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.

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.