Validation of a high performance functional assay for individual radiosensitivity in pediatric oncology: a prospective cohort study (ARPEGE)

Valérie Bernier-Chastagner, Liza Hettal, Véronique Gillon, Laurinda Fernandes, Cécile Huin-Schohn, Marion Vazel, Priscillia Tosti, Julia Salleron, Aurélie François, Elise Cérimèle, Sandrine Perreira, Didier Peiffert, Pascal Chastagner, Guillaume Vogin, Valérie Bernier-Chastagner, Liza Hettal, Véronique Gillon, Laurinda Fernandes, Cécile Huin-Schohn, Marion Vazel, Priscillia Tosti, Julia Salleron, Aurélie François, Elise Cérimèle, Sandrine Perreira, Didier Peiffert, Pascal Chastagner, Guillaume Vogin

Abstract

Background: Approximately 900 children/adolescents are treated with radiotherapy (RT) every year in France. However, among the 80% of survivors, the cumulative incidence of long-term morbidity - including second malignancies - reach 73.4% thirty years after the cancer diagnosis. Identifying a priori the subjects at risk for RT sequelae is a major challenge of paediatric oncology. Individual radiosensitivity (IRS) of children/adolescents is unknown at this time, probably with large variability depending on the age when considering the changes in metabolic functions throughout growth. We previously retrospectively showed that unrepaired DNA double strand breaks (DSB) as well a delay in the nucleoshuttling of the pATM protein were common features to patients with RT toxicity. We aim to validate a high performance functional assay for IRS prospectively.

Methods/design: ARPEGE is a prospective open-label, non-randomized multicentre cohort study. We will prospectively recruit 222 children/adolescents who require RT as part of their routine care and follow them during 15 years. Prior RT we will collect blood and skin samples to raise a primary dermal fibroblast line to carry out in blind the IRS assay. As a primary objective, we will determine its discriminating ability to predict the occurrence of unusual early skin, mucous or hematological toxicity. The primary endpoint is the measurement of residual double-strand breaks 24 h after ex vivo radiation assessed with indirect immunofluorescence (γH2AX marker). Secondary endpoints include the determination of pATM foci at 10 min and 1 h (pATM marker) and micronuclei at 24 h. In parallel toxicity including second malignancies will be reported according to NCI-CTCAE v4.0 reference scale three months of the completion of RT then periodically during 15 years. Confusion factors such as irradiated volume, skin phototype, previous chemotherapy regimen, smoking, comorbities (diabetes, immunodeficiency, chronic inflammatory disease...) will be reported.

Discussion: ARPEGE would be the first study to document the distribution of IRS in the pediatric subpopulation. Screening hypersensitive patients would be a major step forward in the management of cancers, opening a way to personalized pediatric oncology.

Trial registration: ID-RCB number: 2015-A00975-44, ClinicalTrials.gov Identifier: NCT02827552 Registered 7/6/2016.

Keywords: Biomarker; Pediatric oncology; Predictive assay; Radiosensitivity; Radiotherapy; Toxicity.

Conflict of interest statement

Ethics approval and consent to participate

This study was approved by the ethics committee of Nancy-Brabois Hospital (CPP Est III), registered 11/08/2016. The French agency for drug safety and health products ratified this study on 10/26/2016. Three substantial modifications were approved. The French Advisory Committee on the Treatment of Research Information in the field of Health validated ARPEGE on 10/14/2015. Trial registration: ID-RCB number: 2015-A00975–44, ClinicalTrials.gov Identifier: NCT02827552, registered 7/6/2016.

Prior to inclusion of the patient, a written consent is obtained from the holder(s) of parental authority and/or the child (with a document adapted to his age), after they have been fully informed by the investigator during an interview and after free time-lapse. A Childhood Cancer Parents Association validated the information materials and consent forms.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Recruitment modalities and timing of the biopsy. CT: chemotherapy, RT: radiotherapy, Δ: biopsy. • Population A: definitive RT only if the response to neoadjuvant CT in unsatisfactory. • Population B: neoadjuvant CT before RT, eventually followed with CT. • Population C: definitive RT not preceded by CT

References

    1. Desandes E, Lacour B, Belot A, White-Koning M, Velten M, Tretarre B, et al. Cancer incidence and survival among adolescents and young adults in France (1978-1997) Bull Cancer. 2007;94(4):331–337.
    1. Lacour B, Guyot-Goubin A, Guissou S, Bellec S, Desandes E, Clavel J. Incidence of childhood cancer in France: National Children Cancer Registries, 2000-2004. Eur J Cancer Prev. 2010;19(3):173–81.
    1. Desandes E, Bonnay S, Berger C, Brugieres L, Demeocq F, Laurence V, et al. Pathways of care for adolescent patients with cancer in France from 2006 to 2007. Pediatr Blood Cancer. 2010;58(6):924–9.
    1. Oeffinger KC, Mertens AC, Sklar CA, Kawashima T, Hudson MM, Meadows AT, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med. 2006;355(15):1572–1582. doi: 10.1056/NEJMsa060185.
    1. ICRP. ICRP Publication 103: The 2007 Recommendations of the International Commission on Radiological Protection. Ann ICRP 2007;37(2–4)179–90.
    1. UNSCEAR . In: UNSCEAR 2008 Report Vol. II : Effects of ionizing radiation. Publications UN, editor. Vienna: United Nations; 2008. p. 320.
    1. Kleinerman RA. Radiation-sensitive genetically susceptible pediatric sub-populations. Pediatr Radiol. 2009;39(Suppl 1):S27–S31. doi: 10.1007/s00247-008-1015-6.
    1. Rogers PB, Plowman PN, Harris SJ, Arlett CF. Four radiation hypersensitivity cases and their implications for clinical radiotherapy. Radiother Oncol. 2000;57(2):143–154. doi: 10.1016/S0167-8140(00)00249-8.
    1. Rube CE, Fricke A, Schneider R, Simon K, Kuhne M, Fleckenstein J, et al. DNA repair alterations in children with pediatric malignancies: novel opportunities to identify patients at risk for high-grade toxicities. Int J Radiat Oncol Biol Phys. 2010;78(2):359–69.
    1. Granzotto A, Joubert A, Viau M, Devic C, Maalouf M, Thomas C, et al. Individual response to ionising radiation: What predictive assay(s) to choose? C R Biol. 2011;334(2):140–157. doi: 10.1016/j.crvi.2010.12.018.
    1. Jeggo PA, Lobrich M. DNA double-strand breaks: their cellular and clinical impact? Oncogene. 2007;26(56):7717–7719. doi: 10.1038/sj.onc.1210868.
    1. Iliakis G. The role of DNA double strand breaks in ionizing radiation-induced killing of eukaryotic cells. BioEssays. 1991;13(12):641–648. doi: 10.1002/bies.950131204.
    1. Joubert A, Zimmerman KM, Bencokova Z, Gastaldo J, Chavaudra N, Favaudon V, et al. DNA double-strand break repair defects in syndromes associated with acute radiation response: at least two different assays to predict intrinsic radiosensitivity? Int J Radiat Biol. 2008;84(2):107–125. doi: 10.1080/09553000701797039.
    1. Rothkamm K, Lobrich M. Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses. Proc Natl Acad Sci U S A. 2003;100(9):5057–5062. doi: 10.1073/pnas.0830918100.
    1. investigators Cp. Granzotto A, Benadjaoud MA, Vogin G, Devic C, Ferlazzo ML, et al. Influence of Nucleoshuttling of the ATM protein in the healthy tissues response to radiation therapy: toward a molecular classification of human Radiosensitivity. Int J Radiat Oncol Biol Phys. 2016;94(3):450–460. doi: 10.1016/j.ijrobp.2015.11.013.
    1. Vogin G, Bastogne T, Bodgi L, Gillet-Daubin J, Canet A, Pereira S, Foray N. The Phosphorylated ATM Immunofluorescence Assay: A High-performance Radiosensitivity Assay to Predict Postradiation Therapy Overreactions. Int J Radiat Oncol Biol Phys. 2018;101(3):690–93.
    1. Baumann M, Holscher T, Begg AC. Towards genetic prediction of radiation responses: ESTRO's GENEPI project. Radiother Oncol. 2003;69(2):121–125. doi: 10.1016/j.radonc.2003.08.006.
    1. Joubert A, Gamo K, Bencokova Z, Gastaldo J, Rénier W, Chavaudra N, et al. DNA double-strand break repair defects in syndromes associated with acute radiation response: at least two different assays to predict intrinsic radiosensitivity? Int J Radiat Biol. 2008;84(2):1–19. doi: 10.1080/09553000701797039.
    1. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics. 1988;44(3):837–845. doi: 10.2307/2531595.
    1. Harrell F. Regression coefficients and scoring rules. J Clin Epidemiol. 1996;49(7):819. doi: 10.1016/0895-4356(95)00068-2.
    1. Sauerbrei W, Schumacher M. A bootstrap resampling procedure for model building: application to the cox regression model. Stat Med. 1992;11(16):2093–2109. doi: 10.1002/sim.4780111607.
    1. Pixberg C, Koch R, Eich HT, Martinsson U, Kristensen I, Matuschek C, et al. Acute toxicity grade 3 and 4 after irradiation in children and adolescents: results from the IPPARCA collaboration. Int J Radiat Oncol Biol Phys. 2016;94(4):792–799. doi: 10.1016/j.ijrobp.2015.12.353.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe