Sequential Dependency of Radiotherapy for Soft-Tissue Sarcoma S

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 HCI Sarcoma Services

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

Introduction • The sequencing of RT with surgery in softtissue 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 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? HCI Sarcoma Services

Methods • National Oncology Database – IMPAC® Medical Systems (Sunnyvale, CA) – Data entry by certified registrars – Meets regulatory reporting requirements from ACo. S, 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 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 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 HCI Sarcoma Services

Patient Characteristics 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 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 HCI Sarcoma Services

Pre-op vs. Post-op RT Endpoint Multivariate Analyses* 95% CI p-value HR lower upper Overall Survival (n=821) <0. 05 0. 73 0. 57 0. 93 Cause-specific Survival (n=821) <0. 05 0. 64 0. 47 0. 89 Local-failure free Survival (n=709) <0. 05 0. 49 0. 28 0. 88 Distant Metastasesfree Survival (n=707) <0. 001 0. 37 0. 23 0. 58 *Post-op RT as comparator variable Abbreviations: RT, radiotherapy; HR, hazard ratio; CI, confidence interval. HCI Sarcoma Services

Pre-op RT vs. Post-op RT log-rank, p=0. 07 Overall Survival log-rank, p<0. 05 Cause-specific Survival HCI Sarcoma Services

Pre-op RT vs. Post-op RT log-rank, p<0. 05 LF-free Survival log-rank, p<0. 001 DM-free Survival HCI Sarcoma Services

Subgroup Analysis - CSS log rank, p<0. 05 Synovial Sarcoma log rank, p<0. 001 Leiomyosarcoma HCI Sarcoma Services

Pre-op vs. Post-op RT Studies Author Cheng et al (JSO, 1996) O’ Sullivan et al (Lancet 2002) Zagars et al (IJROBP 2003) N 112 190 517 Kuklo et al (AJO 2005) 117 Conclusion No difference in LC No difference in CSS RT sequence not a significant prognostic factor on MVA No diff. in LC 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. 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 p. O 2 >10 mm Hg p. O 2 <10 mm Hg 18 mo. DFS 70% 35% 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 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 HCI Sarcoma Services

Thank You HCI Sarcoma Services