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

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Presentation on theme: "Robert S. Benjamin, M.D. Department of Sarcoma Medical Oncology The SARCOMA Center Department of Sarcoma Medical Oncology The SARCOMA Center Texas Medical."— Presentation transcript:

1 Robert S. Benjamin, M.D. Department of Sarcoma Medical Oncology The SARCOMA Center 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 CANCER INCIDENCE NEW CASESDEATHS NEW CASESDEATHS ALL SITES 1,268,000553,400 BONE & JOINTS 2,900 1,400 SOFT TISSUES 8,700 4,400 PROSTATE 198,100 31,500 BREAST 193,700 40,600 LUNG 169, ,400 COLO-RECTAL 135,400 50,400

4 Histologic Diagnoses Malignant Fibrous Histiocytoma (MFH)Malignant Fibrous Histiocytoma (MFH) Low-grade Fibromyxoid SarcomaLow-grade Fibromyxoid Sarcoma (Fibrosarcoma)(Fibrosarcoma) Sarcomas of Fibrous Tissue Sarcomas of Skeletal Muscle Embryonal RhabdomyosarcomaEmbryonal Rhabdomyosarcoma Alveolar RhabdomyosarcomaAlveolar Rhabdomyosarcoma (Pleomorphic Rhabdomyosarcoma)(Pleomorphic Rhabdomyosarcoma) LeiomyosarcomaLeiomyosarcoma GIGI GUGU SkinSkin VesselVessel OtherOther Sarcomas of Smooth Muscle Sarcomas of Adipose Tissue LiposarcomaLiposarcoma Atypical Lipomatous TumorAtypical Lipomatous Tumor Myxoid LiposarcomaMyxoid Liposarcoma Cellular Myxoid LiposarcomaCellular Myxoid Liposarcoma Dedifferentiated LiposarcomaDedifferentiated Liposarcoma Pleomorphic LiposarcomaPleomorphic Liposarcoma Sarcomas of Blood and Lymph Vessels AngiosarcomaAngiosarcoma HemangiosarcomaHemangiosarcoma LymphangiosarcomaLymphangiosarcoma Epithelioid HemangioendotheliomaEpithelioid Hemangioendothelioma HemangiopericytomaHemangiopericytoma Kaposi’s SarcomaKaposi’s Sarcoma Sarcomas of Peripheral Nervous Tissue Malignant Peripheral Nerve Sheath TumorMalignant Peripheral Nerve Sheath Tumor AKAAKA Malignant SchwannomaMalignant Schwannoma NeurofibrosarcomaNeurofibrosarcoma Neurogenic SarcomaNeurogenic Sarcoma Sarcomas of Unknown Tissue Synovial SarcomaSynovial Sarcoma MonophasicMonophasic BiphasicBiphasic Alveolar Soft Part SarcomaAlveolar Soft Part Sarcoma Epithelioid SarcomaEpithelioid Sarcoma Unclassified SarcomaUnclassified Sarcoma Extraskeletal Sarcomas of Bone Extraskeletal OsteosarcomaExtraskeletal Osteosarcoma Extraskeletal ChondrosarcomaExtraskeletal Chondrosarcoma Extraskeletal Ewing’s Sarcoma (PNET)Extraskeletal Ewing’s Sarcoma (PNET) Soft-tissue Tumors of Melanocytic Tissue Melanoma of Soft PartsMelanoma of Soft Parts AKA - Clear Cell SarcomaAKA - Clear Cell Sarcoma Dermatofibrosarcoma ProtruberansDermatofibrosarcoma Protruberans Desmoid FibromatosisDesmoid Fibromatosis Nodular FasciitisNodular Fasciitis SOFT-TISSUE SARCOMA

5 CYTOGENETICS Specific Translocations 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)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)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)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)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)Synovial Sarcoma t(X:18)(p11.2;q11.2) (SYT-SSX1) and (SYT-SSX2) Alveolar rhabdomyosarcoma t (2:13)(q35;q14) (PAX3-FKHR)Alveolar rhabdomyosarcoma t (2:13)(q35;q14) (PAX3-FKHR)

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 Rhabdomyosarcoma Fibro & Neurofibrosarcoma Leiomyosarcoma Synovial Cell Sarcoma LiposarcomaAngiosarcoma Undifferentiated Sarcoma Unspecified & Misc ALL SOFT TISSUE SARCOMAS # Pts % Response ADRIAMYCININ SOFT TISSUE SARCOMAS # Responses Cell Type

9 AngiosarcomaChondrosarcoma Ewing’s Sarcoma FibrosarcomaLeiomyosarcomaLiposarcomaMesotheliomaNeurofibrosarcomaOsteogenicRhabdomyosarcoma Synovial Cell Sarcoma Undifferentiated Sarcoma # Eval % All R/Eval ADRIAMYCIN-DTIC SWOG 445 FINAL ANALYSIS BY DIAGNOSIS CR/PR 1/2---0/13/97/123/40/43/83/103/40/52/825/67 TOTAL

10 Head & Neck GU & Uterus Retroperitoneum Unk. Prim. & Misc. Limb Pelvis + Trunk GI Tract All # PTS. % RESPONSE LOCATION ADRIAMYCIN-DTIC IN SARCOMAS RESPONSE BY SITE OF PRIMARY

11 IFOSFAMIDE Response by Histology NO. EVAL PTS. % OVERALL RESPONSE HISTOLOGY % CR 30303MFH Synovial sarcoma GI leiomyosarcoma Other leiomyosarcoma Unclassified sarcoma Benjamin et al, CCP 31:S , 1993

12 MFHFibrosarcoma Synovial Sarcoma RhabdomyosarcomaOtherSchwannomaLeiomyosarcomaLiposarcomaAngiosarcomaCarcinosarcoma Extraskeletal osteosarcoma Antman et al, JCO 7: , 1989 IFOSFAMIDE Response by Histology NO. EVAL PTS. % OVERALL RESPONSE HISTOLOGY % CR

13 Leiomyosarcoma Neurosarcoma Fibrosarcoma Synovial Sarcoma MFH Liposarcoma Rhabdomyosarcoma Angiosarcoma Unclassified Le Cesne et al, JCO 13: , NO. EVAL PTS. % OVERALL RESPONSE HISTOLOGY IFOSFAMIDE Response by Histology

14 DOSE-INTENSIVE AI IN STS Treatment Plan Adriamycin mg/m 2 as a 24 hr CI qd x 3, days 1-3. Ifosfamide 2.5 g /m 2 over 3 hrs qd 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. Patel 5/00

15 DOSE-INTENSIVE AI IN STS Eligibility Criteria 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. Patel 5/00

16 DOSE-INTENSIVE AI IN STS Patient Characteristics 149 Patients treated on SEQUENTIAL PROTOCOLS between 1/95-12/ 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 Patel 5/00

17 DOSE-INTENSIVE AI IN STS RESPONSE DATA 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%) Patel 5/00

18 Disease-Specific Therapy Future Perspectives

19

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

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

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

23 Angiosarcomas AngiosarcomasAngiosarcomas Standard chemotherapyStandard chemotherapy Taxol - 8/9 vs 1/27Taxol - 8/9 vs 1/27 Navelbine ?Navelbine ? InterferonInterferon Epithelioid HemangioendotheliomaEpithelioid Hemangioendothelioma EmbolizationEmbolization InterferonInterferon Newer angiogenesis inhibitorsNewer angiogenesis inhibitors

24 Improved Response Assessment Future Perspectives

25 BeforeAfter

26 Functional Response Assessment Dynamic MRI PET Future Perspectives

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


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