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Gastrointestinal Stromal Tumors Twelfth GRW Symposium

Gastrointestinal Stromal Tumors Twelfth GRW Symposium. Surgical Grand Rounds 1-15-04. Gastrointestinal Stromal Tumors. Case Presentation HPI: 31yo male with a recent history of UGI bleed. EUS c/w duodenal mass. EUS bx – GIST tumor. Admitted OUMC 12/122/03

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Gastrointestinal Stromal Tumors Twelfth GRW Symposium

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  1. Gastrointestinal Stromal TumorsTwelfth GRW Symposium Surgical Grand Rounds 1-15-04

  2. Gastrointestinal Stromal Tumors Case Presentation HPI: 31yo male with a recent history of UGI bleed. EUS c/w duodenal mass. EUS bx – GIST tumor. Admitted OUMC 12/122/03 PMHX: Local excision of duodenal GIST in Oct 01 PE: Unremarkable except for well healed abdominal scar

  3. Gastrointestinal Stromal Tumors Hosp course: Underwent pylorus preserving Whipple on 12/12/03 with findings: Mass in second portion of duodenum, no gross tumor elsewhere. Post-op developed RUQ fluid collection, amylase poor, resolved. Patient did well and discharged on 12/23/03 Pathology: 3.0 cm malignant GIST, c-Kit positive, 1 of 7 nodes positive

  4. Gastrointestinal Stromal Tumors Postoperative plans: Referred for consideration of adjuvant Imatinib Mesylate (Gleevec)

  5. Gastrointestinal Stromal Tumors Case Presentation 2 HPI: 39 YO F transferred from outlying hospital 5 days S/P lap for UGI bleed with finding of duodenal mass. Bx c/w GIST tumor. Mass not resected. PMHx: Hepatitis C PE: Neg except for healing midline wound

  6. Gastrointestinal Stromal Tumors Hospital course: Patient had no further UGI bleeding. Was seen in consultation by Med/Onc who recommended D/C until role of neoadjuvant therapy could be defined. Ultimately recommended against neoadjuvant therapy.

  7. Gastrointestinal Stromal Tumors Hospital course: Underwent re-exploration and pylorus preserving Whipple on 10/27/03. Findings – mass in 2nd portion of duodenum without evidence of metastases. Pathology – 4.5 cm, hypercellular GIST tumor, c-Kit positive, no evidence of nodal metastases, uncertain malignant potential. Patient did well and discharged for follow-up by surgery and med/onc.

  8. Gastrointestinal Stromal Tumors What are they? • Soft tissue sarcomas • Arise from interstitial cells of Cajal • Represent 0.1% - 3% of GI cancers • Represent 5% of all soft tissue sarcomas • 10% - 30% are highly malignant • c-kit or PDGFRA positive tumors Int J Cancer 107:2003

  9. Gastrointestinal Stromal Tumors Tyrosine Kinase Receptors • 1 of 4 classes of cell-surface receptors • 1 of 2 types of protein kinases • Lack catalytic activity • Ligand binding forms dimeric receptor • Activates a cytosolic protein-tyrosine kinase

  10. Gastrointestinal Stromal Tumors • All are potentially malignant • 1st tumor to benefit from “targeted” therapy • Criteria to predict behavior tumor behavior • Size • Necrosis • Mitotic rate

  11. Gastrointestinal Stromal Tumors Risk of Metastases Risk group Size Mitotic count Very low <2 cm <5 per 50 HPFs Low 2-5 cm <5 per 50 HPFs Intermediate <5 cm 6-10 per 50 HPFs 5-10 cm <5 per 50 HPFs High >5 cm >5 per 50 HPFs >10 cm any mitotic rate any size >10 per HPFs

  12. Gastrointestinal Stromal Tumors • Incidence appears to be increasing • Mayo clinic study indicates incidence stable but diagnostic criteria changed • Median age at diagnosis 58 years (range 40-80 years ?) • 5 year survival variable (28 –60%) Ann Surg 231:2000

  13. Gastrointestinal Stromal Tumors Location • Stomach 54% • Small bowel 47% • Rectum 6% • Retroperitoneum 7% Clin Cancer Res 9(9):2003

  14. Gastrointestinal Stromal Tumors Presentation • Generally nonspecific • GI bleeding 50% • Abdominal pain pain 20-50% • Obstruction 10-30% • Asymptomatic 20% Int J Cancer 107:2003, Ann Surg 231:2000,Ann Chir Gynaecol 87:1998

  15. Gastrointestinal Stromal Tumors Genetics c-kit, a 145 kD transmembrane glycoprotein • Activating mutation usually at codon 11 • Constitutive ligand-independent activation of kinase

  16. Gastrointestinal Stromal Tumors Genetics Platelet derived growth receptor alpha (PDGFRA) • Tyrosine kinase activator • Similar to c-kit • Helps define GIST

  17. Gastrointestinal Stromal Tumors Treatment • Surgical excision is primary treatment option but recurrence rates are high • Resistant to standard chemotherapy regimens due to over-expression of efflux pumps (p-glycoprotein & MDR-1) • Radiation therapy limited by large tumor sizes and sensitivity of adjacent bowel

  18. Gastrointestinal Stromal Tumors Imatinib Mesylate • Orally bioactive tyrosine kinase inhibitor • Shown to be effective against GIST tumors in two trials in the US and Europe reported in 2001 & 2002 N Engl J Med 347:2002 Lancet 358:2001

  19. Gastrointestinal Stromal Tumors Studies • University of Chicago • Oregon University and Health Sciences • Washington Hospital Center • Johns Hopkins Hospitals

  20. Gastrointestinal Stromal Tumors University of Chicago • Retrospective study 1995-2002 • 57 patients • 96% c-kit positive • Curative resection in 50% • Treatment of metastatic disease 50% Wu, et al. Surgery. 2003;134(4): 656.

  21. Gastrointestinal Stromal Tumors University of Chicago Imatinib mesylate treatment • 29 patients treated for metastatic disease • 3 received adjuvant therapy after resection • Median follow-up 18 months

  22. Gastrointestinal Stromal Tumors University of Chicago Results • 23 (40%) patients alive and NED • 22 (39%) patients alive with disease • 7 (13%) patients died • 5 (10%) lost to follow-up • Overall survival 87% at 18 months

  23. Gastrointestinal Stromal Tumors University of Chicago Results in 26 patients with metastatic disease • All treated with Imatinib mesylate • 5 (2%) died • 22 (84%) stable disease or regression

  24. Gastrointestinal Stromal Tumors University of Chicago Imatinib mesylate adjuvant therapy results • Only 3 patients in adjuvant group • All considered “high risk” due to tumor characteristics • All NED with mean follow-up of 7 months • 1 “high risk” patient who refused adjuvant therapy developed liver mets at 9 months

  25. Gastrointestinal Stromal Tumors University of Chicago Toxicity of Imatinib mesylate • Generally well tolerated • Mild fatigue • Periorbital edema • Mild diarrhia • 2 deaths not due to disease not relate to therapy

  26. Gastrointestinal Stromal Tumors University of Chicago Study summary • No neoadjuvant data • Patients in “low risk”group with R0 resections did well • Patients treated with metastatic disease did well in short term • Adjuvant data group too small for analysis

  27. Gastrointestinal Stromal Tumors Oregon University Study • Prospective study of 127 patients in phase II multi-center trial of Imatinib mesylate • Evaluated relationship between mutation type (c-kit & PDGFR) and clinical outcome • Further evaluated codon mutation site and outcome • Evaluated in-vitro response to Imatinib • Evaluated clinical response to Imatinib Heinrich, et al. J Clin Onc, 1(23), 2003:4342.

  28. Gastrointestinal Stromal Tumors University of Oregon Study Results • Invitro responses differ with mutation and codon site • Clinical responses differ with mutation and codon site • May eventually allow even more directed therapy as newer drugs are developed

  29. Gastrointestinal Stromal Tumors Washington Hospital Center Study • Retrospective • 69 patients with compatible histology and c-kit positivity • Study purposes • Develop prognostic indicators • Establish the natural history of the tumor

  30. Gastrointestinal Stromal Tumors Washington Hospital Center Study Results • Tumor site • Even distribution between stomach and small bowel • Prognostic factors • Tumor size • Peritoneal cancer index • Completeness of cytoreduction

  31. Gastrointestinal Stromal Tumors Johns Hopkins • 38 tumors studied • Evaluated tumor suppressor genes • Assessed degree of hypermethylation House, et al. J Gastroint Surg, 7(8);2003:1004.

  32. Gastrointestinal Stromal Tumors Johns Hopkins • Hypermethylation of CpG-rich islands is common in human malignancies • Occurs in promotor area of gene • Can it be used to predict tumor behavior? • Does it explain resistance to Imatinib?

  33. Gastrointestinal Stromal Tumors Johns Hopkins • 38 tumors resected from 1989 to 2001 • All c-kit positive • 11 candidate tumor suppressor genes studied

  34. Gastrointestinal Stromal Tumors Johns Hopkins • 84% of tumors had hypermethylation of at least 1 gene • Multigene methylation seen in 42% of tumors • E-cadherin hypermethylation and absence of methylation of hMLH1 predicted early recurrence

  35. Gastrointestinal Stromal Tumors Summary • GIST tumors now well characterized • All have malignant potential • Complete surgical resection important • Metastatic disease responds to Imatinib • Role of neoadjuvant therapy unclear • Role adjuvant therapy unclear

  36. Gastrointestinal Stromal Tumors Currently Available Trials Neoadjuvant study • RTOG S-0132/ACRIN 6665 • Patients with recurrent or measurable peritoneal disease • 8 wks Imatinib followed by resection

  37. Gastrointestinal Stromal Tumors Currently Available Trials Adjuvant study EORTC 64024 • Patients with R0 resections eligible • Patients stratified according to risk factors • Patients randomized to either • Imatinib 400 mg/day X 2 years • Observation

  38. Gastrointestinal Stromal Tumors Currently Available Trials Adjuvant study ACOSOG Z9001 • Eligible patients • Complete gross resections • R0 or R1 (microscopic + margins) • Randomization arms • Imatinib 400 mg/day X 1 year • Placebo • Placebo patients with recurrence receive Imatinib for 2 years

  39. Gastrointestinal Stromal Tumors Thank-you

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