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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 “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 Sarcoma Histologies • Over 70 different histologies • No agreement on the cell of origin • Most are sporadic with unknown causes 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 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 Sarcoma Etiologies 6. Bone Abnormalities: • Paget’s disease, bone infarcts – osteosarcoma • Osteochondroma/fibrous displasia of bone: – Osteosarcoma – Chondrosarcoma 7. Lymphedema: • Stuart-Treves Syndrome: angiosarcoma 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 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 Cytogenetic Abnormalities Histology Cytogenetic Change Fusion Gene Frequency Ewing’s/PNET t(11;22) t(21;22) EWS/FL1-1 EWS/ERG 90% Embryonal Rhabdomyosarc +2q, +20 Alveolar Rhabdomyosarc t(2;13) t(1;13) Osteosarcoma 1p-, 6q-, 9p-, 13q-, 17p- 90% Myxoid Chondrosarcoma t(9;22) 50% 80% PAX3/FKHR PAX7/FKHR 80% Cytogenetic Abnormalities Histology Cytogenetic Change Fusion Gene Frequency Synovial t(x;18) SYT/SSX 95% Liposarcoma Myxoid/Round t(12;16) TLS/CHOP 75% Leiomysarcoma 1p deletion Dermatofibros. Protuberans t(17;22) COL1A1-PGFB > 75% Clear Cell Sarcoma t(12;22) EWS/ATF-1 > 75% 75% Sarcoma Annual Statistics 2008 New Cancer Diagnoses Estimated Cancer Deaths Sarcoma Male Female Male Female Soft Tissue 5,720 4,670 1,880 1,800 Bone/Joints 1,270 1,110 820 650 Jemal et al. CA: A Cancer J for Clinicians 58:71-96, 2008. Body Distribution of Cases 40 Lower Extremity 30 Retroperitoneal/Intraabdominal Trunk 25 Upper Extremity 35 Percent of 20 cases 15 10 5 0 Genitourinary Visceral Head and Neck Other Commonest Histology by Age • Children: Rhabdomyosarcoma • Adolescents: Synovial sarcoma • Adults: MFH > liposarcoma > leimyosarcoma 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 The Benefit of Adjuvant Radiation Therapy Local Progression-free Survival Overall Survival • Conservative surgery + RT had similar local progression-free and overall survival when compared to amputation Rosenberg et al. Annals of Surgery, 1982. Neoadjuvant or Adjuvant Chemotherapy • Neoadjuvant or adjuvant chemotherapy indicated for: – Osteosarcoma – Rhabdomyosarcoma – Ewing’s Sarcoma/PNET 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 European Osteosarcoma Intergroup Study I Overall Survival DOX/DDP HDMTX/DOX/DDP Bramwell et al. JCO 1992. 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 COG Phase III Study Meyers et al. JCO, 2005. 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. 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. Ewing’s Sarcoma • Vincristine, Adriamycin/Actinomycin-D, Cytoxan • Ifosfamide and Etoposide 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. Event-free Survival According to Study Group and Tumor Site Among Patients without Metastases Grier H et al. N Engl J Med, 2003. Soft Tissue Sarcomas • Doxorubicin • Ifosfamide • Dacarbazine 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. 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. 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. EORTC 62931: Study Design Adjuvant Chemotherapy 5 Cycles: Definitive Resection of a grade 2-3 STS of any site Doxorubicin 75 mg/m2 Ifosfamide 5 grams/m2 Growth factor support Radiation if indicated No Adjuvant Therapy Woll et al. ASCO 2007, Abs 10008. 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. 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 EORTC 62931: Relapse-free Survival EORTC 62931: Overall Survival Therapy for Metastatic STS • Surgical Resection • Palliative Radiation Therapy • Palliative Chemotherapy 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% Combination Chemotherapy MAI(D) AD Gemcitabine + Docetaxel 28 - 47% 17% 25 - 53% French Sarcoma Study Group Experience with Gemcitabine with Docetaxel Bay et al. Int J Cancer, 2006. 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