Zielsetzung
In France, approximately 900 children/adolescents are treated with radiotherapy (RT) every year. However, among the 80% of survivors, the cumulative incidence of long-term morbidity reaches 73.4% thirty years after the cancer diagnosis. Identifying a priori the subjects at risk for RT sequelae is a major challenge of pediatric oncology. Individual radiosensitivity (IRS) of children/adolescents is unknown at this time. The cellular response to radiation depends on recognizing and repairing radiation-induced DNA double-strand breaks (DSB). Unrepaired DSB and a delay in the intra-nuclear activation of the pATM protein are common features in patients with RT toxicity. From these conclusions, we proposed and retrospectively validated a functional IRS immunofluorescence assay based on Radio-Induced ATM Nucleoshuttling (RIANS) (Granzotto et al., 2016). The purpose of this study was to define prospectively the predictive impact of RIANS assay in children.
Material und Methoden
Patients of the ARPEGE prospective open-label, non-randomized multicentre clinical trial, were included in the study and prospectively evaluated for early toxicities. For each patient, skin samples were collected prior to RT to raise a primary dermal fibroblast line and carry out in blind the RIANS assay. Different endpoints were measured: residual double-strand breaks at 24 h (γH2AX marker), pATM foci at 10 min and 1 h (pATM marker), and micronuclei at 24 h, respectively after ex vivo radiation (2 Gy). In parallel, early toxicity was reported according to NCI-CTCAE v4.0 three months after the completion of RT. Patients with grade <2 or ≥2 toxicity were considered radioresistant (RR) and radiosensitive (RS), respectively. We correlated the parameters of the RIANS assay according to toxicity with logistic regression.
Ergebnisse
Among the 29 analyzable patients, 37 % exhibit brain cancers, 10% Hodgkin lymphomas, 10% nephroblastoma, 10% neuroblastoma, 10% Ewing cancer, and 13% malignant mesenchymal cancer. The mean delivered dose was 32.5 Gy (range 1,5 - 60 Gy) with fractionation between 1.5 to 2 Gy. 16/29 (56%) patients were clinically considered as RS. The two groups had no significant difference in the total dose delivered. A univariable analysis by a logistic regression allows us to identify predictive radiobiological (Micronuclei at 24h and pATM foci at 10 min post-irradiation) and some clinical factors such as the phototype, the fraction dose, and the irradiated volume (p<0,2). When combined into a multivariable analysis with the radiobiological factors, the following performances were obtained: AUC= 0,75, sensitivity = 0,82, and specificity = 0,7. With all elements (clinical + radiobiological), an AUC = 0,91 was obtained.
Schlussfolgerungen
ARPEGE is the first study to document the distribution of IRS in such a population. Screening hypersensitive patients would be a major step forward in the management of cancers, opening the way to personalized pediatric oncology