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Ewing tumours H. Jürgens, M. Paulussen, Münster GER.

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Presentation on theme: "Ewing tumours H. Jürgens, M. Paulussen, Münster GER."— Presentation transcript:

1 Ewing tumours H. Jürgens, M. Paulussen, Münster GER

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

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

4 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

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

6 aus: De Alava et al.: Molecular biology of the Ewing's sarcoma/primitive neuroectodermal tumor family. J Clin Oncol 18: , 2000 Ewing tumours EWS-FLI1 subtypes

7 aus: De Alava et al.: Molecular biology of the Ewing's sarcoma/primitive neuroectodermal tumor family. J Clin Oncol 18: , 2000 Tumour TranslocationGene fusionIncidence (%) ES/PNETt(11;22)(q24;q12)EWS-Fli185 ES/PNETt(21;22)(q22;q12)EWS-ERG10 ES/PNET t(7;22)(p22;q12)EWS-ETV1rare ES/PNETt(17;22)(q12;q12)EWS-E1AFrare ES/PNETt(2;22)(q33;q12)EWS-FEVrare DSRCT t(11;22)(q13;q12)EWS-WT195 Myxoliposarcomat(12;16)(q13;p11)TLS-CHOP95 Myxoliposarcomat(12;22)(q13;q12)EWS-CHOP5 Extraskel. Myxoliposarcomat(9;22)(q22;q12)EWS-CHN75 Mal. soft tissue melanomat(12;22)(q13;q12)EWS-ATF1n.k. Synovial sarcomat(X;18)(p11.23;q11)SYT-SSX165 Synovial sarcomat(X;18)(p11.21;q11)SYT-SSX235 Alveolar RMSt(2;13)(q35;q14)PAX3-FKHR75 Alveolar RMSt(1;13)(p36;q14)PAX7-FKHR10 Dermatofibrosarcoma protuberanst(17;22)(q22;q13)COL1A1-PDGFBn.k. Congenit. FS + mesoblast nephromat(12;15)(p13;q25)ETV6-NTKR3n.k. Ewing tumours Chromosome 22 re-arrangements

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

9 (as of ) Femur22 % Hand 1 % Ulna 1 % Radius 1 % Humerus 5 % Fibula10 % Tibia10 % Foot 3 % Skull 3 % Spine 6 % Pelvis23 % Clavicle 1 % Scapula 4 % Rib 9 % Sternum <1 % Soft tissue <1% Ewing tumours Primary tumour sites

10 Lu+Bone/BM 4 % Other 1 % Bone/BM 7 % Lung13% No mets 75% Ewing tumours Primary dissemination

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

12 Ewing tumour: Multivariate Analyses FACTORp (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 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 OPOP+RADRAD RAD+OP CESS 8134 % 32 %34 % CESS 8622 % 53 %25 % EICESS 9215 %65 %20 %

15 EFS: studies Study % 5yr EFS local therapy in % ================================================== allSTST+RT RTSTST+RTRT ================================================== 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 811 %0 % CESS 862 %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 / 6ALL/NHL 1 / 6Squamous cell carcinoma 1 / 6Liposarcoma CSCR Paulussen et al, Annals of Oncology 12: , 2001

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

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 EURO PEAN E WING TUMOUR W ORKING I NITIATIVE OF N ATIONAL G ROUPS

22 R 1 VIDEx 6 R 2 R 3 VAC x 7 VAI x 7 VIDEx 6 VAI x 7 HDT VIDEx 6HDT VAI Randomisation LOCALTHERAPYLOCALTHERAPY

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

24 EURO-E.W.I.N.G Risk groups 5-year EFS R 171 % R 244 % R 333 %

25 EURO-E.W.I.N.G. 99 Primary objectives Relapses - R 1VIDE - R 2VIDE, HDT - R 3VIDE, HDT Toxicity - R 1VIDE, VAC Role of HDT- R 2Randomisation - R 3Comparison

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

27 Ewing tumour Treatment intensity IESS-II 5-year Survival Standard dose, continuous 63 % High dose, intermittent 73 % Burgert et al., JCO 8:1990

28 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 tumour Treatment intensity

29 EURO-E.W.I.N.G. 99: VIDE V incristin 1.5 mg/m²/d x 1 day I fosfamide3000 mg/m²/d x 3 days D oxorubicin 20 mg/m²/d x 3 days E toposide 150 mg/m²/d x 3 days

30 EURO-E.W.I.N.G. 99 R 1: VAI versus VAC 200 mlOPGood response 1. < 200 mlRAD 2. < 200 mlRAD/OPGood response 3.

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

32 EURO-E.W.I.N.G VAI V incristin 1.5 mg/m²/d x 1 day A ctinomycin D 0.75 mg/m²/d x 2 days I fosfamide3000 mg/m²/d x 2 days

33 EURO-E.W.I.N.G VAC V incristin 1.5 mg/m²/d x 1 day A ctinomycin D 0.75 mg/m²/d x 2 days C yclophosphamide 1500 mg/m²/d x 1 days

34 EURO-E.W.I.N.G. 99 R 2: VAI versus Bu-Mel 200 mlOPPoor Response 1. > 200 mlRAD+/-OP mlLung metastases 3.

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 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

37 Ewing tumours - HDT (selected publ.) OutcomeFU Mel-basedFröhlich 1999EFS 0.19; 35/131 CR(4 y) (+/- TBI,...)Stewart 19963/13 no progression (2 y) Horowitz 1993EFS 0.14 (RMS+ES) (6 y) Ladenstein 1995EFS 0.27; 4/15 CCR(3 y) Burdach 1993EFS 0.45; 8/17 CCR(4 y) ThiotepaLucidarme19982/3 PR Saarinen 19911/3 PR, 1/3 SD TTP+ Cyc+MelChan 19981/6 CR (3 y)

38 Fröhlich 1999: Metastases EFS (10 y) No HDT (n=263)0.24 vs. HDT (n=79) 0.19 p=0.92CESS 81-EICESS 92, 5/99

39 Fröhlich 1999: Lu+Bone metastases EFS (5 y) No HDT (n=42)0.05 vs. HDT (n=20) 0.34 p=0.0001CESS 81-EICESS 92, 5/99

40 HDT: Busulfan OutcomeFU Bu-MelAtra 1997OAS 0,58 (St. IV: 0.30)(2 y) 13/18 survive (St.IV: 6/11)(5 y) Bu-Mel ±Cy Ladenstein 1995EFS 0,5(St. IV / Rel.)(4 y) 8/14 CCR (2 y) Bu-CyGraham 19920/7 CCR

41 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=0.66Bone Marrow Transplant 15: , 1995

42 Acknowledgements Funding Susanne AhrensStatistics Muenster Gabriele Braun-MunzingerOrganisation & Management Regina KlossOffice Michaela KuhlenTrial assistance Michael PaulussenTrial co-ordination Antje SteinhoffData management Carolyn DouglasData management Leicester Claire WestonStatistics Leicester EU BIOMED


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