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Despite aggressive management consisting of surgery, radiation therapy (RT), and systemic therapy given alone or in combination, a significant proportion of patients with brain tumors will experience tumor recurrence. For these patients, no standard of care exists and management of either primary or metastatic recurrent tumors remains challenging. Advances in imaging and RT technology have enabled more precise tumor localization and dose delivery, leading to a reduction in the volume of health brain tissue exposed to high radiation doses. Radiation techniques have evolved from three-dimensional (3-D) conformal RT to the development of sophisticated techniques, including intensity modulated radiation therapy (IMRT), volumetric arc therapy (VMAT), and stereotactic techniques, either stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT). Several studies have suggested that a second course of RT is a feasible treatment option in patients with a recurrent tumor; however, survival benefit and treatment related toxicity of reirradiation, given alone or in combination with other focal or systemic therapies, remain a controversial issue. We provide a critical overview of the current clinical status and technical challenges of reirradiation in patients with both recurrent primary brain tumors, such as gliomas, ependymomas, medulloblastomas, and meningiomas, and brain metastases. Relevant clinical questions such as the appropriate radiation technique and patient selection, the optimal radiation dose and fractionation, tolerance of the brain to a second course of RT, and the risk of adverse radiation effects have been critically discussed. [ABSTRACT FROM AUTHOR]

Purpose: As there is no standard of care treatment for recurrent/progressing pediatric high-grade gliomas (pHGG), we aimed to gain an overview of different treatment strategies. Methods: In a web-based questionnaire, members of the SIOPE-BTG and the GPOH were surveyed on therapeutic options in four case scenarios (children/adolescents with recurrent/progressing HGG). Results: 139 clinicians with experience in pediatric neuro-oncology from 22 European countries participated in the survey. Most respondents preferred further oncological treatment in three out of four cases and chose palliative care in one case with marked symptoms. Depending on the case, 8–92% would initiate a re-resection (preferably hemispheric pHGG), combined with molecular diagnostics. Throughout all case scenarios, 55–77% recommended (re-)irradiation, preferably local radiotherapy > 20 Gy. Most respondents would participate in clinical trials and use targeted therapy (79–99%), depending on molecular genetic findings (BRAF alterations: BRAF/MEK inhibitor, 64–88%; EGFR overexpression: anti-EGFR treatment, 46%; CDKN2A deletion: CDK inhibitor, 18%; SMARCB1 deletion: EZH2 inhibitor, 12%). 31–72% would administer chemotherapy (CCNU, 17%; PCV, 8%; temozolomide, 19%; oral etoposide/trofosfamide, 8%), and 20–69% proposed immunotherapy (checkpoint inhibitors, 30%; tumor vaccines, 16%). Depending on the individual case, respondents would also include bevacizumab (6–18%), HDAC inhibitors (4–15%), tumor-treating fields (1–26%), and intraventricular chemotherapy (4–24%). Conclusion: In each case, experts would combine conventional multimodal treatment concepts, including re-irradiation, with targeted therapy based on molecular genetic findings. International cooperative trials combining a (chemo-)therapy backbone with targeted therapy approaches for defined subgroups may help to gain valid clinical data and improve treatment in pediatric patients with recurrent/progressing HGG. [ABSTRACT FROM AUTHOR]

Purpose: Recurrence incidence for paediatric/adolescent high-grade glioma (HGG) exceeds 80%. Reirradiation (reRT) palliates symptoms and delays further progression. Strategies for reRT are scarce: we retrospectively analysed our series to develop rational future approaches. Methods: We re-evaluated MRI + RT plans of 21 relapsed HGG-patients, accrued 2010–2021, aged under 18 years. All underwent surgery and RT + chemotherapy at diagnosis. Pathologic/molecular re-evaluation allowed classification based on WHO 2021 criteria in 20/21 patients. Survival analyses and association with clinical parameters were performed. Results: Relapse after 1st RT was local in 12 (7 marginal), 4 disseminated, 5 local + disseminated. Re-RT obtained 8 SD, 1 PR, 1PsPD, 1 mixed response, 10 PD; neurological signs/symptoms improved in 8. Local reRT was given to 12, followed again by 6 local (2 marginal) and 4 local + disseminated second relapses in 10/12 re-evaluated. The 4 with dissemination had 1 whole brain, 2 craniospinal irradiation (CSI), 1 spine reRT and further relapsed with dissemination and local + dissemination in 3/four assessed. Five local + disseminated tumours had 3 CSI, 1 spine reRT, further progressing locally (2), disseminated (1), n.a. (1). Three had a third RT; three were alive at 19.4, 29, 50.3 months after diagnosis. Median times to progression/survival after re-RT were 3.7 months (0.6–16.2 months)/6.9 months (0.6–17.9 months), improved for longer interval between 1st RT and re-RT (P = 0.017) and for non-PD after reRT (P < 0.001). First marginal relapse showed potential association with dissemination after re-RT (P = 0.081). Conclusions: This is the biggest series of re-RT in paediatric HGG. Considering the dissemination observed at relapse, our results could prompt the investigation of different first RT fields in a randomized trial. [ABSTRACT FROM AUTHOR]

Introduction: Recently discovered molecular alterations in pediatric low-grade glioma have helped to refine the classification of these tumors and offered novel targets for therapy. Genetic aberrations may combine with histopathology to offer new insights into glioma classification, gliomagenesis and prognosis. Therapies targeting common genetic aberrations in the MAPK pathway offer a novel mechanism of tumor control that is currently under study. Methods: We have reviewed common molecular alterations found in pediatric low-grade glioma as well as recent clinical trials of MEK and BRAF inhibitors. Results: In this topic review, we examine the current understanding of molecular alterations in pediatric low-grade glioma, as well as their role in diagnosis, prognosis and therapy. We summarize current data on the efficacy of targeted therapies in pediatric low-grade gliomas, as well as the many unanswered questions that these new discoveries and therapies raise. Conclusions: The identification of driver alterations in pediatric low-grade glioma and the development of targeted therapies have opened new therapeutic avenues for patients with low-grade gliomas. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to determine outcomes in recurrent pediatric ependymoma. Methods: We performed a systematic review of PubMed, Embase, Web of Science and the Cochrane Library for studies reporting on survival outcomes for pediatric patients with recurrent ependymoma. We then performed a meta-analysis of all eligible results. Survival outcomes were identified across location of recurrence, therapy at recurrence, and age at recurrence. Results: Eleven studies met final inclusion criteria. Pooled median progression free survival (PFS) from date of first recurrence was 6.7 months (95% confidence interval [95% CI] 4.7–8.8). Pooled median overall survival (OS) from date of first recurrence was 11.2 months (95% CI 6.4–16.0). Participants with supratentorial recurrences demonstrated a shorter OS of 8.3 months (95% CI 3.2–13.3) compared to 20.1 months (95% CI 8.4–31.7) for those with infratentorial recurrence. Patients who underwent surgery at recurrence had a median OS of 24.2 months (95% CI 14.2–34.1) compared to 29.2 months (95% CI 17.4–41.1) in those who received radiation compared to 19.3 months (95% CI 10.3–28.3) in those who received chemotherapy. Patients younger than age 3 years at time of recurrence demonstrated a median OS of 31.0 months (95% CI − 25.3–87.3) compared to 17.5 months (95% CI 9.9–25.2) for those that recurred beyond 3 years of age. Conclusions: Our findings illustrate that children with recurrent ependymoma suffer from poor outcomes; however, these outcomes range widely depending on patient, tumor, and treatment characteristics. New therapies and treatment strategies are needed to improve outcomes in this group. [ABSTRACT FROM AUTHOR]

Background: Diffuse intrinsic pontine glioma (DIPG) is a devastating cancer of childhood and adolescence. Methods: The study included patients between 3 and 20 years with clinically and radiologically confirmed DIPG. Primary endpoint was 6-month progression-free survival (PFS) following administration of nimotuzumab in combination with external beam radiotherapy (RT). Nimotuzumab was administered intravenously at 150 mg/m2 weekly for 12 weeks. Radiotherapy at total dose of 54 Gy was delivered between week 3 and week 9. Response was evaluated based on clinical features and MRI findings according to RECIST criteria at week 12. Thereafter, patients continued to receive nimotuzumab every alternate week until disease progression/unmanageable toxicity. Adverse events (AE) were evaluated according to Common Terminology Criteria for Adverse Events (CTC-AE) Version 3.0 (CTC-AE3). Results: All 42 patients received at least one dose of nimotuzumab in outpatient settings. Two patients had partial response (4.8%), 27 had stable disease (64.3%), 10 had progressive disease (23.8%) and 3 patients (7.1%) could not be evaluated. The objective response rate (ORR) was 4.8%. Median PFS was 5.8 months and median overall survival (OS) was 9.4 months. Most common drug-related AEs were alopecia (14.3%), vomiting, headache and radiation skin injury (7.1% each). Therapy-related serious adverse events (SAEs) were intra-tumoral bleeding and acute respiratory failure, which were difficult to distinguish from effects of tumor progression. Conclusions: Concomitant treatment with RT and nimotuzumab was feasible in an outpatient setting. The PFS and OS were comparable to results achieved with RT and intensive chemotherapy in hospitalized setting. [ABSTRACT FROM AUTHOR]

We examined patterns of relapse and prognostic factors in children with intracranial ependymoma. Records of 82 children diagnosed with localized intracranial ependymoma were reviewed. 52% first presented to our institution after relapse. Median age at initial diagnosis was 4 years (range 0-18 years). Gender was 55% male. Initial tumor location was infratentorial in 71% and supratentorial in 29%. Histology was WHO Grade II in 32% and Grade III in 68%. As part of definitive management, 99% had surgery, 70% received RT (26% 2D/3D-conformal RT[CRT], 22% intensity-modulated RT [IMRT], 22% proton), and 37% received chemotherapy. Median follow-up was 4.6 years (range 0.2-32.9). Overall, 74% of patients relapsed (50% local, 17% distant, 7% local + distant) at a median 1.5 (range 0.1-17.5) years. Five-year OS and FFS for patients presenting prior to relapse are 70% (95% confidence interval [CI], 50-83%) and 48% (95% CI 30-64%), respectively. On log-rank, superior overall survival (OS) was demonstrated for gross total resection (p = 0.03). Superior failure-free survival (FFS) was demonstrated for age < 5 years (p = 0.04). No difference in OS or FFS was found between 2D/3D-CRT versus IMRT/proton (p > 0.05). On multivariate analysis, age ≤ 5 was independently associated with a lower risk of death and failure versus older patients (p < 0.05). Contrary to previous reports, young age may not be a poor prognostic factor in patients who can tolerate intensive treatment. Future studies examining patients stratified by clinical and molecular attributes are warranted. [ABSTRACT FROM AUTHOR]

Treatment of infant hypothalamic chiasmatic glioma (iCHG) is challenging, about 30% of the children progress during chemotherapy. Despite subsequent treatments the 5 year overall-survival rate is only 70%. This study investigates treatment strategies currently applied for progressive iCHG. A web-based questionnaire was sent out to the members of the SIOPE Brain Tumour Group asking for current second and third line strategies at progression during and after the end of first line therapy. The questionnaire was answered by 47 paediatric oncologists from 15 countries. iCHG progressing during first line therapy with carboplatin-vincristine would be considered for treatment with alternative chemotherapy by 17 (36%) and with surgery plus chemotherapy by 27 respondents (58%). Components suggested for second line were vinblastine (62%), cisplatin (34%) and cyclophosphamide (26%). For third line therapy bevacizumab (BVZ) was considered as suitable by respondents in 53% (often with irinotecan 40%) and vinblastine by 34% respectively. Experience with BVZ in CHG is shown by 53% of respondents regarding at least 95 patients (median treated 1-5 patients per respondent at any age) with a median BVZ administration over 12 months. Effectiveness was reported varying between stable disease and regression while complications were rarely stated (proteinuria, hypertension, bleeding). BVZ would be available to 85% of respondents as therapeutic option for iCHG patients. Multiple anti-neoplastic drug regimens are applied for progressive iCHG, partly considered in combination with surgery if safely feasible. BVZ is commonly used at a satisfactory level in third line, mainly combined with irinotecan. [ABSTRACT FROM AUTHOR]

The HIT-SIOP-PNET4 randomised trial for standard risk medulloblastoma (MB) (2001-2006) included 338 patients and compared hyperfractionated and conventional radiotherapy. We here report the long-term outcome after a median follow up of 7.8 years, including detailed information on relapse and the treatment of relapse. Data were extracted from the HIT Group Relapsed MB database and by way of a specific case report form. The event-free and overall (OS) survival at 10 years were 76 ± 2 % and 78 ± 2 % respectively with no significant difference between the treatment arms. Seventy-two relapses and three second malignant neoplasms were reported. Thirteen relapses (18 %) were isolated local relapses in the posterior fossa (PF) and 59 (82 %) were craniospinal, metastatic relapses (isolated or multiple) with or without concurrent PF disease. Isolated PF relapse vs all other relapses occurred at mean/median of 38/35 and 28/26 months respectively (p = 0.24). Late relapse, i.e. >5 years from diagnosis, occurred in six patients (8 %). Relapse treatment consisted of combinations of surgery (25 %), focal radiotherapy (RT 22 %), high dose chemotherapy with stem cell rescue (HDSCR 21 %) and conventional chemotherapy (90 %). OS at 5 years after relapse was 6.0 ± 4 %. In multivariate analysis; isolated relapse in PF, and surgery were significantly associated with prolonged survival whereas RT and HDSCR were not. Survival after relapse was not related to biological factors and was very poor despite several patients receiving intensive treatments. Exploration of new drugs is warranted, preferably based on tumour biology from biopsy of the relapsed tumour. [ABSTRACT FROM AUTHOR]

Temporal lobe injury (TLI) is a debilitating complication after radiotherapy for nasopharyngeal carcinoma (NPC), especially in patients who suffer treatment relapses and receive re-irradiation. We explored the clinical characteristics and prognostic factors of TLI in locally recurrent NPC (rNPC) patients after re-irradiation using intensity modulated radiotherapy (IMRT). A total of 454 temporal lobes (TLs) from 227 locally rNPC patients were reviewed. The clinical characteristics of TLI were analyzed. In the two radiotherapy courses, the equivalent dose in 2 Gy per fraction (EQD2) for the TLs was recalculated to facilitate comparison of the individual data. The median follow-up time was 31 (range, 3-127) months. After re-irradiation using IMRT, 31.3 % (71/227) of patients developed TLI. The median latency of TLI was 15 (range, 4-100) months. Univariate and multivariate analysis showed that the interval time (IT) between the two courses of radiotherapy and the summation of the maximum doses of the two radiotherapy courses (EQD2 − ∑) were independent factors influencing TLI. The 5-year incidence of TLI for an IT ≤26 or >26 months was 35.9 and 53.7 % respectively ( p = 0.024). The median maximum doses delivered to the injured TLs were significantly higher than was the case for the uninjured TLs after two courses of radiotherapy (135.3 and 129.8 Gy, respectively: p < 0.001). The incidence of TLI with an EQD2 − ∑ < 125 Gy was <5 %, and with an EQD2 − ∑ <145 Gy it was <50 %. A treatment mode limiting EQD2 − ∑ <125 Gy with a >2-year interval was found to be relatively safe. [ABSTRACT FROM AUTHOR]

Patients with World Health Organization (WHO) grade II supratentorial ependymomas are commonly observed after gross total resection (GTR), although supporting data are limited. We sought to characterize the natural history of such tumors. We used the Surveillance, Epidemiology, and End Results program to identify 112 patients ages 0–77 diagnosed with WHO grade II ependymomas between 1988 and 2007, of whom 63 (56 %) and 49 (44 %) had supratentorial and infratentorial primaries, respectively. Inclusion criteria were strict to ensure patient homogeneity. Of 33 patients with supratentorial tumors after GTR, 18 (55 %) received adjuvant radiation therapy and 15 (45 %) did not. Ependymoma-specific mortality (ESM) was the primary endpoint. With a median follow up of 4.5 years, only 1 of 33 patients with supratentorial ependymoma died of their disease after GTR; the 5-year estimate of ESM in this population was 3.3 % (95 % CI 0.2–14.8 %). Among patients with infratentorial ependymomas after GTR, the 5-year estimate of ESM was 8.7 % (95 % CI 1.4–24.6 %). In patients with subtotally resected tumors, 5-year estimates of ESM in patients with supratentorial and infratentorial primaries were 20.1 % (95 % CI 8.0–36.2 %) and 12.3 % (95 % CI 2.9–28.8 %), respectively. Among the whole cohort, on both univariable and multivariable regression, extent of resection was predictive of ESM, while tumor location and use of radiation were not. After GTR, patients with WHO grade II supratentorial ependymomas have a very favorable natural history with low associated cancer-specific mortality. Observation, with radiation reserved as a salvage option, may be a reasonable postoperative strategy in this population. [ABSTRACT FROM AUTHOR]

We analyzed the treatment outcomes of intracranial ependymomas in Korean children aged <18 years. Data for 96 patients were collected from five hospitals. Survival rates were calculated using the Kaplan-Meier method. Log-rank tests for univariate analyses and Cox regression model for multivariate analysis were conducted to identify prognostic factors for survival. The median age of the patients was 4 years (range, 0.3-17.9 years). The median follow-up was 55 months (range, 2-343 months). Age <3 years was an important factor for selecting adjuvant therapy after surgery. Among children aged <3 and ≥3 years, adjuvant radiotherapy (RT) was applied to 55 and 84 %, respectively, and adjuvant chemotherapy to 52 and 10 %, respectively. The 5 year local progression-free survival (LPFS), disease-free survival (DFS), and overall survival (OS) rates were 54, 52, and 79 %, respectively. Gross total resection was the most significant prognostic factor for all survival endpoints. Age ≥3 years and RT were significant prognostic factors for superior LPFS and DFS. However, the significance of age was lost in multivariate analysis for DFS. LPFS, DFS, and OS were superior in patients who started RT within 44 days after surgery (the median time) than in patients who started RT later in the patients aged ≥3 years. Postoperative RT was a strong prognostic factor for intracranial ependymomas. Our results suggest that early use of RT is an essential component of treatment, and should be considered in young children. [ABSTRACT FROM AUTHOR]

New molecularly targeted therapies are needed for childhood ependymoma. Angiogenesis and the PDGFR pathway could be potential therapeutic targets. This study aimed to screen ependymomas for the expression and clinicopathological correlates of angiogenic factors and potential therapeutic targets including VEGFR, endoglin (CD105), CD34, CD31, c-Kit, PDGFR-α and PDGFR-β. Immunohistochemistry for angiogenesis factors and PDGFR-α and β was performed in 24 archival tumor samples from children and adults treated for ependymoma at our institution. CD31 density, CD105 density and pericyte coverage index (PCI) were calculated. These findings were correlated with clinical outcome. VEGFR2 was overexpressed in tumor cells in only one out of 24 cases, but was found overexpressed in the vessels in 6 cases. PDGFR-α and β were found to be over-expressed in the ependymoma tumor cells in seven out of 24 cases (29.2 %). CD31 density, CD105 density and PCI did not correlate with expression of PDGFRs. Overexpression of PDGFR-α and β in tumor cells and overexpression of PDGFR-α in tumor endothelium had prognostic significance and this was maintained in multivariate analysis for overexpression of PDGFR-α in tumor cells (2 year progression free survival was 16.7 ± 15.2 for cases with overexpression of PDGFR-α in the tumor vs. 74.5 ± 15.2 for those with low/no expression, hazard ratio = 5.78, p = 0.04). A number of angiogenic factors are expressed in ependymoma tumor cells and tumor endothelium. Preliminary evidence suggests that the expression of PDGFRs could have a prognostic significance in ependymoma. This data suggests that PDGFRs should be further evaluated as targets using novel PDGFR inhibitors. [ABSTRACT FROM AUTHOR]

Pediatric infratentorial ependymomas are difficult to cure. Despite the availability of advanced therapeutic modalities for brain tumors, total surgical resection remains the most important prognostic factor. Recently, histological grade emerged as an independent prognostic factor for intracranial ependymoma. We retrospectively reviewed the treatment outcome of 33 pediatric patients with infratentorial ependymoma. Progression-free survival (PFS) and overall survival (OS) rates were calculated and relevant prognostic factors were analyzed. Fourteen patients (42%) were under the age of 3 at diagnosis. Gross total resection was achieved in 16 patients (49%). Anaplastic histology was found in 13 patients (39%). Adjuvant therapies were delayed until progression in 12 patients (36%). Actuarial PFS rates were 64% in the first year and 29% in the fifth year. Actuarial OS rates were 91% in the first year and 71% in the fifth year. On univariate analysis, brainstem invasion ( P = 0.047), anaplastic histology ( P = 0.004), higher mitotic count ( P = 0.001), and higher Ki-67 index ( P = 0.004) were significantly related to a shorter PFS. Gross total resection ( P = 0.029) and a greater age at diagnosis ( P = 0.033) were significantly related to a longer PFS. On multivariate analysis, anaplastic histology alone was significantly related to a shorter PFS ( P = 0.023). Gross total resection ( P = 0.039) was significantly related to a longer overall survival (OS) on multivariate analysis. Anaplastic histology and gross total resection were the most important clinical factors affecting PFS and OS, respectively. Anaplastic histology, mitotic count, and Ki-67 index can be used as universal and easily available prognostic parameters in infratentorial ependymomas. [ABSTRACT FROM AUTHOR]

High-level amplifications of MYC genes are associated with poor outcomes in childhood medulloblastoma (MB). However, the occurrence of MYCN and MYCC copy number increases below the intense amplification pattern is rarely reported, and its clinical impact has not yet been determined. Here, we describe this phenomenon and its prognostic significance in a cohort of 29 MB patients. Using interphase fluorescence in situ hybridization (I-FISH), low-level copy number alterations, i.e. gain of MYCN, were shown in 5/27 (19%) samples, whereas amplification was revealed in only 1/27 (4%) samples. MYCC gain was revealed in 6/29 (21%) MB, while amplification was disclosed in only 2/29 (7%). Hyperploidy and co-incidence of gains in both MYC loci were frequently observed in samples with copy number aberrations. Survival analysis has clearly shown that MYC copy number increases are associated with lowered event-free survival and overall survival in MB. In the case of MYCN, this negative correlation was statistically significant. We conclude that limited numerical alterations in loci 2p24 ( MYCN) and 8q24 ( MYCC), as assessed by I-FISH, are present in MB with a higher frequency than high-level amplifications. Poor prognoses were observed in patients with copy number increases in MYC genes. Our data illustrate the importance of further investigations in multicenter trials to better refine the emerging genomic-based prognostic stratification in MB. [ABSTRACT FROM AUTHOR]

Recent advances in neuroimaging, neurosurgery and radiation therapy have improved disease control and functional outcomes for children with ependymoma, including children under the age of 3 years. The rate of gross-total resection has been increased to 85% in some series and 3 year progression-free survival after radiation therapy as high as 75% has been reported along with significant reductions in neurologic, endocrine and cognitive deficits. Based on these advances and renewed interest in radiation therapy as a frontline treatment modality, attention has been refocused on disease control instead of radiotherapy avoidance. Future research in the treatment of this tumor, that afflicts fewer than 200 children in the US each year, will focus on molecular biology, clarifying risk factors for tumor control and late effects, and testing novel agents. [ABSTRACT FROM AUTHOR]