1. H. Jürgens, M. Paulussen, Münster GER
Ewing tumours
H. Jürgens, M. Paulussen, Münster GER
Goeteborg_2.ppt 2 1 2 2 1 2 1 1 1 1 1 1

2. Ewing tumour - X-ray appearance
right femur + knee
Periosteal lamellation
(circular)
Diaphyseal tumour
Massive swelling of soft tissue

3. Ewing tumour - MR appearance
right femur
Intraossous extension
Soft tissue extension
Topography
Skip lesions?

4. Ewing tumours - Histology
malignant cell population
infiltrating growth
PAS positive (glycogen)
CD99/Mic2 positive
-/+ neuronal differentiation (ES -> atyp. ES -> PNET)
small blue round cell
some mitoses

5. Ewing tumours EWS-FLI1: t(11;22)(q24;q12) from:
De Alava et al.: Molecular biology of the Ewing's sarcoma/primitive neuroectodermal tumor family.
J Clin Oncol 18: , 2000

6. 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: , 2000

7. Chromosome 22 re-arrangements
Ewing tumours
Chromosome 22 re-arrangements
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.
aus: De Alava et al.: Molecular biology of the Ewing's sarcoma/primitive neuroectodermal tumor family. J Clin Oncol 18: , 2000

8. (EICESS 92 Statusanalyse 1.5.2000)
Ewing tumours
Epidemiology - Age, sex
Patienten
weibl.
40%
männl.
60%
Jahre
(EICESS 92 Statusanalyse )

9. Ewing tumours Primary tumour sites Skull 3 % Soft tissue <1%
Clavicle 1 %
Scapula 4 %
Rib 9 %
Sternum <1 %
Humerus 5 %
Spine 6 %
Ulna 1 %
Radius 1 %
Pelvis 23 %
Hand 1 %
Femur 22 %
Fibula 10 %
Tibia 10 %
Foot 3 %
(as of )

10. Primary dissemination
Ewing tumours
Primary dissemination
Lung
13%
Bone/BM 7 %
Lu+Bone/BM 4 %
Other 1 %
No mets
75%

11. CESS 81 - EICESS 92 EFS according to prim. metastases

12. Ewing tumour: Multivariate Analyses
FACTOR p (Wald 2-Test) RR
==========================================================================
Cox Regression - Model 1: Local therapy (n=582)
AGE  15 years
TUMOR VOLUME  200 ml
TUMOR SITE pelvis
LOCAL THERAPY RAD alone
CLINIC SIZE < 10 pts
Cox Regression - Model 2: Response to CT±RT evaluated (n=446)
AGE  15 years
TUMOR VOLUME  200 ml
TUMOR SITE pelvis
HIST. RESPONSE poor
CESS 81 - EICESS 92 (PP, no pMet), April 2002

13. (EI)CESS 81-92 - Relapse pattern acc. to local therapy
25% 5%
65%
27%
>1% 2%
69%
21%
15%
13%
51%
26% 3% 4%
67%

14. Modalities of local therapy
OP OP+RAD RAD RAD+OP
CESS % 32 % 34 %
CESS % 53 % 25 %
EICESS % 65 % 20 %

15. EFS: studies Study % 5yr EFS local therapy in %
==================================================
all ST ST+RT RT ST ST+RT RT
CESS ± 10% 55 ± 18% 67 ± 17% 44 ± 17%
CESS ± 7% 62 ± 15% 63 ± 10% 58 ± 15%
EICESS ± 6% 72 ± 13% 66 ± 7% 46 ± 13%

16. Secondary malignancies acc. to studies
PP FUP
CESS 81 1 % 0 %
CESS 86 2 % 2 %
EICESS % 1 %

17. 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: , 2001

18. EICESS 92 - Second malignancies
6 / 690 pts
2 / 6 MDS/AML
2 / 6 ALL/NHL
1 / 6 Squamous cell carcinoma
1 / 6 Liposarcoma
CSCR
Paulussen et al, Annals of Oncology 12: , 2001

19. EICESS 92 - Second malignancies
Second cancer risk
Paulussen et al, Annals of Oncology 12: , 2001

20. EICESS 92 - Second malignancies
Second leukemia/lymphoma risk
Paulussen et al, Annals of Oncology 12: , 2001

21. EURO-E.W.I.N.G. 99 EUROPEAN EWING TUMOUR WORKING INITIATIVE OF NATIONAL GROUPS
Goeteborg_2.ppt 2 1 2 2 1 2 1 1 1 1 1 1

22. R 1 VIDEx 6 R 2 R 3 VAC x 7 VAI x 7 HDT VAI L O C A T H E R P Y
Randomisation L O C A T H E R P Y
Goeteborg_2.ppt 2 1 2 2 1 2 1 1 1 1 1 1

23. CESS 81 - EICESS 92 PP (no pMet) EFS acc. to risk

24. EURO-E.W.I.N.G. 99 - Risk groups
5-year EFS
R %
R %
R %
Goeteborg_2.ppt 6

25. EURO-E.W.I.N.G. 99 Primary 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
Goeteborg_2.ppt 6

26. EURO-E.W.I.N.G. 99 Secondary 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
Goeteborg_2.ppt 6

27. Ewing tumour Treatment intensity
IESS-II year Survival
Standard dose, continuous %
High dose, intermittent %
Burgert et al., JCO 8:1990
Goeteborg_2.ppt 6

28. Ewing tumour Treatment intensity
IESS-II year EFS
ADR 36 weeks - ActD 36 weeks %
ADR - ActD, 72 weeks alternating %
Smith et al., J Natl Cancer Inst 83:1991
Goeteborg_2.ppt 6

29. Vincristin 1.5 mg/m²/d x 1 day Ifosfamide 3000 mg/m²/d x 3 days
EURO-E.W.I.N.G. 99: VIDE
Vincristin mg/m²/d x 1 day
Ifosfamide mg/m²/d x 3 days
Doxorubicin mg/m²/d x 3 days
Etoposide mg/m²/d x 3 days
Goeteborg_2.ppt 6

30. EURO-E.W.I.N.G. 99 R 1: VAI versus VAC
</> 200 ml OP
Good response 1.
< ml
RAD 2.
RAD/OP 3.
Goeteborg_2.ppt 6

31. CESS 81 - EICESS 92 PP (no pMet)
EFS acc. to R1 subgroups

32. Vincristin 1.5 mg/m²/d x 1 day Actinomycin D 0.75 mg/m²/d x 2 days
EURO-E.W.I.N.G VAI
Vincristin mg/m²/d x 1 day
Actinomycin D mg/m²/d x 2 days
Ifosfamide mg/m²/d x 2 days
Goeteborg_2.ppt 6

33. Vincristin 1.5 mg/m²/d x 1 day Actinomycin D 0.75 mg/m²/d x 2 days
EURO-E.W.I.N.G VAC
Vincristin mg/m²/d x 1 day
Actinomycin D mg/m²/d x 2 days
Cyclophosphamide mg/m²/d x 1 days
Goeteborg_2.ppt 6

34. EURO-E.W.I.N.G. 99 R 2: VAI versus Bu-Mel1.
</> 200 ml OP
Poor Response 2.
> ml
RAD+/-OP 3.
</> 200 ml
Lung metastases
Goeteborg_2.ppt 6

35. CESS 81 - EICESS 92 PP (no pMet)
EFS acc. to R2 subgroups

36. EURO-E.W.I.N.G. 99: HDT Bu/Mel NB: No prior irradiation of axial sites
Busulfan mg/m²
Melphalan mg/m²
Double ME only in case of prior irradiation of axial sites
Melphalan mg/m²
Etopophos mg/m²
Goeteborg_2.ppt 6

37. Ewing tumours - HDT Mel-based Fröhlich 1999 EFS 0.19; 35/131 CR (4 y)
(selected publ.) Outcome FU
Mel-based Fröhlich 1999 EFS 0.19; 35/131 CR (4 y)
(+/- TBI, ...) Stewart /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 /3 PR, 1/3 SD
TTP+ Cyc+Mel Chan /6 CR (3 y)

38. Fröhlich 1999: Metastases No HDT (n=263) 0.24 vs. HDT (n=79) 0.19
EFS (10 y)
No HDT (n=263)
vs.
HDT (n=79)
p= CESS 81-EICESS 92, 5/99

39. Fröhlich 1999: Lu+Bone metastases
EFS (5 y)
No HDT (n=42)
vs.
HDT (n=20)
p= CESS 81-EICESS 92, 5/99

40. HDT: Busulfan Outcome FU
Bu-Mel Atra OAS 0, (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 /7 CCR

41. Ladenstein 1995: Bu vs. TBI Bu + /Mel/Cy/other (n=14) 0.51 vs.
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: , 1995

42. Acknowledgements 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
Funding
EU BIOMED