1. Surgical Approaches to GIST in the Era of Targeted Therapy
Kevin G. Billingsley, M.D.
Hedinger Professsor of Surgery
Chief, Division of Surgical Oncology
Oregon Health and Science University

2. Surgical Therapy for GIST
Surgery remains the only potentially curative therapy for GI stromal tumor
Resection is the treatment of choice for non metastastic GIST
Resection is appropriate in SELECTED patients with metastatic GIST

3. Overview Surgery for Localized GI Stromal Tumor
Gastric
Duodenal
Small Bowel
Other
Surgery for Locally advanced GIST
Surgery for Metastatic GIST

4. Gastric GIST

5. Gastric GIST is not adenocarcinoma
At least 5 cm margin
Lymphadenectomy is critical
Resect all nodes around the stomach possibly others
Wedge gastrectomy not appropriate
Total gastrectomy common
GIST
1 cm margin is acceptable
Lymphadenectomy not helpful
Wedge gastrectomy ideal for small GIST
Total gastrectomy only for massive GIST

6. Exophytic GIST: Only limited gastric resection necessary

7. Lesser curve GIST often requires an anatomic stomach resection

8. Anatomic stomach resection requires reconstruction
Loss of Pylorus
Rapid emptying of the stomach
Diarrhea
“Dumping” syndrome
Hyperosmolar fluid
in small bowel
Flushing,nausea

9. Locally advanced gastric GIST may involve multiple organs

10. Small Bowel GIST ( Non duodenal)

11. Limited small bowel GIST
Segmental bowel resection
No extended lymphadenectomy
5 cm margin not necessary (limited intramural spread)
Primary anastomosis
Consider other diagnoses that require a more extensive operation
Carcinoid tumor
Adenocarcinoma of the small bowel

12. Small bowel GIST may involve other organs

13. Duodenal GIST: Surgical Options
Segmental Duodenal Resection
Whipple Procedure

14. Procedure determined by relation ship to ampulla of vater

15. Pylorus Preserving Whipple
Mortality 2%
Morbidity 40%
10 day Hospital stay
Gastric Emptying
Pancreatic Leak/Fistula

16. Reconstruction after Whipple

17. Segmental resection of duodenum
Remove only the tumor and adjacent wall of duodenum
Procedure Must:
Not narrow duodenum
Obstruct ampulla of vater
Avoids complex Whipple reconstruction
For small duodenal GIST not at the ampulla

18. Laparoscopic Resection of GIST
Technically Feasible and safe in selected cases
Small tumors of the greater curve of the stomach
Small tumors of the small bowel

19. Laparoscopy Might be appropriate for gastric GIST <5 cm
Tumor must be placed into a protective bag to prevent port-site recurrence
Abdomen should be thoroughly explored
Consultation with a pathologist to ensure negative margins is encouraged
Associated with low recurrence rates
At 53 mos: no recurrences for tumors <4 cm
At 3 yrs: 92% of pts are disease free
Raut. J Gastrointest Surg. 2008;12:1592; Otani. Surgery. 2006;139:484; Novitsky. Ann Surg. 2006;243:738.

20. The locally advanced GIST

21. Surgical treatment of the large GIST
En bloc resection of tumor with adjacent organs.
Right Side tumors: Resection of duodenum, liver , gallbladder
Left Side tumors: Stomach, spleen, pancreas, diaphragm, adrenal

22. En Bloc Resection
Stomach, Spleen, tail of pancreas, possible splenic flexure of colon.

23. Preoperative Imatinib in Locally Advanced GIST
Neoadjuvant therapy has proven successful in other GI sites (esophagus, stomach, rectum)
May improve surgical margin control
May allow resection in “unresectable” patients

24. RTOG 0132 Eligibility Protocol > 5 cm KIT positive GIST
Metastatic/Recurrent GIST
Protocol
600mg/day Imatinib for 8-12 weeks
Resection
Eisenberg, B. J. of Surg. Onc. 99, 2009

25. RTOG 0132: Surgical Complications

26. RTOG 0132 Disease Control

27. RTOG 0132 Conclusions
Neoadjuvant Gleevec did not increase surgical complications
Minimal toxicity from therapy
Preoperative treatment not compared with postoperative adjuvant imatinib
Only 1 patient had disease progression

29. Imatinib and locally advanced GIST
For large, resectable GIST: Multivisceral en bloc resection
Borderline resectable lesions
Preoperative imatinib therapy
Surgery at approximately 4 months
Small group of “Unresectable” patients will be rendered resectable after imatinib therapy.

30. Surgical Therapy for Metastatic GIST
Surgical Therapy for Complications of Disease
Bleeding
Obstruction
Operation to treat the problem followed by systemic therapy
Surgery to reduce disease burden is more complicated

31. Management of Patients With Advanced GIST
Patients with unresectable or marginally resectable disease could benefit from preoperative TKI therapy
First line: imatinib
Second line: sunitinib
<5% of patients achieve complete pathologic response
Surgery is most effective in patients who achieve PR or SD but can be effective in patients with limited progressive disease
Resection should occur within 6-12 mos of starting therapy
Resection rates (R0/R1) following TKI therapy range from 46%- 91%
PR=partial response; SD=stable disease; TKI=tyrosine kinase inhibitor.
DeMatteo. Ann Surg. 2007;245:347; Raut. J Clin Oncol. 2006;24:2325; Andtbacka. Ann Surg Oncol. 2007;14:14; Bonvalot. Ann Surg Oncol. 2006;13:1596; Gronchi. Ann Surg. 2007;245:341; Rutkowski. J Surg Oncol. 2006;93:304.

32. Multifocal Resistance
Stratification of Patients with Metastatic Disease based on response to imatinib therapy
Responsive Disease
Partial response or stability prior to surgery
Focal Resistance
Growth in at least one lesion
Multifocal Resistance
Growth in multiple lesions
DeMatteo R. Ann. Surg. 245,3, 2007

33. Aggressive surgery for metastatic disease
Most common operation: Liver resection (43%)
Gastrectomy/ Bowel Resection (48%)
Pancreatectomy (13%)
Median 8 day LOS
DeMatteo R. Ann. Surg. 245,3, 2007

34. Outcome after resection
DeMatteo Ann. Surg. 245,3, 2007

35. Adding Surgery to TKI Therapy
Progression Free Survival
69 consecutive patients who underwent surgery while receiving a TKI (IM 45 pts, IMSU 21 pts)
Status at time of surgery
SD: 33%
Limited progression: 47%
Generalized progression: 20%
Progression-free survival based on presurgery status
SD: median not reached
Limited progression: 8 mos
Generalized progression: 3 mos
Similar results reported by DeMatteo et al
Overall Survival
IM=imatinib; SU=sunitinib.
Reproduced with permission from Raut. J Clin Oncol. 2006;24:2325; DeMatteo. Ann Surg. 2007;245:347.

36. Metastatic GIST: Surgery is Complementary to Medical therapy
Surgery alone is unlikely to achieve long term disease control
Medical Therapy will not completely treat large lesions
Timing is critical
Extent of surgery is
Safety
Function/ Quality of Life

37. Surgery to “Reset” the Clock
Treat Symptoms
Treat isolated resistant lesions
Await new therapies
Treat disease that will not be responding to medical therapy

38. Strategies for the patient with metastatic disease
Resectable Metastatic Disease
Responsive Disease Resect All Disease
Focal Resistance Resect All Disease *
Multifocal Resistance Continued Medical therapy Dose escalation, second line agents
*Limited progression
All Patients receive postoperative imatinib

39. Clinical Course Postop - Decreased Dose of Regorafenib
Fatigue and Hand foot reaction resolve
13 months from surgery - Recurrent Disease

40. New Agent Becomes Available:BLU-285
Inhibits Exon 17 Kit mutations
Inhibits PDGRFA D842V mutations
Selective inhibition

41. Starts Study Drug 15 months after Surgery
Few side effects.
Completion of cycle 4 all lesions responding
Feels Great
Consideration for Dose Escalation

42. Surgical Treatment opens door to future treatments

43. The future is coming quickly
Rapid pace of drug development and approval
Clinical Trial enrollment
Surgery may buy time as new agents come on line

44. Its all about the Team GIST Medical Oncologist Nursing
Clinical Trials Team
Pathologist
GIST Surgical Oncology
Liver, Pancreas, GI tract, Experience
Radiology
Gastroenterology

45. Strategies for the patient with metastatic disease
Metastatic Disease not completely resectable
Treatment with systemic therapy
Surgery for focal progression? ( Single lesion)
Yes in selected cases
PET/CT for functional evaluation
Period of observation to ensure no systemic progression
Prompt return to systemic therapy often with dose escalation or new agent
Control for symptom Relief
Time for new therapies

46. Surgical Therapy for GIST: Summary
Surgery remains the only potentially curative therapy
Gastric GIST may be resected with a conservative excision
Duodenal GIST may require a whipple if the ampulla is involved
Large GIST require multivisceral en bloc resection

47. Summary
Neoadjuvant imatinib may not improve survival but may facilitate the resection of large GIST
Metastastic disease
Resect all disease if possible
Best outcome in responders
Likely not beneficial in patients with progressive disease
Timing, Teamwork is critical

48. Thanks Questions