Soft-tissue Sarcomas

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

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CYTOGENETICSSpecific Translocations

• Ewings Sarcoma/PNET t(1122)(q 24, q
  12) (EWS-FLI1)
  t(2122)(q22, q12) (EWS-ER)
  t(722)(p22q12) (EWS-ETV1)
• Desmoplastic Small Cell Tumor
  t(1222)(q13q12) (EWS ATF1)
  aka (EWS-WT1)
• Extraskeletal myxoid chondrosarcoma
  t(922)(q2212) (EWS-TEC)
  aka (EWS-CHN)
• Myxoid Liposarcoma t (1216) (q13p11)
  (FUS-CHOP) t (122220)
  (EWS-CHOP)
• Synovial Sarcoma t(X18)(p11.2q11.2)
  (SYT-SSX1) and (SYT-SSX2)
• Alveolar rhabdomyosarcoma t
  (213)(q35q14) (PAX3-FKHR)

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State of the Art What is the Best Regimen for
Advanced Soft-Tissue Sarcomas?
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What is the Best Regimen for Advanced
Soft-Tissue Sarcomas? It Depends on Which
Sarcoma and Which Patient
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ADRIAMYCIN IN SOFT TISSUE SARCOMAS
Pts
Response
Responses
Cell Type
79 38 37 22 19 9 16 130 357
27 24 32 32 32 44 19 24 27
Rhabdomyosarcoma Fibro Neurofibrosarcoma Leiomyo
sarcoma Synovial Cell Sarcoma Liposarcoma Angiosar
coma Undifferentiated Sarcoma Unspecified
Misc ALL SOFT TISSUE SARCOMAS
21 6 12 4 6 4 3 31 96
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ADRIAMYCIN-DTIC SWOG 445
FINAL ANALYSIS BY DIAGNOSIS
Eval
All R/Eval
CR/PR
9 12 2 25 38 18 9 24 33 18 9 21 218
33 --- 50 48 50 39 44 46 39 39 55 48 42
Angiosarcoma Chondrosarcoma Ewings
Sarcoma Fibrosarcoma Leiomyosarcoma Liposarcoma Me
sothelioma Neurofibrosarcoma Osteogenic Rhabdomyos
arcoma Synovial Cell Sarcoma Undifferentiated
Sarcoma
1/2 --- 0/1 3/9 7/12 3/4 0/4 3/8 3/10 3/4 0/5 2/8
25/67
TOTAL
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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
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IFOSFAMIDE Response by Histology
NO. EVAL PTS.
OVERALL RESPONSE
HISTOLOGY
CR
31 16 30 22 29
19 31 13 9 21
3 0 3 0 3
MFH Synovial sarcoma GI leiomyosarcoma Other
leiomyosarcoma Unclassified sarcoma
Benjamin et al, CCP 31S174-179, 1993
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IFOSFAMIDE Response by Histology
NO. EVAL PTS.
OVERALL RESPONSE
HISTOLOGY
CR
7 5 10 12 13 6 27 4 2 1 1
57 40 40 17 15 17 7 0 0 0 0
14 0 0 8 0 0 0 0 0 0 0
MFH Fibrosarcoma Synovial Sarcoma Rhabdomyosarcoma
Other Schwannoma Leiomyosarcoma Liposarcoma Angi
osarcoma Carcinosarcoma Extraskeletal
osteosarcoma
Antman et al, JCO 7126-131, 1989
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IFOSFAMIDE Response by Histology
NO. EVAL PTS.
OVERALL RESPONSE
HISTOLOGY
11 7 5 4 2 1 2 2 2
0 29 80 75 0 0 50 50 50
Leiomyosarcoma Neurosarcoma Fibrosarcoma Synovial
Sarcoma MFH Liposarcoma Rhabdomyosarcoma Angiosar
coma Unclassified
Le Cesne et al, JCO 131600-1608, 1995.
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DOSE-INTENSIVE AI IN STSTreatment Plan

• Adriamycin 25-30 mg/m2 as a 24 hr CI qd x 3, days
  1-3.
• Ifosfamide 2.5 g /m2 over 3 hrs qd x 4, days 1-4,
  with MESNA as a 24 hr CI.
• Prophylactic G-CSF 5 µg/Kg/d until AGC1500,
  rHTPO per phase 1 protocol.
• Cycles repeated every 3 weeks, Majority cycles
  given as an outpatient.

Patel 5/00
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DOSE-INTENSIVE AI IN STSEligibility Criteria

• Age 65 yrs., no prior chemotherapy, prior XRT
  to lt 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
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DOSE-INTENSIVE AI IN STSPatient Characteristics

• 149 Patients treated on SEQUENTIAL PROTOCOLS
  between 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

Patel 5/00
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DOSE-INTENSIVE AI IN STSRESPONSE 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
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Disease-Specific Therapy
Future Perspectives
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GI-TRACT SARCOMAS

• 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.

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GIST

• 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.

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Myxoid Liposarcomas

• Defined by a specific translocations t (1216)
  (q13p11) (FUS-CHOP) t (122220)
  (EWS-CHOP)
• Metastasize to Fat
• Pelvis, retroperitoneum, mediastinum
• Sensitive to standard chemotherapy
• Differentiation induced by PPAR-gamma or
  retinoid-X agonists
• Translocation a target

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Angiosarcomas

• Angiosarcomas
• Standard chemotherapy
• Taxol - 8/9 vs 1/27
• Navelbine ?
• Interferon

• Epithelioid Hemangioendothelioma
• Embolization
• Interferon
• Newer angiogenesis inhibitors

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Improved Response Assessment
Future Perspectives
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Before
After
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Functional Response AssessmentDynamic MRIPET
Future Perspectives
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Robert S. Benjamin, M.D.
Department of Sarcoma Medical Oncology The
SARCOMA Center
Texas Medical Center Houston, Texas