Neoadjuvant Imatinib, Surgery and then ?

1. Neoadjuvant Imatinib, Surgery and then ? Frits van Coevorden1, Koert Kuhlmann1, J.Martijn Kerst2and Annemieke Cats2 Department of Surgery1 and Medical Oncology2 Netherlands Cancer Institute - Antoni van Leeuwenhoek ziekenhuis Amsterdam The Netherlands

2. Imatinib has a well established role in metastatic GIST • Studies on Adjuvant Imatinib after surgery are ongoing • ACOSOG Adjuvant Trial • primary endpoint: RFS • Early interim results presented in May 2007 • Scandinavian Sarcoma Group Adjuvant Study • primary endpoint: RFS • EORTC Adjuvant Trial GIST(62024) • primary endpoint : Overall Survival

3. Imatinib has a well established role in metastatic GIST • Studies on Adjuvant Imatinib after surgery are ongoing • the role of surgery after initial treatment with Imatinib for locally advanced or metastatic GIST is evolving

4. Surgical strategy in metastatic GIST • Remove resectable metastasis(es) (for cure ?)

5. Surgical strategy in metastatic GIST • Remove resectable metastasis(es) (for cure ?) • Perform surgical (long term) palliation • residual disease after Imatinib • focal active disease under Imatinib • salvage in widely active residual disease ?

6. When Neoadjuvant Imatinib ? • Locally advanced tumor (Large Size) • (unclear) Involvement of surrounding organs • Primary resection expected to be a R1 resection • Primary resectable but also very restricted metastatic disease ?

7. Several papers have dealt with the role of surgery after initial treatment with Imatinib . Raut et al 2006 . Rutkowski et al 2006 . Bonvalot et al 2006 . Gronchi et al 2007 . DeMatteo et al 2007

8. 1,0 0,8 Stable disease probability 0,6 P = 0.02 0,4 Limited disease progression 0,2 P < 0.0001 Generalized disease progression 0 5 10 15 20 25 30 35 40 Time (months) Progression free and Overall survivalafter surgery after initial treatment with Imatinib for locally advanced or metastatic GIST Raut et al. J Clin Oncol 2006 OS PFS

9. 1,0 0,8 0,6 Responding patients probability 0,4 0,2 Progressive patients 0 10 20 30 40 50 60 Time (mo) PFS and OS after surgery after initial treatment with Imatinib for locally advanced or metastatic GIST Gronchi et al. Ann Surg 2007 DeMatteo Ann Surg 2007 PFS OS PFS

10. Case history Neoadjuvant Imatinib, 60 yr female Locally advanced GIST stomach: start Imatinib feb 2006Result after 8 months

11. Surgery 8 months after start ImatinibR0 resection Partial gastrectomy (greater curvature)

12. Neoadjuvant Imatinib, Surgery and then ? What is the role of Imatinib after resection ? Nobody knows or at least unclear • NKI AvL protocol • Complete resection (R0): Stop Imatinib • Resection dubious • Resection incomplete (R1) Continue Imatinib • or metastases }

13. Gist database in theNKI-AVL • all GIST patients seen in the period 2000-2007 • 119 patients • 15 second opinion only • 6 incidentalomas and/or missing data • 98 evaluable patients56 males, 42 females

14. from date of diagnosis Overall survival all evaluable patients

15. 98 evaluable patients • 23Surgery, no Imatinib in follow up • 7 of them in 62024, 6 refused 62024 • 5 Surgery with adjuvant Imatinib in 62024

16. 98 evaluable patients • 23 Surgery, no Imatinib in follow up • 7 of them in 62024, 6 refused 62024 • 5 Surgery with adjuvant Imatinib in 62024 • 33 Imatinib for LocAdv/Meta-GIST, no secondary surgery

17. 98 evaluable patients • 23 Surgery, no Imatinib in follow up • 7 of them in 62024, 6 refused 62024 • 5 Surgery with adjuvant Imatinib in 62024 • 33 Imatinib for LA/Met GIST, no secondary surgery • 21 Neoadjuvant Imatinib, followed by surgery • 16 Surgery after Imatinib, on other indications • Debulking at max response, salvage (focal) progressive disease, bleeding

18. from date of diagnosis Survival all groups

19. 21 Neoadjuvant Imatinib 400 mg, followed by surgery • Stomach: 15 Small bowel: 5 Rectum: 1 • Median size: 14 cm

20. 21 Neoadjuvant Imatinib 400 mg, followed by surgery • Stomach: 16 Small bowel: 4 Rectum: 1 • Median size: 14 cm • 13 locally advanced but non metastatic disease • 8 locally advanced with (suspicion of) limited metastases • 2 hepatic mets 6 peritoneal mets

21. 21 Neoadjuvant Imatinib 400 mg • RECIST based response: 15 PR 6 SD • CHOI based response: 16 PR 5 SD

22. 21 Neoadjuvant Imatinib 400 mg • RECIST based response: 15 PR 6 SD • CHOI based response: 16 PR 5 SD • Interval start Imatinib – Surgery: 8 months (4-18) • Primary: 7 mo ( 4 – 11 ) Metast: 13 mo ( 5 – 18 )

23. 21 Neoadjuvant Imatinib 400 mg • RECIST based response: 15 PR 6 SD • CHOI based response: 16 PR 5 SD • Interval start Imatinib – Surgery: 8 months (4-18) • Primary: 7 mo ( 4 – 11 ) Metast: 13 mo ( 5 – 18 ) • R0 resection: 14 • R1 resection: 7

24. Pathological response after neoadjuvant Imatinib: 4 CR (no vital tumor) 13 PR (vital and non vital residual disease) 4 NC (no effects of Imatinib)

25. from date of diagnosis Survival neoadjuvant vs others(minus surgery alone)

26. Neoadjuvant Imatinib, Surgery and then ? • Continued Imatinib after surgery in 14 patients • 1 / 14 had recurrent GIST activity ½ yr after surgery • > Radiol and path mixed response with CD117 negative active Gist • > Increase to 800 mg, nor Sunitinib proved beneficial • >Died of disease 21 mo after start Imatinib and 14 mo after surgery • 13 / 14 No relapse so far

27. Discontinued Imatinib in 7 patients • all R0 resection • recurrent GIST in 2 patients

28. Pat 1, female 69 yr • Discontinued Imatinib in 7 patients • had a needle tract metastasis ½ yr after surgery • > Radiol SD and Path > 50% vital tumor • >After resection abdominal wall, restart adjuvant Imatinib • > ½ yr later recurrent Gist, 800 mg, nor Sunitinib proved beneficial • > Died of disease 22 mo after start Imatinib and 17 mo after surgery

29. Pat 2, male 77 yr • Discontinued Imatinib in 7 patients • abd recurrence 2 years after surgery primary tumor • > Radiol SD and at Pathology vital tumor only • >Only short response (3 months) on restart Imatinib • > 18 months favorable response on Sunitinib, after which relapse > Again favorable response on Nilotinib • Alive 63 mo after start Imatinib and 56 mo after surgery

30. Discontinued Imatinib in 7 patients • So, recurrent GIST in 2 patients • would continued Imatinib have prevented this ?? • 5 patients still NED6, 8, 12,14 and 22 months after surgery

31. Neoadjuvant Imatinib, Surgery and then ? • Continued Imatinib in 14 patients 1 failure (7 %) • Discontinued Imatinib in 7 patients 2 failures (28%) • So is the NKI-AvL policy safe ?

32. } • Resection dubious • Resection incomplete (R1) Continue Imatinib ! • or limited metastases • Duration of continued Imatinib unclear • 1 yr, 2 yrs, life long ? • Results of adjuvant studies will hopefully guide us here

33. Complete resection (R0) • Continue Imatinib ? • Proposal: • if imaging and pathology show clear response Imatinib may be discontinued • (restart Imatinib will probably reinduce response) Blay et al. • If imaging and pathology have mixed or no response • Continue Imatinib • or consider adjuvant Sutent • ( preferably in study )

34. Thank you