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A total of 342 previously untreated eligible children were entered into the first Intergroup Ewing's Sarcoma Study (IESS) between May 1973 and November 1978. In group I institutions, patients were randomized between treatment 1 (radiotherapy to primary lesion plus cyclophosphamide, vincristine, dactinomycin, and Adriamycin [doxorubicin; Adria Laboratories, Columbus, OH] [VAC plus ADR]) or treatment 2 (same as treatment 1 without ADR), and group II institutions randomized patients between treatment 2 or treatment 3 (same as treatment 2 plus bilateral pulmonary radiotherapy [VAC plus BPR]). The percentages of patients relapse-free and surviving (RFS) at 5 years for treatments 1, 2, and 3 were 60%, 24%, and 44%, respectively. There was strong statistical evidence of a significant advantage in RFS for treatment 1 (VAC plus ADR) versus 2 (VAC alone) (P less than .001) and 3 (P less than .05) and also of treatment 3 versus 2 (P less than .001). Similar significant results were observed with respect to overall survival. Patients with disease at pelvic sites have significantly poorer survival at 5 years than those with disease at nonpelvic sites (34% v 57%; P less than .001). Among pelvic cases, there was no evidence of differing survival by treatment (P = .81), but among nonpelvic cases, there was strong evidence of differing survival by treatment (P less than .001). The overall percentage of patients developing metastatic disease was 44%; the percentages by treatments 1, 2, and 3 were 30%, 72%, and 42%, respectively. The overall incidence of local recurrence was 15%, and there was no evidence that local recurrence rate differed by treatment. Patient characteristics related to prognosis, both with respect to RFS and overall survival experience, were primary site (nonpelvic patients were most favorable) and patient age (younger patients were more favorable).

Multimodal therapy consisting of radiation therapy to all areas of gross disease and intensive combination chemotherapy was administered to 44 patients with Ewing's sarcoma. Seven of these patients had regional disease and the others had clinical evidence of distant metastases. The median duration of time on study for all patients was 75 weeks. A complete response occurred in 31 of the patients and 17 are currently free of disease. Four deaths resulted from complications of therapy; 2 were due to infection and 2 due to adriamycin-related cardiomyopathy.

This paper is a progress report on the role of radiation therapy (RT) in local tumor control and the decreased incidence of pulmonary metastasis in 251 patients entered in the Intergroup Ewing's Sarcoma Study. All were followed for more that 1 year, and their RT records were reviewed. Doses to the primary tumor in the range of 4,500--6,500 rad were administered over approximately 5 to 6 weeks in combination with 4 drugs, i.e., vincristine (VCR), dactinomycin (DAC), cyclophosphamide (CY), and adriamycin, or only the first 3. One group of patients received the 3 drugs and bilateral pulmonary irradiation (approximately 1,500 rad in 2 wk). Preliminary analysis showed a local primary tumor control of approximately 90%. Patients with lesions in the pelvis and humerus had local failure rates of 13% (7 of 54) and 21.4% (6 of 28), respectively. The treatment groups differed significantly in the incidence of pulmonary metastasis. Patients treated with the 4 drugs (regimen 1) had a 14% incidence, whereas 42% of those treated with only 3 drugs (regimen 2) developed pulmonary metastases. Of all patients treated with 3 drugs and pulmonary irradiation (regimen 3), 18% showed lung metastases. The study indicated that intensive chemotherapy and RT significantly improved the local control and survival of patients with localized Ewing's sarcoma. However, the high incidence of metastasis indicated the need for more effective systemic chemotherapy for further improvement of treatment results. More studies are needed so we can define the volume to be treated and the optimal dose of irradiation to determine a therapeutic strategy that will yield optimal survival and tumor control with the fewest sequelae.

A randomized study of 264 children and adults with previously untreated localized Ewing's sarcoma of bone was undertaken between 1973 and 1978 by 83 institutions of three national study groups: Children's Cancer Study Group, Southwest Oncology Group, and Cancer and Leukemia Group B. The Intergroup Study was designed to determine if the addition of adriamycin (ADR) or bilateral pulmonary radiotherapy (RT) to vincristine, dactinomycin, and cyclophosphamide (VAC therapy) would improve survival and reduce local recurrences and metastases. All patients received RT to the primary lesion, and the survival rate after 3 years was 65%. The most effective treatment regimen was VAC plus ADR; 74% of the patients were free of disease at 2 years. The lengths of disease-free status and survival of patients treated with VAC plus ADR or VAC plus RT did not differ. However, both regimens were significantly superior to treatment with VAC alone. The addition of ADR or bilateral pulmonary RT to VAC was highly advantageous to patients with nonpelvic primaries. Bone and lung were the major sites of distant relapse, but the addition of bilateral pulmonary RT showed no advantage over that of ADR in reducing the occurrence of lung metastases. These recent results should eliminate some of the pessimism that has accompanied a diagnosis of Ewing's sarcoma, although distant metastases continued to be a major reason for failure in the control of this tumor. Survival of these patients can be improved through well-controlled clinical trials designed to determine optimal adjuvant chemotherapy and treatment of the primary lesion.

Patient characteristics of 272 patients entered in a clinical trial conducted by the Pediatric Intergroup Ewing's Sarcoma Committee between June 1972 and November 1978 were examined for their relationship to prognosis. Prognosis was defined as disease-free survival time (time to local recurrence and/or metastatic disease) and overall survival time; all times were measured from the start of treatment. In a multivariate regression model, primary site of disease was the major variable that influenced prognosis, and patients with pelvic sites had the least favorable prognoses, followed by those with proximal and rib sites. The most favorable sites were distal and other. The median disease-free and survival times in weeks by primary site were, respectively: pelvis (69, 112), proximal (102, 141), rib (105, 109+), distal (226+, 240), and other (96+, 199+). Females had better prognoses than males; the median survival times were 197 and 147 weeks, respectively. An abnormal liver function as indicated by an abnormal serum glutamic-oxaloacetic transaminase value (greater than 45 IU) was a bad prognostic sign, although only 8 patients had this finding; their median survival time was 94 weeks. Patients who had resections had a slight advantage in survival compared with those having biopsies, though the difference favoring resection patients was not consistent for both sexes in any primary site. Individual characteristics of the patients that were of prognostic significance were: blood lymphocyte counts (high counts favorable), polymorphonuclear leukocyte counts (high counts unfavorable), and time from symptoms to diagnosis (times less than 1 mol favorable). Patients who received treatment 2 had significantly poorer prognoses than those given treatments 1 or 3. The median disease-free and survival times by treatment were (in wk): 1 (134, 198+), 2 (81, 120), and 3 (123, 182).