M. Eriksson, P. Reichardt, K. Sundby Hall, J. Sch ütte , G. Ramadori ,

1. Needle Biopsy through the Abdominal Wall for the Diagnosis of GIST – Does it Pose any Risk for Tumor Cell Seeding and Recurrence? M. Eriksson, P. Reichardt, K. Sundby Hall, J. Schütte, G. Ramadori, P. Hohenberger, S. Bauer, M. Leinonen, A. Reichardt, M. Rejmyr Davis, T. Alvegård, H. Joensuu Presented at CTOS, Prague, November 17, 2012

2. Background • In GIST, tumor rupture is a well known risk factor for recurrence • Fine or core needle biopsy is frequently used to rule out diagnoses where surgery is not the primary treatment, e.g., lymphoma, and/or to allow pre-operative imatinib treatment • It is not known whether biopsies impose any risk for tumor rupture • Divergent views among experts

3. ESMO guidelines for GIST 2012 ”The risk of peritoneal contamination is negligible if the procedure is properly carried out. Moreover, lesions at risk in this regard (e.g. cystic masses) should be biopsied only in specialized centers”

4. NCCN Guidelines for GIST, version 2, 2012 ”GISTs are soft and fragile tumors. Endoscopic ultrasound guided fine-needle aspiration (EUS-FNA) biopsy of primary site is preferred over percutaneous biopsy (due to the risk for hemorrhage and intra-abdominal tumor dissemination).”

5. Thisquestioninvestigated as a sub-studyto SSG XVIII/AIO • SSG XVIII/AIO – the Scandinavian/German adjuvant study in high risk GIST, which demonstrated…. • …. an increased recurrence free survival, and …. • …. an increased overall survival for 3 years of imatinib as compared to 1 year • Presented at ASCO 2011 • Published in JAMA by Joensuu et al (2012;307(12):1265-72)

6. Question for the sub-study Did a preoperative fine or core needle biopsy of the tumor through the abdominal wall in patients in the SSG XVIII/AIO, regardless of treatment length, lead to an impaired RFS as compared to cases where no such biopsy was performed?

7. Material and Method • All patients in the intention-to-treat population (except for four with missing data) in SSG XVIII/AIO (n=393) were included • Data on whether fine and/or core needle biopsy were performed before surgery were collected from all study centers

8. Results Few patients had a percutaneousbiopsy: Anybiopsy: 47 (11.8%) Fine needle: 22 (5.5%) Coreneedle: 33 (8.3%)

9. Time to any recurrence classified by whether any biopsy was performed or not HR=0.63 (p=0.117) Patients: 346 47 Events: 120 13

10. Time to death classified by whether any biopsy was performed or not HR=0.69 (p=0.491) Patients: 346 47 Events: 23 4

11. Time to anyrecurrenceclassifiedbywhetheranycoreneedlebiopsywasperformedornot HR=0.72 (p=0.323) Patients: 346 33 Events: 120 10

12. Confounding factors? May the lack of association between biopsy and recurrence be explained by confounding factors, i.e., factors correlated with a better prognosis and with probability to have a biopsy, e.g., that smaller tumors were more often biopsied, or that gastric tumors were more often biopsied?

13. Time to any recurrence classified by whether any biopsy was performed or not, TUMOR SIZE ≤ 5 cm HR=1.17 (p=0.884)

14. Time to any recurrence classified by whether any biopsy was performed or not, TUMOR SIZE 5-10 cm HR=0.86 (p=0.765)

15. Time to any recurrence classified by whether any biopsy was performed or not, TUMOR SIZE >10 cm HR=0.86 (p=0.035)

16. Time to any recurrence classified by whether any biopsy was performed or not, TUMOR LOCATION = STOMACH HR=0.51 (p=0.196)

17. Time to anyrecurrenceclassifiedbywhetheranybiopsywasperformedornot, TUMOR LOCATION = SMALL INTESTINES HR=0.85 (p=0.708)

18. Time to any recurrence classified by whether any biopsy was performed or not, NORDIC COUNTRIES HR=0.70 (p=0.390)

19. Time to any recurrence classified by whether any biopsy was performed or not, BERLIN HR=0.65 (p=0.410)

20. Time to any recurrence classified by whether any biopsy was performed or not, GERMANY EXCL. BERLIN HR=0.25 (p=0.142)

21. Discussion Possible explanations for the tendency towards better prognosis after pre-operative biopsies: • A pre-operative diagnosis of GIST makes the surgery more careful with less risk for e.g., per-operative tumor rupture? • Biopsies are most often performed in specialized sarcoma/GIST-centers with e.g., more experienced surgeons?

22. Conclusion This study does not support the occurrence of any risk for impaired prognosis in GIST as a consequence of pre-operative biopsies through the abdominal wall, not even if only core needle biopsies are considered

23. Caution • Retrospective study • Limited number of patients who went through any biopsy • Patients who go through an acute (emergency) surgery may constitute a poor risk group, and they will probably not have a biopsy, but they are few

24. Acknowledgements • Steering Group: T.Alvegård, M.Eriksson, H.Joensuu, P.Reichardt, K.Sundby-Hall. • Investigators:Finland P.Bono, H.Joensuu, R.Kallio, P.-L.Kellokumpu-Lehtinen, K.Pulkkanen, R.Ristamäki Germany S.-E.Al-Batran, S.Bauer, J.Duyster, J.T.Hartmann, P.Hohenberger, D.Pink, G.Ramadori, A.Reichardt, P.Reichardt, M.Schlemmer, J.Schütte Norway O.R.Monge, A.Seternes, E.Smeland, K.Sundby Hall Sweden M.Eriksson, M.Erlanson, H.Hagberg, A.Folin, C. Linder-Stragliotto, B.Nilsson, N.Wall. • Statistician: M.Leinonen. • SSG secretariat: J.Ceberg, E.Johansson, E.-M.Olofsson, M.Rejmyr-Davis.