Four radiation hypersensitivity cases and their implications for clinical radiotherapy

Background and purpose: Over a 20 year period, four out of 2000 paediatric radiotherapy patients, treated at St. Bartholomew's Hospital (three with ly mphoma, one with angiosarcoma), have revealed extreme/fatal clinical hypers ensitivity in normal tissues. Patients and methods: Cellular hypersensitivity was confirmed in vitro and attributed to the ataxia-telangiectasia (A-T) gene in cases I and II, a new ly described defect in the DNA ligase 4 gene in case III, and a novel and a s yet incompletely defined, molecular defect in case IV who presented with xeroderma pigmentosum (XP). Results: The severe clinical hypersensitivity preceded the cellular and mol ecular analysis, but did not manifest as a clinically exaggerated normal ti ssue reaction until 3+ weeks after the start of a conventionally fractionat ed course of radiotherapy, by which time the latent damage had been inflict ed. There were no clinical stigmata to alert the clinician to a predisposin g syndrome in two patients (cases I and II). We point out that approximatel y 20% of A-T patients are classified as variants with delayed expression of clinical symptoms, and case II falls into this category. Conclusions: As lymphoma (incidence, one in 100 000 children) constituted t he majority of the diagnoses, questions arise as to: (1), the probability o f other centres having experienced and being presented in the future with s imilar problems (particularly bearing in mind that other oncologically pred isposing radiosensitivity syndromes have not been not represented in our ex perience); and (2), the appropriateness, efficiency and applicability of pr edictive assays. Unambiguous cellular radiosensitivity would have been appa rent from clonal assays on fibroblast cultures from all four cases prior to treatment, but such assays take 4-6 weeks to produce results. While estima tes of chromosome damage or clonal assays on pre-treatment blood derived ce lls would be faster, there is a health economics issue as to the general ap plicability of such 'screening' assays. (C) 2000 Elsevier Science Ireland L td. All rights reserved.