing Interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated and analyzed during the current study are not publicly available and are available from the corresponding author on reasonable request.