Robert S. Benjamin, M.D.Robert S. Benjamin, M.D.Robert S. Benjamin, M.D.Robert S. Benjamin, M.D.Department of Sarcoma Medical OncologyDepartment of Sarcoma Medical Oncology

The SARCOMA CenterThe SARCOMA CenterDepartment of Sarcoma Medical OncologyDepartment of Sarcoma Medical Oncology

The SARCOMA CenterThe SARCOMA Center

Texas Medical CenterTexas Medical CenterHouston, TexasHouston, Texas

Soft-Tissue Sarcomas: Should they be defined

by patient age, histologic type, or neither?

ACS ESTIMATES - 2001ACS ESTIMATES - 2001 CANCER INCIDENCECANCER INCIDENCE

NEW CASESNEW CASES DEATHSDEATHS

ALL SITESALL SITES 1,268,000 1,268,000 553,400553,400

BONE & JOINTS 2,900BONE & JOINTS 2,900 1,400 1,400SOFT TISSUESSOFT TISSUES 8,700 8,700 4,400 4,400

PROSTATEPROSTATE 198,100 198,100 31,500 31,500BREASTBREAST 193,700 193,700 40,600 40,600LUNGLUNG 169,500 169,500 157,400 157,400COLO-RECTALCOLO-RECTAL 135,400 135,400 50,400 50,400

Histologic DiagnosesHistologic Diagnoses

•Malignant Fibrous Histiocytoma (MFH)Malignant Fibrous Histiocytoma (MFH)•Low-grade Fibromyxoid SarcomaLow-grade Fibromyxoid Sarcoma•(Fibrosarcoma)(Fibrosarcoma)

Sarcomas of Fibrous TissueSarcomas of Fibrous Tissue

Sarcomas of Skeletal MuscleSarcomas of Skeletal Muscle•Embryonal RhabdomyosarcomaEmbryonal Rhabdomyosarcoma•Alveolar RhabdomyosarcomaAlveolar Rhabdomyosarcoma•(Pleomorphic Rhabdomyosarcoma)(Pleomorphic Rhabdomyosarcoma)

•LeiomyosarcomaLeiomyosarcoma•GIGI•GUGU•SkinSkin•VesselVessel•OtherOther

Sarcomas of Smooth MuscleSarcomas of Smooth Muscle

Sarcomas of Adipose TissueSarcomas 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 VesselsSarcomas of Blood and Lymph Vessels•AngiosarcomaAngiosarcoma

•HemangiosarcomaHemangiosarcoma•LymphangiosarcomaLymphangiosarcoma

•Epithelioid HemangioendotheliomaEpithelioid Hemangioendothelioma•HemangiopericytomaHemangiopericytoma•Kaposi’s SarcomaKaposi’s Sarcoma

Sarcomas of Peripheral Nervous TissueSarcomas of Peripheral Nervous Tissue•Malignant Peripheral Nerve Sheath TumorMalignant Peripheral Nerve Sheath Tumor•AKAAKA

•Malignant SchwannomaMalignant Schwannoma•NeurofibrosarcomaNeurofibrosarcoma•Neurogenic SarcomaNeurogenic Sarcoma Sarcomas of Unknown TissueSarcomas of Unknown Tissue

•Synovial SarcomaSynovial Sarcoma•MonophasicMonophasic•BiphasicBiphasic

•Alveolar Soft Part SarcomaAlveolar Soft Part Sarcoma•Epithelioid SarcomaEpithelioid Sarcoma•Unclassified SarcomaUnclassified Sarcoma

Extraskeletal Sarcomas of BoneExtraskeletal Sarcomas of Bone•Extraskeletal OsteosarcomaExtraskeletal Osteosarcoma•Extraskeletal ChondrosarcomaExtraskeletal Chondrosarcoma•Extraskeletal Ewing’s Sarcoma (PNET)Extraskeletal Ewing’s Sarcoma (PNET)

Soft-tissue Tumors of Melanocytic TissueSoft-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 SARCOMASOFT-TISSUE SARCOMA

CYTOGENETICSCYTOGENETICSSpecific TranslocationsSpecific Translocations

• Ewing’s Sarcoma/PNETEwing’s Sarcoma/PNET t( t(11:2211:22)(q 24, q 12) ()(q 24, q 12) (EWS-FLI1EWS-FLI1) ) t( t(21;2221;22)(q22, q12) ()(q22, q12) (EWS-EREWS-ER))

t( t(7;227;22)(p22;q12) ()(p22;q12) (EWS-ETV1EWS-ETV1))

• Desmoplastic Small Cell TumorDesmoplastic Small Cell Tumor t( t(12;2212;22)(q13;q12) ()(q13;q12) (EWS ATF1EWS ATF1) ) aka ( aka (EWS-WT1EWS-WT1) )

• Extraskeletal myxoid chondrosarcoma t(Extraskeletal myxoid chondrosarcoma t(9;229;22)(q22;12) ()(q22;12) (EWS-TECEWS-TEC) ) aka ( aka (EWS-CHNEWS-CHN))

• Myxoid LiposarcomaMyxoid Liposarcoma t ( t (12:1612:16) (q13;p11) () (q13;p11) (FUS-CHOPFUS-CHOP) ) t ( t (12:22:2012:22:20) () (EWS-CHOPEWS-CHOP))

• Synovial SarcomaSynovial Sarcoma t( t(X:18X:18)(p11.2;q11.2) ()(p11.2;q11.2) (SYT-SSX1SYT-SSX1) ) and ( and (SYT-SSX2SYT-SSX2))

• Alveolar rhabdomyosarcomaAlveolar rhabdomyosarcoma t ( t (2:132:13)(q35;q14) ()(q35;q14) (PAX3-FKHRPAX3-FKHR))

State of the Art:

What is the Best Regimen for Advanced

Soft-Tissue Sarcomas?

What is the Best Regimen for Advanced

Soft-Tissue Sarcomas?

It Depends on Which Sarcoma

and

Which Patient

79793838373722221919

991616

130130

357357

27272424323232323232444419192424

2727

RhabdomyosarcomaRhabdomyosarcomaFibro & NeurofibrosarcomaFibro & NeurofibrosarcomaLeiomyosarcomaLeiomyosarcomaSynovial Cell SarcomaSynovial Cell SarcomaLiposarcomaLiposarcomaAngiosarcomaAngiosarcomaUndifferentiated SarcomaUndifferentiated SarcomaUnspecified & MiscUnspecified & Misc

ALL SOFT TISSUE SARCOMASALL SOFT TISSUE SARCOMAS

# Pts# Pts % Response% Response

ADRIAMYCINADRIAMYCINININ

SOFT TISSUE SARCOMASSOFT TISSUE SARCOMAS

# Responses# Responses

212166

121244664433

3131

9696

Cell TypeCell Type

991212

22252538381818

99242433331818

992121

218218

3333------5050484850503939444446463939393955554848

4242

AngiosarcomaAngiosarcomaChondrosarcomaChondrosarcomaEwing’s SarcomaEwing’s SarcomaFibrosarcomaFibrosarcomaLeiomyosarcomaLeiomyosarcomaLiposarcomaLiposarcomaMesotheliomaMesotheliomaNeurofibrosarcomaNeurofibrosarcomaOsteogenicOsteogenicRhabdomyosarcomaRhabdomyosarcomaSynovial Cell SarcomaSynovial Cell SarcomaUndifferentiated SarcomaUndifferentiated Sarcoma

# Eval# Eval % All R/Eval% All R/Eval

ADRIAMYCIN-DTICADRIAMYCIN-DTICSWOG 445SWOG 445

FINAL ANALYSIS BY DIAGNOSIS

CR/PRCR/PR

1/21/2------0/10/13/93/9

7/127/123/43/40/40/43/83/8

3/103/103/43/40/50/52/82/8

25/6725/67TOTALTOTAL

1919

1717

2626

3535

4040

1919

1414

200200

5858

5353

5050

4949

3939

2626

2121

42.542.5

Head & NeckHead & Neck

GU & UterusGU & Uterus

RetroperitoneumRetroperitoneum

Unk. Prim. & Misc.Unk. Prim. & Misc.

LimbLimb

Pelvis + TrunkPelvis + Trunk

GI TractGI Tract

AllAll

# PTS.# PTS. % RESPONSE% RESPONSELOCATIONLOCATION

ADRIAMYCIN-DTICADRIAMYCIN-DTICIN SARCOMASIN SARCOMAS

RESPONSE BY SITE OF PRIMARY

IFOSFAMIDEIFOSFAMIDEResponse by HistologyResponse by Histology

NO. EVAL NO. EVAL PTS.PTS.

% OVERALL % OVERALL RESPONSERESPONSE

3131

1616

3030

2222

2929

1919

3131

1313

99

2121

HISTOLOGYHISTOLOGY % CR% CR

33

00

33

00

33

MFHMFH

Synovial sarcomaSynovial sarcoma

GI leiomyosarcomaGI leiomyosarcoma

Other leiomyosarcomaOther leiomyosarcoma

Unclassified sarcomaUnclassified sarcoma

Benjamin et al, CCP 31:S174-179, 1993Benjamin et al, CCP 31:S174-179, 1993

77

55

1010

1212

1313

66

2727

44

22

11

11

5757

4040

4040

1717

1515

1717

77

00

00

00

00

1414

00

00

88

00

00

00

00

00

00

00

MFHMFH

FibrosarcomaFibrosarcoma

Synovial SarcomaSynovial Sarcoma

RhabdomyosarcomaRhabdomyosarcoma

Other Other

SchwannomaSchwannoma

LeiomyosarcomaLeiomyosarcoma

LiposarcomaLiposarcoma

AngiosarcomaAngiosarcoma

CarcinosarcomaCarcinosarcoma

Extraskeletal osteosarcomaExtraskeletal osteosarcoma

Antman et al, JCO 7:126-131, 1989Antman et al, JCO 7:126-131, 1989

IFOSFAMIDEIFOSFAMIDEResponse by HistologyResponse by Histology

NO. EVAL NO. EVAL PTS.PTS.

% OVERALL % OVERALL RESPONSERESPONSEHISTOLOGYHISTOLOGY % CR% CR

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

Angiosarcoma

Unclassified

Le Cesne et al, JCO 13:1600-1608, 1995.

NO. EVAL PTS.

% OVERALL RESPONSEHISTOLOGY

IFOSFAMIDEResponse by Histology

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 AGC≥1500, rHTPO per phase 1 protocol.

• Cycles repeated every 3 weeks, Majority cycles given as an outpatient.

Patel 5/00

DOSE-INTENSIVE AI IN STSEligibility 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

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

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

Disease-Specific Therapy

Future Perspectives

00

2020

4040

6060

8080

100100

1960 1970 1980 1990 2000 2010 2020 2030 204019601960 19701970 19801980 19901990 20002000 20102010 20202020 20302030 20402040

GI-TRACT GI-TRACT SARCOMASSARCOMAS

• GI stromal tumorGI stromal tumor or or GISTGIST most common histology (also most common histology (also calledcalled leiomyosarcoma leiomyosarcoma).).

• Present with bleeding, anemia, abdominal pain.Present with bleeding, anemia, abdominal pain.

• Most common in the Most common in the stomach (62%),stomach (62%), Small intestine (28%), Small intestine (28%), Colon (10%).Colon (10%).

• Metastasize to the Metastasize to the peritoneum and liver;peritoneum and liver; later to lung. later to lung.

• Refractory to standard systemic chemotherapy.Refractory to standard systemic chemotherapy.

• Chemoembolization of liverChemoembolization of liver with cisplatin can be palliative. with cisplatin can be palliative.

GISTGIST

• Cell of origin is theCell of origin is the Interstitial cell of Cajal. Interstitial cell of Cajal.

• Constitutively expresses Constitutively expresses c-Kitc-Kit

• c. 90% of GISTs are c. 90% of GISTs are c-Kit positive.c-Kit positive.

• C-Kit is one of the few tyrosine kinases C-Kit is one of the few tyrosine kinases specifically inhibited by specifically inhibited by Gleevec Gleevec (STI-571).(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.

Myxoid LiposarcomasMyxoid Liposarcomas

• Defined by a specific translocationsDefined by a specific translocations t (t (12:1612:16) (q13;p11) () (q13;p11) (FUS-CHOPFUS-CHOP) ) t ( t (12:22:2012:22:20) () (EWS-CHOPEWS-CHOP))

• Metastasize to FatMetastasize to Fat– Pelvis, retroperitoneum, mediastinumPelvis, retroperitoneum, mediastinum

• Sensitive to standard chemotherapySensitive to standard chemotherapy

• Differentiation induced by PPAR-gamma or Differentiation induced by PPAR-gamma or retinoid-X agonistsretinoid-X agonists

• Translocation a targetTranslocation a target

AngiosarcomasAngiosarcomas

•AngiosarcomasAngiosarcomas•Standard chemotherapyStandard chemotherapy•Taxol - 8/9 Taxol - 8/9 vs vs 1/271/27•Navelbine ?Navelbine ?•InterferonInterferon

•Epithelioid HemangioendotheliomaEpithelioid Hemangioendothelioma•EmbolizationEmbolization•InterferonInterferon•Newer angiogenesis inhibitorsNewer angiogenesis inhibitors

Improved Response Assessment

Future Perspectives

BeforeBefore AfterAfter

Functional Response Assessment

Dynamic MRIPET

Future Perspectives

Robert S. Benjamin, M.D.Robert S. Benjamin, M.D.Department of Sarcoma Medical Oncology

The SARCOMA CenterDepartment of Sarcoma Medical Oncology

The SARCOMA Center

Texas Medical CenterHouston, Texas