1. Current Management of Gastrointestinal Stromal Tumor (GIST) Joint Hospital Surgical Grand Round Dr. Tony Cheung PYNEH

2. Gastrointestinal Stromal Tumor Neoplasm of interstitial Cajal cells 3000-6000 cases/ year in the US Equal prevalence in male and female

4. Landmark discovery 1998  Majority of GIST have oncogenic gain-of-function mutations of the KIT receptor tyrosine kinase Hirota S et al. Science 1998;279:577–580. 2001  Imatinib (Gleevec) KIT tyrosine kinase inhibitor (TKI) Joensuu et al. N Engl J Med 2001;1052:1052–1056.

5. CXR OGD EUS CT PET

6. Investigations CXR OGD EUS  look for size, irregular borders, echogenic foci, cystic spaces Gastrointest Endosc 2003;57: 469–474. Med Clin North Am 2005;89:139–158, viii. Contrast CT  for size and anatomical location  determine features of GIST – well vascularized, necrotic centre, heterogeneous appearance PET  identify metastatic disease  monitor response to medical tx

7. Risk Stratification of GIST Miettinen et al. Am J Surg Pathol 2005;29:52 – 68. ClassificationSizeMitotic rate (/50 HPF) Prognosis Benign≤ 2cm≤ 5No tumor related mortality Very low malignant potential 2-10cm< 5< 3% recurrence Uncertain or low malignant potential ≤ 2cm> 5No reported recurrence Low to moderate malignant potential > 10cm or 2-5cm ≤ 5 or > 5 12-15% High malignant potential> 5cm> 549-86%

8. Management Primary GIST Advanced / Metastatic GIST

9. Localized GIST Goal of operation  Complete macroscopic resection with an intact pseudocapsule  Negative microscopic margin (R0 resection) If tumor rupture  associated with high risk of intraabdominal dissemination of tumor cells and recurrence However, no additional benefit of wide resection of gastric GIST to obtain generous negative resection margin

10. Laparotomy OR Laparoscopy

11. Laparotomy R0 resection options  Wedge resection, segmental resection  Extensive resection  En bloc contiguous visceral resection Method of choice for all non-gastric GISTs

12. Laparoscopy < 5cm tumor for stomach GIST Laparoscopic wedge resections of stomach GIST Otani et al. Surgery 2006;139(4):484–492. No series on long term outcome with laparoscopy for non-stomach GIST

13. adapted from Otani et al. Surgery 2006;139(4):484–492.

14. But … 5-year overall survival despite negative resection margin  42-52% Crosby et al. Ann Surg Oncol 2001;8(1):50–59. Neoadjuvant or adjuvant use of tyrosine kinase inhibitors

16. Advanced / Metastatic GIST 1. Imatinib alone 2. Imatinib + Cytoreductive surgery

17. Nature of GIST Metastatic spread  peritoneal cavity  liver  uncommonly regional lymph nodes Large GISTs tend to displace rather than invade adjacent organs Miettinen et al. Am J Surg Pathol 2005;29:52–68.

18. Imatinib alone Outcome 1. Response 2. Primary resistance 3. Secondary resistance

19. Treatment response of Imatinib for Advanced unresectable GIST TrialPhaseDoseObjective response (PR + CR, %) Tumor control (PR + CR, %) EORTCI400-800mg6390 EORTCII400mg BD7189 EORTCIII400mg daily5082 EORTCIII400mg BD5486 US-FinnishII400mg daily6683 US-FinnishII600mg daily6683 US- Canadian III400mg daily4875 US- Canadian III400mg BD4874

21. Time response to Imatinib Verweij et al. Lancet 2004;364(9440):1127 – 1134.

22. Overall survival using Imatinib Verweij et al. Lancet 2004;364(9440):1127 – 1134.

23. Response Overall disease control in 70-85% of patient Median progression-free survival is 20- 24 months Overall survival time following imatinib therapy > 36 months

24. Primary resistance / Secondary resistance Do not achieve stable disease Progress within 6 months of initial objective response Develop one or more sites of disease progression after 6 months of measurable benefit

25. Imatinib then surgery Recommended timing: 1. when maximal response to TKI observed 2. after at least 6 months of TKI treatment Optimal time interval from start of TKI to surgery is unclear Minimal tumor shrinkage noted after 9 months of imatinib DeMatteo et al. Ann Surg 2007;245(3):347–352.

26. Resection rates during surgery for advanced GIST after TKI therapy High rate of R0/ R1 after TKI therapy

27. Surgical candidates ongoing response limited disease progression evolving necrosis or impending emergency Non surgical candidates generalized progression

28. Surveillance Surveillance CT thorax/ abdomen/ pelvis q3- 6months for 1 st 5 years, then annually PET not routinely needed Chandrajit et al. J Gastrointest Surg (2008) 12:1592–1599

29. NCCN guideline Feb 2008

30. Thank you!