© 2007 European Society for Medical Oncology
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Follow up of three cases after adjuvant treatment of high risk gastrointestinal stromal tumors with Imatinib
introductionGastrointestinal stromal tumors (GIST) are the most frequent mesenchymal tumors of the gastrointestinal tract. GIST have been shown to arise from interstitial cells of Cajal, the pacemaker cells of the gut. In fact, 95% of GIST immunohistologically stain positive for kit (CD117), and constitutive activation of the intracellular kinase of kit, or PDGF-RA is supposed to be the key for tumorigenesis in GIST [1, 2].
Surgery is the primary therapy of choice and for a long time has been the only effective therapy for GIST with overall 5 years survival rates of 45-55% until 2001 when Imatinib, a small molecule inhibiting the kinase activity of c-kit, PDFG-RA, and BCR-ABL was recognized to be highly effective in metastasized GIST [3–5] and revolutionised the treatment of metastasized and/or unresectable GIST [3–5].
However, an uncertainty remains whether an individual tumor behaves benign or whether it has the potential for metastatic spread. To date, tumor size and the mitotic index shape the risk sheets applied in clinical practice [6]. In fact, local recurrence and/or metastatic spread after surgery have been seen in 40% to 90% of all cases treated surgically [3, 4, 7].
Imatinib has dramatically improved the life expectancy of patients with advanced GIST. The availability of Imatinib has given rise to the question whether patients with high risk of recurrence after a R0-resection of a GIST should be treated to prevent recurrence. For this purpose first study protocols became available [8].
Here we report a series of three patients with high risk GIST who were treated before clinical studies were initiated. As far as we know it is the first report on patients with high risk GIST who underwent resection of the tumor with adjuvant treatment with imatinib for at least 6 months.
patients
patient 1
A 67 year old male patient with altered stool habits had a truecut biopsy of a rectal tumor that revealed a GIST probably of the rectum with infiltration of the prostate and the periprostatic tissue requiring an evisceration of the small pelvis to achieve a complete resection performed in August 2002. The final histopathology revealed a c-kit-positive GIST of the rectum 7 cm in diameter with a proliferation index of 15%. Sequencing analysis of c-kit detected deletion of codons 558 and 559 in exon 11. Staging including abdominal ultrasound, computertomography scans of the chest and of the abdomen were negative. Because of the high risk according to Fletcher and because of the infiltrative growth of the tumor, adjuvant treatment with 400mg of imatinib daily was started and continued for 26 months until January 2005. In January 2005 a FDG-PET scan was performed that was negative. Thereafter, Imatinib treatement was stopped and the patient was surveyed every three months (including a FDG-PET scan three months and six months after ending Imatinib treatment). Twelve months later in January 2006 local tumor recurrence and metastases in the liver and bone were detected (spine, thighbone, multiple ribs) by computertomography scans, abdominal ultrasound, FDG-PET and bone scintigraphy. Imatinib treatment was started again (400mg daily). Follow up performed every 3 months showed a stable disease up to date (April 2007).
patient 2
A 68 year old male patient presented at a nearby hospital in April 2003 with persistent abdominal pain and a weight loss of 10 kg. A computertomography scan of the abdomen showed a large cystic mass in the upper left abdomen. During explorative laparotomy a large cystic GIST of the stomach which ruptured during surgery was removed. The diameter of the tumor was 21cm and the mitotic index was 15 mitoses per 10 HPF classifying it as a high risk GIST according to Fletcher. By sequencing of c-kit a deletion of the last 6 bp of intron 10 and the first 25 bp of exon 11 were found in the tumor. Adjuvant treatment with 400 mg of Imatinib daily was started and performed for 20 months. Follow up during and after treatment was performed every 3 months. To date (April 2007), the patient is free of tumor recurrence 28 months since discontinuation of Imatinib.
patient 3
A 63 year old male patient presented with abdominal pain in June 2003 that was ascribed to an abdominal tumor which had been detected by ultrasound. During laparotomy the tumor was found to be attached to the ileum. It was completely removed, histopathological analysis revealed a c-kit-positive high risk GIST of the ileum, 11cm in diameter with 11 mitoses per 50HPF. No metastases were detected by abdominal ultrasound and computertomography scans. Sequencing of c-kit detected a mutation in exon 11 (deletion of codon 579).
Adjuvant treatment with 400 mg of Imatinib daily was started and continued for 6 months, follow up was performed every 3 months. Twenty months after discontinuing treatment peritoneal metastases were detected by abdominal ultrasound. Laparotomy was performed and visible metastases were removed. Imatinib treatment (400mg) was started thereafter and to date, April 2007, no new metastases could be detected.
discussion
While surgery is still the first line therapy for primary not metastasized high risk GIST up to 90% of patients after a surgical R0 resection, however, have local tumor relapses and/or metastases [3, 4, 7]. As high risk patients develop local relapse and/or metastases and five years survival rates are below 55% the question arose whether or not high risk patients should be treated with imatinib after surgery.
Before study protocols became available we started to treat patients with a high probability of recurrence according to criteria established in retrospective analysis.
We report three cases of not metastasized high risk GIST managed by curative surgical R0-resection. Patients had primary GIST of the rectum, of the small intestine and of the stomach. In all cases PCR-analysis of the c-kit-gene showed c-kit mutations in exon 11. Patients obtained adjuvant treatment with 400 mg imatinib daily for 26, 20 or 6 months. In the first and in the third case tumor recurrence was detected 12 months and 20 months after the treatment had been stopped. The patient with GIST of the stomach who even had intraoperative tumor rupture is still free of tumor 18 months after discontinuing treatment.
This small series of patients indicates the possibility of recurrence in spite of quite long adjuvant treatment. This assumption could be supported by case reports [9], where treatment with imatinib was performed more in palliative intention than in adjuvant. Data on exact patterns for the recurrence after surgery as well as factors to identify patients who need a long term treatment after surgery are still rare and in urgent need.
Department of Gastroenterology and Endocrinology, Georg-August-University, Göttingen, Germany
* E-mail: gramado{at}med.uni-goettingen.de
References
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