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Robert S. Benjamin, M.D.

Robert S. Benjamin, M.D. Department of Sarcoma Medical Oncology The SARCOMA Center. Texas Medical Center Houston, Texas. Soft-Tissue Sarcomas: Should they be defined by patient age, histologic type, or neither ?. ACS ESTIMATES - 2001 CANCER INCIDENCE. NEW CASES DEATHS

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Robert S. Benjamin, M.D.

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  1. Robert S. Benjamin, M.D. Department of Sarcoma Medical Oncology The SARCOMA Center Texas Medical Center Houston, Texas

  2. Soft-Tissue Sarcomas: Should they be defined by patient age, histologic type, or neither?

  3. ACS ESTIMATES - 2001 CANCER INCIDENCE NEW CASESDEATHS ALL SITES 1,268,000 553,400 BONE & JOINTS 2,900 1,400 SOFT TISSUES 8,700 4,400 PROSTATE 198,100 31,500 BREAST 193,700 40,600 LUNG 169,500 157,400 COLO-RECTAL 135,400 50,400

  4. SOFT-TISSUE SARCOMA Histologic Diagnoses Sarcomas of Fibrous Tissue Sarcomas of Blood and Lymph Vessels • Malignant Fibrous Histiocytoma (MFH) • Low-grade Fibromyxoid Sarcoma • (Fibrosarcoma) • Angiosarcoma • Hemangiosarcoma • Lymphangiosarcoma • Epithelioid Hemangioendothelioma • Hemangiopericytoma • Kaposi’s Sarcoma • Dermatofibrosarcoma Protruberans • Desmoid Fibromatosis • Nodular Fasciitis Sarcomas of Peripheral Nervous Tissue Sarcomas of Skeletal Muscle • Malignant Peripheral Nerve Sheath Tumor • AKA • Malignant Schwannoma • Neurofibrosarcoma • Neurogenic Sarcoma • Embryonal Rhabdomyosarcoma • Alveolar Rhabdomyosarcoma • (Pleomorphic Rhabdomyosarcoma) Sarcomas of Unknown Tissue • Synovial Sarcoma • Monophasic • Biphasic Sarcomas of Smooth Muscle • Leiomyosarcoma • GI • GU • Skin • Vessel • Other • Alveolar Soft Part Sarcoma • Epithelioid Sarcoma • Unclassified Sarcoma Extraskeletal Sarcomas of Bone • Extraskeletal Osteosarcoma • Extraskeletal Chondrosarcoma • Extraskeletal Ewing’s Sarcoma (PNET) Sarcomas of Adipose Tissue • Liposarcoma • Atypical Lipomatous Tumor • Myxoid Liposarcoma • Cellular Myxoid Liposarcoma • Dedifferentiated Liposarcoma • Pleomorphic Liposarcoma Soft-tissue Tumors of Melanocytic Tissue • Melanoma of Soft Parts • AKA - Clear Cell Sarcoma

  5. Ewing’s Sarcoma/PNET t(11:22)(q 24, q 12) (EWS-FLI1) t(21;22)(q22, q12) (EWS-ER) t(7;22)(p22;q12) (EWS-ETV1) Desmoplastic Small Cell Tumor t(12;22)(q13;q12) (EWS ATF1) aka (EWS-WT1) Extraskeletal myxoid chondrosarcoma t(9;22)(q22;12) (EWS-TEC) aka (EWS-CHN) Myxoid Liposarcoma t (12:16) (q13;p11) (FUS-CHOP) t (12:22:20) (EWS-CHOP) Synovial Sarcoma t(X:18)(p11.2;q11.2) (SYT-SSX1) and (SYT-SSX2) Alveolar rhabdomyosarcoma t (2:13)(q35;q14) (PAX3-FKHR) CYTOGENETICSSpecific Translocations

  6. State of the Art: What is the Best Regimen for Advanced Soft-Tissue Sarcomas?

  7. What is the Best Regimen for Advanced Soft-Tissue Sarcomas? It Depends on Which Sarcoma and Which Patient

  8. ADRIAMYCIN IN SOFT TISSUE SARCOMAS # Pts # Responses % Response Cell Type Rhabdomyosarcoma Fibro & Neurofibrosarcoma Leiomyosarcoma Synovial Cell Sarcoma Liposarcoma Angiosarcoma Undifferentiated Sarcoma Unspecified & Misc ALL SOFT TISSUE SARCOMAS 79 38 37 22 19 9 16 130 357 21 6 12 4 6 4 3 31 96 27 24 32 32 32 44 19 24 27

  9. ADRIAMYCIN-DTIC SWOG 445 FINAL ANALYSIS BY DIAGNOSIS # Eval CR/PR % All R/Eval Angiosarcoma Chondrosarcoma Ewing’s Sarcoma Fibrosarcoma Leiomyosarcoma Liposarcoma Mesothelioma Neurofibrosarcoma Osteogenic Rhabdomyosarcoma Synovial Cell Sarcoma Undifferentiated Sarcoma 9 12 2 25 38 18 9 24 33 18 9 21 218 1/2 --- 0/1 3/9 7/12 3/4 0/4 3/8 3/10 3/4 0/5 2/8 25/67 33 --- 50 48 50 39 44 46 39 39 55 48 42 TOTAL

  10. ADRIAMYCIN-DTIC IN SARCOMAS RESPONSE BY SITE OF PRIMARY # PTS. % RESPONSE LOCATION Head & Neck GU & Uterus Retroperitoneum Unk. Prim. & Misc. Limb Pelvis + Trunk GI Tract All 19 17 26 35 40 19 14 200 58 53 50 49 39 26 21 42.5

  11. IFOSFAMIDE Response by Histology NO. EVAL PTS. % OVERALL RESPONSE HISTOLOGY % CR MFH Synovial sarcoma GI leiomyosarcoma Other leiomyosarcoma Unclassified sarcoma 31 16 30 22 29 3 0 3 0 3 19 31 13 9 21 Benjamin et al, CCP 31:S174-179, 1993

  12. IFOSFAMIDE Response by Histology NO. EVAL PTS. % OVERALL RESPONSE HISTOLOGY % CR 7 5 10 12 13 6 27 4 2 1 1 MFH Fibrosarcoma Synovial Sarcoma Rhabdomyosarcoma Other Schwannoma Leiomyosarcoma Liposarcoma Angiosarcoma Carcinosarcoma Extraskeletal osteosarcoma 14 0 0 8 0 0 0 0 0 0 0 57 40 40 17 15 17 7 0 0 0 0 Antman et al, JCO 7:126-131, 1989

  13. IFOSFAMIDE Response by Histology NO. EVAL PTS. % OVERALL RESPONSE HISTOLOGY Leiomyosarcoma Neurosarcoma Fibrosarcoma Synovial Sarcoma MFH Liposarcoma Rhabdomyosarcoma Angiosarcoma Unclassified 11 7 5 4 2 1 2 2 2 0 29 80 75 0 0 50 50 50 Le Cesne et al, JCO 13:1600-1608, 1995.

  14. Adriamycin 25-30 mg/m2 as a 24 hr CIqd x 3, days 1-3. Ifosfamide 2.5g /m2 over 3 hrsqd x 4, days 1-4, with MESNA as a 24 hr CI. Prophylactic G-CSF 5 µg/Kg/d until AGC≥1500, rHTPO per phase 1 protocol. Cycles repeated every 3 weeks, Majority cycles given as an outpatient. DOSE-INTENSIVE AI IN STSTreatment Plan Patel 5/00

  15. Age ≤ 65 yrs., no prior chemotherapy, prior XRT to < 20% bone marrow. Histologically confirmed sarcomas, excluding GI leios, ASPS, Clear cell sarcoma Zubrod PS 0-2. Adequate organ (especially renal) function. No other concurrent chemo/immunotherapy. Informed consent. DOSE-INTENSIVE AI IN STSEligibility Criteria Patel 5/00

  16. 149 Patients treated onSEQUENTIAL PROTOCOLSbetween 1/95-12/99 122 with measurable disease, 27 adjuvant 78 males, 71 females Median age = 46 years (range, 15-68) years Histology: 35 MFH, 25 leios, 21 Synovial, 18 Unclassified, 13 lipos, 9 angios, 28 others DOSE-INTENSIVE AI IN STSPatient Characteristics Patel 5/00

  17. Responses by Histology: 15/17 Synovial sarcomas (88%) 5/6 Angiosarcomas (83%) 22/32 MFH (69%) 9/15 Unclassified sarcomas (60%) 5/9 Liposarcomas (56%) 9/18 Non-GI Leiomyosarcomas (50%) 2/5 Neurofibrosarcomas (MPNST) (40%) 9/20 Other histologies (45%) DOSE-INTENSIVE AI IN STSRESPONSE DATA Patel 5/00

  18. Future Perspectives Disease-Specific Therapy

  19. 100 100 80 80 60 60 40 40 20 20 0 0 1960 1970 1980 1990 2000 2010 2020 2030 2040 1960 1970 1980 1990 2000 2010 2020 2030 2040

  20. GI stromal tumor or GIST most common histology (also called leiomyosarcoma). Present with bleeding, anemia, abdominal pain. Most common in the stomach (62%), Small intestine (28%), Colon (10%). Metastasize to the peritoneum and liver; later to lung. Refractory to standard systemic chemotherapy. Chemoembolization of liver with cisplatin can be palliative. GI-TRACT SARCOMAS

  21. Cell of origin is the Interstitial cell of Cajal. Constitutively expresses c-Kit c. 90% of GISTs are c-Kit positive. C-Kit is one of the few tyrosine kinases specifically inhibited by Gleevec (STI-571). Preliminary data suggest 50-90% activity An intergroup study started 12/15/00. GIST

  22. Defined by a specific translocations t (12:16) (q13;p11) (FUS-CHOP) t (12:22:20) (EWS-CHOP) Metastasize to Fat Pelvis, retroperitoneum, mediastinum Sensitive to standard chemotherapy Differentiation induced by PPAR-gamma or retinoid-X agonists Translocation a target Myxoid Liposarcomas

  23. Angiosarcomas • Angiosarcomas • Standard chemotherapy • Taxol - 8/9 vs 1/27 • Navelbine ? • Interferon • Epithelioid Hemangioendothelioma • Embolization • Interferon • Newer angiogenesis inhibitors

  24. Future Perspectives Improved Response Assessment

  25. Before After

  26. Future Perspectives Functional Response AssessmentDynamic MRIPET

  27. Robert S. Benjamin, M.D. Department of Sarcoma Medical Oncology The SARCOMA Center Texas Medical Center Houston, Texas

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