Ewing tumours H. Jürgens, M. Paulussen, Münster GER.
-
Upload
lily-james -
Category
Documents
-
view
217 -
download
1
Transcript of Ewing tumours H. Jürgens, M. Paulussen, Münster GER.
Ewing tumours
H. Jürgens, M. Paulussen, Münster GER
Ewing tumour - X-ray appearanceright femur + knee
Periosteal lamellation
(circular)
Massive swelling of
soft tissue
Diaphyseal tumour
• Intraossous extension
• Soft tissue extension
• Topography
• Skip lesions?
Ewing tumour - MR appearanceright femur
• malignant cell population
• infiltrating growth
• small blue round cell
• some mitoses
• PAS positive (glycogen)• CD99/Mic2 positive
• -/+ neuronal differentiation (ES -> atyp. ES -> PNET)
Ewing tumours - Histology
from:
De Alava et al.: Molecular biology of the
Ewing's sarcoma/primitive neuroectodermal
tumor family.
J Clin Oncol 18:204-213, 2000
Ewing tumours EWS-FLI1: t(11;22)(q24;q12)
aus: De Alava et al.: Molecular biology of the Ewing's sarcoma/primitive neuroectodermal tumor family. J Clin Oncol
18:204-213, 2000
Ewing tumours EWS-FLI1 subtypes
aus: De Alava et al.: Molecular biology of the Ewing's sarcoma/primitive neuroectodermal tumor family. J Clin Oncol 18:204-213, 2000
Tumour Translocation Gene fusion Incidence (%)
ES/PNET t(11;22)(q24;q12) EWS-Fli1 85
ES/PNET t(21;22)(q22;q12) EWS-ERG 10
ES/PNET t(7;22)(p22;q12) EWS-ETV1 rare
ES/PNET t(17;22)(q12;q12) EWS-E1AF rare
ES/PNET t(2;22)(q33;q12) EWS-FEV rare
DSRCT t(11;22)(q13;q12) EWS-WT1 95
Myxoliposarcoma t(12;16)(q13;p11) TLS-CHOP 95
Myxoliposarcoma t(12;22)(q13;q12) EWS-CHOP 5
Extraskel. Myxoliposarcoma t(9;22)(q22;q12) EWS-CHN 75
Mal. soft tissue melanoma t(12;22)(q13;q12) EWS-ATF1 n.k.
Synovial sarcoma t(X;18)(p11.23;q11) SYT-SSX1 65
Synovial sarcoma t(X;18)(p11.21;q11) SYT-SSX2 35
Alveolar RMS t(2;13)(q35;q14) PAX3-FKHR 75
Alveolar RMS t(1;13)(p36;q14) PAX7-FKHR 10
Dermatofibrosarcoma protuberans t(17;22)(q22;q13) COL1A1-PDGFB n.k.
Congenit. FS + mesoblast nephroma t(12;15)(p13;q25) ETV6-NTKR3 n.k.
Ewing tumours Chromosome 22 re-arrangements
0
5
10
15
20
25
30
35
40
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35Jahre
Patienten
weibl.
40%
männl.
60%
(EICESS 92 Statusanalyse 1.5.2000)
Ewing tumours Epidemiology - Age, sex
(as of 1.5.2000)
Femur 22 %
Hand 1 %
Ulna 1 %Radius 1 %
Humerus 5 %
Fibula 10 % Tibia 10 %
Foot 3 %
Skull 3 %
Spine 6 %
Pelvis 23 %
Clavicle 1 %Scapula 4 %Rib 9 %Sternum <1 %
Soft tissue <1%
Ewing tumours Primary tumour sites
Lu+Bone/BM 4 %Other 1 %
Bone/BM 7 %
Lung 13%
No mets75%
Ewing tumours Primary dissemination
CESS 81 - EICESS 92 EFS according to prim. metastases
Ewing tumour: Multivariate Analyses
FACTOR p (Wald 2-Test) RR==========================================================================Cox Regression - Model 1: Local therapy (n=582)
AGE 15 years 0.07 1.28TUMOR VOLUME 200 ml 0.0002 1.72TUMOR SITE pelvis 0.12 1.28LOCAL THERAPY RAD alone 0.0002 1.78CLINIC SIZE < 10 pts. 0.0052 1.52==========================================================================Cox Regression - Model 2: Response to CT±RT evaluated (n=446)
AGE 15 years 0.08 1.33TUMOR VOLUME 200 ml 0.12 1.30TUMOR SITE pelvis 0.14 1.34HIST. RESPONSE poor 0.0001 2.00
CESS 81 - EICESS 92 (PP, no pMet), April 2002
(EI)CESS 81-92 - Relapse pattern(EI)CESS 81-92 - Relapse patternacc. to local therapyacc. to local therapy
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Total group ST ST+RT RT
Remission Local Relapse Combined relapse Systemic relapse
25% 5% 5%65%
27%>1% 2%69%
21%15%13%51%
26% 3% 4%67%
Modalities of local therapy
OP OP+RAD RADRAD+OP
CESS 81 34 % 32 % 34 %
CESS 86 22 % 53 % 25 %
EICESS 92 15 % 65 % 20 %
EFS: studies
Study % 5yr EFS local therapy in %==================================================
all ST ST+RT RT ST ST+RT RT
==================================================CESS 81 54 ± 10% 55 ± 18% 67 ± 17% 44 ± 17% 34 32 34
CESS 86 61 ± 7% 62 ± 15% 63 ± 10% 58 ± 15% 22 53 25
EICESS 92 64 ± 6% 72 ± 13% 66 ± 7% 46 ± 13% 15 65 20
Secondary malignancies acc. to studies
PP FUP
CESS 81 1 % 0 %
CESS 86 2 % 2 %
EICESS 92 0.5 % 1 %
EICESS 92 - Second malignancies
Second malignancies after Ewing tumor treatment in 690 patients from a cooperative German/Austrian/Dutch study
Paulussen M, Ahrens S, Lehnert M, Taeger D, Hense HW, Wagner A, Dunst J, Harms D, Reiter A, Henze G, Niemeyer C, Göbel U, Kremens B, Fölsch UR, Aulitzky WE, Voûte PA, Zoubek A, Jürgens H
Annals of Oncology 12:1619-1630, 2001
EICESS 92 - Second malignancies
6 / 690 pts
2 / 6 MDS/AML2 / 6 ALL/NHL1 / 6 Squamous cell carcinoma1 / 6 Liposarcoma
CSCR 0.0093
Paulussen et al, Annals of Oncology 12:1619-1630, 2001
EICESS 92 - Second malignancies
Paulussen et al, Annals of Oncology 12:1619-1630, 2001
Second cancer risk
EICESS 92 - Second malignancies
Second leukemia/lymphoma risk
Paulussen et al, Annals of Oncology 12:1619-1630, 2001
EURO-E.W.I.N.G. 99
EUROPEAN EWING TUMOUR WORKING INITIATIVE OF NATIONAL GROUPS
R 1 VIDEx 6
R 2
R 3
VAC x 7
VAI x 7
VIDEx 6VAI x 7
HDT
VIDEx 6 HDT
VAI
VAI
VAI
VAI
VAI
Randomisation
Randomisation
LOCAL
THERAPY
CESS 81 - EICESS 92 PP (no pMet) EFS acc. to risk
EURO-E.W.I.N.G. 99 - Risk groups
5-year EFS
R 1 71 %
R 2 44 %
R 3 33 %
EURO-E.W.I.N.G. 99Primary objectives
Relapses - R 1 VIDE
- R 2 VIDE, HDT
- R 3 VIDE, HDT
Toxicity - R 1 VIDE, VAC
Role of HDT - R 2 Randomisation
- R 3 Comparison
EURO-E.W.I.N.G. 99Secondary objectives
Molecular Classification - Transcript subclassification
- Bone marrow dissemination
- Residual disease
- Bone marrow
- Stem cells
New strategies (Phase I, II) - R 3 window
- R 3 remission maintenance
Ewing tumourTreatment intensity
IESS-II 5-year Survival
Standard dose, continuous 63 %
High dose, intermittent 73 %
Burgert et al., JCO 8:1990
IESS-II 5-year EFS
ADR 36 weeks - ActD 36 weeks 68 %
ADR - ActD, 72 weeks alternating 48 %
Smith et al., J Natl Cancer Inst 83:1991
Ewing tumourTreatment intensity
EURO-E.W.I.N.G. 99: VIDE
Vincristin 1.5 mg/m²/d x 1 day
Ifosfamide 3000 mg/m²/d x 3 days
Doxorubicin 20 mg/m²/d x 3 days
Etoposide 150 mg/m²/d x 3 days
EURO-E.W.I.N.G. 99 R 1: VAI versus VAC
</> 200 ml OP Good response1.
< 200 ml RAD2.
< 200 ml RAD/OP Good response3.
CESS 81 - EICESS 92 PP (no pMet)
EFS acc. to R1 subgroups
EURO-E.W.I.N.G. 99 - VAI
Vincristin 1.5 mg/m²/d x 1 day
Actinomycin D 0.75 mg/m²/d x 2 days
Ifosfamide 3000 mg/m²/d x 2 days
EURO-E.W.I.N.G. 99 - VAC
Vincristin 1.5 mg/m²/d x 1 day
Actinomycin D 0.75 mg/m²/d x 2 days
Cyclophosphamide 1500 mg/m²/d x 1 days
EURO-E.W.I.N.G. 99 R 2: VAI versus Bu-Mel
</> 200 ml OP Poor Response1.
> 200 ml RAD+/-OP2.
</> 200 ml Lung metastases3.
CESS 81 - EICESS 92 PP (no pMet)
EFS acc. to R2 subgroups
EURO-E.W.I.N.G. 99: HDT
Bu/Mel NB: No prior irradiation of axial sites
Busulfan 600 mg/m²
Melphalan 140 mg/m²
Double ME only in case of prior irradiation of axial sites
Melphalan 140 mg/m²
Etopophos 1800 mg/m²
Ewing tumours - HDT
(selected publ.) Outcome FU
• Mel-based Fröhlich 1999 EFS 0.19; 35/131 CR (4 y)
(+/- TBI, ...) Stewart 1996 3/13 no progression (2 y)
Horowitz 1993 EFS 0.14 (RMS+ES) (6 y)
Ladenstein 1995 EFS 0.27; 4/15 CCR (3 y)
Burdach 1993 EFS 0.45; 8/17 CCR (4 y)
• Thiotepa Lucidarme1998 2/3 PR
Saarinen 1991 1/3 PR, 1/3 SD
• TTP+ Cyc+Mel Chan 1998 1/6 CR (3 y)
Fröhlich 1999: Metastases
EFS (10 y)
No HDT (n=263) 0.24
vs.
HDT (n=79) 0.19p=0.92 CESS 81-EICESS 92,
5/99
Fröhlich 1999: Lu+Bone metastases
EFS (5
y)
No HDT (n=42) 0.05
vs.
HDT (n=20) 0.34p=0.0001 CESS 81-EICESS 92, 5/99
HDT: Busulfan
Outcome FU
Bu-Mel Atra 1997 OAS 0,58 (St. IV: 0.30) (2 y)
13/18 survive (St.IV: 6/11) (5
y)
Bu-Mel ±Cy Ladenstein 1995 EFS 0,5 (St. IV / Rel.) (4
y)
8/14 CCR (2
y)
Bu-Cy Graham 1992 0/7 CCR
Ladenstein 1995: Bu vs. TBI
EFS (3
y)
Bu + /Mel/Cy/other (n=14) 0.51
vs.
TBI + Mel/other (n=15) 0.27
p=0.66 Bone Marrow Transplant 15:697-705, 1995
AcknowledgementsAcknowledgements
Funding
Susanne Ahrens Statistics Muenster
Gabriele Braun-Munzinger Organisation & Management
Regina Kloss Office
Michaela Kuhlen Trial assistance
Michael Paulussen Trial co-ordination
Antje Steinhoff Data management
Carolyn Douglas Data management Leicester Claire Weston Statistics Leicester
EU BIOMED