Development of curative therapies for Ewing sarcomas by interdisciplinary cooperative groups in Europe.

Curative therapies for Ewing sarcoma have been developed within cooperative groups. Consecutive clinical trials have systematically assessed the impact and timing of local therapy and the activity of cytotoxic drugs and their combinations. They have led to an increase of long-term disease-free survival to around 70% in patients with localized disease. Translational research in ES remains an area in which interdisciplinary and international cooperation is essential for future progress. This article reviews current state-of-the art therapy, with a focus on trials performed in Europe, and summarizes novel strategies to further advance both the cure rates and quality of survival.

[EICESS 92 (European Intergroup Cooperative Ewing's Sarcoma Study)-- preliminary results]. / EICESS 92 (European Intergroup Cooperative Ewing's Sarcoma Study)--Erste Ergebnisse.

BACKGROUND: Ewing tumor patients' outcome is 50% to 60% with current treatment strategies. Questions concerning toxicity and secondary malignancies are of increasing importance. PATIENTS AND METHODS: 631 patients were registered with the German EICESS study center of the European Intergroup Cooperative Ewing's Sarcoma Study, 369 patients were randomized. Treatment apart from local therapy consisted of 14 courses of Vincristine, Actinomycin D, Cyclophosphamide or Ifosfamide, Adriamycin (Doxorubicin), with or without Etoposide. First results concerning event-free survival (EFS), toxicity, and the rate of secondary malignancies three years after diagnosis are presented. RESULTS: Three year EFS was 0.66 for patients with localized tumors, 0.43 for patients with primary pulmonary/pleural metastases, and 0.29 for patients with other metastases, respectively. Large tumor volume or pelvic site, especially if inoperable, were adverse prognostic factors. Both histological and MRT-defined response were positively correlated to outcome. Up to 67% of patients experienced WHO grade IV toxicity, mostly related to bone marrow depression. The treatment related mortality was 1% (6/631). Until 15.02.1999, six of 687 patients have suffered secondary malignancies, two of six after (additional) myeloablative therapy. CONCLUSIONS: EICESS 92 treatment is toxic, but manageable and compares favorably to international results. New strategies must be sought for certain risk groups of patients.

Evaluation of prognostic factors in a tumor volume-adapted treatment strategy for localized Ewing sarcoma of bone: the CESS 86 experience. Cooperative Ewing Sarcoma Study.

BACKGROUND: The Cooperative Ewing Sarcoma Study (CESS 86), conducted by the German Society of Pediatric Oncology and Hematology (GPOH), was planned on the basis of the results of the preceding CESS 81 study. The prognostic significance of tumor volume in localized Ewing sarcoma of bone was well documented in the CESS 81 trial. As a consequence, the treatment intensity was adapted to volume in the follow-up CESS 86 trial: the four-drug combination used in CESS 81 was amended for patients with large tumor volume (> or = 100 ml), where ifosfamide was substituted for cyclophosphamide. PROCEDURE: From January 1986 to June 1991, 177 protocol patients with localized Ewing sarcoma of bone were registered in CESS 86. The prognostic implication of tumor volume and several covariates was evaluated using Kaplan-Meier life table analysis and Cox's proportional hazard model. RESULTS: The estimated 5- and 8-year event-free survival (EFS) rates were both 59%. Age, gender, tumor site, and a tumor volume of 100 ml did not distinguish groups of patients with different prognosis. However, the prognosis of patients with tumors >200 ml (8-year EFS rate: 42%) was significantly inferior compared to patients with tumors both of 100 to 200 ml (70%) and of <100 ml (63%). In contrast to CESS 81, the histological response to chemotherapy was no longer a significant prognostic factor (EFS: 64% for good and 50% for poor responders, respectively). CONCLUSIONS: Despite risk-adapted treatment intensity, tumor volume retained its prognostic significance; the cut point, however, was shifted toward larger volumes.

[Results of treatment of primary exclusively pulmonary metastatic Ewing sarcoma. A retrospective analysis of 41 patients]. / Behandlungsergebnisse beim primär ausschliesslich pulmonal metastasierten Ewingsarkom. Eine retrospektive Analyse von 41 Patienten.

41 patients presenting with primary metastatic Ewing's sarcoma or malignant peripheral neuroectodermal tumor (PNET) with initial metastases restricted to the lungs and/or pleural space were analysed with respect to clinical manifestation and treatment results retrospectively. All patients were treated according to the protocols CESS 81 and CESS 86 of the German Society of Pediatric Oncology and Hematology (GPOH). The time since diagnosis ranges from 19 to 137 months, with a median of 72 months. Median relapse-free survival time was 21.8 months. 18 patients were female, 23 were male. The majority of primary tumors exceeded 100 ml of volume. Preferred sites were the pelvis with 16 cases, the limbs with 14 cases and the chest wall with 6 cases. The histological specification of the tumor was Ewing's sarcoma in 22 and PNET in 11 patients, in 8 cases no specific distinction was given. As to local therapy of the primary tumor, 12 patients underwent radiotherapy, 11 surgery, and 18 a combination of both. Patients were allocated to one of these three options on an individual basis. Cytostatic drug treatment was given according to the GPOH-CESS 81 and CESS 86 protocols. As calculated by means of the Kaplan-Meier analysis, relapse-free survival was 30% ten years after diagnosis. Surgery or pulmonary irradiation of 12-20 Gy was applied to lung metastases. 12 of 27 patients are in continuous complete remission following this therapeutic approach.