Targeted radiotherapy for neuroblastoma.

Background Biologically targeted radiotherapy is an established treatment for thyrotoxicosis and thyroid cancer. The principle is to take advantage of the ability of the thyroid and, to a lesser degree, diVerentiated thyroid carcinoma to concentrate and retain iodide. In this situation the radionuclide (I) in ionic form is a natural substrate for targeting thyroid tissue, thus acting both as the vector, or ‘missile’, and the ‘warhead’. The success of this form of radiotherapy in metastatic papillary and follicular thyroid carcinoma is due to the specificity of targeting and the resulting concentration and retention of I in cells of thyroid origin, after the ablation of residual normal thyroid tissue, being suYcient to result in tumour eradication. Unfortunately the thyroid is unique and targeted radioiodine treatment for other tumours requires specific vectors to carry the ‘warhead’.With the development of monoclonal antibodies in 1975 it was hoped that Erlich’s concept of an immunological magic bullet would quickly be realised, but more than 20 years later the applications of targeted monoclonal antibody treatment are distinctly limited in clinical oncology. There are several reasons for this failure of monoclonal antibodies to produce results: firstly, antigen expression on tumour cells is variable and tumour antigens are often expressed to some degree on normal cells, so the specificity is poor. Furthermore there is often poor penetration of large immune globulin molecules into tumours, a problem which has not been overcome to any significant degree by employing smaller molecular weight fragments. Furthermore murine monoclonal antibodies are themselves immunogenic and this precludes repeated administration. Despite these limitations, there have been attempts to employ targeted monoclonals in the treatment of neuroblastoma 5 and regional targeting of leukaemia within the cerebrospinal fluid has produced responses. The search has continued for low molecular weight compounds, which utilise metabolic pathways with high tumour specificity. Currently one of the most promising compounds is metaiodobenzylguanidine (mIBG) which exploits the active uptake pathway for noradrenaline expressed in sympathetic nervous tissues and in tumours of neural crest origin. Radioiodinated adrenergic blocking agents were originally developed as adrenomedullary imaging agents and the first human studies were described in adults with phaeochromocytoma and soon after in children with neuroblastoma. Laboratory studies have elucidated the mechanism of uptake of mIBG in neural crest tumours, while clinical studies have exploited the high aYnity of I-mIBG for neuroblastoma in particular and targeted treatment is now moving into front line investigational protocols in Europe.