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Surgical Approaches to GIST in the Era of Targeted Therapy

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. Surgical Therapy for GIST.

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Surgical Approaches to GIST in the Era of Targeted Therapy

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  1. Surgical Approaches to GIST in the Era of Targeted Therapy Kevin G. Billingsley, M.D. HedingerProfesssor 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 • 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 • > 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

  28. 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.

  29. 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

  30. 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.

  31. 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

  32. 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

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

  34. 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.

  35. 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

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

  37. 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

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

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

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

  41. Surgical Treatment opens door to future treatments

  42. 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

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

  44. 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

  45. 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

  46. 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

  47. ThanksQuestions

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