Multiagent chemotherapy studied in a xenograft model of medulloblastoma/primitive neuroectodermal tumour: Analysis of the VETOPEC regimen

Brain tumours remain the most important challenge in the treatment of childhood cancer. The intraocular (io) xenograft model was used to study components and variations of the VETOPEC multiagent chemotherapy regimen in the medulloblastoma/primitive neuroectodermal tumour (MB/PNET) xenograft cell line JRMB-6. VETOPEC, a combination of vincristine (VCR), etoposide (VP-16) and escalated dose cyclophosphamide (CPA), has been shown to be highly active in clinical trials. A total of 190 xenografted tumours were treated with one of nine regimens: saline; single agent CPA, VP-16 (single dose [sd], five dosages daily [d × 5] or continuous infusion, [ci]) or VCR; combinations of CPA (d × 5) + VP-16 (d × 5 or ci) or CPA (d × 5) + VP-16 (ci) + VCR (sd). Results were calculated using both response (volume reduction >50%) and ‘time to progression’ (TtP). Effectiveness of CPA was confirmed. Single-agent VCR or VP-16 produced no response. No difference was documented in TtP with VCR, VP-16 (sd) or VP-16 (d × 5) versus control, but a significant prolongation occurred when VP-16 was given by ci (p = 0.001). With the 3-agent combination of CPA + VP-16 (ci) + VCR a significantly prolonged TtP was documented versus both single agent CPA (p = 0.003) and the combination of CPA + VP-16 (d × 5) (p = 0.004). The results suggest improved efficacy of VP-16 when given as ci in both single-agent and combination settings. The addition of VP-16 (ci) + VCR to an already effective dosage of CPA further prolongs TtP. These data support and progress VETOPEC phase II clinical studies and suggest potential further benefits of prolonged exposure to VP-16 by ci.