A phase III trial of biologically-based therapy reduction for intermediate risk neuroblastoma

Abstract

9504 Background: Infants with advanced neuroblastoma (stage 3 and 4) and children >1 year with favorable biology stage 3 disease have had a survival exceeding 80% with aggressive chemotherapy. The primary objective of Childrens Oncology Group A3961 was to maintain a 3-year event-free and overall survival rate above 90% for intermediate risk (IR) neuroblastoma with a reduction in therapy compared to historical trials for similarly defined risk patients. Methods: IR patients were defined by selected clinical (age, INSS stage, histopathology) and biologic (MYCN status and DNA index) factors. All eligible IR patients were MYCN non-amplified and were divided into subcategories defined as favorable or unfavorable biology. Therapy consisted of 2 to 3 agent combinations of carboplatin, etoposide, cyclophosphamide and doxorubicin given every 3 weeks for a total of 4 cycles (favorable biology) or 8 cycles (unfavorable biology). Patients with favorable biology failing to achieve CR/VGPR after 4 cycles and surgery, received 8 cycles. All patients were required to enter a companion neuroblastoma biology study and to enroll on A3961 within 28 days of diagnosis. Results: Between March 1997 and May 2005, 467 eligible patients were enrolled on study. These included 261 stage 3 (105 children; 156 infants), 174 stage 4 infants, and 32 stage 4s infants. 362 (78%) were less than 12 months of age at diagnosis. 330 (71%) patients had favorable and 137 (29%) unfavorable biology. There were 40 (12.1%) of 330 favorable biology patients who went onto cycles 5–8. There were 52 events in 467 cases including 15 deaths and two secondary AML. Conclusions: The primary hypothesis of this study was confirmed and survival rates greater than 90% were maintained for IR neuroblastoma with reduced therapy compared to historical trials. The successor trial will prescribe duration of therapy based, in part, on loss of heterozygosity states at 1p36 and 11q23 as well as initial response to treatment in an endeavor to further reduce therapy for this group of patients. [Table: see text] No significant financial relationships to disclose.