FINDING OUR SENSITIVE PATIENTS

The practice of radiation oncology requires balancing tumor control probability against the risk of normal tissue injury. Using radiation to eradicate disease is acceptable only if life-threatening or severe normal tissue injury is avoided. Despite a number of advances in the field of radiation oncology, the understanding of the genetic and epigenetic phenomenon that determine an individual’s risk for normal tissue radiation injury remains rudimentary. Patients display a diverse spectrum of toxicity for any given treatment schedule. While toxicity risks for populations of patients are known, the determination of an individual’s normal tissue radiosensitivity is rarely possible prior to treatment. Therefore, current practice standards commonly prescribe radiation dose schedules according to clinical scenarios, without regard to the genotype or phenotype of the individual being irradiated. Moving away from considering normal tissue risk of radiation injury as a population phenomenon towards determining the risk for the individual being irradiated is a worthy task. For patients with a radiosensitive genotype or phenotype, the risk-benefit ratio of radiation could be more clearly defined, and lower dosages or alternatives to radiation could be explored. Equally important, the ability to identify the most radiosensitive patients has the potential to improve the tumor control probability in the remaining population. In general, practice standards limit radiation dosages to those predicted to cause serious late complications in 10% or less of the treated population. Accordingly, this dose is below the threshold for radiation injury in the remaining 90%. A normal tissue predictive assay that successfully identified the 10% most radiosensitive patients would allow radiation dosages to be escalated in the remaining 90%. Tucker et al. have mathematically modeled this concept using a set of human fibroblast radiosensitivity data (1). Their results estimated that dose escalation of 10% would be possible if the identified radiosensitive patients were excluded from treatment. For clinical situations in which dose escalation would occur over the steep portion of the tumor control probability curve, this dose increase could achieve clinically meaningful results. Despite the theoretical appeal, normal tissue predictive assays have not proven clinically useful. The major limitation of laboratory-based normal tissue predictive assays is that most radiation complications result from a number of genetic and epigenetic phenomenon. Target cells have different intrinsic radiosensitivity and cellular environments dramatically affect radiation response. In addition, host factors that impair microvasculature (diabetes, atherosclerosis) or alter immune response (scleroderma, lupus) are known to predispose to radiation injury. The contributions of epigenetic factors and the cellular environment to radiation response are difficult to reproduce in laboratory settings. Correspondingly, most in vitro predictive assays have focused on studying the genetic predisposition of an individual to radiation injury. The excitement for this strategy arose after individuals with ataxia telangiectasia (AT) were found to have a radiosensitive phenotype. In vitro studies of fibroblasts and lymphocytes from these individuals revealed an exquisite normal tissue radiosensitivity that was directly attributable to a specific genetic defect. Based on this paradigm, a number of functional normal tissue predictive assays have been developed. These assays commonly use such cells as fibroblasts and lymphocytes to predict clinical injuries that develop independently of the cell type used in the assay. The theory underlying these assays is that germline factors affecting radiosensitivity will be present in any cell, and therefore fibroblasts and lymphocytes are appropriate surrogates for the target cell of the normal tissue injury. In this issue of the IJROBP, Crompton et al. report a pilot study using a new predictive assay based, in part, on this paradigm. Their study examines the value of a lymphocyte apoptosis assay in predicting radiation injury risk. The methodology of the study compares the degree of in vitro radiation-induced apoptosis of peripheral lymphocytes in a 12-patient radiosensitive cohort with age-matched controls and with a cohort of 9 patients with AT. Their results indicated a decreased rate of radiation-induced apoptosis in the AT and hypersensitive patients compared with controls. This result seems paradoxical, in that unlike fibroblast clo-