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Challenges in the Treating of Bone and Soft Tissue Sarcomas

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

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Challenges in the Treating of Bone and Soft Tissue Sarcomas

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  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 • Ionizing Radiation: • 2000-7800 cGy • Osteosarcoma, MFH, angio- and fibrosarcoma • Chemical Exposure: • Dioxin, phenoxyacetic acids, agent orange • Hepatic angiosarcoma: vinyl chloride, arsenic

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

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

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

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

  9. Cytogenetic Abnormalities

  10. Cytogenetic Abnormalities

  11. Sarcoma Annual Statistics 2008 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. Local Progression-free Survival Overall Survival The Benefit of Adjuvant Radiation Therapy • Conservative surgery + RT had similar local progression-free and overall survival when compared to amputation Rosenberg et al. Annals of Surgery, 1982.

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

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

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

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

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

  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 Grier H et al. N Engl J Med, 2003.

  26. Soft Tissue Sarcomas • Doxorubicin • Ifosfamide • Dacarbazine

  27. Meta-Analysis of the Benefitof 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 Benefitof Adjuvant Chemotherapy in STS Sarcoma Meta-Analysis Group. Lancet , 1997.

  29. Meta-Analysis of the Benefitof Adjuvant Chemotherapy in STSConfounding 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. Adjuvant Chemotherapy 5 Cycles: Doxorubicin 75 mg/m2 Ifosfamide 5 grams/m2 Growth factor support Definitive Resection of a grade 2-3 STS of any site Radiation if indicated No Adjuvant Therapy EORTC 62931: Study Design 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. 2nd 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 Experiencewith 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

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