Local and Distant Failure According to Mode of Local Control in Localized Ewing Sarcoma of Bone

1. Local and Distant Failure According to Mode of Local Control in Localized Ewing Sarcoma of Bone Steven DuBois, MD UCSF Department of Pediatrics

2. Local Control in Ewing Sarcoma • Options for local control of primary tumor • Definitive surgical resection • Definitive radiation • Surgery with radiation • Optimal mode of local control unknown • Studies confounded by selection bias • Randomized study not feasible

3. Impact of Mode of Local Control on EFS and Overall Survival • Previous COG multivariate analysis of 465 patients with localized Ewing sarcoma of bone • Used two different methods to control for selection bias • Both methods concluded no impact of mode of local control on EFS or overall survival

4. Objectives • To compare risk of distant failure according to mode of local control in localized EWS of bone • To compare risk of local failure according to mode of local control in localized EWS of bone

5. Patient Inclusion Criteria • EWS of bone • Localized disease only • No primary tumors arising in the head • Treated on INT-0091, INT-0154, or AEWS0031 • Treated with VDC / IE administered every 3 weeks • Experimental arm of INT-0091 • Standard arms of INT-0154 and AEWS0031 • Received neoadjuvant chemotherapy • Complete local control data

6. Endpoints • Time from start of local control procedures to first episode of distant failure • Time from start of local control procedures to first episode of local failure • Used competing risks methods to account for potential impact of treatment for relapse at one site on risk of relapse at another site

7. Statistical Methods • Primary approach • Propensity score method • Model likelihood of patient receiving surgery or radiation based on predictors of local control choice • Balances confounders between groups of patients • Use scores as covariates in competing risks regression models • Confirmatory approach • Conventional Cox proportional hazards methods • Variables used to generate propensity scores used as covariates in competing risks regression models

8. Patient Characteristics Differ According to Chosen Mode of Local Control ** p< 0.001

9. Generation of Propensity Scores • Serial logistic regression models • Variables predictive of choice of local control • Age • Tumor site • Year of diagnosis

10. Risk of Distant Failure Does not Differ According to Mode of Local Control Definitive surgery group is reference group, with hazard ratio of 1.

11. Risk of Local Failure Differs According to Mode of Local Control Definitive surgery group is reference group, with hazard ratio of 1.

12. Strengths and Limitations Strengths • Large group of uniformly treated patients • Two methods to control for confounding Limitations • Possibility of uncontrolled confounding • Data based on non-interval compressed chemotherapy

13. Conclusions • Choice of local control modality does not impact risk of distant failure • Patients treated with definitive radiation have higher risk of local failure

14. Conclusions • Previous study showed no difference in EFS or overall survival by local control group • Low rates of local failure are not enough to allow differences in local failure by mode of local control to impact overall disease control on a population level • For a specific patient, results favor surgical resection when feasible, with radiation reserved for selected cases

15. Acknowledgments Coauthors Mark Krailo Mark Gebhardt Sarah Donaldson Karen Marcus John Dormans Robert Shamberger Richard Nicholas John Healey Nancy Tarbell Linda Granowetter Richard Womer Mark Bernstein Neyssa Marina Holcombe Grier Funding Sources WWWW Foundation ASCO Foundation Campini Foundation NCI 1K23CA154530

17. Patient Selection

18. Propensity Scores Similar with and without Tumor Size Data

19. Cumulative Incidence of Failure