View
256
Download
1
Category
Tags:
Preview:
Citation preview
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
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))
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
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
Recommended