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Orthopaedic Proceedings
Vol. 92-B, Issue SUPP_III | Pages 432 - 433
1 Jul 2010
Ladenstein R Pötschger U Delay M Whelan J Paulussen M Oberlin O Craft A
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The Euro-E.W.I.N.G. 99 trial aimed to improve the dismal prognosis of patients with primary disseminated multifocal Ewing tumors (PDM-ET) with a dose-intense treatment concept.

From 1999 to 2005, 281 patients with PDM-ET were enrolled onto the EURO-E.W.I.N.G. 99 trial. Median age was 16.2 years (0.4–49). Recommended treatment consisted of 6 VIDE, one VAI cycle, local treatment (surgery and/or radiotherapy), and high-dose busulfan-melphalan followed by autologuous stem cell transplantation (HDT/SCT).

After a median follow up of 3.8 years, event-free survival (EFS) and overall survival (OS) at 3 years for all 281 patients were 27%±3% and 34%±4%. Six VIDE cycles were completed by 250 patients (89%); 169 (60%) received HDT/SCT. Forty-six children less than 14 years and HDT/SCT achieved a 3-year EFS of 45%. Cox regression analyses demonstrated increased risk at diagnosis for patients over 14 years (HR 1.6), a primary tumor volume > 200ml (HR 1.8), more than one bone metastatic site (hazard ratio: HR 2.0, bone marrow metastases (HR 1.6) and additional lung metastases (HR 1.5). An “up front” risk score based on these HR factors identified three groups with EFS rates of 50% for score ≤3 (82 patients), 25% for score > 3 to < 5 (102 patients), and 10% for score ≥5 (70 patients), p< 0.0001.

PDM-ET patients may survive with intensive multimodal therapy. Age, tumor volume, and extent of meta-static spread are relevant risk factors. A score based on these factors identifies PDM-ET patients may facilitate risk adapted treatment approaches.


Orthopaedic Proceedings
Vol. 92-B, Issue SUPP_III | Pages 460 - 460
1 Jul 2010
Stark M Dantonello T Winkler P Leuschner I Bölling T Seitz G Hallmen E Veit-Friedrich I Bielack S Paulussen M Ladenstein R Kazanowska B Ljungman G Klingebiel T Koscielniak E
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Tumour volume reduction (i.e. response), assessed following induction chemotherapy, has been identified as a prognostic factor for localized embryonal rhabdomyosarcoma (RME) in the CWS studies. In combination with other risk factors, it has been used to stratify secondary local and systemic treatment. It is however unclear whether the poor outcome of non-responders is due to insufficient local and/or systemic post-induction treatment.

We analyzed post-induction therapy of RME-patients < 21 years with unresected localized tumours (IRS-III) and poor response (NR, i.e. < 33% tumour volume reduction) treated 1980–2005 in five consecutive CWS-trials. The NR were reviewed and subclassified (Objective Response (OR; i.e.< 33%–0%) vs. Stable Disease/Progression (PD; i.e. no reduction)).

From 758 IRS-III RME-patients, 59 were NR (n=34 OR, n=25 PD). Induction for NR included dactinomycin, vincristine, alkylators ± anthracyclines in all patients. There were no significant differences in comparison of the control group and NR with regard to age, size, TN-classification, apart from site (p=0.04), and no differences regarding these parameters between OR and PD. Twenty-four NR received continued induction chemotherapy, n=32 other combinations, and n=3 no further chemotherapy following response assessment. Four patients were treated with additional high-dose chemotherapy. Fourty-two NR were irradiated with a median dose of 48Gy (control group: 45Gy). In 20 NR, the tumours were completely resected. As of 9/2008, with a median follow-up of 4.5 years (range: 0.9–12.1) for NR survivors, 34 NR are alive in CR. Reasons for the 25 deaths were: local/combined failure (n=21), systemic failure (n=1), and other reasons (n= 3). 5-yrs-OS was 71±4% for the control group, 78±15% for OR, but only 43±15% for PD (p< 0.01).

Response is an important surrogate marker of outcome, but per se associated with a poor prognosis only in tumours without any volume regression to induction chemotherapy. Ineffective local control drives mortality in these patients.


Orthopaedic Proceedings
Vol. 92-B, Issue SUPP_III | Pages 458 - 458
1 Jul 2010
Exner G Harasta E Honegger H von Hochstetter A Paulussen M
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Rationale: Osteosarcoma predominantly affects adolescents and young adults. Reduced fertility in men is well documented following treatment for osteosarcoma and related to chemotoxicity.

We have however not found data about the health of children of patients formerly treated for osteosarcoma.

Among our few patients we have had one offspring with an infantile fibrosarcoma successfully treated with high dose chemotherapy and surgery. One mother has secondary gastric malignancy after successful pregnancy.

With this contribution we want to draw the attention to include data of children in the long-term implications of osteosarcoma and its treatment.

Materials and Methods: Patients: Of 75 patients with osteosarcoma 11 patients (5 women, 6 men) have 16 children‚ produced’ after completed oncologic treatment

All women became pregnant as planned. There are no female patients evidently infertile. One man among our patients shows azoospermia and is infertile. One man with oliogespermia has a healthy daughter after successful vitro fertilisation.

All patients have had treatment for osteosarcoma after puberty.

Offsprings: Pregnancy and delivery were uneventful for all children. The one girl mentioned above at birth showed a tumor of the Plexus brachialis which was a biopsy proven infantile fibrosarcoma. She received high dose chemotherapy. Resection of the tumor retaining the brachial at 9 months of age showed only scarce tumor residuals; she is disease free at 4 years of age. Her two siblings are healthy

Conclusion: We want to stress that in follow up studies events during pregnancy and health of offsprings should be included.


Orthopaedic Proceedings
Vol. 92-B, Issue SUPP_III | Pages 432 - 432
1 Jul 2010
Juergens H Manner D Gerss J Ranft A Paulussen M Dirksen U
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Tumor size and metastases are known risk factors in Ewing tumors. Adequate staging is essential to stratify treatment intensity, but TNM staging is not established.

The validity of TNM staging was tested based on tumor volume (T1 ≤200 ml; T2 > 200 ml ≤500 ml; T3, > 500 ml), the presence or absence of lymph node metastases (N0, N1), and distant metastases (M0, no metastases; M1 lung/pleura metastases; M1a ≤5 nodules; M1b > 5 lesions; M2 bone metastases; M2a, 1 lesion; M2b > 1 lesion and/or microscopic bone marrow contamination; M3, multi-system metastases). 1799 Ewing sarcoma patients of the (EI)CESS/EE99 studies entered into the Muenster database from 1981–2008 were analyzed.

Ten-year event-free survival (EFS) was 0.46. EFS in patients without metastases (T1-3N0M0) was 0.56 compared to 0.22 in metastatic patients (T1-3N0,1M1-3), p< .0001. In non-metastatic patients, tumor volume discriminated EFS: T1:0.62; T2:0.43; T3:0.40, p< .0001. The rare event of lymph node metastases correlated with unfavorable prognosis (N0:0.47, N1:0.12, p< .0001). The difference in EFS between pulmonary, skeletal and multi-system dissemination was significant: M1:0.29, M2:0.23; M3:0.12, p< .0001. The discrimination of M1 subgroups (M1a/M1b) was of prognostic relevance (p=.0050); M2 subgroups (M2a/M2b) discriminated outcome less clearly (p=.0457).

TNM staging is appropriate in Ewing tumors and should be incorporated in future trials.


Orthopaedic Proceedings
Vol. 92-B, Issue SUPP_III | Pages 433 - 433
1 Jul 2010
Carrle D Blank B Paulussen M Reichardt P Bielack S
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Purpose: Compared to paediatric cancer patients adolescents and young adults may have disadvantaged access to care. Therefore we investigated the correlation of patient, tumour and institutional characteristics with the outcome of osteosarcoma in this age group.

Method: Analysis of consecutive patients aged 15–24 years with newly diagnosed high-grade osteosarcoma entered into the Cooperative Osteosarcoma Study Group(COSS) registry 1980–2004 and treated in pediatric (PO) or medical oncology institutions (MO). Standardised multimodal therapy according to a COSS-protocol. Event-free survival rates (EFS) evaluated in relation to patient demographics and registering institution (MO vs PO and treatment volume as: < 1, 1–3 or > 3 osteosarcoma/year).

Results: 944 patients identified (median age: 17.35 years; range: 15.01–24.99; 79% aged < 20 years). Patients > 20 years were more likely than younger patients to be treated in centers with low treatment volume (p< .0001) and MO (p< .0001) but otherwise comparable. After a median follow-up of 5.59 years (range: 0.12 – 27.92) for all patients and 8.08 years (range: 0.19 – 27.92) for 617 survivors, actuarial 5/10 year event-free survival probability (EFS) was 58%/54%. Upon univariate analysis of the total cohort neither of the institutional variables correlated significantly with EFS. There was a correlation between treatment in PO and improved EFS for patients > 20 years (p=.001) and for those with primary metastases (p=.009). Upon multivariate testing type of center (odds ratio: 1.26; p=.022) but not treatment volume were significant.

Conclusion: Within a framework of standardised regimens and consultation supportby our group’s infrastructure, similar EFS-probabilites were obtained regardless of institutional treatment volumes. Observed variations in outcome between PO and MO may be partly due to different distributions of presenting factors but deserve further investigation.


Orthopaedic Proceedings
Vol. 92-B, Issue SUPP_III | Pages 434 - 434
1 Jul 2010
Paulussen M Ranft A Dirksen U Jürgens H
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Background: Intensive chemotherapy in sarcoma treatment may lead to weight loss, and in turn reduce dose intensity. A possible correlation between weight loss under treatment and outcome has never been analysed in sarcoma treatment. Ewing sarcoma (ES) patients undergoing intensive non-corticosteroid-containing chemotherapy commonly experience weight loss. The German Paediatric Oncology/Haematology Society (GPOH) Ewing sarcoma trials (CESS, EICESS) registry was analysed with respect to weight loss and outcome.

Patients and Methods: Body weight (BW) both at diagnosis and after a median of 12 courses of chemotherapy was available in 837 of 1549 ES patients, excluding amputees. Changes in BW were calculated as percentage of initial BW; outcome was determined as event-free-survival (EFS) from diagnosis according to Kaplan-Meier. Correlations of BW and outcome and potential confounders like disease stage or tumour volume were estimated uni- and multivariately.

Results: Weight loss was not correlated with inferior outcome: A loss of 10%–20% of BW was associated with a slightly more favourable outcome (3-year EFS 0.64 +/−0.106, N=82) than weight gain of 10%–20% of BW (3-year EFS 0.58 +/−0.098, N=97), p=0.101. Multivariate analyses revealed no confounders interfering with these results.

Conclusions: In 837 ES-patients analysed, weight loss did not correlate with inferior outcome. This should be observed in discussions about tube feeding and/or parenteral nutrition under cytostatic therapy. Future analyses of the prognostic impact of extreme under- or overweight both at diagnosis or under treatment are warranted in order to develop appropriate guidelines. Validity of this observation should be analysed for other solid tumours.

Supported by EC Biomed and Deutsche Krebshilfe