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 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

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

Gastric GIST

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

Exophytic GIST: Only limited gastric resection necessary

Lesser curve GIST often requires an anatomic stomach resection

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

Locally advanced gastric GIST may involve multiple organs

Small Bowel GIST ( Non duodenal)

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

Small bowel GIST may involve other organs

Duodenal GIST: Surgical Options Segmental Duodenal Resection Whipple Procedure

Procedure determined by relation ship to ampulla of vater

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

Reconstruction after Whipple

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

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

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.

The locally advanced GIST

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

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

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

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

RTOG 0132: Surgical Complications

RTOG 0132 Disease Control

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

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.

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

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.

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

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

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

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.

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

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

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

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

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

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

Surgical Treatment opens door to future treatments

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

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

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

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

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

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