1. Gastrointestinal Stromal Tumors Twelfth 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

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

6. 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

8. 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.

9. Gastrointestinal Stromal Tumors Hospital course: Underwent re-exploration and pylorus preserving Whipple on 10/27/03. Findings – mass in 2 nd 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.

10. Gastrointestinal Stromal Tumors What are they? 1. Soft tissue sarcomas 2. Arise from interstitial cells of Cajal 3. Represent 0.1% - 3% of GI cancers 4. Represent 5% of all soft tissue sarcomas 5. 10% - 30% are highly malignant 6. c-kit or PDGFRA positive tumors Int J Cancer 107:2003

11. 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

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

13. Gastrointestinal Stromal Tumors Risk of Metastases Risk groupSizeMitotic count Very low<2 cm<5 per 50 HPFs Low2-5 cm<5 per 50 HPFs Intermediate<5 cm6-10 per 50 HPFs 5-10 cm<5 per 50 HPFs High>5 cm>5 per 50 HPFs >10 cmany mitotic rate any size>10 per HPFs

14. 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

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

16. 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

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

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

19. 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

20. 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

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

22. 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.

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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.

30. 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

31. 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

32. 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

33. 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.

34. 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?

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

36. 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

37. 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

38. 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

39. 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

40. 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

41. Gastrointestinal Stromal Tumors Thank-you