Bartels, Ute

Abstract Response Assessment in Pediatric Neuro-Oncology (RAPNO) is an international working group dedicated to developing standardized recommendations for response assessment in children with central nervous system tumors enrolled on clinical trials. This standardization facilitates easier and more reliable comparison of responses across trials. Since the first RAPNO publication in 2013, response guidelines have been issued for medulloblastoma (MB), low-grade glioma (LGG), high-grade glioma (HGG), diffuse intrinsic pontine glioma, ependymoma, and craniopharyngioma. Many of these guidelines have already been incorporated into clinical trials to evaluate their effectiveness and accuracy. RAPNO has always been predicated on the idea that these consensus recommendations will require updates over time as they are applied in practice given technological advancements, evolving treatment approaches, and growing knowledge of disease pathology. A half-day RAPNO symposium sponsored by the Society of Neuro-Oncology was held in San Diego, California, United States, on May 15, 2025. This event coincided with the 8th Biennial Pediatric Society of Neuro-Oncology meeting. The main objectives were to identify ongoing RAPNO challenges, discuss potential updates, and plan future initiatives across 3 specific groups: (1) LGG/Craniopharyngioma, (2) HGG/diffuse midline glioma (DMG)/Ependymoma, and (3) MB and other seeding tumors. This manuscript reviews the symposium proceedings and highlights key topics and challenges discussed, as well as outlining future RAPNO initiatives.

Abstract BACKGROUND ACNS1123 was a Phase 2 study to determine whether irradiation could be safely reduced without impacting survival in a subgroup of NGGCT patients. METHODS Patients with localized disease who achieved a complete (CR) or partial response (PR) to induction chemotherapy were eligible to receive reduced dose/volume of irradiation to 30.6Gy whole ventricular field with 54Gy tumor-bed boost. RESULTS 107 eligible NGGCT patients were accrued. The median age of patients at enrollment was 11 years (3.7-21.6). Eighty patients (75%) were male. Location was pineal in 58 (55%), suprasellar in 37 (35%), ventricles in 6 (6%), and bifocal in 6 patients (6%). Sixty-six (61.7%) patients achieved a CR/PR post-induction and were eligible and evaluable for the primary objective and received reduced dose and volume of irradiation. Eight patients progressed; 6 had a distant spinal relapse (outside the irradiation field) and 2 had a local plus distant relapse. As of December 31, 2023, the median follow-up time for eligible and evaluable patients was 5.6 years (0.9-7.9) from enrollment. Except for an unrelated death due to SARS-CoV-2 at 5.5 years from enrollment, there were no grade 3 or higher adverse events at the 60-month follow-up timepoint and no disease progressions beyond 2 years. The 5-year progression-free and overall survival for all eligible and evaluable patients are 87.9% (95% CI:79%-94.8%) and 92.4% (95% CI:82.8%- 96.8%), respectively. CONCLUSION Although the study was closed prematurely due to the concern of increased spinal relapse, the current data suggest that most patients with localized NGGCT and a CR/PR to chemotherapy will survive long-term, and, in fact, have similar survival (PFS and OS) to patients enrolled on ACNS0122 who received full dose craniospinal irradiation. The key to future biologic studies and clinical trials is identifying at diagnosis those patients at high risk for relapse.

Abstract BACKGROUND Primary intracranial germ cell tumors (GCTs) are rare heterogeneous tumors; germinoma accounts for two-thirds of cases. While neoadjuvant chemotherapy followed by response-based reduced radiotherapy dose and field is the established approach for managing localized CNS germinomas, controversy persists regarding the treatment of primary metastatic disease. Additionally, limited research exists on the utilization of neoadjuvant chemotherapy in primary metastatic germinoma. METHODS A retrospective multi-institutional analysis was conducted to assess overall survival (OS) and event-free survival (EFS) among patients diagnosed with metastatic germinoma who were treated with various modalities. RESULTS We identified 88 patients, including 63 males and 25 females. The median age at presentation was 13.5 years. All patients, who had undergone both brain and spine MRIs, had their diagnoses confirmed through a biopsy, positive CSF cytology, and/or positive CSF tumor markers at presentation. Primary Tumor location was pineal (n=37), suprasellar (n=27), bifocal (n=14) and others (n=9). Eight patients underwent subtotal resection. Craniospinal irradiation (CSI; 21-24 Gy) was administered to 71 patients (81%), while eight patients (9%) received whole ventricular irradiation (WVI; 23.4-30 Gy). Whole brain radiation was given to four patients (5%; 24 Gy), and two patients (2%) had unknown fields. Boosts to primary and/or metastatic sites were administered in all but seven patients. Notably, thirty patients (34%) received CSI without neoadjuvant chemotherapy. At the end of therapy, 69 patients had complete response, 10 partial response and the response was unknown in six. Three patients did not receive irradiation, all died of disease progression. The median follow-up was 64 months (range 6-159 months), yielding an OS of 96.6%. Ongoing multi-institutional data collection and analysis will be presented at the meeting. CONCLUSION Our study is one of the largest studies to date in metastatic germinoma and may provide insight into the role of neoadjuvant chemotherapy with lower CSI doses.

Abstract Background Craniopharyngioma is a histologically benign tumor of the suprasellar region for which survival is excellent but quality of life is often poor secondary to functional deficits from tumor and treatment. Standard therapy consists of maximal safe resection with or without radiation therapy. Few prospective trials have been performed, and response assessment has not been standardized. Methods The Response Assessment in Pediatric Neuro-Oncology (RAPNO) committee devised consensus guidelines to assess craniopharyngioma response prospectively. Results Magnetic resonance imaging is the recommended radiologic modality for baseline and follow-up assessments. Radiologic response is defined by 2-dimensional measurements of both solid and cystic tumor components. In certain clinical contexts, response to solid and cystic disease may be differentially considered based on their unique natural histories and responses to treatment. Importantly, the committee incorporated functional endpoints related to neuro-endocrine and visual assessments into craniopharyngioma response definitions. In most circumstances, the cystic disease should be considered progressive only if growth is associated with acute, new-onset or progressive functional impairment. Conclusions Craniopharyngioma is a common pediatric central nervous system tumor for which standardized response parameters have not been defined. A RAPNO committee devised guidelines for craniopharyngioma assessment to uniformly define response in future prospective trials.

Abstract INTRODUCTION: Craniopharyngioma (CP) is a histologically benign tumor of the pituitary stalk that accounts for 4% of pediatric central nervous system (CNS) tumors. Given its location, CP often causes neuro-endocrine, hypothalamic, and vision dysfunction. Standard therapy consists of maximally safe resection +/- radiation therapy (RT). Medical management, including intra-cystic therapy, may have utility in certain contexts. Survival after CP is excellent, but quality of life is often poor secondary to functional deficits from the tumor and/or treatment. Few prospective CP trials have been performed, and response assessment has not been standardized. METHODS: The Response Assessment in Pediatric Neuro-Oncology (RAPNO) committee, formed of international experts in relevant subspecialties, devised consensus guidelines from published literature and/or expert opinion to assess CP response in prospective clinical trials. RESULTS: Magnetic resonance imaging (MRI) is the recommended radiological modality for baseline and follow-up CP assessment. Computed tomography can be useful for identification of calcification in the initial diagnostic work-up. The committee defined specific standard MRI-based sequences focused on comprehensive evaluation of the suprasellar space. Radiologic CP response is defined by two-dimensional measurements of both solid and cystic tumor components. Three-dimensional measurements are also encouraged in prospective trials. In certain clinical contexts, response of solid and cystic disease may be differentially considered based on their unique natural histories and responses to treatment (including transient cyst growth during or after RT). Importantly, the committee incorporated functional endpoints related to neuro-endocrine and visual assessments into CP response definitions. In most circumstances, cystic disease should be considered progressive only if growth is associated with acute, new-onset or progressive functional impairment. CONCLUSION: CP is a common pediatric CNS tumor for which standardized response parameters have not been defined. A RAPNO committee devised guidelines for baseline and longitudinal assessments of CP to uniformly define response in future prospective trials.

Abstract BACKGROUND: Central Nervous System- Non-Germinomatous Germ Cell Tumors (CNS-NGGCT) are rare but curable tumors. Due to their rarity, treatment failures remain a poorly characterized disease with unfavorable outcomes. In this study, we sought to characterize the treatment failures in a large cohort of prospectively treated patients. METHODS: European and North American clinical trials for patients with CNS-NGGCT (SIOP-GCT96, SFOP-TGM TC 90/92, COG-ACNS0122 and COG-ACNS1123) were pooled for analysis. Additionally, patients included and treated in the UK and France national registries under strict protocol-guidelines were included as an independent, non-overlapping cohort. RESULTS: A total of 118 patients experienced a treatment failure. Twenty-four patients had progressive disease during therapy and additional eleven patients were diagnosed with growing teratoma syndrome (GTS). Patients with GTS are significantly younger and present with local failures and negative tumor markers. Eighty-three individuals experienced disease relapses after treatment ended. Patients’ metastatic relapses presented significantly earlier than local relapses and were associated with tumor marker elevation (OR: 4.39; p=0.026). In our analysis, focal or whole ventricular (WVI) radiation therapy was not associated with an increased risk of metastatic relapses. CONCLUSIONS: Herein, we present the largest pooled dataset of prospectively treated patients with relapsed CNS-NGGCT. Our study identified younger age and negative tumor markers to be characteristic of GTS. Additionally, we elucidated that metastatic relapses occur earlier than local relapses, are associated with elevated tumor markers, and are not associated with the field of radiation therapy. These findings are of utmost importance for the planning of future clinical trials and the implementation of surveillance strategies in these patients.

Abstract BACKGROUND: Primary intracranial germ cell tumors (GCTs) are rare heterogeneous tumors, with germinoma accounting for two-thirds of cases. Neoadjuvant chemotherapy with response-based reduced radiotherapy dose and field has become the standard management of localized CNS germinomas, however, treatment of primary metastatic disease has remained controversial. Furthermore, there is limited published research on the use of neoadjuvant chemotherapy in primary metastatic germinoma. METHODS: We performed a retrospective multi-institutional data collection and analysis of patients diagnosed with metastatic germinoma since 2000 to assess the overall survival (OS) and event-free survival (EFS) of the different treatment modalities administered. RESULTS: We identified 78 patients with germinoma, in two tertiary care centers, of which nine patients (11.5%; eight males) had metastatic disease. The median age at presentation was 13.3 years. All patients had a biopsy at presentation confirming the diagnosis. Three patients had positive CSF cytology (M1). Six patients received craniospinal irradiation (CSI) with boost to primary and metastatic sites, of which five patients received total CSI dose of 24 Gy, while the dose was unknown for one patient. One patient required one cycle of chemotherapy prior to CSI due to worsening visual changes, which subsequently resolved. One patient received two cycles followed by whole ventricular irradiation (WVI) of 23.4 Gy with a boost to the primary bed. One patient received WVI without neoadjuvant chemotherapy. One patient developed anoxic brain injury and only received chemotherapy. He died of recurrent progressive disease 15 months post-diagnosis. The median follow-up time was 77.5 months (range 15-130.5 months), with an OS of 88.9%. Further multi-institutional data collection and analysis is underway and will be presented at the meeting. CONCLUSION: We anticipate our results may elucidate the role of neoadjuvant chemotherapy in the treatment of metastatic germinoma, and whether when combined with lower CSI doses did not compromise EFS/OS.

Abstract Background Central Nervous System Non-Germinomatous Germ Cell Tumors (CNS-NGGCT) are rare but curable tumors. Due to their rarity, patients with treatment failures remain a poorly characterized group with unfavorable outcomes. In this study, we sought to characterize patients with treatment failures in a large, prospectively treated cohort. Methods European and North American clinical trials for patients with CNS-NGGCT (SIOP-GCT-96, SFOP-TGM-TC 90/92, COG-ACNS0122, and COG-ACNS1123) were pooled for analysis. Additionally, patients included and treated in the UK and France national registries under strict protocol guidelines were included as an independent, non-overlapping cohort. Results A total of 118 patients experienced a treatment failure. Twenty-four patients had progressive disease during therapy, and additional 11 patients were diagnosed with growing teratoma syndrome (GTS). Patients with GTS are significantly younger and present with local failures and negative tumor markers. Eighty-three individuals experienced disease relapses after treatment ended. Patients’ metastatic relapses presented significantly earlier than local relapses and were associated with tumor marker elevation (OR: 4.39; P = .026). In our analysis, focal or whole-ventricular radiation therapy was not associated with an increased risk of metastatic relapses. Conclusions Herein, we present the largest pooled dataset of prospectively treated patients with relapsed CNS-NGGCT. Our study identified younger age and negative tumor markers to be characteristic of GTS. Additionally, we elucidated that metastatic relapses occur earlier than local relapses are associated with elevated tumor markers and are not associated with the field of radiation therapy. These findings are of utmost importance for the planning of future clinical trials and the implementation of surveillance strategies in these patients.

Abstract Background The study aimed to evaluate whether simplified chemotherapy followed by dose-reduced irradiation was effective for treating patients (ages 3–21 years) with localized germinoma. The primary endpoint was 3-year progression-free survival (PFS) rate. Methods Patients with a complete response to chemotherapy with carboplatin and etoposide received 18 Gy WVI + 12 Gy boost to the tumor bed. Patients with partial response proceeded to 24 Gy WVI + 12 Gy. Longitudinal cognitive functioning was evaluated prospectively on ALTE07C1 and was a primary study aim. Results One hundred and fifty-one patients were enrolled; 137 were eligible. Among 90 evaluable patients, 74 were treated with 18 Gy and 16 with 24 Gy WVI. The study failed to demonstrate noninferiority of the 18 Gy WVI regimen compared to the design threshold of 95% 3-year PFS rate, where, per design, patients who could not be assessed for progression at 3 years were counted as failures. The Kaplan-Meier (KM)-based 3-year PFS estimates were 94.5 ± 2.7% and 93.75 ± 6.1% for the 18 Gy and 24 Gy WVI cohorts, respectively. Collectively, estimated mean IQ and attention/concentration were within normal range. A lower mean attention score was observed at 9 months for patients treated with 24 Gy. Acute effects in processing speed were observed in the 18 Gy cohort at 9 months which improved at 30-month assessment. Conclusions While a failure according to the prospective statistical noninferiority design, this study demonstrated high rates of chemotherapy responses, favorable KM-based PFS and OS estimates in the context of reduced irradiation doses and holds promise for lower long-term morbidities for patients with germinoma.

PURPOSE SJMB03 (ClinicalTrials.gov identifier: NCT00085202 ) was a phase III risk-adapted trial that aimed to determine the frequency and clinical significance of biological variants and genetic alterations in medulloblastoma. PATIENTS AND METHODS Patients 3-21 years old were stratified into average-risk and high-risk treatment groups based on metastatic status and extent of resection. Medulloblastomas were molecularly classified into subgroups (Wingless [WNT], Sonic Hedgehog [SHH], group 3, and group 4) and subtypes based on DNA methylation profiles and overlaid with gene mutations from next-generation sequencing. Coprimary study end points were (1) to assess the relationship between ERBB2 protein expression in tumors and progression-free survival (PFS), and (2) to estimate the frequency of mutations associated with WNT and SHH tumors. Clinical and molecular risk factors were evaluated, and the most robust were used to model new risk-classification categories. RESULTS Three hundred thirty eligible patients with medulloblastoma were enrolled. Five-year PFS was 83.2% (95% CI, 78.4 to 88.2) for average-risk patients (n = 227) and 58.7% (95% CI, 49.8 to 69.1) for high-risk patients (n = 103). No association was found between ERBB2 status and PFS in the overall cohort ( P = .74) or when patients were stratified by clinical risk ( P = .71). Mutations in CTNNB1 (96%), DDX3X (37%), and SMARCA4 (24%) were most common in WNT tumors and PTCH1 (38%), TP53 (21%), and DDX3X (19%) in SHH tumors. Methylome profiling classified 53 WNT (17.4%), 48 SHH (15.7%), 65 group 3 (21.3%), and 139 group 4 (45.6%) tumors. A comprehensive clinicomolecular risk factor analysis identified three low-risk groups (WNT, low-risk SHH, and low-risk combined groups 3 and 4) with excellent (5-year PFS > 90%) and two very high-risk groups (high-risk SHH and high-risk combined groups 3 and 4) with poor survival (5-year PFS < 60%). CONCLUSION These results establish a new risk stratification for future medulloblastoma trials.