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

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