1. Pre-operative Imatinib for metastatic, recurrent and locally advanced GISTs E. Efthimiou, S Mudan E. Efthimiou, S Mudan On behalf of the Sarcoma Group The Royal Marsden Hospital

2. Incidence Gastrointestinal Stromal Tumours GIST are the most common mesenchymal tumours of the gastrointestinal tract. Gastrointestinal Stromal Tumours GIST are the most common mesenchymal tumours of the gastrointestinal tract. The incidence is 15 to 20 cases per million population per year for symptomatic and clinically detected GIST. The incidence is 15 to 20 cases per million population per year for symptomatic and clinically detected GIST. Kindblom, LG et al : Ann Oncol 2002: 13 (Suppl 5):157, 2002. Kindblom, LG et al : Ann Oncol 2002: 13 (Suppl 5):157, 2002.

3. Organ distribution Organ distribution Stomach - 70% Stomach - 70% Small bowel - 20% Small bowel - 20% Colorectum, oesophagus, EGIST - 10%. Colorectum, oesophagus, EGIST - 10%.

4. Omental GIST Gastric GIST

6. Background Background Surgical resection is feasible in approximately two thirds of patients with primary non-metastatic disease. Surgical resection is feasible in approximately two thirds of patients with primary non-metastatic disease. Approximately half of these patients eventually develop intra-peritoneal recurrence or liver metastases. Approximately half of these patients eventually develop intra-peritoneal recurrence or liver metastases. The 5- and 10-year survival after curative resection is 32% to 78% and 19% to 63%, respectively. The 5- and 10-year survival after curative resection is 32% to 78% and 19% to 63%, respectively. Roberts PJ,et al Eur J Cancer 2002 Roberts PJ,et al Eur J Cancer 2002 Lehnet T, et al Ann Chir Gynaecol 2003 Lehnet T, et al Ann Chir Gynaecol 2003

7. Background Background Imatinib is the effective therapy for metastatic and inoperable GIST. Imatinib is the effective therapy for metastatic and inoperable GIST. A sufficient down staging may allow surgical resection either with a curative intent before or at the time of resistance. A sufficient down staging may allow surgical resection either with a curative intent before or at the time of resistance.

8. Background Background Stable disease rate 30% Stable disease rate 30% Partial response rate 50% Partial response rate 50% Complete response rate 2%. Complete response rate 2%.

9. Patients Patients Twenty five cases of locally advanced primary, recurrent or metastatic GIST treated preoperatively with Imatinib were identified from the sarcoma database in our Unit. Twenty five cases of locally advanced primary, recurrent or metastatic GIST treated preoperatively with Imatinib were identified from the sarcoma database in our Unit.

10. Design Design Sex, race, age at presentation. Sex, race, age at presentation. Site of primary tumour and extent of disease at presentation. Site of primary tumour and extent of disease at presentation. Dose of Imatinib prior to the operation, side effects and duration of treatment. Dose of Imatinib prior to the operation, side effects and duration of treatment. Maximal tumour diameter and radiological response. Maximal tumour diameter and radiological response. Surgical procedure and completeness of resection. Surgical procedure and completeness of resection. Disease status at last follow-up. Disease status at last follow-up.

11. Gender Gender 13 female12 male

12. Site of primary tumour origin 0GJ Small bowel Gastric greater curve Gastric lesser curve rectum 10 8 1 2 4

13. State of response at the time of surgery Stable disease 20 Progressive disease 5 progression stable

14. Histological Grade Histological Grade High 20 Intermediate 4 Low 1

15. Pathologic response to Imatinib Pathologic response to Imatinib No resection 3 No response 2 Partial response 20

16. Resection Resection R1 OC R0 R2 13 pts (52%) 6 pts (24%) 3pts (12%)

17. Recurent/metastatic Locally advanced Recurent/metastatic Locally advanced Number ofpatients 7 18 Number ofpatients 7 18 Male/Female 1/6 11/7 Male/Female 1/6 11/7 Median age at diagnosis 48 63 Median age at diagnosis 48 63 Side effects of Imatinib 7 11 Side effects of Imatinib 7 11 Diarrhea 1 3 Diarrhea 1 3 Rash 1 5 Rash 1 5 Neutropenia 1 - Neutropenia 1 - Peri-orbital oedema 4 4 Peri-orbital oedema 4 4 Indigestion 2 2 Indigestion 2 2 Pleural effusion 1 - Pleural effusion 1 - Ankle edema - 3 Ankle edema - 3 Pre Imatinib diameter 6.7cm 14.1cm Pre Imatinib diameter 6.7cm 14.1cm Post imatinib diameter 6.6cm 9.8cm Post imatinib diameter 6.6cm 9.8cm

18. Recurent/metastatic Locally advanced Recurent/metastatic Locally advanced Pathological response Pathological response Partial response 5 15 Partial response 5 15 No response 2 - No response 2 - Tumour not resected - 3 Tumour not resected - 3 Median Glivec Duration 27 months (range 6-62) 9 months (range 5-32) Median Glivec Duration 27 months (range 6-62) 9 months (range 5-32) Median Overall survival 46 months (range 20-77) 9.5 months (range 5-52) Median Overall survival 46 months (range 20-77) 9.5 months (range 5-52) Disease status at follow up Disease status at follow up Disease free 2 11 Disease free 2 11 Liver and peritoneal metastases 3 4 Liver and peritoneal metastases 3 4 Primary disease - 2 Primary disease - 2 Dead 2 1 Dead 2 1

19. Postoperative survival in metastatic and recurrent versus locally advanced GISTS Locally advanced GISTs 94% Reccurent/metastatic GISTS 71%

20. Survival and site of origin of primary GIST 77%

21. Gastric GISTs Gastric GISTs 33% 90%

22. Survival and extent of resection 50%

23. Survival in R2 resections Survival in R2 resections

24. Survival and pathologic response 50% 90% 50%

25. Post operative survival and status of response at operation 90% 80%

26. Overall survival Overall survival Median 32monts (range 8-77 months)

27. Summary 1 Summary 1 2/7 of the metastatic and recurrent GIST patients achieved macroscopic clearance. 2/7 of the metastatic and recurrent GIST patients achieved macroscopic clearance. 5/7 alive after a median period of 46 months (range 20-77) 5/7 alive after a median period of 46 months (range 20-77)

28. Summary 2 Summary 2 94% of the locally advanced group are alive at median FU 9.5 months 94% of the locally advanced group are alive at median FU 9.5 months (range 5-52). (range 5-52). Median duration on Imatinib was 27 months for recurrent and metastatic GIST versus 9 months for locally advanced. Median duration on Imatinib was 27 months for recurrent and metastatic GIST versus 9 months for locally advanced.

29. Summary 3 R2 resection was associated with worse survival. R2 resection was associated with worse survival. Absence of pathological response was associated with 50% survival versus 90% for partial response. Absence of pathological response was associated with 50% survival versus 90% for partial response.

30. Conclusions Recurrent /metastatic patients required longer duration of treatment before surgery and were less likely to achieve the goal of complete macroscopic clearance. Recurrent /metastatic patients required longer duration of treatment before surgery and were less likely to achieve the goal of complete macroscopic clearance. Hence the survival was inferior to the locally advanced group. Hence the survival was inferior to the locally advanced group.