Dosimetric analysis of hearing loss after cranial radiation therapy in children: A single-institution study from the French national registry PediaRT.

PURPOSE: To identify dosimetric predictive factors of sensorineural hearing loss (SNHL) in children after cranial radiation therapy (RT) in a single institution using dosimetric data from the French National Registry PediaRT. METHODS AND MATERIALS: Complete audiological follow-up data were available for 44 children treated with cranial RT between 2014 and 2021 at our institution. The median age at the time of RT initiation was 9 years (range: 2-17 years). No children presented with hearing loss prior to treatment. SNHL was defined as a Chang ototoxicity grade ≥ 1a or higher. RESULTS: Median audiometric follow-up duration was 51 months. Seven children (16 %) developed SNHL with a median time to occurrence of 33 months (range, 18-46 months). The estimated SNHL cumulative rate at 2 years post-RT was 4,5% ± 3,1% and at 5 years was 21 % ± 7.2 %. Multiple Cox regression models showed that the association of the age at radiotherapy and the dosimetric values to the inner ear canal and cochlea were the most significant predictive factors of SNHL occurrence. No child who received less than 35 Gy on average to both cochleae (n = 26) suffered from SNHL, whereas the 5-year SNHL cumulative incidence for the children who received greater than or equal to 35 Gy on average to either cochlea (n = 18) was 51.8 % ± 15.1 %. CONCLUSION: Doses received by the inner ear canal and cochlea, associated with the age at RT initiation, are the main predictive factors for radiation-induced SNHL. A median dose to either cochlea over 35 Gy significantly increases the risk of SNHL and justify close audiometric monitoring to detect and equip hearing loss at an early stage.

Brainstem toxicity after proton or photon therapy in children and young adults with localized intracranial ependymoma: A French retrospective study.

BACKGROUND AND PURPOSE: Ependymoma is the third most frequent childhood braintumor. Standard treatment is surgery followed by radiation therapy including proton therapy (PBT). Retrospective studies have reported higher rates of brainstem injury after PBT than after photon therapy (XRT). We report a national multicenter study of the incidence of brainstem injury after XRT versus PBT, and their correlations with dosimetric data. MATERIAL AND METHODS: We included all patients aged < 25 years who were treated with PBT or XRT for intracranial ependymoma at five French pediatric oncology reference centers between 2007 and 2020. We reviewed pre-irradiation MRI, follow-up MRIs over the 12 months post-treatment and clinical data. RESULTS: Of the 83 patients, 42 were treated with PBT, 37 with XRT, and 4 with both (median dose: 59.4 Gy, range: 53­60). No new or progressive symptomatic brainstem injury was found. Four patients presented asymptomatic radiographic changes (punctiform brainstem enhancement and FLAIR hypersignal), with median onset at 3.5 months (range: 3.0­9.4) after radiation therapy, and median offset at 7.6 months (range: 3.7­7.9). Two had been treated with PBT, one with XRT, and one with mixed XRT-PBT. Prescribed doses were 59.4, 55.8, 59.4 and 54 Gy. CONCLUSION: Asymptomatic radiographic changes occurred in 4.8% of patients with ependymoma in a large national series. There was no correlation with dose or technique. No symptomatic brainstem injury was identified.

Post-operative flank irradiation using conformal versus highly conformal radiotherapy techniques for paediatric renal tumours: Results from the French registry PediaRT.

PURPOSE: Three-dimensional conformal RT (3D-RT) techniques are gold standard for post-operative flank radiotherapy (RT) in paediatric renal tumours. Recently, highly conformal RT (HC-RT) techniques have been implemented without comparative clinical data. The main objective of this multicentre study was to compare locoregional control (LRC) in children treated either with HC-RT or 3D-RT techniques. METHODS: Patients treated with post-operative flank RT for renal tumour registered in the national cohort PediaRT between March 2013 and September 2019 were included. Treatment and follow-up data, including toxicities and outcomes, were retrieved from the database. LRC was calculated, and dose reconstruction was performed in case of an event. RESULTS: Seventy-nine patients were included. Forty patients were treated with HC-RT and 39 with 3D-RT. Median follow-up was 4.5 years. Three patients had locoregional failure (LRF; 4%). HC-RT was not associated with a higher risk of LRF. Three-year LRC were 97.4% and 94.7% in the HC-RT and 3D-RT groups, respectively. The proportion of planning target volumes receiving 95% or more of the prescribed dose did not significantly differ between both groups (HC-RT 88%; 3D-RT 69%; p = .05). HC-RT was better achieving dose constraints, and a significant mean dose reduction was observed in the peritoneal cavity and pancreas associated with lower incidence of acute gastrointestinal toxicity. CONCLUSION: LRF after post-operative flank RT for renal tumours was rare and did not increase using HC-RT versus 3D-RT techniques. Dose to the pancreas and the peritoneal cavity, as well as acute toxicity, were reduced with HC-RT compared to 3D-RT.

Respective Roles of Surgery, Chemotherapy, and Radiation Therapy for Recurrent Pediatric and Adolescent Ependymoma: A National Multicentric Study.

PURPOSE: Half of the children and adolescents treated for intracranial ependymoma experience recurrences that are not managed in a standardized manner. This study aimed to retrospectively evaluate recurrence treatments. METHODS AND MATERIALS: We assessed overall survival (OS) and progression-free survival (PFS) after a first relapse in a population of patients from the Pediatric Ependymoma Photons Protons and Imaging study (PEPPI study) who were treated with surgery and radiation therapy in French Society of Childhood Cancer reference centers between 2000 and 2013. Data were analyzed using the Cox model as well as a landmark analysis at 4 months that accounted for the guarantee-time bias. RESULTS: The median follow-up of the whole population of 202 patients was 105.1 months, with a 10-year OS of 68.2% and PFS of 45.5%. Among the 100 relapse cases, 68.0% were local relapses, 20.0% were metastatic, and 12.0% were combined (local and metastatic). Relapses were treated by surgery (n = 79) and/or reirradiation (n = 52) and/or chemotherapy (n = 22). The median follow-up after relapse was 77.8 months. The OS and PFS at 5 years were 43.1% and 16.2%, respectively. After surgery or radiation therapy of the first relapse, OS and PFS were more favorable, whereas treatments that included chemotherapy with or without focal treatment were associated with worse OS and PFS. In the multivariate analysis, stereotactic hypofractionated reirradiation after surgery was associated with a significantly better outcome (OS, P = .030; PFS, P = .008) and chemotherapy with a worse outcome (OS, P = .028; PFS, P = .033). CONCLUSIONS: This analysis of relapse treatments within the PEPPI study determined that irrespective of whether the relapse was localized or metastatic, treatments that included surgery and/or reirradiation had better outcomes.

Management of the vertebrae as an organ at risk in paediatric radiotherapy clinical trials: Initial QUARTET experience.

Irradiation of the vertebrae in prepubertal patients, if non-homogenous, can result in future growth deformities including kyphoscoliosis. Vertebral delineation and dosimetry were assessed for 101 paediatric cases reviewed within QUARTET-affiliated trials. Despite the availability of published consensus guidelines, a high variability in vertebral delineation was observed, with impact on dosimetry.

Brain radiotherapy in patients treated for a newly diagnosed primary central nervous system lymphoma: professional practice evaluation in 19 French centers.

INTRODUCTION: The objective of this study was a multicentric evaluation of professional practices, analyzing the irradiation technique itself and its impact on survival and recurrence sites, in primary central nervous system lymphomas (PCNSLs). METHODS: We retrospectively analyzed the technical and clinical records of 79 PCNSL patients included in the database of the national expert network for oculocerebral lymphoma ('LOC') who were treated with brain radiotherapy as first-line treatment for newly diagnosed primary central nervous system lymphoma between 2011 and 2018. RESULTS: The number of patients treated with brain radiotherapy gradually decreased over time. The heterogeneity of radiotherapy prescriptions was significant, and 55% of them did not comply with published recommendations in terms of irradiation dose and/or volume. The proportion of complete responders to induction chemotherapy treated with reduced-dose radiotherapy increased over time. Partial brain radiotherapy was associated with significantly lower overall survival in univariate analysis. In partial responders to induction chemotherapy, increasing the total dose to the brain >30 Gy and adding a boost to the WBRT induced a trend toward improved progression-free and overall survival. Five recurrences (13%) occurred exclusively in the eyes, all in patients whose eyes had been excluded from the irradiation target volume and including 2 patients without ocular involvement at diagnosis. CONCLUSION: The visibility of recommendations for prescribing brain radiotherapy for the treatment of newly diagnosed primary central nervous system lymphoma needs to be improved to harmonize practices and improve their quality. We propose an update of the recommendations.

Dosimetric predictive factors for facial nerve paralysis after cyberknife® stereotactic radiotherapy for vestibular schwannomas: A single institution experience of 88 patients.

PURPOSE: To identify dosimetric predictive factors of facial nerve paralysis for patients with vestibular schwannomas (VS) treated in a single institution with Cyberknife® (CK) hypofractionated stereotactic radiotherapy (SRT). METHODS AND MATERIALS: Eighty-eight patients were treated from 2010 to 2020. Different treatment schedules were used over that period, some prescribed to the 80% isodose line (4 × 5 Gy, 3 × 7 Gy, 3 × 8 Gy and 5 × 5 Gy) and one to the 70% isodose line (3 × 7.7 Gy). Local control tumor and facial nerve toxicity were recorded, as well as various dosimetric indicators. RESULTS: Median follow-up 37 months (range, 7-96). Of the 88 stereotactic treatments, 20 patients (23%) developed objectively diagnosed radiation-induced facial nerve paralysis. The 2-year and 5-year local tumor control were respectively 95% and 88%, and the overall 2-year facial nerve preservation was 76%. Prescriptions with a maximum dose point (Dmax) of 33 Gy were at a substantially higher risk of facial paralysis than prescriptions with a Dmax less than or equal to 30 Gy (HR = 4.51, 95% CI = [1.04;19.6], p = 0.045). The 2-years cumulative incidences of facial paralysis were 32% [20%;44%] in the case of a 33 Gy Dmax, against 7% [1%;21%] otherwise. We identified four significative dosimetric predictive factors for radiation-induced facial nerve dysfunction: a GTV minimal dose over 22 Gy (EQD2 = 45.5 Gy, p = 0.019), a GTV mean dose over 29 Gy (EQD2 = 73.5 Gy, HR = 2.84, 95% CI = [1.10;7.36], p = 0.024), a PTV mean dose over 27 Gy (EQD2 = 64.8 Gy, HR = 10.52, 95% CI = [1.39;79.76], p = 0.002) and a PTV maximal dose of 32 Gy (EQD2 = 87.5 Gy,HR = 5.09, 95% CI = [1.17;22.15], p = 0.013). CONCLUSION: We identified four dosimetric predictive factors for post-treatment facial paralysis. Increasing the doses of hypofractionated stereotactic radiotherapy for vestibular schwannomas leads to higher facial nerve toxicity and may lead to lower local control rates than other published series. Our three-hypofractionated regimens may have also played a role in these results.

QUARTET: A SIOP Europe project for quality and excellence in radiotherapy and imaging for children and adolescents with cancer.

The European Society for Paediatric Oncology (SIOPE) Radiation Oncology Working Group presents the QUARTET Project: a centralised quality assurance programme designed to standardise care and improve the quality of radiotherapy and imaging for international clinical trials recruiting children and adolescents with cancer throughout Europe. QUARTET combines the paediatric radiation oncology expertise of SIOPE with the infrastructure and experience of the European Organisation for Research and Treatment of Cancer to deliver radiotherapy quality assurance programmes for large, prospective, international clinical trials. QUARTET-affiliated trials include children and adolescents with brain tumours, neuroblastoma, sarcomas including rhabdomyosarcoma, and renal tumours including Wilms' tumour. With nine prospective clinical trials and two retrospective studies within the active portfolio in March 2022, QUARTET will collect one of the largest repositories of paediatric radiotherapy and imaging data, support the clinical assessment of radiotherapy, and evaluate the role and benefit of radiotherapy quality assurance for this cohort of patients within the context of clinical trials.

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

BACKGROUND: 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, 17ßestradiol 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.

Rhabdomyosarcoma.

Rhabdomyosarcoma is a heterogeneous disease both in presentation and histology. Improvements in a multimodality therapy resulted in the improved overall survival for patients with a low-risk and intermediate-risk disease but not for patients with a metastatic disease. We reviewed and contrasted the North American and European practice patterns, though ultimately the principles of staging, surgery, radiation therapy, and chemotherapy are similar in both Children's Oncology Group and International Society of Paediatric Oncology treatment approaches. Efforts are underway to investigate improved local control rates in higher risk patients using radiation dose escalation strategies, and delayed primary excision in select cases. The prognostic significance of imaging-based chemotherapy response, proton therapy, novel biomarkers, and targeted drugs will be determined in upcoming clinical trials.

Quality assurance in radiation oncology.

The Children's Oncology Group (COG) has a strong quality assurance (QA) program managed by the Imaging and Radiation Oncology Core (IROC). This program consists of credentialing centers and providing real-time management of each case for protocol compliant target definition and radiation delivery. In the International Society of Pediatric Oncology (SIOP), the lack of an available, reliable online data platform has been a challenge and the European Society for Paediatric Oncology (SIOPE) quality and excellence in radiotherapy and imaging for children and adolescents with cancer across Europe in clinical trials (QUARTET) program currently provides QA review for prospective clinical trials. The COG and SIOP are fully committed to a QA program that ensures uniform execution of protocol treatments and provides validity of the clinical data used for analysis.

Prognostic relevance of clinical and molecular risk factors in children with high-risk medulloblastoma treated in the phase II trial PNET HR+5.

BACKGROUND: High-risk medulloblastoma is defined by the presence of metastatic disease and/or incomplete resection and/or unfavorable histopathology and/or tumors with MYC amplification. We aimed to assess the 3-year progression-free survival (PFS) and define the molecular characteristics associated with PFS in patients aged 5-19 years with newly diagnosed high-risk medulloblastoma treated according to the phase II trial PNET HR+5. METHODS: All children received postoperative induction chemotherapy (etoposide and carboplatin), followed by 2 high-dose thiotepa courses (600 mg/m2) with hematological stem cell support. At the latest 45 days after the last stem cell rescue, patients received risk-adapted craniospinal radiation therapy. Maintenance treatment with temozolomide was planned to start between 1-3 months after the end of radiotherapy. The primary endpoint was PFS. Outcome and safety analyses were per protocol (all patients who received at least one dose of induction chemotherapy). RESULTS: Fifty-one patients (median age, 8 y; range, 5-19) were enrolled. The median follow-up was 7.1 years (range: 3.4-9.0). The 3 and 5-year PFS with their 95% confidence intervals (95% CI) were 78% (65-88) and 76% (63-86), and the 3 and 5-year OS were 84% (72-92) and 76% (63-86), respectively. Medulloblastoma subtype was a statistically significant prognostic factor (P-value = 0.039) with large-cell/anaplastic being of worse prognosis, as well as a molecular subgroup (P-value = 0.012) with sonic hedgehog (SHH) and group 3 being of worse prognosis than wingless (WNT) and group 4. Therapy was well tolerated. CONCLUSIONS: This treatment based on high-dose chemotherapy and conventional radiotherapy resulted in a high survival rate in children with newly diagnosed high-risk medulloblastoma.

[Influence of age on indications and modalities of radiation therapy: What to keep in mind for adolescents and young adults?] / Impact de l'âge et radiothérapie : points clés chez les AJA.

When 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.

Pediatric Localized Intracranial Ependymomas: A Multicenter Analysis of the Société Française de lutte contre les Cancers de l'Enfant (SFCE) from 2000 to 2013.

PURPOSE: The objective of this study was to analyze survival and prognostic factors for children, adolescents, and young adults treated with postoperative radiation therapy (RT) for intracranial ependymoma. METHODS AND MATERIALS: Between 2000 and 2013, 202 patients aged ≤25 years were treated in the 13 main French pediatric RT reference centers. Their medical records were reviewed for information, treatments received, and survival rates. All children had received postoperative RT- conformal, intensity modulated, or proton beam. In 2009, the prescribed standard dose in France rose from 54 Gy to 59.4 Gy. RESULTS: Median follow-up was 53.8 months (95% confidence interval [CI] 47-63.5). Median age at RT was 5 years (range 1-22), and 32% of the children treated were aged <3 years. Regarding treatment, 85.6% of patients underwent gross total resection, 62% of patients received conformal RT (vs 29% for intensity modulated RT and 8% for proton beam RT), 62.4% of patients received a dose >54 Gy, and 71% received chemotherapy. Of the 84 relapses, 75% were local. The cumulative incidence of local relapse was 24.4% (95% CI 18.2-31.2) at 3 years and 31.3% (95% CI 24-38.9) at 5 years. The 5-year disease-free survival (DFS) and overall survival rates were 50.4% (95% CI 42.2-58) and 71.4% (95% CI 63.1-78.2). Tumor grade was the only prognostic factor for local relapse and DFS. Tumor grade, age, and extent of resection were independent prognostic factors for overall survival. CONCLUSIONS: We confirmed several clinical and tumoral prognostic factors in a large French multicenter study. DFS for intracranial ependymoma remains low, and new biological and imaging markers are needed to distinguish among different subtypes, adapt treatments, and improve survival.

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

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.

Modern robot-assisted radiosurgery of cerebral angiomas-own experiences, system comparisons, and comprehensive literature overview.

Cerebral arteriovenous malformations (AVMs) are rare vascular lesions potentially responsible for substantial neurological morbidity and mortality. Over the past four decades, radiosurgery has become a valid therapeutic option for many patients with small intracranial AVMs, but reports describing the use of robotic stereotactic radiosurgery (SRS) are rare. The purposes of this study are to describe the efficacy and toxicity of robotic SRS for AVMs and to review the literature. The reports of 48 consecutive patients treated with SRS were reviewed. A total dose of 18 Gy in a single fraction was prescribed to the 70% isodose line. Efficacy (i.e., total obliteration of the AVM) and toxicity were analyzed. Literature search was performed on Embase and PubMed for the terms "Radiosurgery and AVMs", "Cyberknife and AVMs" and "Radiation therapy and AVMs." The median follow-up was 41 months. The median AVM volume was 2.62 cm3. The incidence of obliteration was 59% at 3 years. Regarding toxicity, 92% of patients remained symptom-free, 66% developed radiogenic edema on MRI, and none developed radionecrosis. Forty-one patients (85%) had embolization prior to SRS. Our study was incorporated in an exhaustive review of 25 trials categorized by SRS technique. In this review, the median follow-up was 60 months. The median nidus volume was 2 cm3. The median overall obliteration rate for SRS was 68% (range 36 to 92). The median embolization rate prior to SRS was 31% (range 8.23 to 90). Compared to other studies, tolerability was excellent and the obliteration rate was acceptable but probably affected by the high embolization rate prior to radiosurgery. Our study suggests that a higher dose is feasible. A larger cohort with a longer follow-up period will be needed to confirm the safety and effectiveness, and subsequently validate different prognosis and predictive scores with this treatment modality to maximize the benefits of this technology for selected patients in the long term.

Vestibular schwannomas treated with Cyberknife®: clinical outcomes.

PURPOSE: Fractionated stereotactic radiotherapy (FSR) is a recognized treatment for vestibular schwannomas (VS). This study's aim is to present clinical outcomes and local control (LC) results for patients with VS treated with FSR using the Cyberknife® (CK) in 2 French cancer centers. METHODS: Patients treated with FSR for VS between 2007 and 2012 were retrospectively analyzed. Local control was determined using follow-up MRI. The hearing preservation (HP) rate was determined by analyzing pretreatment and posttreatment audiograms. RESULTS: Forty patients were treated for VS with the CK in both centers. The mean maximal VS dimension was 18.3 mm (range 3-30). The median follow-up was 36 months and the LC was 97% at 3 years of follow-up and 89% after 5 years. The HP rate was 83% and no facial nerve impairment was reported. CONCLUSIONS: Our results in terms of LC and HP rate are congruent with similar studies that use the CK to treat VS. It appears that the CK is safe and efficient in VS management even for large lesions. Further studies with larger cohorts are warranted.