BACKGROUND: The appropriate therapy for Stage C neuroblastoma (NB) is uncertain. Because of the need for information applicable to the development of new randomized trials, we deemed it appropriate to investigate the patient characteristics, survival, patterns of failure, and complications of therapy in these children. METHODS: Search of the medical records of Duke University Medical Center from 1/1/60 to 3/1/95 disclosed 146 patients with NB, which included 13 Stage C patients. RESULTS: Mean age at diagnosis was 3.6 years. Twelve patients had primary abdominal tumors (92%) and one had a thoracic primary (8%). Twelve (92%) of the patients received chemotherapy including cyclophosphamide. 11 (85%). Adriamycin, 6 (46%), cisplatinum, 4 (30%), and VP 16, 4 (30%). All patients received radiotherapy (RT, mean dose administered 22.6 +/- 8 Gy). With a mean follow-up of 8 years, the 10-year overall survival was 54% and the relapse-free survival was 46%. Four patients relapsed in the primary operative tumor bed and primary RT field, two relapsed in mediastinal or left supraclavicular lymph nodes as well as distantly following treatment of upper abdominal primaries, and in one the site of relapse is unknown. Long-term complications of therapy included two children who developed secondary malignancies associated with RT, two girls who developed primary ovarian failure, five children with clinically significant kyphosis and scoliosis, and one who suffered postoperative wound dehiscence following RT. CONCLUSIONS: Although this study did not include modern techniques of staging with n-myc amplification and DNA index, the occurrence of next echelon nodal failures gives credence to the continuation of the dialogue concerning the appropriate role of "prophylactic" irradiation to mediastinal and left supraclavicular nodes in locally advanced upper abdominal NB. Documentation of significant long-term ill effects reinforces the need to critically evaluate the indications for RT.