Intensive multi-modality therapy for extra-ocular retinoblastoma (RB): A Children's Oncology Group (COG) trial (ARET0321)

10506 Background: Metastatic RB is associated with a poor prognosis. Previous small series suggested that intensified systemic chemotherapy with or without radiation therapy (RT) may improve outcomes in this population. COG opened this prospective, multi-institutional, international trial to study the effectiveness of this approach. Methods: Patients with regional extra-ocular RB (stage 2 or 3) were treated with 4 cycles of intensive conventional chemotherapy (vincristine 0.05 mg/kg/day, cisplatin 3.5 mg/kg/day, cyclophosphamide 65 mg/kg x 2 days, etoposide 4 mg/kg x 2 days) followed by involved-field RT (4500 cGy). Two strata of patients with metastatic RB [stage 4a: distant metastases not involving the central nervous system involvement (CNS); and stage 4b (CNS metastases)/trilateral RB)] were treated with 4 cycles of the same chemotherapy. Patients with ≥ partial response then received 1 cycle of high-dose carboplatin (Calvert formula with AUC = 7/day, maximum 16.7 mg/kg/day) on days -8 to -6, thiotepa (10 mg/kg/day), & etoposide (8.3 mg/kg/day) on days -5 to -3 with autologous hematopoietic stem cell rescue on day 0. Patients with metastatic RB who did not achieve an adequate response to chemotherapy also received RT. Results: Sixty subjects (20 in each stratum) were enrolled; 57 were eligible and included in the analyses (based on data current to June 30, 2016). Toxicity was significant as expected and there were 2 therapy related deaths. Event-free survival (EFS) at 36 months was 87.7% (90% CI 65.4 to 96.0%) for subjects with stage 2 or 3 disease, 79.3% (90% CI 54.2 to 91.6%) for subjects with stage 4a disease and 8.0% (90% CI 1.0 to 25.1%) for subjects with stage 4b/trilateral disease. The observed results significantly improved the EFS in each stratum compared with historical results used for planning the study. Conclusions: This is the first prospective, multi-institutional, international study to show that intensive multi-modality therapy is highly effective for patients with regional extra-ocular RB and metastatic RB not involving the CNS. More effective therapy is required for patients with CNS RB. Clinical trial information: NCT00554788.