1. HCI Sarcoma Services Sequential Dependency of Radiotherapy for Soft-Tissue Sarcoma S Sampath TE Schultheiss YJ Hitchcock RL Randall DC Shrieve JYC Wong CTOS, Miami Beach, FL November 7, 2009

2. HCI Sarcoma Services Disclosures None No financial relationship with the database described

3. HCI Sarcoma Services Introduction The sequencing of RT with surgery in soft- tissue sarcoma remains controversial O’Sullivan et al (Lancet 2002): first and only randomized trial comparing pre-op vs. post-op RT –Primary endpoint: Rate of wound complications at 4 months  increased with pre-op RT –No difference in sarcoma-specific survival but slight improvement in OS

4. HCI Sarcoma Services Study Questions Is there clinical justification using pre-op over post-op RT on the basis of a survival endpoint? Besides stage and grade, are there other robust prognostic factors for survival? Are there specific subgroups who may benefit from a pre-op RT approach?

5. HCI Sarcoma Services Methods National Oncology Database –IMPAC® Medical Systems (Sunnyvale, CA) –Data entry by certified registrars –Meets regulatory reporting requirements from ACoS, NAACCR, NPCR, AJCC, SEER, IACR –Aggregate of merged tumor registries from over 150 institutions across the United States –Superior to SEER/Medicare as it contains local and distant failure information, RT dosing, and chemotherapy –1984-2005

6. HCI Sarcoma Services Connective soft-tissues of the head/neck/face, extremity, thorax, abdomen, pelvis, peritoneum, retroperitoneum Age< 18 years Ewing’s sarcoma Rhabdomyosarcoma Desmoid DFSP Recurrent disease at database entry Unknown variables: Stage, grade, dates of last contact, status 3,110 Patients

7. HCI Sarcoma Services Cox proportional HRs, K-M Log Rank Analysis SPSS® 12.0 software (SPSS Inc., Chicago, IL). clinical stage grade histology site size cause of death race gender margin status types of failures dates of failures surgery RT sequence chemotherapy Surgery –local tumor removal NOS –simple excision –wide limb-sparing resection –amputation –surgery NOS

8. HCI Sarcoma Services Patient Characteristics

9. HCI Sarcoma Services Results Multivariate analysis for OS for the 3,110 patients showed RT sequence to be a significant variable in model –pre-op RT associated with improved OS compared to post-op RT (HR 0.76, 95% CI 0.6-0.95, p<0.05) Remainder of study consisted of 821 patients who received surgery and either pre-op or post-op RT Median follow-up 63 months (0-19 years) Median RT doses: Pre-op 50.4 Gy, Post-op 60 Gy Prognostic factors balanced

10. HCI Sarcoma Services Results Predictors for Overall Survival (p<0.05): –Age –Tumor site –Histology –RT sequence –Tumor size –Stage Predictors for Cause-specific Survival (p<0.05): –Age –Histology –RT sequence –Grade –Tumor size –Stage

11. HCI Sarcoma Services Pre-op vs. Post-op RT 95% CI Endpoint p-valueHRlowerupper Overall Survival (n=821) <0.050.730.570.93 Cause-specific Survival (n=821) <0.050.640.470.89 Local-failure free Survival (n=709) <0.05 0.490.280.88 Distant Metastases- free Survival (n=707) <0.001 0.370.230.58 *Post-op RT as comparator variable Abbreviations: RT, radiotherapy; HR, hazard ratio; CI, confidence interval. Multivariate Analyses*

12. HCI Sarcoma Services Pre-op RT vs. Post-op RT Overall SurvivalCause-specific Survival log-rank, p=0.07 log-rank, p<0.05

13. HCI Sarcoma Services Pre-op RT vs. Post-op RT LF-free Survival DM-free Survival log-rank, p<0.05 log-rank, p<0.001

14. HCI Sarcoma Services Subgroup Analysis - CSS Synovial Sarcoma Leiomyosarcoma log rank, p<0.001 log rank, p<0.05

15. HCI Sarcoma Services Pre-op vs. Post-op RT Studies AuthorNConclusion Cheng et al (JSO, 1996) 112No difference in LC O’ Sullivan et al (Lancet 2002) 190No difference in CSS Zagars et al (IJROBP 2003) 517No difference in CSS RT sequence not a significant prognostic factor on MVA Kuklo et al (AJO 2005)117No diff. in LC

16. HCI Sarcoma Services Synovial Sarcoma & Sequential Dependency Guadagnolo et al: IROBP 2007 –150 patients with non-metastatic SS –Pre-op RT led to an increased risk of distant failures versus post-op RT (50% vs. 40%) but not significant –No difference in LF or OS.

17. HCI Sarcoma Services Why did Pre-op RT do better? Hypothesis: –Post-operative hypoxia may increase development of distant metastases(P=0.01) –Brizel et al, Cancer Res 1996 P=0.01 pO2 >10 mm Hg pO2 <10mm Hg 18mo. DFS 70%35%

18. HCI Sarcoma Services Criticism: “If nothing bad is ever said, then nothing good will ever get done” Retrospective outcomes study: –Unable to account for: performance status Institutional bias of larger volume sarcoma centers Not always clear if grading was a 3 vs. 4 tier –Under-reporting of chemotherapy (17%) –Heterogeneity of post-treatment follow-up

19. HCI Sarcoma Services Conclusions Hypothesis-generating study shows that pre-op RT is associated with improved sarcoma-specific survival compared to post-op RT –Via improved local control  decreased distant metastases –LMS, SS may be particularly advantaged Additional comparative or randomized studies are necessary

20. HCI Sarcoma Services Thank You