Ewing tumours

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Ewing tumours
H. Jürgens, M. Paulussen, Münster GER
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Ewing tumour - X-ray appearance right femur
knee
Periosteal lamellation (circular)
Diaphyseal tumour
Massive swelling of soft tissue
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Ewing tumour - MR appearance right femur

• Intraossous extension
• Soft tissue extension
• Topography
• Skip lesions?

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Ewing tumours - Histology

• small blue round cell
• some mitoses

• malignant cell population
• infiltrating growth

• PAS positive (glycogen)
• CD99/Mic2 positive
• -/ neuronal differentiation (ES -gt atyp. ES -gt
  PNET)

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Ewing tumours EWS-FLI1 t(1122)(q24q12)
from De Alava et al. Molecular biology of the
Ewing's sarcoma/primitive neuroectodermal tumor
family. J Clin Oncol 18204-213, 2000
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Ewing tumours EWS-FLI1 subtypes
aus De Alava et al. Molecular biology of the
Ewing's sarcoma/primitive neuroectodermal tumor
family. J Clin Oncol 18204-213, 2000
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Ewing tumours Chromosome 22 re-arrangements
Tumour Translocation Gene fusion Incidence
() ES/PNET t(1122)(q24q12) EWS-Fli1 85 ES/PNET
t(2122)(q22q12) EWS-ERG 10 ES/PNET
t(722)(p22q12) EWS-ETV1 rare ES/PNET t(1722)(q
12q12) EWS-E1AF rare ES/PNET t(222)(q33q12) EWS
-FEV rare DSRCT t(1122)(q13q12) EWS-WT1 95 Myxo
liposarcoma t(1216)(q13p11) TLS-CHOP 95 Myxolipo
sarcoma t(1222)(q13q12) EWS-CHOP 5 Extraskel.
Myxoliposarcoma t(922)(q22q12) EWS-CHN 75 Mal.
soft tissue melanoma t(1222)(q13q12) EWS-ATF1 n.
k. Synovial sarcoma t(X18)(p11.23q11) SYT-SSX1 6
5 Synovial sarcoma t(X18)(p11.21q11) SYT-SSX2 35
Alveolar RMS t(213)(q35q14) PAX3-FKHR 75 Alveol
ar RMS t(113)(p36q14) PAX7-FKHR 10 Dermatofibros
arcoma protuberans t(1722)(q22q13) COL1A1-PDGFB
n.k. Congenit. FS mesoblast nephroma t(1215)(p1
3q25) ETV6-NTKR3 n.k.
aus De Alava et al. Molecular biology of the
Ewing's sarcoma/primitive neuroectodermal tumor
family. J Clin Oncol 18204-213, 2000
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Ewing tumours Epidemiology - Age, sex
Patienten
Jahre
(EICESS 92 Statusanalyse 1.5.2000)
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Ewing tumours Primary tumour sites
Skull 3
Soft tissue lt1
Clavicle 1 Scapula 4 Rib 9 Sternum
lt1
Humerus 5
Spine 6
Ulna 1 Radius 1
Hand 1
Pelvis 23
Femur 22
Fibula 10 Tibia 10
Foot 3
(as of 1.5.2000)
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Ewing tumours Primary dissemination
Lung
13
Bone/BM 7
LuBone/BM 4
Other 1
No mets
75
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CESS 81 - EICESS 92 EFS according to prim.
metastases
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Ewing tumour Multivariate Analyses
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(EI)CESS 81-92 - Relapse patternacc. to local
therapy
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(No Transcript)
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EFS studies
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Secondary malignancies acc. to studies
PP FUP CESS 81 1 0 CESS 86 2 2 EICESS
92 0.5 1
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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
121619-1630, 2001
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EICESS 92 - Second malignancies
6 / 690 pts 2 / 6 MDS/AML 2 / 6 ALL/NHL 1 /
6 Squamous cell carcinoma 1 / 6 Liposarcoma CSCR
0.0093 Paulussen et al, Annals of Oncology
121619-1630, 2001
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EICESS 92 - Second malignancies
Second cancer risk
Paulussen et al, Annals of Oncology 121619-1630,
2001
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EICESS 92 - Second malignancies
Second leukemia/lymphoma risk
Paulussen et al, Annals of Oncology 121619-1630,
2001
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EURO-E.W.I.N.G. 99 EUROPEAN EWING TUMOUR
WORKING INITIATIVE OF NATIONAL GROUPS
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(No Transcript)
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CESS 81 - EICESS 92 PP (no pMet) EFS acc. to
risk
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EURO-E.W.I.N.G. 99 - Risk groups
5-year EFS R 1 71 R 2 44 R 3 33

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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
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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
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Ewing tumourTreatment intensity
IESS-II 5-year Survival Standard dose,
continuous 63 High dose,
intermittent 73
Burgert et al., JCO 81990
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Ewing tumourTreatment intensity
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 831991
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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
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EURO-E.W.I.N.G. 99 R 1 VAI versus VAC
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CESS 81 - EICESS 92 PP (no pMet)
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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
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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
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EURO-E.W.I.N.G. 99 R 2 VAI versus Bu-Mel
lt/gt 200 ml
OP
Poor Response
1.
gt 200 ml
RAD/-OP
2.
lt/gt 200 ml
Lung metastases
3.
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CESS 81 - EICESS 92 PP (no pMet)
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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
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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 (RMSES) (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 CycMel Chan 1998 1/6 CR (3 y)

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Fröhlich 1999 Metastases

• EFS (10 y)
• No HDT (n263) 0.24
• vs.
• HDT (n79) 0.19
• p0.92 CESS 81-EICESS 92, 5/99

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Fröhlich 1999 LuBone metastases

• EFS (5 y)
• No HDT (n42) 0.05
• vs.
• HDT (n20) 0.34
• p0.0001 CESS 81-EICESS 92, 5/99

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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

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Ladenstein 1995 Bu vs. TBI

• EFS (3 y)
• Bu /Mel/Cy/other (n14) 0.51
• vs.
• TBI Mel/other (n15) 0.27
• p0.66 Bone Marrow Transplant 15697-705, 1995

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Acknowledgements
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
Funding