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

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

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

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

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 18:204-213, 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

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 18:204-213, 2000

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

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 1.5.2000)

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

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 1.28 TUMOR VOLUME  200 ml 0.0002 1.72 TUMOR SITE pelvis 0.12 1.28 LOCAL THERAPY RAD alone 0.0002 1.78 CLINIC SIZE < 10 pts. 0.0052 1.52 Cox Regression - Model 2: Response to CT±RT evaluated (n=446) AGE  15 years 0.08 1.33 TUMOR VOLUME  200 ml 0.12 1.30 TUMOR SITE pelvis 0.14 1.34 HIST. RESPONSE poor 0.0001 2.00 CESS 81 - EICESS 92 (PP, no pMet), April 2002

(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%

Modalities of local therapy OP OP+RAD RAD RAD+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/AML 2 / 6 ALL/NHL 1 / 6 Squamous cell carcinoma 1 / 6 Liposarcoma CSCR 0.0093 Paulussen et al, Annals of Oncology 12:1619-1630, 2001

EICESS 92 - Second malignancies Second cancer risk Paulussen et al, Annals of Oncology 12:1619-1630, 2001

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 Goeteborg_2.ppt 2 1 2 2 1 2 1 1 1 1 1 1

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

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 % Goeteborg_2.ppt 6

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

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

Ewing tumour Treatment intensity IESS-II 5-year Survival Standard dose, continuous 63 % High dose, intermittent 73 % Burgert et al., JCO 8:1990 Goeteborg_2.ppt 6

Ewing tumour Treatment 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 83:1991 Goeteborg_2.ppt 6

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 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 Goeteborg_2.ppt 6

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

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

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. 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 Goeteborg_2.ppt 6

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. 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 Goeteborg_2.ppt 6

EURO-E.W.I.N.G. 99 R 2: VAI versus Bu-Mel 1. </> 200 ml OP Poor Response 2. > 200 ml RAD+/-OP 3. </> 200 ml Lung metastases Goeteborg_2.ppt 6

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 Goeteborg_2.ppt 6

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 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 No HDT (n=263) 0.24 vs. HDT (n=79) 0.19 EFS (10 y) No HDT (n=263) 0.24 vs. HDT (n=79) 0.19 p=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) 0.34 p=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 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 15:697-705, 1995

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