Preoperative Imatinib Therapy Research Articles

Optimal management options for esophageal gastrointestinal stromal tumors (E-GIST)

ObjectiveTo explore the different treatment modalities for esophageal gastrointestinal stromal tumors (E-GIST) and their respective applicability and clinical outcomes. MethodsThis is a retrospective study in which consecutive patients diagnosed with E-GIST at our hospital from January 2017 to August 2023 were included. The clinical characteristics of all the patients as well as long-term quality of life were recorded and analyzed. ResultsA total of 23 (12 males, 11 females) E-GIST patients with a mean age of 56.7 ± 12.0 years were included in this study. Common symptoms, including upper abdominal pain, acid reflux, and heartburn, accounted for over 60 % of cases. Fifteen patients underwent endoscopic resection, five patients underwent surgical resection, two patients underwent surgical resection after receiving preoperative imatinib therapy, and one patient received conservative management. ConclusionDifferent treatment strategies may be applied to the patients with E-GIST depending on the their clinical features. Our study provides insights into precise treatment for different patients. However, due to the rarity of the disease, it is challenging to collect a large sample size from a single center, necessitating more multicenter prospective large-scale studies.

Surgical outcomes of locally advanced gastrointestinal stromal tumors after multivisceral resection: A retrospective study of 64 patients at a single institution.

To analyze the outcome in patients who have undergone multivisceral resection (MVR) for locally advanced gastrointestinal stromal tumors (GISTs), and identify the risk factors for tumor recurrence and postoperative morbidity. Sixty-four patients who operated for locally advanced GISTs with MVR in PPeking University Cancer Hospital Sarcoma Center (PUCHSC) between 2013 and 2021 were identified. Clinicopathologic characteristics, surgical outcomes, recurrence, and 5-year recurrence-free and overall survival were evaluated. The mean age of the patients was 60 years. Mean tumor size was 11.1 cm. Complete resection was achieved in all patients. The estimated 5-year recurrence-free and overall survival were 86.6% and 90.0%, respectively. Independent factor of recurrence following surgery was mitotic count on multivariate analysis. Overall postoperative morbidity was 53.1% (n = 34). Severe morbidity was 21.9% (n = 14). The most common severe complication was clinically relevant pancreatic fistula (n = 12, 18.8%), followed by anastomotic leakage (n = 4, 6.3%) and Intraabdominal abscess (n = 4, 6.3%). Multivariate analysis showed that preoperative imatinib therapy could reduce overall morbidity. Long operation time, combined colectomy and pancreatectomy were independent risk factors for postoperative severe morbidity. Compared to partial pancreatectomy, pancreaticoduodenectomy (PD) was significantly increased the incidence of severe morbidity. In conclusion, compared to systemic therapy alone, the outcome of locally advanced GISTs after MVR was more favorable. Despite the high overall morbidity, the postoperative severe morbidity and mortality of MVR were acceptable. Preoperative imatinib therapy should be recommended whenever possible. Combined pancreatectomy and colectomy are associated with significant postoperative severe morbidities. PD should be thoroughly discussed and be subject to MDT approach before surgery.

P-264 The effect of preoperative imatinib therapy in gastrointestinal stromal tumors: A multicenter study

P-264 The effect of preoperative imatinib therapy in gastrointestinal stromal tumors: A multicenter study

Abstract 4139: Dual energy analysis of TKI response in GIST - results of a prospective trial

Abstract Objective: Within in a prospectively conducted trial (‘Unifying Advanced Treatment With Advanced Imaging’, GISTm3, NCT 03404076) we aimed at developing and validating a CT radiomics model to predict to response to tyrosine kinase inhibitors in GIST patients. We used the intratumoral iodine concentration which is less corroborated by tumor sclerosis or intratumoral hemorrhage than classical CT criteria. Materials and Methods: This is a prospective multi-center study of 94 patients (mean age 61 years; age range 28-83 years; 51m, 43f) who underwent a single-energy contrast-enhanced staging CT in a portal venous phase. All patients underwent subsequent preoperative imatinib therapy for at least 6 months (median 12 months, range 4-36 months) and follow-up CT examination. Patients were graded binary as responders and non-responders using their best response throughout the drug treatment course according to the vascular tumor burden to account for pseudo-progression under therapy. Response assessment was performed using RECIST 1.1, modified Choi (mChoi), vascular tumor burden (VTB), DECT vital iodine TB. Two radiologists performed a 3D-segmentation analysis of the GIST lesions on the pre-treatment CT using a dedicated radiomics software (Radiomics Version 1.0.9, Siemens Healthineers, Forchheim, Germany) and a visual evaluation of enhancement and non-enhancement parameters of each GIST lesion. Using a training dataset (n=17), a multivariable logistic regression by least absolute shrinkage and selection operator identified features that predicted therapy response was build. This model was then evaluated in the independent cohort (n=78) for temporal validation. Results: 77 GIST lesions responded to the drug. A total of 53 radiological visual features and radiomic features were rated reproducible (intraclass correlation >0.8). The radiological visual grading and the radiomic features alone resulted in a similar AUC (0.62, 95%CI 0.49-0.76 vs 0.64 95%CI 0.50-0.77). The final model which combined both radiological visual grading (3 features) and also 3 radiomic features had a significantly higher AUC (0.75, 95%CI 0.64-0.86; both p<0.01) when compared to both separate predictive models alone. Using DECT vital iodine TB, median PFS was significantly different between non-responders and responders (18.8 mos vs. 5.6 mos, resp.; p=.02). HR for progression for DECT vital iodine TB non-responders vs. responders was 6.9, 3.3 for VTB, 2.3 for RECIST 1.1, and 2.1 for mChoi. Conclusion: The study presents a predictive model that incorporates radiologist grading and radiomics features. DECT vital iodine TB criteria outperformed RECIST 1.1, VTB and mChoi for response assessment of metastatic GIST under TKI therapy. The technique should be very useful in guiding early management decisions in patients. Citation Format: Peter Hohenberger, Mathias Meyer, Thomas Henzler, Richard F. Riedel, Christina Messiou, Daniele Marin, Stefan Schoenberg. Dual energy analysis of TKI response in GIST - results of a prospective trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4139.

Treatment options for giant gastrointestinal stromal tumours and related prognosis: a single-centre retrospective study.

Controversy persists about the best treatment for giant gastrointestinal stromal tumours (GISTs). This retrospective study aimed to investigate the different treatments for giant GISTs and the effect on outcomes. A total of 71 patients with GIST ≥10 cm in diameter were separated into four groups according to treatment received: emergency surgery group (n = 17), preoperative targeted (imatinib) therapy group (n = 12), palliative resection group (n = 17) and R0 resection group (n = 25). Baseline, intraoperative and post-operative findings were compared between the groups. Long-term follow-up was conducted to assess outcomes. Preoperative gastrointestinal bleeding was significantly higher (P = 0.003) and haemoglobin level was significantly lower (P < 0.05) in the emergency surgery group than in the other groups. Mean tumour diameter was significantly more in the palliative resection group than in the other groups (P = 0.023). Overall survival was significantly higher in the R0 resection group and the preoperative targeted therapy group than in the other two groups (P < 0.05). In patients with giant GISTs, the best outcomes appear to be achieved with preoperative imatinib therapy plus surgery or R0 resection followed by imatinib therapy.

A Case of Esophageal Gastrointestinal Stromal Tumor Managed With Endoscopic Ultrasound Surveillance

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. They are classified based on their immunohistochemical studies with the expression of c-kit and typically present between 40-50-year-olds. GIST predominantly occur in the stomach (50%) and intestine (25%), followed by the colon and rectum (10%) and rarely in the esophagus (< 5%). Due to the rarity of esophageal GIST (ESOGIST), they are poorly understood and there is a paucity of research evaluating tumor characteristics and management. Our patient is an 83-year-old Hispanic male with a history of prior esophageal impactions due to known Schatzki's rings, presenting with postprandial vomiting. He denies any constitutional symptoms, dysphagia or odynophagia. His initial physical exam and labs are unremarkable. Endoscopy on admission shows a Schatzki's ring at the gastroesophageal junction and new 5mm nodule in the distal esophagus with three ulcers in the esophagus, stomach and duodenum respectively. Pathology of the nodule demonstrates squamous cell mucosa with smooth muscle bundles positive for desmin and negative for S100. Stomach biopsy is positive for H. pylori, which is treated with triple therapy. Endoscopic ultrasound (EUS) guided fine needle aspiration shows a spindle cell neoplasm that is C-kit, DOG-1, and SMA positive and desmin negative. Management of lesions < 2cm are controversial. Thus, given the tumor size and no high risk features on EUS, shared-decision-making was utilized to pursue management with EUS surveillance and planned resection if progressive. ESOGIST is uncommon and comprises less than 1% of all GIST. For lesions < 2cm with suspicious features on EUS, resection is indicated. Surgical resection is also directed for localized ESOGIST ≥2cm or which are symptomatic, with increased overall survival and disease-free survival with adjuvant Imatinib therapy. Enucleation is recommended for management of small tumors (2-5cm) with esophagectomy recommended for tumors >90mm. More research on the management of tumors between 60-90mm needs to be conducted. For larger tumors preoperative Imatinib therapy should be considered. This can improve resectability and is also the standard of therapy when surgery is contraindicated. This case is unique given the rarity of EOSGIST, and highlights the importance of further research on the management of these tumors to establish continued guidelines for care.

The role of neoadjuvant imatinib therapy of patients with primary locally advanced GIST.

11037 Background: percutaneous biopsy of gastrointestinal tumors is contraindicated, that is why prospective randomized trials of efficiency of preoperative imatinib therapy weren't conducted. According to the results of theRTOG S-0132/ACRIN 6665, CST1571-BDE43 and other studies, neoadjuvant imatinib therapy increase tumor resectability and improve progression-free and disease-specific survival. The optimal timing of surgical intervention is likely during the maximal response on treatment (6 to 12 months as a rule). Methods: We have analyzed the treatment results of 86 patients with locally advanced GIST which were treated since January 1st 2002 till 20 January 2016 at N.N. Blokhin Russian Cancer Centre. The primary tumor was located in the stomach - 32 pts (37,2%), duodenum and small bowel - 37 (43,1%), other (colon, rectum and extraorgan) – 17 pts ( 19,7%). The median follow-up time was 4.9 years. There are 4 groups in the trail: group 1 - 29 patients received only surgical treatment, group 2 - 12 pts– surgical resection with adjuvant imatinib therapy for 1 year; group 3 - 25 pts – adjuvant imatinib therapy for 3 years and group 4 - 17 pts– surgical resection with neoadjuvant and adjuvant imatinib therapy (1 - 3 years). The remained 3 patients received surgical resection with adjuvant imatinib therapy for 5 years. Results: Survival analyses showed a significant improvement of RFS and OS in patients who received combined treatment with neoadjuvant and adjuvant imatinib therapy. The five-year RFS in first group of patients was 10,8%, in 2 group - 16,7%, in 3 group - 68,4%, and 4 group - 79,8% (p = 0.0001). The 5-year overall survival in these groups was 42,6%, 66,7%, 76,1% and 91.6% ( p = 0,0072) respectively. In the patients with 5-years adjuvant therapy, diseases progression was not noted. During neoadjuvant therapy disease progression has been registered in two patients. The median time of preoperative imatinib therapy was 11 month (from 3 to 24 month). Neoadjuvant imatinib therapy increased the rate of R0 (14 pts – 82,4%) and organ-sparing (12 pts – 70,6%) resections. Conclusions: The optimal approach in patients with locally advanced GIST is combined surgical treatment with neoadjuvant and adjuvant (at least for 3 years) imatinib therapy.

Patterns of care and clinical outcomes in primary oesophageal gastrointestinal stromal tumours (GIST): A retrospective study of the French Sarcoma Group (FSG)

BackgroundOesophageal GIST (ESOGIST) are very rare tumours requiring special consideration regarding diagnosis, surgical management, and perioperative treatment. MethodsA retrospective study was conducted across 9 centres in the French Sarcoma Group (FSG) to characterize all patients in the years 2000–2014. ResultsSeventeen patients (pts) with primary localized ESOGIST were identified, with median age 69 years (36–81) and 11 females. Eight tumours (T) occurred in the lower third of the oesophagus, five in the oesophageal gastric junction, two in the superior third, and two in the middle third. All pts underwent oesophagoscopy and/or endoscopic ultrasound (EUS) and CT scan. Fifteen had EUS guided biopsy. Nine pts received Imatinib (IM) as initial treatment resulting in six PR, three SD. Tumours were resected in nine pts (53%) (7 upfront, 2 after IM); via enucleation in four (44%) [median size 4 cm], oesophagectomy in five (56%) [median size 10 cm]. Resections were R0 in three pts (33%), R1 in six (66%). Eight pts (47%) had no tumour resection, and one patient was never treated. Six pts received adjuvant IM. With a median follow-up of 24 months (7–101), 11 pts are alive (64.7%), five died (29.4%), one was lost to follow-up. Two pts of 4 pts relapsed following enucleation. ConclusionsESOGIST can be reliably identified pre-operatively by EUS-guided biopsy. Surgery for ESOGIST is either enucleation or oesophagectomy depending on tumour size, location, and patient's individual surgical risk. Preoperative IM therapy could improve resectability and should be considered if surgery is contraindicated or would lead to negative impact on the functional status of the patient.

Primary localized rectal/pararectal gastrointestinal stromal tumors: results of surgical and multimodal therapy from the French Sarcoma group.

BackgroundRectal and pararectal gastrointestinal stromal tumors (GISTs) are rare. The optimal management strategy for primary localized GISTs remains poorly defined.MethodsWe conducted a retrospective analysis of 41 patients with localized rectal or pararectal GISTs treated between 1991 and 2011 in 13 French Sarcoma Group centers.ResultsOf 12 patients who received preoperative imatinib therapy for a median duration of 7 (2-12) months, 8 experienced a partial response, 3 had stable disease, and 1 had a complete response. Thirty and 11 patients underwent function-sparing conservative surgery and abdominoperineal resection, respectively. Tumor resections were mostly R0 and R1 in 35 patients. Tumor rupture occurred in 12 patients. Eleven patients received postoperative imatinib with a median follow-up of 59 (2.4-186) months. The median time to disease relapse was 36 (9.8-62) months. The 5-year overall survival rate was 86.5%. Twenty patients developed local recurrence after surgery alone, two developed recurrence after resection combined with preoperative and/or postoperative imatinib, and eight developed metastases. In univariate analysis, the mitotic index (≤5) and tumor size (≤5 cm) were associated with a significantly decreased risk of local relapse. Perioperative imatinib was associated with a significantly reduced risk of overall relapse and local relapse.ConclusionsPerioperative imatinib therapy was associated with improved disease-free survival. Preoperative imatinib was effective. Tumor shrinkage has a clear benefit for local excision in terms of feasibility and function preservation. Given the complexity of rectal GISTs, referral of patients with this rare disease to expert centers to undergo a multidisciplinary approach is recommended.

Treatment strategy of rectal gastrointestinal stromal tumor (GIST)

Rectal gastrointestinal stromal tumor (GIST) is a rare entity. A retrospective analysis of outcomes from a single institution to identify treatment strategies associated with improved outcomes. Records of patients with GIST of the rectum were retrospectively reviewed. Patient and tumor characteristics, treatment details, and outcome were evaluated. Compared with the trans-abdominal approach group, the local excision group patients had smaller size and lower location tumors (P < 0.05). Positive resection margin was an important hazard factor for DFS (OR, 7.63; P = 0.015). Among the patients with the tumor size >5 cm, those with preoperative Imatinib therapy had higher rate of a negative resection margin than those without (100% vs. 20%, P = 0.048). Among the patients with intermediate and high-risk tumors, those who received peri-operative Imatinib therapy had longer DFS compared with those without (61.3 ± 6.1 months vs. 20.2 ± 4.4 months, P = 0.030). The location of rectal GIST impacts the choice of resection type. Most patients with tumors within 5 cm of the anal verge can be treated with local excision. Positive resection margin is the independent hazard factor for poorer survival. Peri-operative Imatinib therapy is associated with a prolonged DFS in patients with intermediate and high-risk tumors.

Neoadjuvant Imatinib in Locally Advanced Gastrointestinal Stromal Tumors (GIST): The EORTC STBSG Experience

Preoperative imatinib therapy of locally advanced GIST may facilitate resection and decrease morbidity of the procedure. We have pooled databases from 10 EORTC STBSG sarcoma centers and analyzed disease-free survival (DFS) and disease-specific survival (DSS) in 161 patients with locally advanced, nonmetastatic GISTs who received neoadjuvant imatinib. OS was calculated from start of imatinib therapy for locally advanced disease until death or last follow-up (FU) after resection of the GIST. DFS was calculated from date of resection to date of disease recurrence or last FU. Median FU time was 46 months. The primary tumor was located in the stomach (55%), followed by rectum (20%), duodenum (10%), ileum/jejunum/other (11%), and esophagus (3%). The tumor resection after preoperative imatinib (median time on therapy, 40 weeks) was R0 in 83%. Only two patients have demonstrated disease progression during neoadjuvant therapy. Five-year DSS/DFS rates were 95/65%, respectively, median OS was 104 months, and median DFS was not reached. There were 56% of patients who continued imatinib after resection. Thirty-seven GIST recurrences were diagnosed (only 5 local relapses). The most common mutations affected exon 11 KIT (65%). Poorer DFS was related to primary tumor location in small bowel and lack of postoperative therapy with imatinib. Our analysis comprising the largest group of GIST patients treated with neoadjuvant imatinib in routine practice indicates excellent long-term results of combined therapy in locally advanced GISTs.

One-stage laparoscopic resection for a large gastric gastrointestinal stromal tumor and synchronous liver metastases following preoperative imatinib therapy: A case report

Laparoscopic partial gastrectomy without lymph node dissection has been accepted worldwide for the treatment of small gastric gastrointestinal stromal tumors (GISTs). However, the role of laparoscopic surgery in the treatment of large gastric GISTs remains under debate due to the risk of tumor spillage or rupture of the tumor capsule leading to peritoneal seeding. To the best of our knowledge, one-stage laparoscopic resection for a large gastric GIST and synchronous liver metastases following preoperative imatinib therapy has not been previously reported. Here, we present our initial experience of this method of treatment.

The effect of neoadjuvant Imatinib therapy on outcome and survival after rectal gastrointestinal stromal tumour

The study aimed to characterize the pathological and clinical response of rectal gastrointestinal stromal tumours (GISTs) to neoadjuvant Imatinib. The medical records of patients with rectal GISTs who were diagnosed and treated in five medical centres in Israel between January 2002 and January 2009 were retrospectively examined. Twelve patients who fulfilled the inclusion criteria of nonmetastatic rectal GIST for which preoperative neoadjuvant treatment with Imatinib was considered were suitable for enrollment. Of the 12 patients, nine received neoadjuvant treatment with Imatinib. The three patients who had immediate surgery were excluded. There were five men and four women with a median age of 63 years and a median follow up of 32 months. All tumours were located in the lower two-thirds of the rectum. One patient had a complete clinical response, six had a partial response and two had stable disease. Seven patients subsequently underwent surgery; six had an R0 resection and one had an R1 resection. Three patients had recurrence. There was no disease-related mortality. The reduction in both tumour size and mitotic activity during preoperative Imatinib therapy was significant. Preoperative Imatinib therapy can shrink large rectal GISTs, improving the chances of successful radical surgery and decreasing the risk of considerable morbidity.

Dramatic regression and bleeding of a duodenal GIST during preoperative imatinib therapy: case report and review

BackgroundGastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. The majority of GISTs is located in the stomach. Only 3-5% of GISTs are located in the duodenum associated with an increased risk of gastrointestinal bleeding as primary manifestation. With response rates of up to 90%, but complications like bleeding due to tumor necrosis in 3%, imatinib mesylate dramatically altered the pre- and postoperative therapy for GIST patients.Case presentationA 58-year-old female patient presented with acute upper gastrointestinal bleeding 2 weeks after a giant GIST of the duodenum had been diagnosed. Neoadjuvant imatinib therapy had been initiated to achieve a tumor downsizing prior to surgery. During emergency laparotomy a partial duodenopancreatectomy was performed to achieve a complete resection of the mass. Histology revealed a high-malignancy GIST infiltrating the duodenal wall. Adjuvant imatinib therapy was initiated. At follow-up (19 months) the patient is still alive and healthy.ConclusionGiant GISTs of the duodenum are rare and - in contrast to other localizations - harbour a higher risk of serious bleeding as primary manifestation. Tumor necrosis and tumor bleeding are rare but typical adverse effects of imatinib therapy especially during treatment of high-malignancy GIST. In GIST patients with increased risk of tumor bleeding neoadjuvant imatinib therapy should thoroughly be performed during hospitalization. In cases of duodenal GIST primary surgery should be considered as treatment alternative.

Gastrointestinal stromal tumor (GIST) of the rectum and pararectal space: A French Sarcoma Group (FSG) retrospective review.

10055 Background: GIST of rectum and pararectal space are rare entities with limited clinicopathologic series reported. We conducted a retrospective analysis of rectal GIST during the past 9 years in FSG centers. Methods: Patients (pts) with rectal GIST cases were identified in two ways: (1) advanced/metastatic rectal/pararectal GISTs enrolled in the BFR14 trial (36 pts); and (2) a separate group of 45 pts reported via survey from 14 FSG centers. Results: Characteristics for the BFR14 group showed male predominance (57%), median age 62 years, majority of pts (68%) had metastatic GIST. All pts received imatinib (IM), 65% underwent resection of the primary tumor. With a median follow up (FU) of 29 months, the 2-years PFS and OS are 58% and 87% respectively. In the survey group, all rectal GISTs were localized except 5 with metastatic disease. Men were predominant (66%), tumors ranged from asymptomatic (discovered incidentally in 9 pts), to large masses causing pelvic symptoms (pain, bleeding, constipation; in 28 pts), median tumor size was 65 mm (6-130). Twelve pts received preoperative IM therapy (median duration 7 months; 2-10); 8 (67%) experienced PR, 3 minor responses and one had SD. IM treatment allowed sphincter conservation in 7 cases. 40/45 pts underwent surgery. Anterior resection was performed in 13 pts, transanal/transperineal resection in 13 pts, and amputation in 11 pts. Tumor resections were mostly R0/R1 (22/13, 87%), without tumor rupture (72%). 13 tumors had ≤ 5 mitotic index and 21 had >5 mitotic index. Mutations, mostly in exon 11, were documented in 9 of 12 cases. Ten pts received adjuvant IM. With a median FU of 55 months (1-170), 10 pts have died. Twenty pts (50%) developed local recurrence [18 (72%) after surgery alone, 2 (13.5%) after resection combined with preoperative ± postoperative IM], and 8 secondary metastases, in a median of 17 months (5- 87). Conclusions: Preoperative IM treatment results in substantial tumor shrinkage in most pts and facilitates function-preserving surgery. Since rectal GISTs have a high risk for local relapse, postoperative IM should be systematically considered for these pts. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis, Pfizer, PharmaMar Amgen, Novartis, Pfizer, PharmaMar Bayer

Nanoneoadjuvant Therapy of Gastrointestinal Stromal Tumor (GIST)

Although it is clear that imatinib mesylate is highly effective in metastatic gastrointestinal stromal tumor (GIST), its optimal perioperative use is undefined. McAuliffe and colleagues now report a provocative study of a brief preoperative imatinib therapy. Seventeen patients were randomized to receive 3, 5, or 7 days of 600 mg imatinib, underwent surgery immediately thereafter, and then received 2 years of adjuvant imatinib therapy. Radiologic, histologic, and surgical outcome measures were analyzed. By the authors’ criteria, the response rate to FDG-PET (F-fluoro-2-deoxy-D-glucose positron emission tomography) and dynamic computed tomography (CT) was approximately 70% after transient preoperative therapy. There was no mention of change in tumor density by CT, which has been the basis of the Choi criteria developed at their institution. Presumably it was unchanged. Pathologic analysis of 10 preoperative biopsy samples and their matched surgical specimens revealed that apoptosis (the primary endpoint of the trial) increased by a mean of 12%. Early apoptosis has been shown previously in a mouse model of GIST after treatment with imatinib. Because early necrosis can be observed by TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) staining as well, in the present study, it is uncertain whether apoptosis is the only mechanism responsible for tumor death. Interestingly, histologic cytoreduction was not apparent despite the high radiologic response rate. Whether patients without a radiologic response had evidence of apoptosis was not stated. One item that will be of primary practical interest to surgeons is the fact that there was no difference in intraoperative blood loss, even though blood flow was reduced as measured by dynamic CT. This is surprising and disappointing. It may just reflect patient selection, small sample size, and the constraints of using historical controls. The authors also conclude that compared with historical controls who did not receive neoadjuvant imatinib, there was no change in perioperative morbidity. However, the complication rate was 18% in the present series, versus 44% in controls (P = .1). Similarly, postoperative complications did not appear to be altered in 45 patients with GIST treated with neoadjuvant imatinib on a Radiation Therapy Oncology Group phase II trial. Larger studies with proper controls are needed to identify whether neoadjuvant imatinib alters the rate of surgical complications. Long-term outcome was assessed, although the analysis is limited by the mixture of patients with primary (n = 13) and metastatic (n = 6) disease. Recurrence-free survival exceeded 90% at 1 year, consistent with the preliminary data from the American College of Surgeons Oncology Group intergroup Z9001 adjuvant trial and metastatic GIST trials. Although the current trial has primarily provided biologic and radiologic correlative information regarding neoadjuvant imatinib therapy in GIST, can the data be used in clinical practice? Is there a rationale to treat patients with resectable primary GIST for 1 week with neoadjuvant imatinib if intraoperative blood loss and perioperative morbidity are not affected? In patients with resectable primary GIST, there is a theoretical possibility that intraoperative tumor dissemination may be decreased by diminished tumor blood flow. This unproven benefit must be weighed against the rare occurrence of intraperitoneal tumor rupture induced by imatinib therapy. As more targeted drugs are developed, the other principal reason to use nanoneoadjuvant therapy for resectable GIST could be to select the most effective drug for adjuvant therapy in a given patient. However, until there is a strong clinical rationale, nanoneoadjuvant therapy for GIST may otherwise have a short life span. Society of Surgical Oncology 2009 Published Online: 24 January 2009

Neoadjuvant imatinib in a locally advanced gastrointestinal stromal tumour (GIST) of the rectum: a rare case of two GISTs within a family without a familial GIST syndrome

Gastrointestinal stromal tumours are rare tumours of the gastrointestinal tract. We describe the case of a 57-year-old man with a locally advanced gastrointestinal stromal tumour of the rectum. We started Gleevec. The pathological examination documented a complete pathological response. An already described mutation in KIT exon 11 was observed in the gastrointestinal stromal tumour of the rectum. At the same time as the treatment of our patient, his brother received a neoadjuvant therapy for a locally advanced rectal adenocarcinoma. During the surgical procedure, a gastric lesion was excised and the pathological examination showed a low-grade gastrointestinal stromal tumour. We analysed DNA extracted from the tumoral mass and normal tissue of both patients. No mutations, either in KIT or in PDGFRA, were detected in the subserosal stomach gastrointestinal stromal tumour. After 18 months, both patients are free from recurrence. Our clinical case suggests that preoperative imatinib therapy may enable radical surgery in patients with an inoperable disease.

Surgical Management After Neoadjuvant Imatinib Therapy in Gastrointestinal Stromal Tumours (GISTs) with Respect to Imatinib Resistance Caused by Secondary KIT Mutations

In metastasized GISTs, resistance to imatinib after initial tumour response has been associated with observation of secondary mutations in the activation loop of KIT. The aim of the current study was to evaluate the tumour response and observance of secondary KIT mutations in a case of GIST undergoing neoadjuvant imatinib therapy. We report on a case of an initially unresectable gastric GIST with curative resection after 10 months of neoadjuvant imatinib therapy. Mutation analysis of KIT was performed on a pretherapeutic biopsy specimen, as well as on the resected tumour specimen. The pretherapeutic biopsy revealed cKit positive tumour cells with mutation of KIT exon 11 Del 560-576. The remaining tumour mass after neoadjuvant imatinib therapy almost exclusively consisted of hypocellular myxohyalinale stroma with rare microfoci of cKit positive tumour cells. Laser microdissection of several tumour microfoci revealed two additional point mutations located in the activation loop of KIT exon 17, C809G and N822Y, each observed separately in a distinct microfocus. Neither of these two point mutations has been reported in a GIST so far. Neoadjuvant imatinib therapy successfully reduces tumour size in GISTs. Since resistance relevant secondary mutations of the activation loop of KIT may be observed after neoadjuvant imatinib therapy, the time elapse with preoperative imatinib therapy should be chosen as short as curative tumour resection or function sparing surgery can be carried out. The determination of the optimal time point for surgery is therefore a critical event and will be discussed.