1. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 Neoadjuvant Imatinib, Surgery and then ? Department of Surgery 1 and Medical Oncology 2 Netherlands Cancer Institute - Antoni van Leeuwenhoek ziekenhuis Amsterdam The Netherlands Frits van Coevorden 1, Koert Kuhlmann 1, J.Martijn Kerst 2 and Annemieke Cats 2

2. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 Imatinib has a well established role in metastatic GISTImatinib has a well established role in metastatic GIST Studies on Adjuvant Imatinib after surgery are ongoingStudies on Adjuvant Imatinib after surgery are ongoing ACOSOG Adjuvant TrialACOSOG Adjuvant Trial primary endpoint: RFS Early interim results presented in May 2007 Scandinavian Sarcoma Group Adjuvant StudyScandinavian Sarcoma Group Adjuvant Study primary endpoint: RFS EORTC Adjuvant Trial GIST(62024)EORTC Adjuvant Trial GIST(62024) primary endpoint : Overall Survival

3. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 Imatinib has a well established role in metastatic GISTImatinib has a well established role in metastatic GIST Studies on Adjuvant Imatinib after surgery are ongoingStudies on Adjuvant Imatinib after surgery are ongoing the role of surgery after initial treatment with Imatinib for locally advanced or metastatic GIST is evolvingthe role of surgery after initial treatment with Imatinib for locally advanced or metastatic GIST is evolving

4. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 Surgical strategy in metastatic GIST Remove resectable metastasis(es) (for cure ?)Remove resectable metastasis(es) (for cure ?)

5. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 Surgical strategy in metastatic GIST Remove resectable metastasis(es) (for cure ?)Remove resectable metastasis(es) (for cure ?) Perform surgical (long term) palliationPerform surgical (long term) palliation residual disease after Imatinib residual disease after Imatinib focal active disease under Imatinib focal active disease under Imatinib salvage in widely active residual disease ? salvage in widely active residual disease ?

6. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 When Neoadjuvant Imatinib ? Locally advanced tumor (Large Size)Locally advanced tumor (Large Size) (unclear) Involvement of surrounding organs(unclear) Involvement of surrounding organs Primary resection expected to be a R1 resectionPrimary resection expected to be a R1 resection Primary resectable but also very restricted metastatic disease ?Primary resectable but also very restricted metastatic disease ?

7. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 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. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 Progression free and Overall survival after surgery after initial treatment with Imatinib for locally advanced or metastatic GIST Raut et al. J Clin Oncol 2006 OS PFS

9. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 PFS and OS after surgery after initial treatment with Imatinib for locally advanced or metastatic GIST Gronchi et al. Ann Surg 2007DeMatteo Ann Surg 2007 Responding patients Progressive patients 1,01,01,01,0 0,80,80,80,8 0,60,60,60,6 0,40,40,40,4 0,20,20,20,2 0 probability Time (mo) 10101010 40404040 20202020 50505050 30303030 60606060 PFS OSPFS

10. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 Locally advanced GIST stomach: start Imatinib feb 2006 Result after 8 months Case history Neoadjuvant Imatinib, 60 yr female

11. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 Partial gastrectomy (greater curvature) (greater curvature) Surgery 8 months after start Imatinib R0 resection

12. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 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 or metastases }

13. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 Gist database in the NKI-AVL Gist database in the NKI-AVL all GIST patients seen in the period 2000-2007all GIST patients seen in the period 2000-2007 119 patients119 patients 15 second opinion only15 second opinion only 6 incidentalomas and/or missing data6 incidentalomas and/or missing data 98 evaluable patients56 males, 42 females98 evaluable patients56 males, 42 females

14. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 Overall survival all evaluable patients from date of diagnosis

15. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 98 evaluable patients98 evaluable patients 23 Surgery, no Imatinib in follow up23 Surgery, no Imatinib in follow up 7 of them in 62024, 6 refused 62024 7 of them in 62024, 6 refused 62024 5 Surgery with adjuvant Imatinib in 62024 5 Surgery with adjuvant Imatinib in 62024

16. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 98 evaluable patients98 evaluable patients 23 Surgery, no Imatinib in follow up23 Surgery, no Imatinib in follow up 7 of them in 62024, 6 refused 62024 7 of them in 62024, 6 refused 62024 5 Surgery with adjuvant Imatinib in 62024 5 Surgery with adjuvant Imatinib in 62024 33 Imatinib for LocAdv/Meta-GIST, no secondary surgery33 Imatinib for LocAdv/Meta-GIST, no secondary surgery

17. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 98 evaluable patients98 evaluable patients 23 Surgery, no Imatinib in follow up23 Surgery, no Imatinib in follow up 7 of them in 62024, 6 refused 62024 7 of them in 62024, 6 refused 62024 5 Surgery with adjuvant Imatinib in 62024 5 Surgery with adjuvant Imatinib in 62024 33 Imatinib for LA/Met GIST, no secondary surgery33 Imatinib for LA/Met GIST, no secondary surgery 21 Neoadjuvant Imatinib, followed by surgery21 Neoadjuvant Imatinib, followed by surgery 16 Surgery after Imatinib, on other indications16 Surgery after Imatinib, on other indications Debulking at max response, salvage (focal) progressive disease, bleeding Debulking at max response, salvage (focal) progressive disease, bleeding

18. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 Survival all groups from date of diagnosis

19. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 21 Neoadjuvant Imatinib 400 mg, followed by surgery Stomach: 15 Small bowel: 5 Rectum: 1Stomach: 15 Small bowel: 5 Rectum: 1 Median size: 14 cmMedian size: 14 cm

20. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 21 Neoadjuvant Imatinib 400 mg, followed by surgery Stomach: 16 Small bowel: 4 Rectum: 1Stomach: 16 Small bowel: 4 Rectum: 1 Median size: 14 cmMedian size: 14 cm 13 locally advanced but non metastatic disease13 locally advanced but non metastatic disease 8 locally advanced with (suspicion of) limited metastases 8 locally advanced with (suspicion of) limited metastases 2 hepatic mets6 peritoneal mets 2 hepatic mets6 peritoneal mets

21. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 21 Neoadjuvant Imatinib 400 mg RECIST based response: 15 PR 6 SDRECIST based response: 15 PR 6 SD CHOI based response: 16 PR 5 SD CHOI based response: 16 PR 5 SD

22. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 21 Neoadjuvant Imatinib 400 mg RECIST based response: 15 PR 6 SDRECIST based response: 15 PR 6 SD CHOI based response: 16 PR 5 SD CHOI based response: 16 PR 5 SD Interval start Imatinib – Surgery: 8 months (4-18)Interval start Imatinib – Surgery: 8 months (4-18) Primary: 7 mo ( 4 – 11 ) Metast: 13 mo ( 5 – 18 )

23. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 21 Neoadjuvant Imatinib 400 mg RECIST based response: 15 PR 6 SDRECIST based response: 15 PR 6 SD CHOI based response: 16 PR 5 SD CHOI based response: 16 PR 5 SD Interval start Imatinib – Surgery: 8 months (4-18)Interval start Imatinib – Surgery: 8 months (4-18) Primary: 7 mo ( 4 – 11 ) Metast: 13 mo ( 5 – 18 ) R0 resection: 14R0 resection: 14 R1 resection: 7R1 resection: 7

24. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 Pathological response after neoadjuvant Imatinib: 4 CR (no vital tumor) 4 CR (no vital tumor) 13 PR (vital and non vital residual disease) 4 NC (no effects of Imatinib) 4 NC (no effects of Imatinib)

25. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 Survival neoadjuvant vs others (minus surgery alone) from date of diagnosis

26. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 Neoadjuvant Imatinib, Surgery and then ? Continued Imatinib after surgery in 14 patientsContinued Imatinib after surgery in 14 patients 1 / 14 had recurrent GIST activity ½ yr after surgery 1 / 14 had recurrent GIST activity ½ yr after surgery > Radiol and path mixed response with CD117 negative active Gist > Radiol and path mixed response with CD117 negative active Gist > Increase to 800 mg, nor Sunitinib proved beneficial > Increase to 800 mg, nor Sunitinib proved beneficial > Died of disease 21 mo after start Imatinib and 14 mo after surgery > Died of disease 21 mo after start Imatinib and 14 mo after surgery 13 / 14 No relapse so far 13 / 14 No relapse so far

27. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 Discontinued Imatinib in 7 patientsDiscontinued Imatinib in 7 patients all R0 resection all R0 resection recurrent GIST in 2 patients recurrent GIST in 2 patients

28. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 Discontinued Imatinib in 7 patientsDiscontinued Imatinib in 7 patients had a needle tract metastasis ½ yr after surgeryhad a needle tract metastasis ½ yr after surgery > Radiol SD and Path > 50% vital tumor > Radiol SD and Path > 50% vital tumor > After resection abdominal wall, restart adjuvant Imatinib > After resection abdominal wall, restart adjuvant Imatinib > ½ yr later recurrent Gist, 800 mg, nor Sunitinib proved beneficial > ½ yr later recurrent Gist, 800 mg, nor Sunitinib proved beneficial > Died of disease 22 mo after start Imatinib and 17 mo after surgery > Died of disease 22 mo after start Imatinib and 17 mo after surgery Pat 1, female 69 yr

29. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 Discontinued Imatinib in 7 patientsDiscontinued Imatinib in 7 patients abd recurrence 2 years after surgery primary tumor abd recurrence 2 years after surgery primary tumor > Radiol SD and at Pathology vital tumor only > Radiol SD and at Pathology vital tumor only > Only short response (3 months) on restart Imatinib > 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 Pat 2, male 77 yr

30. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 Discontinued Imatinib in 7 patientsDiscontinued Imatinib in 7 patients So, recurrent GIST in 2 patients So, recurrent GIST in 2 patients would continued Imatinib have prevented this ?? would continued Imatinib have prevented this ?? 5 patients still NED 6, 8, 12,14 and 22 months after surgery 5 patients still NED 6, 8, 12,14 and 22 months after surgery

31. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 Continued Imatinib in 14 patients 1 failure (7 %)Continued Imatinib in 14 patients 1 failure (7 %) Discontinued Imatinibin 7 patients 2 failures (28%)Discontinued Imatinibin 7 patients 2 failures (28%) So is the NKI-AvL policy safe ?So is the NKI-AvL policy safe ? Neoadjuvant Imatinib, Surgery and then ?

32. Seattle 2007 Resection dubious Resection incomplete (R1) Continue Imatinib ! or limited metastases or limited metastases } Duration of continued Imatinib unclearDuration of continued Imatinib unclear 1 yr, 2 yrs, life long ? Results of adjuvant studies will hopefully guide us hereResults of adjuvant studies will hopefully guide us here

33. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 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. Neoadjuvant Imatinib, Surgery and then ? Seattle 2007 Thank you