1. Surgical Management of Advanced GIST Following KIT- Directed Therapy Chandrajit P. Raut, Jayesh Desai, Jeffrey A. Morgan, Suzanne George, Matthew Posner, David Zahrieh, Christopher D. M. Fletcher, George D. Demetri, and Monica M. Bertagnolli Brigham and Women’s Hospital Dana-Farber Cancer Institute Harvard Medical School November 20, 2005

2. Gastrointestinal Stromal Tumor (GIST): Therapy in Advanced Disease Imatinib therapy results in disease regression or stabilization in approximately 80% of patients with advanced GIST Sunitinib may achieve significant anti-tumor responses in imatinib-resistant tumors However, response to KIT-directed therapy is not maintained indefinitely, resulting in disease progression

3. GIST: Therapy in Advanced Disease Once drug resistance occurs, disease progression may be: 1.Limited Drug responsiveness or growth stability in most metastatic tumor deposits Progressive growth in isolated lesions 2.Generalized Progressive growth in most tumor deposits Traditional role of surgery in advanced disease: palliation

4. Survival in Advanced GIST Verweij et al. (2004), Lancet 364:1127 964 pts with advanced GIST Randomized to imatinib 400 qd vs. bid Median f/u 760 days Progression-Free Survival 25-mo PFS: 50-56% Overall Survival 12-mo OS: 85-86% 24-mo OS: 69-74%

5. Should Advanced GIST Be Managed More Aggressively? Treatment with imatinib has altered the natural course of the disease However, drug resistance may limit long-term efficacy Re-evaluation of the role of surgery in advanced GIST

6. Study Objective Determine if resection or debulking of stable or progressive advanced GIST after treatment with KIT-directed therapy impacted survival?

7. Patient Cohort March, 2002 – November, 2004 69 consecutive patients with advanced, biopsy-proven GIST Diagnosis confirmed by review of tumor pathology Multidisciplinary team approach: Treatment with KIT-directed therapy Surgery

8. Patient Characteristics No. Patients (%) N=69 Age Median57.1 yrs Range21.3-76.5 yrs Gender Male46 (67) Female23 (33) Extent of disease at presentation Unresectable primary without metastases9 (13) Metastatic disease60 (87) Tumor KIT immunoreactivity Positive68 (99) Negative1 (1)

9. Preoperative Therapy Treatment Regimen No. Patients (%) N=69 Imatinib only45 (65) Imatinib, then sunitinib21 (30.5) Imatinib, then doxorubicin1 (1.5) Observation2 (3)

10. Patient Cohort: Extent of Disease Stable disease Initially unresectable primary or metastatic disease who demonstrated maximal response to drug No tumor progression prior to surgery for a median of 211 days (range 62-1196 days) All sites were resectable Limited disease progression Metastatic disease with limited progression on drug All progressing sites were resectable Generalized disease progression Metastatic disease with generalized progression on drug All progressing sites were not resectable 43% were emergent procedures Remaining patients had excellent performance status

11. Indications for Surgery No. Patients (%) N=69 Indications for surgery Stable disease23 (33) Limited progression32 (47) Generalized progression14 (20) Emergency Surgery Indications10 (14) Intestinal perforation4 Gastrointestinal bleeding4 Intratumoral abscess1 Intratumoral abscess with fistula1

12. Extent of Surgical Resection Surgical ProcedureNo. Patients Gastrectomy  splenectomy 6 Gastrectomy + other bowel resection4 Hepatic resection7 Hepatic resection + other bowel resection10 LAR / APR / transanal resection rectal tumor7 Resection of single bowel segment7 Resection of multiple bowel segments14 Pancreatic and/or duodenal resection5 Partial cystectomy + other bowel resection2 Resection pelvic tumor1 Resection retroperitoneal tumor1 Hysterectomy and bilateral salpingo-oophorectomy1 Resection abdominal wall tumor4 Additional localized peritoneal stripping / omentectomy – 43/69 (62%)

13. Postoperative Therapy Treatment Regimen No. Patients N=69 Imatinib alone33 Sunitinib alone19 Imatinib, then sunitinib10 Imatinib, then phase I agent3 Imatinib, then sunitinib, then phase I agent2 Sunitinib, then imatinib plus rapamycin1 No additional therapy1

14. Surgical Outcome Results of operation were recorded as: No evidence of disease (NED) No grossly visible residual disease Minimal residual disease Visible tumor nodule(s) < 1 cm Bulky residual disease Visible tumor nodule(s) ≥ 1 cm

15. Surgical Outcome According to Disease Presentation NED Minimal Residual Disease Bulky Residual Disease TOTAL Stable disease (%)18 (78)4 (17)1 (4)23 Limited progression (%)8 (25)19 (59)5 (16)32 Generalized progression (%)1 (7)7 (50)6 (43)14 TOTAL27301269 Disease presentation prior to surgery strongly correlated with surgical result (p<0.0001)

16. Progression-Free Survival 12-mo PFS ± SE (%) Median TTP (mo) Stable disease 80% ± 9%NR Limited progression 33% ± 9%7.7 Generalized progression 0%2.9 Median follow-up 14.6 mo

17. Overall Survival 12-mo OS ± SE (%) Median Survival (mo) Stable disease 95% ± 5%NR Limited progression 86% ± 6%29.8 Generalized progression 0%5.6 Median follow-up 14.6 mo

18. Stable Disease 21/23 (91%) pts with stable disease prior to surgery were treated with imatinib preoperatively Outcomes: 5/21 (24%) recurred PFS recalculated from the time imatinib commenced (median follow-up 25 mo) 12-mo PFS100% 24-mo PFS88% ± 8% 36-mo PFS59% ± 15% 2/21 (9.5%) died

19. Conclusions Patients with stable disease on KIT- directed therapy have prolonged PFS/OS after resection Patients with limited disease progression may benefit from debulking procedures Benefits of surgery in patients with generalized disease progression are limited

20. Future Directions Prospective clinical trial in patients with stable advanced GIST randomized to KIT-directed therapy alone vs. surgery plus KIT-directed therapy Patients with stable metastatic gastrointestinal stromal tumor ConsentConsent Registration and randomization Arm 1: KIT- directed therapy plus surgery Arm 2: KIT- directed therapy Follow

21. Dana-Farber / Brigham and Women’s Cancer Center: Sarcoma Center Medical Oncology Karen Albritton, MD George Demetri, MD Suzanne George, MD Jeffrey Morgan, MD Rhaea Photopoulos, NP Kathleen Polson, NP Surgical Oncology Monica Bertagnolli, MD Chandrajit Raut, MD Radiation Oncology Elizabeth Baldini, MD Philip Devlin, MD Karen Marcus, MD Orthopedic Oncology John Ready, MD Pathology Christopher Fletcher, MD Jonathan Fletcher, MD

23. Surgical Complications No. Patients Post-operative bleeding requiring re-operation2 Anastomotic leak3 Enterocutaneous fistula2 Abscess requiring drainage4 Ureteral leak1 Wound infection requiring readmission1 Urinary tract infection2 Prolonged ileus2 Urinary retention1 Delayed gastric emptying2 Postoperative myocardial infarction1 Postoperative atrial fibrillation1 Pulmonary embolus1 Transfusion reaction1

24. Surgical Complications Overall complication rate33% Complication rate, generalized progression pts 50% Complication rate, emergency surgery40%

25. Postoperative Therapy Treatment Regimen No. Patients (%) N=69 Imatinib alone33 (48) Sunitinib alone19 (28) Imatinib, then sunitinib10 (14) Imatinib, then phase I agent3 (4) Imatinib, then sunitinib, then phase I agent2 (3) Sunitinib, then imatinib plus rapamycin1 (1.5) No additional therapy1 (1.5)