|Year : 2018 | Volume
| Issue : 4 | Page : 162-166
Surgical intervention of a giant gastric gastrointestinal stromal tumor following neoadjuvant therapy with imatinib
Chien-Yang Wang1, Kong-Han Ser1, Wai-Sang Kuan2, Wei-Jei Lee1
1 Department of Surgery, Division of General Surgery, Min-Sheng General Hospital, Taoyuan, Taiwan
2 Department of Pathology, Min-Sheng General Hospital, Taoyuan, Taiwan
|Date of Submission||05-Jun-2017|
|Date of Decision||27-Sep-2017|
|Date of Acceptance||21-Dec-2017|
|Date of Web Publication||22-Aug-2018|
Dr. Chien-Yang Wang
Number 168, Jingguo Road, Taoyuan District 330, Taoyuan City
Source of Support: None, Conflict of Interest: None
Gastrointestinal stromal tumors (GISTs) treatment has improved remarkably in recent years. However, giant and unresectable lesions could still be challenging, especially from the surgical aspect. We reported a case of a 44-year-old male patient who complained about abdominal pain and distention. Computed tomography scans, upper GI endoscopy, and tissue biopsy proved the diagnosis of a giant GIST which was considered unresectable. With the aid of neoadjuvant imatinib therapy, the tumor shrank tremendously, and we successfully performed en bloc resection with clean margins. Therefore, we suggested combining imatinib therapy and surgery in managing giant and unresectable GIST lesions.
Keywords: Gastrointestinal stromal tumor, imatinib, neoadjuvant therapy
|How to cite this article:|
Wang CY, Ser KH, Kuan WS, Lee WJ. Surgical intervention of a giant gastric gastrointestinal stromal tumor following neoadjuvant therapy with imatinib. Formos J Surg 2018;51:162-6
|How to cite this URL:|
Wang CY, Ser KH, Kuan WS, Lee WJ. Surgical intervention of a giant gastric gastrointestinal stromal tumor following neoadjuvant therapy with imatinib. Formos J Surg [serial online] 2018 [cited 2020 Oct 24];51:162-6. Available from: https://www.e-fjs.org/text.asp?2018/51/4/162/239557
| Introduction|| |
Gastrointestinal stromal tumors (GISTs), originating from the interstitial cells of Cajal, can be found throughout the GI tract. They are relatively rare, but the most common mesenchymal malignancies that arise in the GI tract, mostly found in the stomach and small intestine., The symptoms of GISTs are nonspecific and depend on the size and location of the lesion including GI tract bleeding, pain, general malaise, and palpable mass in large lesions. The principal treatment for GISTs is complete resection to remove the tumor. However, huge GISTs could still be challenging for surgeons due to the potential involvement of crucial structure and difficulty in maintaining a clear resection margin. In recent years, with the development of imatinib as novel target therapy which could inhibit KIT signal transduction pathway, downstaging the tumor is possible preoperatively. Surgeons have higher successful rate in complete resection of lesions that were considered unresectable before.,
| Case Report|| |
A 44-year-old male patient came to our hospital complaining about abdominal pain in the past 2 days. He also stated that he had progressive abdominal distention with poor digestion lasting 2 months. A physical examination revealed a low-grade fever and distended upper abdomen with a huge hard mass inside. The computed tomography (CT) scan of the abdomen [Figure 1] showing one huge intra-abdominal mass over the central-to-left abdomen which encased major vascular structure along with fluid collection inside the tumor with the space connecting to gastric lumen. Both CT-guided and upper GI endoscopic biopsies were arranged, pathological report of both biopsies revealed spindle cell proliferation with cells positive for CD117 and CD34 protein, suggesting GIST. The mitotic count was about five or lower/50 high-power fields (HPFs) from the biopsied specimen. According to the size and the location, the tumor was deemed unresectable. Therefore, we prescribed imatinib for him as of neoadjuvant therapy, which started with 300 mg twice a day.
|Figure 1: Abdominal computed tomography scan at the point of diagnosis, showing giant mass occupying the abdominal cavity (arrow: Gastrointestinal stromal tumor mass)|
Click here to view
During the following 5 months, the patient had total four readmissions due to abdominal discomfort, GI tract bleeding, and minor side effects including nausea and vomiting, but he could tolerate the treatment quite well. The volume of the tumor mass was found shrinking tremendously (about 60%) in the following CT scans [Figure 2]. The largest diameter of the mass, which was 28 cm in length before the neoadjuvant therapy, shrank to about 22 cm in length, and the encasement of the major vessels also disappeared. The density of the mass also decreased, indicating the necrotic change of the GIST. After nearly 6 months of the treatment, the last CT scan showed that the tumor had shrunk to a resectable size. Therefore, the patient underwent an operation of en bloc resection of the tumor and surrounding tissues involved including the stomach, distal pancreas, spleen, and partial left colon. The total operation time was about 5 hours with no significant blood loss.
|Figure 2: Abdominal computed tomography scans followed months after initiation of neoadjuvant imatinib therapy, showing shrinkage of the gastrointestinal stromal tumor mass. (arrow: Gastrointestinal stromal tumor mass)|
Click here to view
After the operation, the patient recovered slowly but smoothly. One fever episode was noted on postoperative day (POD) 9. CT scan followed revealed some fluid accumulation over the operative field. With the suspect of abscess formation, pigtail catheter was inserted for drainage. After the drainage, no further fever episode occurred. The patient was discharged on POD 33. We started the adjuvant therapy with imatinib 200 mg twice a day after the discharge. Follow-up CT scan 3 months later showed no recurrence of the tumor, and the patient could tolerate the imatinib therapy well.
The surgical specimen measured 22 cm × 15 cm × 13 cm [Figure 3], which obvious myxoid and cystic change was found with hemorrhage and necrosis, originating from the stomach [Figure 4]. Free section margin and no lymph node metastasis were noted (American Joint Committee on Cancer, pT4pN0M0). Histologically, immmunohistochemistry demonstrated positive staining for CD117 and DOG-1 [Figure 5] while only partially positive for desmin, proving the diagnosis of GIST. The mitotic count was five or fewer/50 HPFs [Figure 6]. The presence of two small foci of neuroendocrine tumor was found incidentally in the pancreas specimen, measuring up to 2 mm (American Joint Committee on Cancer, pT1).
|Figure 3: A large mass including stomach, partial pancreas, spleen, and one segment of colon measured 22 cm × 15 cm × 13 cm|
Click here to view
|Figure 4: The tumor arised from subserosa of stomach. (MP: muscularis propria; S: subserosa; T: tumor)|
Click here to view
|Figure 6: The mitotic figure counts less than 5 per 50 high-power fields|
Click here to view
| Discussion|| |
The standard treatment of localized GISTs is complete surgical resection of the lesion with negative margins. However, lesions considered unresectable or incompletely resected usually led to poor outcomes before the introduction of imatinib. Median survival times ranging from 10 to 20 months and a 5-year survival of <10% was reported. Since the introduction of tyrosine kinase inhibitor agents including imatinib, sunitinib, and regorafenib, the treatment strategy of GISTs has changed fundamentally. In locally advanced inoperable and metastatic GISTs, imatinib is the standard treatment. Preoperative imatinib administered as neoadjuvant therapy in locally advanced disease could decrease the risk of tumor rupture and possibility of incomplete resection, as a result of lowering the chances of tumor cells spillage into the peritoneal cavity and the rate of relapse. Stiekema et al. reported a consecutive series of 47 patients surgically treated for gastric GISTs showing that patients receiving preoperative imatinib had major reduction in tumor size. Median duration of preoperative imatinib treatment for 8.4 months led to a 33% reduction in tumor size. Shrikhande et al. analyzed 29 patients who were administered neoadjuvant imatinib for borderline resectable and locally advanced GISTs followed by surgery. The median duration of neoadjuvant imatinib administration was 8.5 months, and the response rate with neoadjuvant imatinib was 79.3%. They concluded that although surgery is still the standard treatment of GISTs, neoadjuvant imatinib for locally advanced GISTs is a safe concept for downsizing, improving resectability, and aiding organ-preserving surgery. In our case, the tumor was inoperable at the time of diagnosis due to the involvement of important vascular structure such as portal vein and superior mesenteric vessels. After 6 months of neoadjuvant imatinib treatment, about 60% reduction in tumor size was noted. The encasement of the great vessels also disappeared, which led to complete resection. Our result was comparable to the previous studies.
The recommended starting dose of imatinib is 400 mg/day, which could be escalated to 800 mg/day if necessary. In 2004, Verweij et al. reported a randomized trial with 946 patients randomly being allocated imatinib 400 mg either once or twice a day. The result showed that although 400 mg/day would be sufficient for the tumor response, 800 mg/day could achieve significantly longer progression-free survival. Blanke et al. reported a study in 2008 randomly assigning patients to 400 or 800 mg/day. While no significant difference was noted in response rates or overall survival between the two groups, it was found that 33% of patients who were crossed over to the high-dose regimen, after disease progression on the standard dose, achieved either an objective response or stable disease. In 2009, Eisenberg et al. conducted a phase II study evaluating safety and efficacy of neoadjuvant imatinib (600 mg/day) for patients with primary GIST or the preoperative use of imatinib in patients with operable metastatic GIST. The estimated 2-year overall survival rate was 93% and 91% for patients with primary GIST and those with recurrent or metastatic GIST, respectively. The estimated 2-year progression-free survival rate was 83% and 77%, respectively. Complications of surgery and imatinib toxicity were also minimal. Considering the tumor size, the extension of the lesion, patient's age, and performance status, we decided to initiate the imatinib therapy with 600 mg/day in our patient although no evidence has shown that larger dose would guarantee more significant improvement so far according to the report by Blanke et al. in 2008. Nevertheless, if progressive GIST lesions are found under the dose of 400 mg daily, escalation of imatinib to 600 mg or 800 mg daily may still show some benefit. Furthermore, Debiec-Rychter et al. in 2006 reported that patients with advanced GISTs presenting KIT exon 9 mutant would benefit the most from the 800 mg daily dose of imatinib for longer progression-free survival and overall survival comparing to 400 mg. However, our hospital lacked the facility to do the test of the mutations in KIT, so we could not provide the related information. Although with higher dose, no major side effect was found during the therapy, and remarkable response was noted in the following image studies. He was once admitted due to UGI bleeding, but the cause was much likely due to the tumor degrading change instead of hematologic side effect of imatinib. Furthermore, the treatment was not interrupted even during the admission, given that interruption of treatment could result in rapid disease progression in most patients with advance GISTs.
Regarding the duration of the postoperative therapy, complete resection only may not be enough for the cure of GIST, especially for high-risk GIST. Joensuu et al. conducted a randomized trial on 397 patients with high-risk GIST lesions surgically removed between 2004 and 2008. Compared with 12 months of adjuvant imatinib, 36 months of imatinib improved recurrence-free survival and overall survival. A recent study by Lin et al. on 234 patients even showed that both recurrence-free survival and overall survival improved significantly among high-risk patients receiving imatinib treatment for more than 5 years. For the postoperative treatment of our patient, it seems to be rational to keep adjuvant imatinib therapy for at least 5 years due to the high-risk pattern of his lesion. Furthermore, according to the National Comprehensive Cancer Network guidelines and recent studies, we will keep following abdominal and pelvic CT images 3 to 6 months at least 5 years after the operation to survey for possible recurrence.,
| Conclusion|| |
In conclusion, neoadjuvant therapy with imatinib could provide surgeons the opportunity to treat unresectable GIST lesions. Prolonged postoperative imatinib therapy is also recommended to reduce the risk for tumor relapse.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Connolly EM, Gaffney E, Reynolds JV. Gastrointestinal stromal tumors. Br J Surg 2003;90:1178-86.
DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF, et al.
Two hundred gastrointestinal stromal tumors: Recurrence patterns and prognostic factors for survival. Ann Surg 2000;231:51-8.
Reichardt P. Practical aspects of managing gastrointestinal stromal tumors. Monogr Gastrointest Stromal Tumors 2003;1:3-8.
ESMO/European Sarcoma Network Working Group. Gastrointestinal stromal tumours: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014;25 Suppl 3:iii21-6.
Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: Origin and molecular oncology. Nat Rev Cancer 2011;11:865-78.
Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, et al.
Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002;347:472-80.
Tielen R, Verhoef C, van Coevorden F, Gelderblom H, Sleijfer S, Hartgrink HH, et al.
Surgery after treatment with imatinib and/or sunitinib in patients with metastasized gastrointestinal stromal tumors: Is it worthwhile? World J Surg Oncol 2012;10:111.
von Mehren M, Randall RL, Benjamin RS, Boles S, Bui MM, Conrad EU 3rd
, et al.
Soft tissue sarcoma, version 2.2016, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2016;14:758-86.
Stiekema J, Kol S, Cats A, Yazdi AT, van Coevorden F, van Sandick JW, et al.
Surgical treatment of gastrointestinal stromal tumors located in the stomach in the imatinib era. Am J Clin Oncol 2015;38:502-7.
Shrikhande SV, Marda SS, Suradkar K, Arya S, Shetty GS, Bal M, et al.
Gastrointestinal stromal tumors: Case series of 29 patients defining the role of imatinib prior to surgery. World J Surg 2012;36:864-71.
Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, et al.
Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: Randomised trial. Lancet 2004;364:1127-34.
Blanke CD, Rankin C, Demetri GD, Ryan CW, von Mehren M, Benjamin RS, et al.
Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol 2008;26:626-32.
Eisenberg BL, Harris J, Blanke CD, Demetri GD, Heinrich MC, Watson JC, et al.
Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): Early results of RTOG 0132/ACRIN 6665. J Surg Oncol 2009;99:42-7.
Blanke CD, Demetri GD, von Mehren M, Heinrich MC, Eisenberg B, Fletcher JA, et al.
Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 2008;26:620-5.
Hislop J, Quayyum Z, Elders A, Fraser C, Jenkinson D, Mowatt G, et al.
Clinical effectiveness and cost-effectiveness of imatinib dose escalation for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours that have progressed on treatment at a dose of 400 mg/day: A systematic review and economic evaluation. Health Technol Assess 2011;15:1-78.
Debiec-Rychter M, Sciot R, Le Cesne A, Schlemmer M, Hohenberger P, van Oosterom AT, et al.
KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 2006;42:1093-103.
Blay JY, Le Cesne A, Ray-Coquard I, Bui B, Duffaud F, Delbaldo C, et al.
Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: The French sarcoma group. J Clin Oncol 2007;25:1107-13.
Joensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Schütte J, et al.
One vs. three years of adjuvant imatinib for operable gastrointestinal stromal tumor: A randomized trial. JAMA 2012;307:1265-72.
Lin JX, Chen QF, Zheng CH, Li P, Xie JW, Wang JB, et al.
Is 3-years duration of adjuvant imatinib mesylate treatment sufficient for patients with high-risk gastrointestinal stromal tumor? A study based on long-term follow-up. J Cancer Res Clin Oncol 2017;143:727-34.
Wada N, Takahashi T, Kurokawa Y, Nakajima K, Masuzawa T, Nakatsuka R, et al.
Appropriate follow-up strategies for gastrointestinal stromal tumor patients based on the analysis of recurrent interval and patterns. Digestion 2017;95:115-21.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]