Change in Anatomic Distribution of Relapses with Accelerated Chemotherapy in Ewing Sarcoma

1. Change in Anatomic Distribution of Relapses with Accelerated Chemotherapy in Ewing Sarcoma RB Womer, AR Weiss, DC West, MD Krailo, PS Dickman, B Pawel, for the Children’s Oncology Group AEWS0031 Committee

2. VDCA VDC VDCA + I/E VDC + I/E INT-0091: Design L O C A L C O N T R O L R A N D O M I Z E

3. INT-0091: Addition of IE Improved EFS Grier et al., NEJM 348:698, 2003

4. INT-0091: IE Decreased Local Relapses Grier et al., NEJM 348:699, 2003

5. Regimen A Local Control VCR Dox CPM VCR Dox CPM VCR Dox CPM VCR Dox CPM RANDOMIZE IFOS ETOP IFOS ETOP IFOS ETOP IFOS ETOP q3w x 2 q3w x 5 Regimen B Local Control q2w x 3 q2w x 4 AEWS0031 Design

6. AEWS0031 Accrual • Open May 2001-August 2005 • Localized ESFT, age <50 years • Total 587 patients enrolled • 19 ineligible • 12 wrong diagnosis • 4 metastases at diagnosis • 3 treatment before enrollment or randomization • Thus 568 eligible patients

7. AEWS0031 Accrual by Strata* *ineligible patients included

8. AEWS0031 Randomization Age Group | Standard Intensive | Total -----------+----------------------+---------- -17 | 253 248 | 501 18+ | 31 36 | 67 -----------+----------------------+---------- Total | 284 284 | 568 | Standard Intensive | Total -----------+----------------------+---------- Non-Pelvic | 237 243 | 480 Pelvic | 47 41 | 88 -----------+----------------------+---------- Total | 284 284 | 568

9. AEWS0031 Patient Characteristics

10. AEWS0031 Patient Characteristics 2

11. AEWS0031: Primary Tumor Treatment Percentages of patients who had:

12. 1.00 0.75 Estimated Proportion Event-Free Regimen 0.50 Standard Intensive 0.25 0.00 0 2 4 6 Years AEWS0031: EFS for all eligible patients p=0.023

13. 1.00 0.75 Regimen Estimated Proportion Surviving 0.50 Standard Intensive 0.25 0.00 0 2 4 6 Years AEWS0031: OS for all eligible patients p=0.026

14. AEWS0031: Events • 126 relapses • 74 Standard, 52 Intensive • 15 SMN (8 Reg. A, 7 Reg. B) • 11 secondary AML/MDS • 5 Standard, 6 Intensive • 3 secondary OS • 1 Diffuse large B cell lymphoma • 1 toxic death (Intensive) • 1 narcotic overdose (recreational)

15. AEWS0031: Patterns of Relapse 123 Relapses* 72 Standard 51 Intensive 18 Local only 39 Distant only 15 Combined 16 Local only 27 Distant only 8 Combined 54 Distant 35 Distant 20 Lung 16 Bone 11 Other 7 Multiple 11 Lung 15 Bone 6 Other 3 Multiple

16. AEWS0031: Patterns of Relapse 123 Relapses* 72 Standard 51 Intensive 18 Local only 39 Distant only 15 Combined 16 Local only 27 Distant only 8 Combined 54 Distant 35 Distant 20 Lung 16 Bone 11 Other 7 Multiple 11 Lung 15 Bone 6 Other 3 Multiple

17. AEWS0031: “Other” Sites of Relapse

18. A few statistics • P (local recurrence) Reg. A v. Reg B: 0.86 • P (distant recurrence) Reg A. v. Reg B: 0.06 • P (distant or combined) Reg A v. Reg B: 0.017 • P (CNS recurrence) Reg A v. Reg B: 0.02

19. AEWS0031: Conclusions • Accelerated chemotherapy reduces lung and “other” (especially CNS) relapses • It has no effect on local or skeletal relapses

20. AEWS0031: Implications of Relapse Patterns • Either accelerated (q2w) chemotherapy is particularly effective against micrometastases in the lungs and CNS, • Or there is a biologically distinct group of Ewing sarcomas with a particular propensity for lung and CNS relapse, that is especially sensitive to accelerated chemotherapy • Or both, • Or neither

22. VDC/IE Regimens for ESFT