Medulloblastoma in childhood: revisiting intrathecal therapy in infants and children.
BACKGROUND
Intrathecal chemotherapy is being explored in medulloblastoma in pre-school children as part of brain-sparing strategies and as an alternative to unacceptably neurotoxic cranio-spinal radiotherapy. The range of drugs suitable for this route of administration is restricted by the lack of research evidence of pharmacological suitability and efficacy of other drugs in medulloblastoma.


METHODS
Ideal clinical, biological, physicochemical and pharmaceutical properties for intrathecal administration were defined through literature review of pharmaceutical texts, Medline, Embase and consulting the manufacturers. A total of 126 chemotherapy agents were assessed against these criteria by searching the academic domain of pharmaceutical texts, computer databases and consultation with manufacturers.


RESULTS
Of the 126 candidate drugs, 99 were rejected because of documentation of their irritant nature, neurotoxicity and requirement for hepatic activation in standard pharmaceutical texts. Fifty were rejected for a single identifiable reason including, neurotoxicity (n = 24), irritant (n = 15), needs enzyme activation (n = 5), clinical evidence of intrathecal neurotoxicity (n = 4) and no evidence of tumour-specific efficacy (n = 2). Where two reasons were cited the justifications were: neurotoxic and irritant (n = 3) and needs activation and systemic administration results in equivalent concentration (n = 1). Twenty-seven drugs remained of which 12 were selected as eligible for further clinical investigation, and 15 were selected for further pre-clinical investigation.


CONCLUSIONS
The pre-determined criteria were not applicable, in their entirety, in the majority of drugs, due to lack of information in the academic domain, emphasising the importance of a more open approach for sharing basic drug information. The prioritised list of 12 candidate drugs for clinical trial and 15 for pre-clinical investigation justify that a concerted research effort in this area of practice is made.
Children's Brain Tumour Research Centre, University of Nottingham, University Park, Nottingham, NG7 2RD, UK.
Sharon
S
Conroy
Martin
M
Garnett
Michael
M
Vloeberghs
Richard
R
Grundy
Ian
I
Craven
David
D
Walker
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002528:Cerebellar Neoplasms / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D006801:Humans; D007223:Infant; D007278:Injections, Spinal; D008527:Medulloblastoma / Q000188:drug therapy*; D016896:Treatment Outcome
D000970:Antineoplastic Agents