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Gastrointestinal Stromal Tumors (GISTs) Efraim Idelevich, MD, PhD Gastro-Intestinal Oncology Unit Kaplan Medical Center GISTs Originally classified as other tumors: leiomyoma, leiomyoblastoma, leiomyosarcoma or schwannomas 1998- the discovery of gain-of-function mutations in the c-KIT proto-oncogene in GISTs that allowed GISTs to be distinguished reliably from these other histopathological subtypes of GI tumors GISTs The most common mesenchymal neoplasm of the GI tract. 0.1%-3% of GI malignant tumors Recently described as a distinct clinical and histopathological entity: Type of sarcoma, a tumor of mesenchymal (connective tissue) origin Epidemiology 4000-6000 new cases in the USA each year with annual incidence of 11-14 per 106 Occur mostly in patients with a median age of 60 years (40-80) No predilection for either gender Familial GISTs- autosomal dominant Type I neurofibromatosis (7% mostly in the small intestine without KIT mutations) Carney triad (GISTs + paraganglioma +pulmonary chondroma) GIST: Involved Sites Occurs anywhere in GI tract/abdomen Site Incidence % Gastric 60-70 Small intestine 20-30 Colon <5 Other (omentum, mesentery, esophagus) <5 Clinical Presentation Often asymptomatic, especially early in tumor development, discovered incidentally by CT or endoscopy Symptomatic: Signs/symptoms related to location of tumor – Vague GI pain or discomfort – GI hemorrhage – Anorexia, weight loss, nausea, anemia, and additional GI complaints Diagnostic studies CT – for initial evaluation and surveillance for recurrence EUS – determines size and extent of the tumor FDG-PET – reveals small metastases and establish baseline metabolic activity and assess therapy response Routine use of PET for surveillance after resection is not yet recommended 8 9 Histopathology of GIST: Biological Markers Used in Diagnosis of GIST GISTs positive for – CD117 (c-Kit receptor tyrosine kinase) • Positive in >95% – CD34 (mesenchymal/haematopoietic precursor cell marker) • Positive in 60% to 70% – Vimentin and smooth muscle actin • Positive in 15% to 60% • DOG1 – Desmin – S-100 (rare- in small intestine 10%) – Keratin (rare 10%) CD117 (c-Kit)–positive staining GIST The need for a biopsy is debatable FNA- cytologic morphology immunohistochemistry PCR analysis for KIT mutations FNA- not consistently diagnostic FNA- controversial due to risk of rupture and dissemination Resectable lesion in the absence of metastatic diseasea preoperative diagnosis may be unnecessary If diagnosis would impact the extent of resection or if unresectable or metastatic disease is present , biopsy is warrant Biopsy should be open or by endoscopy and not percutaneous Traditional Treatment Options Pre-Imatinib Mesylate (Glivec) Surgery is primary treatment modality for GISTs – 5-year survival 50% to 65% – Recurrence have been reported up to 20 years after surgery If incomplete resection/metastatic at presentation – Median survival <1 year – 5-year survival <35% 14 Management of localized disease Surgical resection – complete gross resection with preservation of an intact pseudocapsule without any tumor rupture Segmental resection with negative microscopic margins is the preferred intervention Laparoscopic resection cannot be recommended routinely yet Routine lymphadenectomy is not recommended Endoscopic resection of small GISTs is still controversial due to its inherent risks of positive margins and tumor spillage Is adjuvant treatment recommended? Imatinib (Glivec) Small molecule tyrosine kinase inhibitor with activity against ABL , BCR-ABL , KIT , PDGFRA , PDGFRB and CSF1R Its structure mimics ATP and it binds competitively to the ATP binding site of the target kinases Imatinib Mesylate: Mechanism of Action Imatinib mesylate occupies the ATP binding pocket of the c KIT kinase domain c KIT This prevents substrate phosphorylation and signaling A lack of signaling inhibits Imatinib mesylate P ATP P P P proliferation and survival SIGNALING Savage and Antman. N Engl J Med. 2002;346:683. 19 20 21 22 23 Survival according to tumor size 25 26 27 28 29 30 31 32 33 Neoadjuvant Imatinib in primary GISTs Still investigational May be use to downstage primary or metastatic disease before surgery many reports have been published of this approach to convert an unresectable mass to one that is surgically approachable, or to reduce the morbidity of a procedure The use of neoadjuvant imatinib, with or without adjuvant imatinib, to reduce or eradicate micrometastatic disease is also being assessed _______________________ _______________________ ___________ 36 ____________________ 37 38 39 40 41 42 43 44 45 Conclusions Surgery in M1 patients still an individual decision. No data from randomized or prospectively controlled yet available Residual tumor resection is safe Resection of progressive tumor is less rewarding Multifocal resection is not recommended without considering the patient’s personal situation Our experience with systemic therapy is: it more often avoids emergency surgery 47 48 Resistance to Imatinib Primary resistance : no achievement of stable disease or progressing disease within 6 months of an initial clinical response (KIT exon 9 mutation or no detectable kinase mutation – wild-type tumors) Secondary resistance: disease progression after more than 6 months clinical response (new acquired kinase mutation in KIT or PDGF-R that interfere with Imatinib activity) Dose escalation of imatinib is the first step Use of other kinase inhibitors (Sunitinib) Surgery, radiofrequency ablation or hepatic artery chemoembolisation Continuous vs. Intermittent Imatinib in Advanced GIST Prospective multicenter phase III Imatinib treatment study: continuous vs. interrupted (46 patients randomized to two groups) After 3 months: 0 and 5 (21%) patients had reprogression respectively Conclusion: Advanced GIST patients stopping Glivec experience frequent re-progression at 3 months Based on these results imatinib should not be discontinued ASCO 2004 SUTENT (Sunitinib Malate) Capsules Conclusions: SUTENT in GIST Final thoughts Neoadjuvant treatment with IM is still investigational Adjuvant treatment with IM is “standard of care” for high (moderate) risk recurrence GIST (3 year and >) Metastatic and unresectable GIST should be treated with IM (genotype evaluation is suggested) Retrospective studies have defined the subset of pts most likely to potentially benefit from “adjuvant cytoreductive surgery” Benefit of cytoreductive surgery in pts on SU is less clear 55 Thank you