Value of local treatment in extrapulmonary metastatic Ewing sarcoma Uta Dirksen , Julia Häusler, Andreas Ranft, Tobias Bölling, Georg Gosheger, Volker Vieth, Heribert Jürgens Dear colleagues, Mr chairman/ It is a great honor to present our data on the value of local treatment in extrapulmonary metastasized Ewing tumor today on this wonderful SIOP meeting. The data collection – exspecially on local treatment of non pulmonary metasases was performed by Julia Häusler, who did her doctoral thesis on this important issue LONDON 2008

Ewing sarcoma require multimodal treatment concepts Current paradigm: Ewing sarcoma cannot be cured by chemotherapy alone, but require additional local treatment 1,2,3,4,5,6,7,8. What then is the impact of local treatment in the therapeutic concept in primary disseminated Ewing sarcoma with extrapulmonary metastases (EPMET)? 1) Jurgens H et al. Cancer 1988, 2) Paulussen M et al. J Clin Oncol 2001, 3) Burgert EO et al. J Clin Oncol 1990, 4) Nesbit ME et al. J Clin Oncol 1990, 5) Craft AW et al. Eur J Cancer 1997, 6) Bacci G et al. Cancer 1998, 7) Rosito P et al. Cancer 1999, 8) Elomaa I et al. Eur J Cancer 2000 As we all know, there is a paradigm in the treatment of Ewing sarcoma: citation The value of local treatment on the outcome in primary metastasized patients is not well known, therefore we focused on analysing the impact of local treatment in the therapeutic concept in primary disseminated Ewing Tumors with EPMETS.

Patients 120 patients age 16.2 y (4.2-54.1 y) EURO-E.W.I.N.G. 99 trial centre Münster (1999-2006) age 16.2 y (4.2-54.1 y) median follow-up 1.38 y (0.3-8 y) sex 54 f (45%); 66 m (55%) 3-year EFS 0.24 [95% CI 0.16-0.33] median tumour volume 493 ml Data on local treatment was available from 120 patients, registered in the EURO E.W.I.N.G. 99 trial center Münster. Data on the treatment of extrapulmonary metastases had to be collected seperatly , as the EURO E.W.I.N.G. 99 trial does not provide CRFs for this treatment. Age…..

Patients` characteristics Primary tumour 82 pts (68%) central axial (pelvis, spine, abdomen, chest, head, neck) 34 pts (28.5%) extremities (upper and lower extremities) 4 pts (3.5%) not defined Primary tumors were located centrally in 68% of the patients, at the extremities in 28.5% of the patients and in 3 % of pts, a primary tumor could not be defined.

Patients` characteristics Metastatic sites 97 pts (82.2%) bone 1 met (11 pts; 11.7%), 2-5 met (30 pts; 31.9%), >5 met (53 pts; 56.4%) 49 pts (43.8%) (+) bone marrow 47 pts (39.5%) + lung 48 pts (40%) (+) other ln (26 pts; 22.8%), liver (11 pts; 9.4%), CNS (1 pt; 0.9%), other (10 pts; 9.3%) 82% of the patients presented with bony metastases, approximately 44% presented with or with additional bone marrow metastases , 39% presented with additional lung metastases and 40% had other metastases e.g. lymphnode, liver, CNS and other more rare locations

Analyses of risk factors Prognostic factors: - number of bone metastases - tumour volume - age Treatment: - value of high dose chemotherapy - value of local therapy to primary tumour and /or metastases We analyzed the following factors: Citation And concerning the treatment modalities , the impact of HD Chtx, and the value of Loc Tx on PT and Mets were analyzed -

Number of bone metastases 1 3y-EFS:0.61 (N=11) 2-5 3y-EFS:0.16 (N=30) >5 3y-EFS:0.19 (N=53) p<.001 Time from diagnosis (years) Cumulative Survival This curve shows the impact of bony metastases on the survival of R3 patients. While patients with only one bony metastases have a good prognosis, the prognosis for patients with more than one bony metastases is extremely poor.

Tumour volume of the primary tumour <200ml 3y-EFS: 0.33 (n=36) >200ml 3y-EFS: 0.23 (n=65) p=.188 Time from diagnosis (years) Cumulative Survival The tumor volume did not influence the 3- years EFS in our R3 cohort.

Time from diagnosis (years) Age <15y 3y-EFS: 0.30 (n=49) >15y 3y-EFS: 0.21 (n=71) p=.114 Time from diagnosis (years) Cumulative Survival Age was also no significant prognostic factor, although after the cut off point at three years a more pronounced distribution amongst pts younger than 15 years and older than 15 years occurs.

EURO - E.W.I.N.G. 99 10 We analyzed the following factors: Citation And concerning the treatment modalities , the impact of HD Chtx, and the value of Loc Tx on PT and Mets were analyzed - Treo-Mel 10

High dose chemotherapy other HD 3y-EFS: 0.41 (n=15) Bu-Mel 3y-EFS: 0.26 (n=71) no HD 3y-EFS: 0.13 (n=34) p<.001 Time from diagnosis (years) Cumulative Survival HD treatment did influence the prognosis in the 120 analyzed R3 patients: Patients, who received no HD Tx showed the most unfavorable prognosis, patients treated with BuMel HDTx fared a little better but the best prognosis was observed in patients treated with other HD regiments.

Local therapy of primary tumour and/or metastases LT of PT and MET 3y-EFS: 0.37 (n=49) LT of PT or MET 3y-EFS: 0.17 (n=41) no LT 3y-EFS: 0.15 (n=30) p<.001 Time from diagnosis (years) Cumulative Survival Next we analyzed the impact of local treatment to PT and MET Vs PT or MET vs no local treatment. Our data clearly show, that patients, who received local treatment to both PT plus Mets had the best prognosis, the prognosis in pts, who received local treatment to either PT or Mets was just at the cut off time point (3 years) not above those lacking local treatment, but just a few weeks later, the effect of local treatment to either PT or Met S becomes more evident.

Local treatment modalities of primary tumour OP&RT 3y-EFS:0.47 (n=21) RT 3y-EFS:0.23 (n=40) OP 3y-EFS:0.25 (n=26) no LT 3y-EFS:0.13 (n=33) p<.001 Time from diagnosis (years) Cumulative Survival Next, we analyzed whether different local treatment modalities as there are: OP plus RT, RT or OP alone and no local treatment had an influence on the prognosis in R3 patients. It is clear from our analysis, that those patients, who received combined modality treatment had the best prognosis. Patient who received either surgery or radiotherapy had a better prognosis that patient who any local treatment.

Risk profile Risk factor X comb. LT of PT (N=21) Ø comb. LT of PT (N=99) X1: TV >200 ml 68% 63% X2: bone metastases 86% 81% X3: >1 bone metastases 67% (of X2) 93% (of X2) To exclude, that these data were biased by other favorable risk factors in the group of patients with combined modality local treatment, we analyzed the subgroup of pts There was no significant difference in TV, or presence of bone metastases. But there was a difference in the amount of bone metastases, although not significant. comb. LT= combined local treatment (surgery and radiotherapy), PT= primary tumour, PT-Vol.= tumour volume of the primary tumour no significant difference in risk profile between patients with combined LT vs no combined LT.

Modalities of local treatment to extrapulmonary metastases OP&RT 3y-EFS: 0.86 (n=7) RT 3y-EFS: 0.27 (n=37) OP 3y-EFS: 0.25 (n=8) no LT 3y-EFS: 0.17 (n=68) p=.002 Time from diagnosis (years) Cumulative Survival Next we analysed the value of local treatment modalities in metastases. We found a small group of patients treated with OP plus RT with an excellent prognosis. But also those patients who received one local treatemnt modality on the metastases showed a more favourable prognosis than those who received no local treatment.

Risk profile Risk factor comb. LT of EPM (N=7) Ø comb. LT of EPM (N=113) X1: PTV >200 ml 67% 64% X2: bone metastases 86% 82% X3: >1 bone metastases 67% (of X2) 90% (of X2) Again, we analysed the subgroup with the most favorable outcome vs the subgroup with the poorest outcome for other, well known risk factors as TV and bone metastases. Thjere was no difference in Tv and presence of bone metastases , but a difference in the amount of bone metastases comb. LT= combined local treatment (surgery and radiotherapy), EPM= extrapulmonary metastases, PTV = primary tumour volume comparable risk profile between patients with combined LT vs no combined LT.

Multivariate analyses (N=101) Variable Label Risk Ratio p Local treatment PT and EPM 1 (.002) PT or EPM 1.37 (0.73-2.57) .328 none 2.93 (1.60-5.35) .000 High dose chemotherapy no 3.45 (1.94-6.16) Age >15 y 1.11 (0.68-1.80) .672 Tumor volume >200 ml 1.66 (0.93-2.95) .085 Bone metastasis (.153) 1 met 0.47 (0.15-1.46) .194 >1 met 1.31 (0.68-2.54) .417 Next we performed a multivariate analysis. The multivariate analysis in all patients showed, that no local treatment and absence of HD chemotherpay were significant risk factors.

Multivariate Analyses (N=101) Bias: Patients showing progression within the first 6 months of treatment receive - no local treatment - no high dose chemotherapy  Exclusion of patients showing progressive disease within the first 6 months of therapy However, this analysis might be biased by the fact, that some of the R3 patients would present with progressive disease prior to HD Tx and/or local treatment. Therefore, we performed another multivariate analysis and excluded those pts with progression within the first 6 month after diagnosis.

Multivariate analyses (N=87) Variable Label Risk ratio p Local treatment PT and EPM 1 (.066) PT or EPM 1.64 (0.85-3.16) .141 none 2.15 (1.07-4.33) .031 High dose chemotherapy no 1.59 (0.73-3.44) .240 Age >15 y 1.04 (0.61-1.76) .899 Tumour volume >200 ml 1.54 (0.83-2.84) .169 Bone metastases (.186) 1 met 0.72 (0.22-2.32) .581 >1 met 1.64 (0.78-3.47) .194 In this group of pts only the absence pf local treatment was a significant risk factor

Conclusion Combined local treatment (OP&RT) of primary tumour and /or extrapulmonary metastases significantly improves the prognosis in pts with primary disseminated Ewing tumor. Local treatment of primary tumour and /or extrapulmonary metastases significantly improves the prognosis in pts with primary disseminated Ewing tumor. High dose chemotherapy must be compatible with local treatment. We conclude…..

Interdisciplinary care We conclude….. 21

THANKS to you Regina Kloss Gabriele Braun-Munzinger Institutions for their support in completing the data set concerning local treatment of metastases. Regina Kloss Gabriele Braun-Munzinger ewing@uni-muenster.de