Étude AVARTHEC : complications vasculaires de l’irradiation crânienne pour tumeur cérébrale durant l’enfance et l’adolescence

International audienceIn France, as in other developed countries, primary tumors of central nervous system (CNS) represent the second most frequent neoplasm (after leukemia) and the leading cause of cancer-related deaths in childhood. They account for approximately 25% of incident malignancies in children < 15 years of age at diagnosis. For all CNS tumors combined, the 5-year-overall survival is about 65–70%. The goal of neurosurgery is ideally to complete microsurgical removal of the tumor. In pediatric oncology, combined-treatment strategies using surgery, craniospinal radiation, and chemotherapy could be indicated depending on the stage, the grade and the histology of primitive tumor. The potential combined-treatment-associated morbidity must always be taken into consideration. Few studies have investigated the role of radiotherapy and chemotherapy in the long-term risk of cerebrosvascular disease following childhood cancer treatment. The aim of the AVARTHEC study is to describe clinical and imaging characteristics of cerebrosvascular disease in survival patients after radiation treatment of CNS tumor during childhood or adolescence. The short-term goal will be to have information of neurovascular sequelea following new radiation techniques for CNS tumor. The long-term goal will be to identify high-risk patients to develop cerebrosvascular diseases after CNS radiation and to adapt their long-term follow-up at potential primary and secondary prevention. The AVARTHEC study could help French health-care government policies to elaborate recommendations on new radiation therapy techniques considering potential risk factors of cerebrosvascular morbidity.Les tumeurs du système nerveux central (SNC) représentent la principale cause de morbidité et de mortalité par type de cancer chez les personnes âgées de 0 à 18 ans. Dans cette population, environ 500 tumeurs sont diagnostiquées annuellement et la survie à 5 ans est de l’ordre de 65–70 %. La chirurgie est le traitement de référence, mais une chimiothérapie et/ou radiothérapie (RT) peuvent néanmoins être indiquée selon le stade, le grade et la malignité tumorale. La RT est très efficace pour contrôler les tumeurs cérébrales de l’enfant avec près de 90 % de survie sans récidive à cinq ans dans la plupart des études, mais elle est grevée d’un grand nombre de complications tardives. Peu de données existent concernant les complications cérébrovasculaires engendrées par l’irradiation des tumeurs cérébrales chez l’enfant. L’objectif principal de l’étude AVARTHEC est d’estimer la proportion d’anomalies cérébrovasculaires chez les survivants d’une tumeur cérébrale prise en charge durant l’enfance et traitée par radiothérapie et de décrire leurs caractéristiques cliniques et radiologiques. Il s’agira à court terme d’obtenir des informations sur les effets secondaires des techniques de radiothérapie en incluant les nouvelles modalités d’irradiations. À plus long terme, il serait ainsi possible d’identifier des patients à haut risque de développer des complications cérébrovasculaires après une irradiation du SNC et de mettre en place une surveillance accentuée. Enfin, cette étude pourrait orienter les sociétés savantes dans l’élaboration de recommandations sur les modalités d’irradiation en fonction des facteurs de risque. Cet article présente le protocole de l’étude AVARTHEC

High prevalence of anterior pituitary deficiencies after cranial radiation therapy for skull base meningiomas

International audienceBackground: Cranial irradiation represents one of the first line treatment proposed in skull base meningiomas. While cranial irradiation is associated with a high risk of secondary hypopituitarism, few studies focused on the specific location of skull base meningiomas. Methods: Fifty-two adults receiving photon-beam therapy for skull base meningiomas between 2003 and 2014 in our Institution were included. Anterior pituitary (ACTH, FSH, GH, LH, TSH and prolactin) as well as corresponding peripheral hormones (8 am-Cortisol, IGF-1, fT3, fT4, 17βestradiol or testosterone) were biologically screened before radiotherapy (baseline), then yearly until March 2019. The pituitary gland (PG) was delineated on CT and the mean dose delivered to it was calculated. Results: Mean age at diagnosis was 56 +/− 14 years. Median follow-up was 7 years. Up to 60% of patients developed at least ≥2 pituitary deficiencies, 10 years after radiotherapy. Gonadotroph, thyrotroph, corticotroph and somatotroph deficiencies occurred in 37, 28, 18 and 15% of patients, respectively. Hyperprolactinemia was found in 13% of patients. None patient had only one pituitary deficiency. In the multivariate analysis, a delivered dose to the PG ≥ 50 Gy or a meningioma size ≥40 mm significantly increased the risk of developing hypopituitarism. Conclusions: Over a long-term follow-up, cranial radiation therapy used in skull base meningiomas led to a high prevalence of hypopituitarism, further pronounced in case of tumor ≥4 cm. These results advocate for an annual and prolonged follow-up of the pituitary functions in patients with irradiated skull base meningiomas

Impact de l’âge et radiothérapie: points clés chez les AJA

International audienceWhen using radiation therapy for adolescents and young adults (AYA), paediatricians, adults’ oncologists and radiation oncologists need to keep in mind several particularities through the whole therapeutic process. They embrace the indication, target volumes, prescribed dose, treatment techniques and follow-up. Indeed, the young age and the cancer features that characterised this population influence the modalities of irradiation. This article highlights the key points of AYA care with radiation therapy

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

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

Hypofractionated Stereotactic Radiotherapy for Patients with Intracranial Meningiomas: impact of radiotherapy regimen on local control

Abstract We evaluated efficacy and tolerance of hypofractionated stereotactic radiation treatment (hFSRT) in the management of intracranial meningiomas. Between December 2008 and June 2016, 126 patients with 136 intracranial meningiomas were treated with robotic hFSRT. hFSRT was performed as primary irradiation and as a salvage option for the local recurrence after prior radiotherapy. The median prescription dose was 25 Gy (12–40) with a median number of fractions of 5 (3–10). After a median follow-up of 20.3 months (range 1–77 months), the 24-months local control (LC) rate was 81% in the primary hFSRT group and 39% after hFSRT in the re-irradiation group (p=0.002). The clinical control rate of symptoms in the overall population was 95% (95% CI: 89–98%). Progression-free survival (PFS) in the overall population at 24 months was 70% (95% CI: 60%–79%). In the primary hFSRT group, PFS was significantly lower with the most hypofractionated schedules of 21–23 Gy in 3 fractions vs. 25–40 Gy in 5–10 fractions: 62% vs. 92% (p = 0.0006). The incidence of radionecrosis at 24 months was significantly lower in the primary hFSRT group, at 2% vs. 20% in the re-irradiation hFSRT group (p = 0.002)

Synergistic Antitumor Effect between Gefitinib and Fractionated Irradiation in Anaplastic Oligodendrogliomas Cannot Be Predicted by the Egfr Signaling Activity

<div><p>In high-grade gliomas, the identification of patients that could benefit from EGFR inhibitors remains a challenge, hindering the use of these agents. Using xenografts models, we evaluated the antitumor effect of the combined treatment “gefitinib + radiotherapy” and aimed to identify the profile of responsive tumors. Expression of phosphorylated proteins involved in the EGFR-dependent signaling pathways was analyzed in 10 glioma models. We focused on three models of anaplastic oligodendrogliomas (TCG2, TCG3 and TCG4) harboring high levels of phospho-EGFR, phospho-AKT and phospho-MEK1. They were treated with gefitinib (GEF 75 mg/kg/day x 5 days/week, for 2 weeks) and/or fractionated radiotherapy (RT: 5x2Gy/week for 2 weeks). Our results showed that GEF and/or RT induced significant tumor growth delays. However, only the TCG3 xenografts were highly responsive to the combination GEF+RT, with ∼50% of tumor cure. Phosphoproteins analysis five days after treatment onset demonstrated in TCG3 xenografts, but not in TCG2 model, that the EGFR-dependent pathways were inhibited after GEF treatment. Moreover, TCG3-bearing mice receiving GEF monotherapy exhibited a transient beneficial therapeutic response, rapidly followed by tumor regrowth, along with a major vascular remodeling. Taken together, our data evoked an “EGFR-addictive” behavior for TCG3 tumors. This study confirms that combination of gefitinib with fractionated irradiation could be a potent therapeutic strategy for anaplastic oligodendrogliomas harboring EGFR abnormalities but this treatment seems mainly beneficial for “EGFR-addictive” tumors. Unfortunately, neither the usual molecular markers (<i>EGFR</i> amplification, PTEN loss) nor the basal overexpression of phosphoproteins were useful to distinguish this responsive tumor. Evaluating the impact of TKIs on the EGFR-dependent pathways during the treatment might be more relevant, and requires further validation.</p></div