A multi-disciplinary study investigating radiotherapy in Ewing's sarcoma - a final report of POG 8346

Purpose: To determine if involved field radiation (IF) is equivalent to standard whole bone radiation (SF) in local tumor control; to establish patterns of failure following treatment; and to determine response, event free (EFS) and overall survival rates from multi-disciplinary therapy in Ewing's Sarcoma (ES). Materials and Methods: Between 1983 and 1988, 184 children with ES were enrolled onto POG 8346. 178 (97%) met eligibility criteria; 6 had non-ES pathology. Induction treatment of Cyclophosphamide/Adriamycin (C/A) x 12 weeks was followed by local treatment either surgery or radiation therapy (XRT) and C/A, Dactinomycin and Vincristine for 50 weeks. Resection was advised for patients with small primary tumors if accomplished without functional loss. 40 patients were randomized to receive SF, whole bone XRT to 39.6 Gy plus a 16.2 Gy boost (total 55.8 Gy) or IF to 55.8 Gy while 84 were assigned to IF XRT. Results: Of 179 eligible patients, 141 (79%) had localized disease and 37 (21%) had metastases. Their 5 yr. EFS was 51% (SE = 5%) and 23% (SE = 7%) respectively. The response rate (RR) to induction chemotherapy was 88% (28% complete, 60% partial), but after XRT the RR increased to 98%. 37 of the localized patients underwent resection of whom 16 (43%) required post-operative XRT with 5 yr. EFS of 80% (SE = 7%). 104 of the localized patients received XRT and had a 5 year EFS of 41% (SE = 5%), with no difference in EFS between those randomized to SF vs. IF. Site of primary tumor correlated with 5 year EFS: Distal extremity - 65% (SE = 8%), Central - 63% (SE = 9%), Proximal extremity - 46% (SE = 8%), and Pelvis - 24% (SE = 10%). Tumor size did not influence EFS. Patterns of failure among the 141 localized patients were: local only - 18 (13%), local and systemic 14 (10%), systemic only 28 (20%). There were 4 (11%) local failures among those resected +/- XRT, but 28 (27%) following XRT alone. By protocol, patients suffering a relapse were required to undergo a biopsy of the primary tumor whether the site of relapse was systemic or local. Of 21 irradiated patients with primary site biopsy, 11 had pathologically confirmed local failure; 10 patients were symptomatic and in only 1 patient was it unsuspected. Patients with major radiotherapy protocol deviations in dose or volume had inferior 5 yr. local control than those with no deviations. Adequate treatment volume was most critical with only 45% local control for patients with XRT volume deviations vs. 72% for those treated to the protocol specified volume. Conclusion: As most failures in ES are systemic, satisfactory EFS requires effective systemic chemotherapy. Involved Field XRT requires giving full doses and appropriate volumes. Systematic use of MRI and 3-D conformal XRT (which were not used in this study) should also improve outcome