1. Challenges in the Treating of Bone and Soft Tissue Sarcomas Margaret von Mehren, MD Director Sarcoma Oncology Fox Chase Cancer Center Philadelphia, PA

2. Definition of Sarcomas “Sarcoma is a malignant tumor composed cells of connective-tissue type. This definition is based on the morphology of the tumor cells and on their histogenesis.” James Ewing, MD Pathologist

3. Sarcoma Histologies Over 70 different histologies No agreement on the cell of origin Most are sporadic with unknown causes

4. Sarcoma Etiologies 1.Ionizing Radiation: 2000-7800 cGy Osteosarcoma, MFH, angio- and fibrosarcoma 2.Chemical Exposure: Dioxin, phenoxyacetic acids, agent orange Hepatic angiosarcoma: vinyl chloride, arsenic

5. Sarcoma Etiologies 3.Immunosuppression: Kaposi’s Sarcoma 4.Viral: HSV-8, KSHV- Kaposi’s Sarcoma EBV- smooth muscle tumors 5.Trauma/Scars: Fibro- and osteosarcoma

6. Sarcoma Etiologies 6.Bone Abnormalities: Paget’s disease, bone infarcts – osteosarcoma Osteochondroma/fibrous displasia of bone: –Osteosarcoma –Chondrosarcoma 7.Lymphedema: Stuart-Treves Syndrome: angiosarcoma

7. Genetic Syndromes 1.Hereditary Retinoblastoma: 13q deletion 1000x more likely to get osteosarcoma Risk increased with exposure to XRT or alkylating agents 2.Neurofibromatosis: 17q deletion 7-15% risk of developing a malignant schwanoma 3.Gardner’s Syndrome: 5q deletion Associated with intra-abdominal desmoid tumors

8. Genetic Syndromes-p53 related 1.Li-Fraumeni Syndrome: 17p deletion resulting in abnormal p53 Phenotype: multiple tumors at an early age –Including breast, leukemia, glioma, and sarcomas 2.MDM2 mutations: Amplification of 12q cluster resulting in abnormal p53 function

9. Cytogenetic Abnormalities Histology Cytogenetic Change Fusion GeneFrequency Ewing’s/PNET t(11;22) t(21;22) EWS/FL1-1 EWS/ERG 90% Embryonal Rhabdomyosarc +2q, +2080% Alveolar Rhabdomyosarc t(2;13) t(1;13) PAX3/FKHR PAX7/FKHR 80% Osteosarcoma 1p-, 6q-, 9p-, 13q-, 17p- 90% Myxoid Chondrosarcoma t(9;22) 50%

10. Cytogenetic Abnormalities Histology Cytogenetic Change Fusion GeneFrequency Synovialt(x;18)SYT/SSX95% Liposarcoma Myxoid/Round t(12;16)TLS/CHOP75% Leiomysarcoma1p deletion75% Dermatofibros. Protuberans t(17;22)COL1A1-PGFB> 75% Clear Cell Sarcoma t(12;22)EWS/ATF-1> 75%

11. Sarcoma Annual Statistics 2008 New Cancer DiagnosesEstimated Cancer Deaths SarcomaMaleFemaleMaleFemale Soft Tissue5,7204,6701,8801,800 Bone/Joints1,2701,110820650 Jemal et al. CA: A Cancer J for Clinicians 58:71-96, 2008.

12. Body Distribution of Cases

13. Commonest Histology by Age Children:Rhabdomyosarcoma Adolescents:Synovial sarcoma Adults:MFH > liposarcoma > leimyosarcoma

14. Treatment for Localized Disease Surgery: main stay of treatment for majority of tumors –Extremity tumors: in the past required often required amputations –Most undergo limb salvage surgeries today Consider role of radiation Consider role of chemotherapy

15. The Benefit of Adjuvant Radiation Therapy Local Progression-free Survival Overall Survival Rosenberg et al. Annals of Surgery, 1982. Conservative surgery + RT had similar local progression-free and overall survival when compared to amputation

16. Neoadjuvant or Adjuvant Chemotherapy Neoadjuvant or adjuvant chemotherapy indicated for: –Osteosarcoma –Rhabdomyosarcoma –Ewing’s Sarcoma/PNET

17. Osteogenic Sarcoma Surgery with adjuvant chemotherapy increased long term survival from 20% to 80% Effective agents: –Cisplatin and doxorubicin –Addition of high dose methotrexate is controversial –Ifosfamide is also active

18. European Osteosarcoma Intergroup Study I Bramwell et al. JCO 1992. DOX/DDP HDMTX/DOX/DDP Overall Survival

19. European Osteosarcoma Intergroup III Lewis et al. JNCI, 2007 No difference in disease-free and overall survival ─Higher rate of greater than 90% necrosis in dose intensive arm

20. COG Phase III Study Meyers et al. JCO, 2005.

21. GPG Phase III Study Meyers et al. JCO, 2005. Event-free Survival 3-year EFS ─71% Standard chemotherapy arm ─68% MTP + standard chemotherapy ─61% Ifosfamide + standard chemotherapy ─78% Ifosfamide + MTP + standard chemotherapy

22. Intergroup Rhabdomyosarcoma Study-IV Crist et al. JCO, 2001. VAC remained standard even in patients with high-risk disease ─No difference in progression-free and overall survival

23. Ewing’s Sarcoma Vincristine, Adriamycin/Actinomycin-D, Cytoxan Ifosfamide and Etoposide

24. Event-free Survival Utilizing VAC Alone or in Combination with IE in Patients with or without Metastatic Ewing’s Sarcoma Grier H et al. N Engl J Med, 2003.

25. Event-free Survival According to Study Group and Tumor Site Among Patients without Metastases

26. Soft Tissue Sarcomas Doxorubicin Ifosfamide Dacarbazine

27. Meta-Analysis of the Benefit of Adjuvant Chemotherapy in STS 14 clinical trials of adjuvant therapy –1568 patients with STS Doxorubicin containing regimens Some trials also included radiation therapy Sarcoma Meta-Analysis Group. Lancet, 1997.

28. Meta-Analysis of the Benefit of Adjuvant Chemotherapy in STS Hazard Ratio Absolute benefit at 10 years Local RFS 0.73 (0.56-0.94) P = 0.016 6% Overall RFS 0.75 (0.64-0.87) P = 0.0001 10% Overall Survival 0.89 (0.76-1.03) P = 0.12 4% Sarcoma Meta-Analysis Group. Lancet, 1997.

29. Meta-Analysis of the Benefit of Adjuvant Chemotherapy in STS Confounding Factors Studies with mixed patient populations –Extremity sarcomas –Uterine sarcomas –Retroperitoneal sarcomas Doses and regimens non-uniform Some trials utilized local radiation therapy as well as adjuvant chemotherapy Sarcoma Meta-Analysis Group. Lancet, 1997.

30. EORTC 62931: Study Design Definitive Resection of a grade 2-3 STS of any site Adjuvant Chemotherapy 5 Cycles: Doxorubicin 75 mg/m 2 Ifosfamide 5 grams/m 2 Growth factor support No Adjuvant Therapy Radiation if indicated Woll et al. ASCO 2007, Abs 10008.

31. EORTC 62931: Key Eligibility Criteria Grade 2-3 soft tissue sarcoma Gross resection of a primary of locally recurrent sarcoma No metastatic disease Radiation therapy after chemotherapy for: –Microscopic residual disease –Local recurrence –Inadequate surgical margins Woll et al. ASCO 2007, Abs 10008.

32. EORTC 62931: Adjuvant Chemotherapy Administration N = 173 –73% received all 5 cycles –37% required a dose reduction or cycle delay Reasons all planned therapy was not given included: –Progressive disease –Toxicity –Patient refusal Woll et al. ASCO 2007, Abs 10008

33. EORTC 62931: Relapse-free Survival

34. EORTC 62931: Overall Survival

35. Therapy for Metastatic STS Surgical Resection Palliative Radiation Therapy Palliative Chemotherapy

36. 2 nd Line Chemotherapy for STS Single agent RR in pretreated STS Ifosfamide 18 - 35% Doxorubicin 17% DTIC 27% Paclitaxel 7% Docetaxel 0 - 17% Gemcitabine 18%

37. Combination Chemotherapy MAI(D) 28 - 47% AD 17% Gemcitabine + Docetaxel 25 - 53%

38. French Sarcoma Study Group Experience with Gemcitabine with Docetaxel Bay et al. Int J Cancer, 2006.

39. Conclusions Childhood sarcomas are more responsive to chemotherapy –Improves overall survival Chemotherapy in adult sarcomas does not improve overall survival Chemotherapy can palliate patients with metastatic disease Median survival for metastatic disease in adults is 12-24 months We need new therapeutic options for treatment of sarcomas