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Background: Shortages and unequal access to anticancer medicines for children and adolescents are a reality in Europe. The aim of the European Society for Paediatric Oncology (SIOPE) Essential Anticancer Medicines Project was to provide a list of anticancer medicines that are considered essential in the treatment of paediatric cancers to help ensure their continuous access to all children and adolescents with cancer across Europe. Methods: This pan-European project, done between Jan 20, 2020, and Feb 18, 2022, was designed to be a systematic collection and review of treatment protocols and strategies that are used to treat childhood cancer in Europe. We formed 16 working groups on the basis of paediatric cancer types, and which were based on the existing SIOPE Clinical Trial Groups. Workings groups consisted of representatives from the SIOPE Clinical Trial Groups, Young SIOPE members, and senior paediatric oncology experts. Each group collected existing treatment protocols that are used to treat the respective cancer types in Europe. Medicines from the standard group of each protocol were extracted. For medicines not on the WHO Essential Medicines List for children (EMLc) 2017, working groups did a literature search to determine whether the medicines should be defined as essential, promising, or neither essential nor promising. Each group provided an individual summary, and all medicines that were considered essential by at least one group were combined in a joint list. Findings: The working groups identified 73 treatment protocols used in Europe and defined 66 medicines as essential. For several newer medicines, such as kinase inhibitors or tisagenlecleucel, the supporting evidence was insufficient to consider them essential, so these medicines were defined as promising. 25 medicines were considered promising by at least one working group. 22 (33%) of the 66 essential and none of the promising medicines were included in the WHO EMLc 2017. The WHO EMLc 2021 included two new medicines (everolimus and vinorelbine) following applications we made as a result of this project. Interpretation: Medicines that were defined as essential within this project should be available for the treatment of childhood and adolescent cancer continuously and across Europe. This list can be used to support and guide stakeholders and policy makers in negotiations on a national and European level regarding shortages, accessibility, and affordability of these medicines. Funding: None.

Abstract MAPPYACTS (NCT02613962) is an international prospective precision medicine trial aiming to define tumor molecular profiles in pediatric patients with recurrent/refractory malignancies in order to suggest the most adapted salvage treatment. From February 2016 to July 2020, 787 patients were included in France, Italy, Ireland, and Spain. At least one genetic alteration leading to a targeted treatment suggestion was identified in 436 patients (69%) with successful sequencing; 10% of these alterations were considered “ready for routine use.” Of 356 patients with follow-up beyond 12 months, 107 (30%) received one or more matched targeted therapies—56% of them within early clinical trials—mainly in the AcSé-ESMART platform trial (NCT02813135). Overall, matched treatment resulted in a 17% objective response rate, and of those patients with ready for routine use alterations, it was 38%. In patients with extracerebral tumors, 76% of actionable alterations detected in tumor tissue were also identified in circulating cell-free DNA (cfDNA). Significance: MAPPYACTS underlines the feasibility of molecular profiling at cancer recurrence in children on a multicenter, international level and demonstrates benefit for patients with selected key drivers. The use of cfDNA deserves validation in prospective studies. Our study highlights the need for innovative therapeutic proof-of-concept trials that address the underlying cancer complexity. This article is highlighted in the In This Issue feature, p. 1171

MAPPYACTS (NCT02613962) is an international prospective precision medicine trial aiming to define tumor molecular profiles in pediatric patients with recurrent/refractory malignancies in order to suggest the most adapted salvage treatment. From February 2016 to July 2020, 787 patients were included in France, Italy, Ireland, and Spain. At least one genetic alteration leading to a targeted treatment suggestion was identified in 436 patients (69%) with successful sequencing; 10% of these alterations were considered “ready for routine use.” Of 356 patients with follow-up beyond 12 months, 107 (30%) received one or more matched targeted therapies—56% of them within early clinical trials—mainly in the AcSé-ESMART platform trial (NCT02813135). Overall, matched treatment resulted in a 17% objective response rate, and of those patients with ready for routine use alterations, it was 38%. In patients with extracerebral tumors, 76% of actionable alterations detected in tumor tissue were also identified in circulating cell-free DNA (cfDNA).Significance:MAPPYACTS underlines the feasibility of molecular profiling at cancer recurrence in children on a multicenter, international level and demonstrates benefit for patients with selected key drivers. The use of cfDNA deserves validation in prospective studies. Our study highlights the need for innovative therapeutic proof-of-concept trials that address the underlying cancer complexity.This article is highlighted in the In This Issue feature, p. 1171

Supplementary Data from The European MAPPYACTS Trial: Precision Medicine Program in Pediatric and Adolescent Patients with Recurrent Malignancies

Pediatric patients with recurrent and refractory cancers are in most need for new treatments. This study developed patient-derived-xenograft (PDX) models within the European MAPPYACTS cancer precision medicine trial (NCT02613962). To date, 131 PDX models were established following heterotopical and/or orthotopical implantation in immunocompromised mice: 76 sarcomas, 25 other solid tumors, 12 central nervous system tumors, 15 acute leukemias, and 3 lymphomas. PDX establishment rate was 43%. Histology, whole exome and RNA sequencing revealed a high concordance with the primary patient’s tumor profile, human leukocyte-antigen characteristics and specific metabolic pathway signatures. A detailed patient molecular characterization, including specific mutations prioritized in the clinical molecular tumor boards are provided. Ninety models were shared with the IMI2 ITCC Paediatric Preclinical Proof-of-concept Platform (IMI2 ITCC-P4) for further exploitation. This new PDX biobank of unique recurrent childhood cancers provides an essential support for basic and translational research and new treatments development in advanced pediatric malignancies.

Internationally, a single standard chemotherapy treatment for Ewing sarcoma is not defined. Because different chemotherapy regimens were standard in Europe and the USA for newly diagnosed Ewing sarcoma, and in the absence of novel agents to investigate, we aimed to compare these two strategies.EURO EWING 2012 was a European investigator-initiated, open-label, randomised, controlled phase 3 trial done in 10 countries. We included patients aged 2-49 years, with any histologically and genetically confirmed Ewing sarcoma of bone or soft tissue, or Ewing-like sarcomas. The eligibility criteria originally excluded patients with extrapulmonary metastatic disease, but this was amended in the protocol (version 3.0) in September, 2016. Patients were randomly assigned (1:1) to either the European regimen of vincristine, ifosfamide, doxorubicin, and etoposide induction, and consolidation using vincristine, actinomycin D, with ifosfamide or cyclophosphamide, or busulfan and melphalan (group 1); or the US regimen of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide induction, plus ifosfamide and etoposide, and consolidation using vincristine and cyclophosphamide, or vincristine, actinomycin D, and ifosfamide, with busulfan and melphalan (group 2). All drugs were administered intravenously. The primary outcome measure was event-free survival. We used a Bayesian approach for the design, analysis, and interpretation of the results. Patients who received at least one dose of study treatment were considered in the safety analysis. The trial was registered with EudraCT, 2012-002107-17, and ISRCTN, 54540667.Between March 21, 2014, and May 1, 2019, 640 patients were entered into EE2012, 320 (50%) randomly allocated to each group. Median follow-up of surviving patients was 47 months (range 0-84). Event-free survival at 3 years was 61% with group 1 and 67% with group 2 (adjusted hazard ratio [HR] 0·71 [95% credible interval 0·55-0·92 in favour of group 1). The probability that the true HR was less than 1·0 was greater than 0·99. Febrile neutropenia as a grade 3-5 treatment toxicity occurred in 234 (74%) patients in group 1 and in 183 (58%) patients in group 2. More patients in group 1 (n=205 [64%]) required at least one platelet transfusion compared with those in group 2 (n=138 [43%]). Conversely, more patients required blood transfusions in group 2 (n=286 [89%]) than in group 1 (n=277 [87%]).Dose-intensive chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide is more effective, less toxic, and shorter in duration for all stages of newly diagnosed Ewing sarcoma than vincristine, ifosfamide, doxorubicin, and etoposide induction and should now be the standard of care for Ewing sarcoma.The European Union's Seventh Framework Programme for Research, Technological Development, and Demonstration; The National Coordinating Centre in France, Centre Léon Bérard; SFCE; Ligue contre le cancer; Cancer Research UK.

Endoscopic extended transsphenoidal surgery (EETSS) has gained popularity for treatment of craniopharyngiomas. The aim of this study is to assess the outcome of endoscopic extended transsphenoidal surgery (EETSS) for newly diagnosed paediatric craniopharyngiomas. Patient details were obtained from a prospective database of all endoscopic transnasal operations performed by a single surgeon. Outcomes including visual function, pituitary function, body mass index (BMI), postoperative neurological deficit, extent of resection and recurrence on follow-up were obtained. Obesity was defined as BMI percentile of equal to or greater than 95%. Between January 2011 and January 2020, 15 of 16 children (5–18 years old) with newly diagnosed craniopharyngiomas underwent EETSS. Four patients had a conchal-type sphenoid sinus. Gross total resection (GTR) was achieved in 4 patients and near total resection (NTR) in 5 patients. The remaining 6 had subtotal resection (STR). Postoperative radiotherapy was used in 6 patients (4 with STR, 2 with NTR). There were no postoperative deaths, strokes or CSF leaks. Normalisation of visual fields (VF) occurred in 9/13 patients with preoperative VF defects. One patient developed a new visual field defect. During a median follow-up period of 74 (8–104) months, 2 patients have required further surgery for tumour progression following initial STR, where a tumour remnant was left in situ to preserve the pituitary stalk. 6/11 patients developed new anterior pituitary dysfunction as a result of surgery and 9/12 developed new diabetes insipidus (DI). At the time of last follow-up, 14/15 children had anterior panhypopituitarism, 13/15 had DI and 1 patient developed new onset obesity. Two patients, who were obese preoperatively, were no longer obese at last follow-up. EETSS can be performed as the first option in the majority of children with newly diagnosed craniopharyngioma, despite factors such as small nose, non-pneumatised sphenoid sinus, small sella or purely suprasellar tumour location. Preservation of the pituitary stalk at the expense of leaving residual tumour may not be in the best interests of the patient.

Purpose: Childhood cancer is rare, and treatment is frequently associated with long-term morbidity. Disparities in survival and long-term side effects encourage the establishment of networks to increase access to complex organ-conservative strategies, such as brachytherapy. We report our experience of an international cooperation model in childhood cancers. Methods and Materials: We examined the outcome of all children referred to our center from national or international networks to be treated according to a multimodal organ-conservative approach, including brachytherapy. Results: We identified 305 patients whose median age at diagnosis was 2.2 years (range, 1.4 months to 17.2 years). Among these patients, 99 (32.4%) were treated between 2015 and 2020; 172 (56.4%) were referred from national centers; and 133 (43.6%) were international patients from 31 countries (mainly Europe). Also, 263 patients were referred for primary treatment and 42 patients were referred for salvage treatment. Genitourinary tumors were the most frequent sites, with 56.4% bladder/prostate rhabdomyosarcoma and 28.5% gynecologic tumors. In addition to brachytherapy, local treatment consisted of partial tumor resection in 207 patients (67.9%), and 39 patients (13%) had additional external radiation therapy. Median follow-up was 58 months (range, 1 month to 48 years), 93 months for national patients, and 37 months for international patients (P < .0001). Five-year local control, disease-free survival, and overall survival rates were 90.8% (95% confidence interval [CI], 87.3%-94.4%), 84.4% (95% CI, 80.1%-89.0%), and 93.3% (95% CI, 90.1%-96.5%), respectively. Patients referred for salvage treatment had poorer disease-free survival (P < .01). Implementation of image guided pulse-dose-rate brachytherapy was associated with better local control among patients with rhabdomyosarcoma referred for primary treatment (hazard ratio, 9.72; 95% CI, 1.24-71.0). At last follow-up, 16.7% patients had long-term severe treatment-related complications, and 2 patients (0.7%) had developed second malignancy. Conclusions: This retrospective series shows the feasibility of a multinational referral network for brachytherapy allowing high patient numbers in rare pediatric cancers. High local control probability and acceptable late severe complication probability could be achieved despite very challenging situations. This cooperation model could serve as a basis for generating international reference networks for high-tech radiation such as brachytherapy to increase treatment care opportunities and cure probability.

10039 Background: Children with relapsed and refractory neuroblastoma (RR-NBL) have poor outcomes. Early identification of children at greatest risk of relapse could mean timelier modifications of treatment to improve outcomes. High levels of adrenergic neuroblastoma mRNAs in blood of children with stage M neuroblastoma receiving frontline treatment predict poor outcome (Viprey PMID: 24590653). Since these markers have not been thoroughly studied in the RR-NBL population, we have prospectively evaluated the prognostic potential of the adrenergic neuroblastoma mRNAs paired-like homeobox 2B (PHOX2B ) and tyrosine hydroxylase (TH) in blood from children with RR-NBL treated in the BEACON-Neuroblastoma trial (NCT02308527). Methods: Blood samples collected at baseline from 88 children were analysed by reverse transcriptase polymerase chain reaction (RTqPCR) for PHOX2B and TH mRNAs. The prognostic power of these mRNAs was evaluated using Kaplan-Meier survival curves and Cox proportional hazards regression. Progression-free (PFS) and overall survival (OS) were calculated from the date that the blood sample was taken at screening to the date of an event; progression, disease recurrence, death or censored alive at the last clinical evaluation. Results: Of the children in this cohort, 58 (66%) had relapsed and 30 (34%) had refractory disease. Twenty-three (26%) had MYC-N amplified tumours. TH and PHOX2B mRNAs were detected in 55% and 60% of blood samples respectively; the correlation coefficient between TH and PHOX2B was 0.75. Higher levels of TH, PHOX2B mRNAs or both combined were associated with reduced PFS and OS (Table). For TH, median PFS for children with TH levels below the median was 12 months (95%CI, 4.6–13 months) versus 5.5 months (95%CI, 1.8–9.4 months) for those children with TH levels above the median. For PHOX2B, median PFS for children with PHOX2B levels below the median was 11.5 months (95%CI, 7.6–34 months), compared to 5.7 months (95%CI, 1.8–10.5 months) where levels were above the median. Conclusions: TH and PHOX2B mRNAs in blood collected at baseline identify children with refractory or relapsed neuroblastoma at greatest risk of progression or death. In the RR-NBL setting, this simple blood test could be used to stratify treatment strategies. Clinical trial information: NCT02308527. [Table: see text]

PURPOSE Induction therapy is a critical component of the therapy of high-risk neuroblastoma. We aimed to assess if the Memorial Sloan Kettering Cancer Center (MSKCC) N5 induction regimen (MSKCC-N5) would improve metastatic complete response (mCR) rate and 3-year event-free survival (EFS) compared with rapid COJEC (rCOJEC; cisplatin [C], vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C]). PATIENTS AND METHODS Patients (age 1-20 years) with stage 4 neuroblastoma or stage 4/4s aged < 1 year with MYCN amplification were eligible for random assignment to rCOJEC or MSKCC-N5. Random assignment was stratified according to national group and metastatic sites. Following induction, therapy comprised primary tumor resection, high-dose busulfan and melphalan, radiotherapy to the primary tumor site, and isotretinoin with ch14.18/CHO (dinutuximab beta) antibody with or without interleukin-2 immunotherapy. The primary end points were mCR rate and 3-year EFS. RESULTS A total of six hundred thirty patients were randomly assigned to receive rCOJEC (n = 313) or MSKCC-N5 (n = 317). Median age at diagnosis was 3.2 years (range, 1 month to 20 years), and 16 were younger than 1 year of age with MYCN amplification. mCR rate following rCOJEC induction (32%, 86/272 evaluable patients) was not significantly different from 35% (99/281) with MSKCC-N5 ( P = .368), and 3-year EFS was 44% ± 3% for rCOJEC compared with 47% ± 3% for MSKCC-N5 ( P = .527). Three-year overall survival was 60% ± 3% for rCOJEC compared with 65% ± 3% for MSKCC-N5 ( P = .379). Toxic death rates with both regimens were 1%. However, nonhematologic CTC grade 3 and 4 toxicities were higher with MSKCC-N5: 68% (193/283) versus 48% (129/268) ( P < .001); infection 35% versus 25% ( P = .011); stomatitis 25% versus 3% ( P < .001); nausea and vomiting 17% versus 7% ( P < .001); and diarrhea 7% versus 3% ( P = .011). CONCLUSION No difference in outcome was observed between rCOJEC and MSKCC-N5; however, acute toxicity was less with rCOJEC, and therefore rCOJEC is the preferred induction regimen for International Society of Pediatric Oncology European Neuroblastoma Group.

10002 Background: The BEACON phase II trial (NCT02308527) addressed a number of questions in children with relapsed/refractory high-risk neuroblastoma (RR-HRNB). Here we report the chemo-immunotherapy randomisation, assessing if anti-GD2 (dB) demonstrates activity when added to chemotherapy. Methods: Patients aged 1-21 years with RR-HRNB with adequate organ function and performance status were randomised in a 1:2 ratio to receive chemotherapy alone or with dB, given concurrently as a 7 day continuous infusion (10 mg/m2/24hr). As the trial had a factorial design, some patients were also randomised between chemotherapy regimens (temozolomide (T) versus Temozolomide-Topotecan (TTo); this randomisation closed soon after the dB randomisation opened and all patients subsequently received TTo chemotherapy. Cross-over to dB with topotecan and cyclophosphamide was allowed for patients randomised to chemotherapy alone who experienced disease progression. The primary outcome measure was best response (complete or partial) at any point during the first 6 courses of treatment, by RECIST or International Neuroblastoma Response Criteria for patients with measurable and evaluable disease respectively. Progression free and overall survival (PFS & OS) and safety were secondary outcomes. The success criterion for proceeding to a Phase 3 trial was a one-sided p-value (1p) less than 0.23 for Objective Response Rate (ORR). Results: From Aug 2019 to Feb 2021, 65 patients were randomised to chemotherapy alone (3 T, 19 TTo) or with dB (6 dBT, 37 dBTTo). Median age was 4 years; 48 and 17 had measurable and evaluable disease respectively; 29 and 36 had refractory and relapsed disease respectively; 19 had MYCN amplification. Baseline characteristics were balanced between arms. Response was assessable in all patients. The ORR was 18% with chemotherapy alone and 35% for patients receiving chemotherapy with dB (risk ratio 1.66, 80% confidence interval (CI) 0.9 to 3.06, 1p = 0.19). 1-year PFS was 27% for chemotherapy alone, and 57% for those receiving chemotherapy +dB (HR 0.63, 95% CI 0.32 to 1.25, p = 0.19). Twelve patients in the chemotherapy only arm crossed over to receive dB at progression. OS did not differ between the arms: HR = 0.99, 95% CI 0.42 to 2.36, p = 0.99. Nine (41%) patients receiving chemotherapy alone and 13 (30%) receiving chemotherapy plus dB had grade ≥3 toxicities (CTCAE v4.0). Neurotoxicities were more common in patients receiving dB compared to chemotherapy alone (Grade 1-2: 67.4% vs 13.6%, Grade 3: 9.3 vs 0%). Other toxicities were similar with and without dB. Conclusions: The Phase 2 success criterion for ORR was met and PFS is also encouraging. The addition of dB to temozolomide-based chemotherapy shows promising activity in patients with RR-HR-NB. Clinical trial information: NCT02308527.

Endoscopic extended transsphenoidal surgery (EETSS) has gained popularity for treatment of craniopharyngiomas. The aim of this study is to assess the outcome of endoscopic extended transsphenoidal surgery (EETSS) for newly diagnosed paediatric craniopharyngiomas.Patient details were obtained from a prospective database of all endoscopic transnasal operations performed by a single surgeon. Outcomes including visual function, pituitary function, body mass index (BMI), postoperative neurological deficit, extent of resection and recurrence on follow-up were obtained. Obesity was defined as BMI percentile of equal to or greater than 95%.Between January 2011 and January 2020, 15 of 16 children (5-18 years old) with newly diagnosed craniopharyngiomas underwent EETSS. Four patients had a conchal-type sphenoid sinus. Gross total resection (GTR) was achieved in 4 patients and near total resection (NTR) in 5 patients. The remaining 6 had subtotal resection (STR). Postoperative radiotherapy was used in 6 patients (4 with STR, 2 with NTR). There were no postoperative deaths, strokes or CSF leaks. Normalisation of visual fields (VF) occurred in 9/13 patients with preoperative VF defects. One patient developed a new visual field defect. During a median follow-up period of 74 (8-104) months, 2 patients have required further surgery for tumour progression following initial STR, where a tumour remnant was left in situ to preserve the pituitary stalk. 6/11 patients developed new anterior pituitary dysfunction as a result of surgery and 9/12 developed new diabetes insipidus (DI). At the time of last follow-up, 14/15 children had anterior panhypopituitarism, 13/15 had DI and 1 patient developed new onset obesity. Two patients, who were obese preoperatively, were no longer obese at last follow-up.EETSS can be performed as the first option in the majority of children with newly diagnosed craniopharyngioma, despite factors such as small nose, non-pneumatised sphenoid sinus, small sella or purely suprasellar tumour location. Preservation of the pituitary stalk at the expense of leaving residual tumour may not be in the best interests of the patient.

PURPOSE To evaluate the impact of surgeon-assessed extent of primary tumor resection on local progression and survival in patients in the International Society of Pediatric Oncology Europe Neuroblastoma Group High-Risk Neuroblastoma 1 trial. PATIENTS AND METHODS Patients recruited between 2002 and 2015 with stage 4 disease > 1 year or stage 4/4S with MYCN amplification < 1 year who had completed induction without progression, achieved response criteria for high-dose therapy (HDT), and had no resection before induction were included. Data were collected on the extent of primary tumor excision, severe operative complications, and outcome. RESULTS A total of 1,531 patients were included (median observation time, 6.1 years). Surgeon-assessed extent of resection included complete macroscopic excision (CME) in 1,172 patients (77%) and incomplete macroscopic resection (IME) in 359 (23%). Surgical mortality was 7 (0.46%) of 1,531. Severe operative complications occurred in 142 patients (9.7%), and nephrectomy was performed in 124 (8.8%). Five-year event-free survival (EFS) ± SE (0.40 ± 0.01) and overall survival (OS; 0.45 ± 0.02) were significantly higher with CME compared with IME (5-year EFS, 0.33 ± 0.03; 5-year OS, 0.37 ± 0.03; P < .001 and P = .004). The cumulative incidence of local progression (CILP) was significantly lower after CME (0.17 ± 0.01) compared with IME (0.30 ± 0.02; P < .001). With immunotherapy, outcomes were still superior with CME versus IME (5-year EFS, 0.47 ± 0.02 v 0.39 ± 0.04; P = .038); CILP was 0.14 ± 0.01 after CME and 0.27 ± 0.03 after IME ( P < .002). A hazard ratio of 1.3 for EFS associated with IME compared with CME was observed before and after the introduction of immunotherapy ( P = .030 and P = .038). CONCLUSION In patients with stage 4 high-risk neuroblastoma who have responded to induction therapy, CME of the primary tumor is associated with improved survival and local control after HDT, local radiotherapy (21 Gy), and immunotherapy.

Some studies indicate that survival of adolescents and young adults (AYA) with cancer may be inferior to that of younger children with similar cancers, possibly related (in part) to differences in access to centralized or standardized treatment. This study aims to evaluate differences in survival for AYA patients when compared with paediatric patients treated in Ireland over a 20-year time period. This study compares relative survival for patients diagnosed in Ireland at ages 0–15 (paediatric group) and 16–24 (AYA group) during 1994–2013, followed to the end of 2014, for cancers defined by the International Classification of Childhood Cancer (ICCC) (Third Edition) group or subgroup. Five-year relative survival estimates, and excess hazard ratios (EHR) comparing excess mortality associated with a cancer diagnosis among AYA with that in the paediatric group, are presented. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Significantly higher excess mortality was found for AYA with leukaemias, lymphomas, astrocytomas, malignant bone tumours, and Ewing and related bone sarcomas, soft tissue sarcomas and ‘other/unspecified’ epithelial cancers, rhabdomyosarcomas, and ‘other and unspecified’ carcinomas. In contrast, lower excess mortality was found in the AYA group for all cancers and intracranial/intraspinal tumours, and for gliomas other than astrocytomas or ependymomas. Comparing 1994–2003 and 2004–2013 cohorts, age-related survival differences narrowed for lymphoid leukaemias, but widened for all cancers combined and intracranial/intraspinal tumours combined. Centralization of services varied depending upon cancer subtype, with leukaemias, CNS tumours and bone sarcomas most centralized. Within these, improvements in survival for leukaemias and CNS tumours have been seen for the AYA population. Reasons for age-related survival differences, and differences in time-trend by age group, are not clear. The significant narrowing of survival differences by age in more recent years for lymphoid leukaemias reflects a more marked recent increase in survival among AYA. More work is required to explain and improve other age-related survival differences.

[Background] Although there have been multiple randomised trials in newly diagnosed Ewing sarcoma family of tumours (ESFT) and these have been conducted over many years and involved many international cooperative groups, the outcomes for all stages of disease have plateaued. Internationally, the standard treatment of ESFT is not defined, and there is a need to add new agents other than conventional chemotherapy to improve outcomes. This trial will compare two different induction/consolidation chemotherapy regimens: (1) vincristine, ifosfamide, doxorubicin and etoposide (VIDE) induction and vincristine, actinomycin D, ifosfamide or cyclophosphamide, or busulfan and mephalan (VAI/VAC/BuMel) consolidation and (2) vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide (VDC/IE) induction and ifosfamide and etoposide, vincristine and cyclophosphamide, vincristine, actinomycin D and ifosfamide, or busulfan and mephalan (IE/VC/VAI/BuMel) consolidation (randomisation 1, or R1). A second randomisation (R2) will determine whether the addition of zoledronic acid to consolidation chemotherapy, as assigned at R1, is associated with improved clinical outcome., [Methods] EURO EWING 2012 is an international, multicentre, phase III, open-label randomised controlled trial. There are two randomisations: R1 and R2. Patients are randomly assigned at two different time points: at entry to the trial (R1) and following local control therapy (R2). The primary outcome measure is event-free survival. The secondary outcome measures include overall survival, adverse events and toxicity, histological response of the primary tumour, response of the primary tumour, regional lymph nodes or metastases (or both), and achievement of local control at the end of treatment., [Discussion] This study will establish which is the “standard regimen” of chemotherapy, taking into account both clinical outcomes and toxicity. This will form the chemotherapy backbone for future interventional studies where we may want to add new targeted agents. It will also determine the role of zoledronic acid in conjunction with the separate EE2008 trial. Any trial in ESFT needs to take into account the rarity of the tumour and consider that international cooperation is needed to provide answers in a timely manner., [Trial registration] Registered with EudraCT number 2012-002107-17 on 26 February 2012. Registered with ISRCTN number 92192408 on 4 November 2013., This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement n°602856. The NCC in France, CLB, receives additional funding from SFCE and Ligue contre le cancer. The coordinating sponsor (the University of Birmingham, Birmingham, UK) is funded by Cancer Research UK (grant award reference C5952/A14745).

To explore the effects of immunotherapy in the International Society of Paediatric Oncology Europe Neuroblastoma Group SIOPEN high-risk neuroblastoma 1 trial (HR-NBL1 trial), two cohorts were studied: one prior to and one after the introduction of dinutuximab beta. All patients received standard induction and high-dose therapy (HDT) with autologous stem cell rescue (ASCR), the local control comprised surgery and radiotherapy to the primary tumour site, followed by isotretinoin. A landmark timepoint of 109 days, resulting from the median time between ASCR and initiation of immunotherapy, was used to define patients&rsquo, eligibility in the pre-immunotherapy analysis cohort. Median follow-up was 5.8 years (inter-quartile range (IQR): 4.2&ndash, 8.2 years) for 844 eligible patients balanced for risk factors, such as age, sex, stage 4, MYCN amplification and response prior to HDT. The five-year event-free and overall survival (95% confidence interval (CI) of 466 patients not receiving immunotherapy was 42% (38&ndash, 47%) and 50% (46&ndash, 55%) but was 57% (51&ndash, 62%) and 64% (59&ndash, 69%) for 378 patients receiving immunotherapy (p &lt, 0.001). A multivariate analysis identified absence of immunotherapy (p = 0.0002, hazard ratio (HR) 1.573), type of HDT (p = 0.0029, HR 1.431), less than complete response prior to maintenance therapy (p = 0.0043, HR 1.494) and &gt, 1 metastatic compartment at diagnosis (p &lt, 0.001, HR 2.665) as risk factors for relapse or progression. Results suggest an important role for dinutuximab beta-based immunotherapy within the treatment concepts applied in HR-NBL1/SIOPEN.

Introduction Data regarding real-world impact on cancer clinical research during COVID-19 are scarce. We analysed the impact of the COVID-19 pandemic on the conduct of paediatric cancer phase I-II trials in Europe through the experience of the Innovative Therapies for Children with Cancer (ITCC). Methods A survey was sent to all ITCC-accredited Early-Phase Clinical Trial Hospitals including questions about impact on staff activities, recruitment, patient care, supply of investigational products and legal aspects, between 1/March and 30/April/2020. Results Thirty-one out of 53 hospitals from 12 countries participated. Challenges reported included staff constraints (30% drop), reduction in planned monitoring activity (67% drop of site initiation visits and 64% of monitoring visits) and patient recruitment (61% drop compared to 2019). The percentage of phase I, phase II trials and molecular platforms closing to recruitment in at least one site was 48.5%, 61.3% and 64.3%, respectively. Additionally, 26% of sites had restrictions on performing trial assessments due to local contingency plans. Almost half of the units suffered impact upon pending contracts. Most hospitals (65%) are planning on improving organizational and structural changes. Conclusion The study reveals a profound disruption of paediatric cancer early phase clinical research due to the COVID-19 pandemic across Europe. Reported difficulties affected both patient care and monitoring activity. Efforts should be made to reallocate resources to avoid lost opportunities for patients and to allow the continued advancement of oncology research. Identified adaptations to clinical trial procedures may be integrated to increase preparedness of clinical research to futures crises., Highlights • The COVID-19 pandemic has profoundly disrupted paediatric cancer clinical research. • A drastic drop in recruitment in phase I/II trials compared to 2019 was observed. • Current research needs reorganization to avoid loss of opportunities for children.

Abstract Background Despite multiple randomised trials in newly diagnosed Ewing sarcoma family of tumours (ESFT), over many years, and involving many international co-operative groups, the outcomes for all stages of disease have plateaued. Internationally, the standard treatment of ESFT is not defined, and there is a need to add new agents other than conventional chemotherapy to improve outcomes. This trial will compare two different induction/consolidation chemotherapy regimens vincristine, ifosfamide, doxorubicin and etoposide (VIDE) induction and vincristine, actinomycin D, ifosfamide or cyclophosphamide, or Busulfan and Mephalan (VAI/VAC/BuMel) consolidation compared with vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide (VDC/IE) induction and ifosfamide and etoposide, vincristine and cyclophosphamide, vincristine, actinomycin D and ifosfamide, or Busulfan and Mephalan (IE/VC/VAI/ BuMel) consolidation- randomisation 1 (R1). A second randomisation (R2) will determine whether the addition of zoledronic acid to consolidation chemotherapy, as assigned at R1, is associated with improved clinical outcome. Methods EURO EWING 2012 is an international, multicentre, phase III, open-label randomised controlled trial. There are two randomisations: R1 and R2. Patients are randomised at two different time points, at entry to the trial (R1) and following local control therapy (R2). The primary outcome measure is event-free survival. The secondary outcome measures include overall survival, adverse events and toxicity, histological response of the primary tumour, response of the primary tumour, regional lymph nodes and/or metastases, and achievement of local control at the end of treatment. Discussion This study will establish which is the "standard regimen" of chemotherapy, taking into account both clinical outcomes and toxicity. This will form the chemotherapy backbone for future interventional studies where we may want to add new targeted agents. It will also determine the role of zoledronic acid, in conjunction with the separate EE2008 trial. Any trial in ESFT needs to take into account the rarity of the tumour and that international co-operation is needed to provide answers in a timely manner. Trial registration Registered with EudraCT number 2012-002107-17 on 26th February 2012. Registered with ISRCTN number 54540667 on 4th November 2013.

Some studies indicate that survival of AYAs with cancer may be inferior to that of younger children with similar cancers, possibly related (in part) to differences in access to centralised or standardised treatments. We sought to examine the comparative survival of paediatric & AYA patients in Ireland across a 20-year period. Methods Using the National Cancer Registry Ireland (NCRI) database, all patients diagnosed with a sarcoma age 0–24 between 1994–2014 were identified. Survival was based on matching of cases against national death certificate data complete up to 31 December 2014 &amp grouped in 2 diagnostic cohorts: 1994–2003 and 2004–2014 and examined according to the ICCC. Results 577 patients less than 25 years were diagnosed with a sarcoma between 1994–2014; 321 under 15. Significantly poorer survival was noted for the AYA patients compared with paediatric patients for the following sarcoma groups and diagnosis periods Malignant bone tumours, 1994–2013 (EHR 1.62, 1.05–2.48, P=0.026) and 1994–2003 (EHR 1.87, 1.05–3.33, P=0.032); Ewing & related tumours), 1994–2013 (EHR 2.04, 95% CI 1.11–3.72, P=0.021) and 1994–2003 (EHR 2.68, 95% CI 1.22–5.87, P=0.014); Soft tissue sarcomas), 1994–2013 (EHR 2.14, 1.29–3.53, P=0.03) and 2004–2013 (EHR 2.52, 1.20–5.25, P=0.014). Conclusions This study highlights the disparities that exist in outcomes for AYA patients with sarcomas treated in Ireland. The exact cause for this is unclear and is likely multifactorial, possibly owing to lack of standardised/centralised services. Future development on a national level is imperative.

Introduction Childhood cancer is the second commonest cause of death in children in developed countries. Childhood cancer survival rates has improved over the last decade with the advancement of diagnostic procedures and continuous improvement of multimodal treatment strategies. According to the National Cancer Registry of Ireland, an average of 137 cancers were diagnosed per year in children under the age of 15 between 1994 and 2014. The 5-year overall survival rate for this entire cohort was 81%. It is well documented that survival rates in paediatric oncology vary depending on specific cancer diagnosis, age of the patient at diagnosis and disease stage. Aim We describe the incidence of cancer in very young children and the influence of age on outcome in children diagnosed with cancer in Ireland under the age of 1 between 2007–2017. Method Data were extracted from the database of the National Children’s Cancer Service (NCCS) based at Our Lady’s Children’s Hospital, Dublin. The data presented refer to the International Classification of Childhood Cancer (ICCC) version 3 with the inclusion of Langerhans Cell Histiocytosis (LCH). Result 185 patients were diagnosed with paediatric cancer under the age of 1 at the time of their initial diagnosis. 159 (85.5%) patients were diagnosed with solid tumours or LCH. 86 (46.5%) were male. The average age at diagnosis was 5.24 (range 0–12) months. 19 (10.3%) patients were diagnosed following an abnormal antenatal scan. The most common cancers diagnosed were neuroblastoma (22.7%), CNS tumours (19.5%) and leukaemia (13.5%). 158 (85.5%) patients received treatment. 124 (78.4%) patients received chemotherapy as part of their treatment. 20 (12.7%) patients received radiotherapy. The mean age for radiotherapy was 1.35 years (range 0.17–4). 18 (9.7%) patients received stem cell transplant/rescue. The cumulative overall survival rate at 5 years is 80%. CNS tumours have the worst prognosis followed by leukaemias. 35 (18.9%) patients have relapsed during follow up, and 20 are alive in follow-up. Conclusion Incidence rates of specific paediatric cancer types vary according to the age at diagnosis. There is no difference in survival rates between children diagnosed with cancer under 1 year of age and older children. Outcomes at the NCCS compare favourably with international standards.

Background More than half of children with high-risk neuroblastoma (NB) will experience recurrence. Radiologic imaging is used for initial staging and during therapy to assess response. However, the role of surveillance imaging in the detection of relapse has not been well studied. Surveillance potentially results in high cumulative exposure to ionizing radiation, which may be associated with an increased risk of developing second malignancies. Procedure We reviewed NB cases at our institution between 2000 and 2011. We calculated radiation exposure due to imaging (during diagnosis, treatment, and posttherapy surveillance) using cumulative effective dose (CED) estimates and determined whether cross-sectional imaging identified recurrences. Results Fifty of 183 patients with NB experienced a recurrence. The median time from diagnosis to relapse was 1.20 years (range: 0.18–6.66 years). Most patients had evidence of metastases and only 4 of 50 patients presented with isolated primary tumor site recurrences. The mean CED prior to relapse was 125.2 mSv (range: 24.5–259.7), 64% of which was from computed tomography (CT) scans. Thirty-seven of 50 patients had clinically evident or measurable disease detected by X-ray (XR), ultrasound (US), or urinary catecholamines (UCats), and the addition of metaiodobenzylguanidine (MIBG) scans identified eight additional recurrences. Thus, cross-sectional imaging (CT/MRI, where MRI is magnetic resonance imaging) was only required to identify 10% (5/50) of cases. Conclusion Relapsed disease was detected in most patients by symptoms/exam, MIBG scan, UCats, and/or XR/US, supporting reduced use of CT imaging in posttherapy surveillance, thereby decreasing cumulative radiation dose. Refinement of surveillance imaging may be further guided by risk stratification, disease sites, and potentially biomolecular markers.

Objectives Langerhans cell histiocytosis is an uncommon condition and it is unusual for it to present in children under one year of age. Our aim is to review the clinical presentation, and present the radiologic findings and clinical outcome in this particular cohort of patients and determine how this differs from the imaging features of older children presenting with LCH. Materials and methods A database of 17 patients with LCH who presented between 0 and 12 months of age was retrospectively reviewed. Radiologic findings, initial clinical presentation and ultimate clinical outcome were documented in table format. Results Eight patients (47 %) initially presented with cutaneous stigmata, seven patients (41 %) had skeletal involvement, five patients (29 %) had splenic involvement, two patients (24 %) had central nervous system involvement either at presentation or at follow-up, three patients (18 %) had lymphadenopathy, two patients (12 %) had liver involvement, and two patients (12 %) had gastrointestinal (GI) involvement. Four patients (24 %) had multisystem involvement either at presentation or at follow-up. One patient died during follow-up. Conclusion LCH in children under one year of age is uncommon and may have an unusual clinical presentation. The radiologic findings are varied and may differ from the classical imaging appearance more commonly seen in the older age group, with multisystem involvement seen more readily in younger patients.

BACKGROUND TRK fusion proteins are oncogenic drivers of various CNS and non-CNS tumors. Larotrectinib, a highly selective FDA- and EMA-approved TRK inhibitor, demonstrated an objective response rate (ORR) of 79% across various non-CNS cancers (Hong et al. Lancet Oncol. 2020). We report data in an expanded set of TRK fusion primary CNS tumors treated with larotrectinib. METHODS Patients with primary CNS tumors harboring an NTRK gene fusion treated with larotrectinib in two clinical trials (NCT02637687, NCT02576431) were identified. Disease status was investigator-assessed (RANO). Data cutoff: July 15, 2019. RESULTS Twenty-four patients with TRK fusion primary CNS tumors were identified. Eighteen patients had gliomas (13 high-grade and five low-grade). Median age was 8.0 years (range 1.3–79.0), with 20 patients < 18 years old. ORR was 29% (95% CI 13–51%); best responses were two complete responses, five partial responses (two pending confirmation), 15 stable disease, and two progressive disease. The 24-week disease control rate was 63% (95% CI 41–81%). For the five confirmed responders, median time to best response was 1.8 months and median duration of response was 4.9 months (range 1.7+ to 10.1+). Median progression-free survival was 11.0 months (range 1.1 to 19.8+) and median overall survival was not reached (range 1.9+ to 21.4+) at a median follow-up of 6.0 months. Treatment duration ranged from 1.2 to 21.4+ months; three patients continued treatment beyond progression. Treatment-emergent adverse events (TEAEs) were mainly Grade 1 and 2. Grade 3–4 TEAEs occurred in 10 patients, with two deemed related to larotrectinib. The most common neurological TEAE was headache in three patients (Grade 1–2). No patients discontinued larotrectinib due to AEs. CONCLUSIONS Larotrectinib was active and well tolerated in patients with TRK fusion primary CNS tumors. These results support testing for NTRK gene fusions in patients with primary CNS tumors.

10536 Background: We previously developed a risk factor model in HR-NBL1/SIOPEN patients treated without DB including age, LDH and metastatic site index (MSI). We tested if this score (Morgenstern, PBC 2018) would provide meaningful information in DB treated HR-NBL1/SIOPEN patients. Methods: High-risk patients (stage 4 ≥1yr.; stage 4 < 1yr. with MYCN amplification (MNA); stage 2, 3, 0-21y with MNA) received intensive induction, surgery, high dose therapy (HDT) and local radiotherapy (21Gy). Patients with a ≤9 months intervall till HDT/SCT, ≥ partial response prior and no progression received up to 5 cycles of 100mg/m2 DB: as short-term (STI: 5 days) or long-term infusion (LTI: 10 days ) ± 6 (STI) or 3 (LTI) x 106 IU/m2 subcutaneous interleukin 2 (scIL2 over 2 x 5 days) followed by 2 weeks of 160mg/m2 oral isotretinoin. Results: DB was used in 1018 patients [512 males; 89% Stage, 1% Stage 4s, 10% loc. MNA; 2.8 yrs median age at diagnosis] in 18 countries. STI was used in 61% patients, LTI in 39% and DB without scIL2 in 62% patients. 2-yrs. event-free (EFS)/overall survival (OS) was 0.65±0.02/0.78±0.01 and 5-yrs. EFS/OS of 0.56±0.02/0.63±0.02. 891/1018 patients were evaluable for risk factor analysis. EFS multivariate analysis included age, MSI, LDH ≥1250U/L, HDT typ, response prior DB, DB schedule and use of scIL2: only age > 1.5yrs.(p = 0.002) and MSI > 1 (p = 0.002) had independent prognostic prediction. If restricted to stage 4 only, LDH ≥1250U/L was also an independent factor (p = 0.049). Points were allocated in proportion to the log-cumulative hazard ratio (cHR): cHR for LDH > 1250U/L was 1.33 (score of 1), cHR for age > 5 years and metastatic site involvement (MSI) > 1 were 1.79 and 1.86 (scores of 2). Using the score (0 to 5) relevant risk groups can be identified: 5-yrs. EFS/OS for scores 0&1 are 0.80±0.06&0.77±0.04, score 2/3 are 0.58±0.03&0.57±0.04 and for scores 4/5 are 0.50±0.06&0.43±0.08. Conclusions: The score adds value in DB treatment groups as it differentiates prognostic subgroups facilitating decision making for future DB add on treatments. Clinical trial information: NCT01704716.

10501 Background: BEACON is a randomized phase 2 trial assessing whether inhibiting angiogenesis with bevacizumab adds to the activity of chemotherapy and evaluating chemotherapy regimens for children with RR-HRNB. Methods: Patients with RR-HRNB were eligible. There were randomizations (rand), in a 3x2 factorial design, to: T, IT or topotecan (To)-T, +/- B. Toxicity and response were reported in 2019 (ASCO, ESMO). Survival outcomes – progression-free (PFS) and overall (OS) – for the I and B rands are reported here (To rand is still open). The B rand used a relaxed alpha (1-sided p=0.2) for PFS as its phase 2 success criterion; the I rand was Bayesian. Cox model hazard ratios (HR)

BackgroundRisk stratification is crucial to treatment decision-making in neuroblastoma. This study aimed to explore factors present at diagnosis affecting outcome in patients aged18 months with metastatic neuroblastoma and to develop a simple risk score for prognostication. ProcedureData were derived from the European high-risk neuroblastoma 1 (HR-NBL1)/International Society for Paediatric Oncology European Neuroblastoma (SIOPEN) trial with analysis restricted to patients aged 18 months with metastatic disease and treated prior to the introduction of immunotherapy. Primary endpoint was 5-year event-free survival (EFS). Prognostic factors assessed were sex, age, tumour MYCN amplification (MNA) status, serum lactate dehydrogenase (LDH)/ferritin, primary tumour and metastatic sites. Factors significant in univariate analysis were incorporated into a multi-variable model and an additive scoring system developed based on estimated log-cumulative hazard ratios. ResultsThe cohort included 1053 patients with median follow-up 5.5years and EFS 271%. In univariate analyses, age; serum LDH and ferritin; involvement of bone marrow, bone, liver or lung; and >1 metastatic system/compartment were associated with worse EFS. Tumour MNA was not associated with worse EFS. A multi-variable model and risk score incorporating age (>5 years, 2 points), serum LDH (>1250U/L, 1 point) and number of metastatic systems (>1, 2 points) were developed. EFS was significantly correlated with risk score: EFS 52 +/- 9% for score=0versus 6 +/- 3% for score=5 (P

BACKGROUND: Immunotherapy with the chimeric anti-GD2 monoclonal antibody dinutuximab, combined with alternating granulocyte-macrophage colony-stimulating factor and intravenous interleukin-2 (IL-2), improves survival in patients with high-risk neuroblastoma. We aimed to assess event-free survival after treatment with ch14.18/CHO (dinutuximab beta) and subcutaneous IL-2, compared with dinutuximab beta alone in children and young people with high-risk neuroblastoma.METHODS: We did an international, open-label, phase 3, randomised, controlled trial in patients with high-risk neuroblastoma at 104 institutions in 12 countries. Eligible patients were aged 1-20 years and had MYCN-amplified neuroblastoma with stages 2, 3, or 4S, or stage 4 neuroblastoma of any MYCN status, according to the International Neuroblastoma Staging System. Patients were eligible if they had been enrolled at diagnosis in the HR-NBL1/SIOPEN trial, had completed the multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide, with or without topotecan, vincristine, and doxorubicin), had achieved a disease response that fulfilled prespecified criteria, had received high-dose therapy (busulfan and melphalan or carboplatin, etoposide, and melphalan) and had received radiotherapy to the primary tumour site. In this component of the trial, patients were randomly assigned (1:1) to receive dinutuximab beta (20 mg/m2 per day as an 8 h infusion for 5 consecutive days) or dinutuximab beta plus subcutaneous IL-2 (6 × 106 IU/m2 per day on days 1-5 and days 8-12 of each cycle) with the minimisation method to balance randomisation for national groups and type of high-dose therapy. All participants received oral isotretinoin (160 mg/m2 per day for 2 weeks) before the first immunotherapy cycle and after each immunotherapy cycle, for six cycles. The primary endpoint was 3-year event-free survival, analysed by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT01704716, and EudraCT, number 2006-001489-17, and recruitment to this randomisation is closed.FINDINGS: Between Oct 22, 2009, and Aug 12, 2013, 422 patients were eligible to participate in the immunotherapy randomisation, of whom 406 (96%) were randomly assigned to a treatment group (n=200 to dinutuximab beta and n=206 to dinutuximab beta with subcutaneous IL-2). Median follow-up was 4·7 years (IQR 3·9-5·3). Because of toxicity, 117 (62%) of 188 patients assigned to dinutuximab beta and subcutaneous IL-2 received their allocated treatment, by contrast with 160 (87%) of 183 patients who received dinutuximab beta alone (pINTERPRETATION: There is no evidence that addition of subcutaneous IL-2 to immunotherapy with dinutuximab beta, given as an 8 h infusion, improved outcomes in patients with high-risk neuroblastoma who had responded to standard induction and consolidation treatment. Subcutaneous IL-2 with dinutuximab beta was associated with greater toxicity than dinutuximab beta alone. Dinutuximab beta and isotretinoin without subcutaneous IL-2 should thus be considered the standard of care until results of ongoing randomised trials using a modified schedule of dinutuximab beta and subcutaneous IL-2 are available.FUNDING: European Commission 5th Frame Work Grant, St. Anna Kinderkrebsforschung, Fondation ARC pour la recherche sur le Cancer.

Background In neuroblastoma (NB), the most powerful prognostic marker, the MYCN amplification (MNA), occasionally shows intratumoural heterogeneity (ITH), i.e. coexistence of MYCN-amplified and non-MYCN-amplified tumour cell clones, called heterogeneous MNA (hetMNA). Prognostication and therapy allocation are still unsolved issues. Methods The SIOPEN Biology group analysed 99 hetMNA NBs focussing on the prognostic significance of MYCN ITH. Results Patients 18 m: 0.67 ± 0.14, p = 0.011; metastatic: 18 m: 0.28 ± 0.09, p = 0.084). The genomic 'background’, but not MNA clone sizes, correlated significantly with relapse frequency and OS. No relapses occurred in cases of only numerical chromosomal aberrations. Infiltrated bone marrows and relapse tumour cells mostly displayed no MNA. However, one stage 4s tumour with segmental chromosomal aberrations showed a homogeneous MNA in the relapse. Conclusions This study provides a rationale for the necessary distinction between heterogeneous and homogeneous MNA. HetMNA tumours have to be evaluated individually, taking age, stage and, most importantly, genomic background into account to avoid unnecessary upgrading of risk/overtreatment, especially in infants, as well as in order to identify tumours prone to developing homogeneous MNA.

Background BEACON-Neuroblastoma is a randomized phase II trial to assess the activity of backbone chemotherapy regimens for children with RR-HRNB and to determine if inhibiting angiogenesis with bevacizumab adds to the activity of this chemotherapy. Methods Patients aged 1-21 years with RR-HRNB with adequate organ function and performance status were randomized in a factorial design to: temozolomide (T) versus irinotecan-temozolomide (IT) or topotecan-temozolomide (TTo), with or without bevacizumab (Bev). The Bev randomization (Bev versus no-Bev) had two parts: Part 1 had a 2-stage Minimax Jung design with overall response (OR) as primary endpoint. Part 1 success criterion was ≥4 more responses in Bev arm compared to no-Bev. Protocol was amended to incorporate Part 2 (40 additional patients), including progression-free survival (PFS) as co-primary endpoint. OR was defined as complete or partial response (CR, PR) by RECIST (INRC for patients without measurable disease). OR and toxicity data for the Bev randomization is reported. Results For Part 1 (n=106), 17 of 52 pts on Bev had responses [33%] and 8 of 54 pts on no-Bev had responses [15%]. The trial success criterion for the primary endpoint of ORR was met. Including Part 2 (total n=154), 21 of 77 patients on Bev (7CR, 14PR) and 13 of 77 patients on no-Bev (1CR, 12PR) had responses. Response data was not available for 6 patients; 13 patients not assessable for response (discontinued before first assessment) were considered to be non-responders. OR rate [with 90% CI] was 27% [18-35%] for patients on Bev and 17% [10-24%] for patients on no-Bev. In subgroup analysis, there was no interaction between T, IT and TTo and treatment with/without Bev (heterogeneity test, p=0.8). 86% Bev and 58% no-Bev patients had grade ≥3 toxicities as per CTCAE v4.0; the most common grade ≥3 toxicities associated with Bev were platelet count decrease and anemia. Conclusions Bev reached the Phase II success criterion for OR within Part 1 of the trial when added to temozolomide-based chemotherapy in RR-HRNB. The toxicity profile for Bev is acceptable. Longer follow-up is needed before assessing whether it impacts PFS or overall survival. Clinical trial identification NCT02308527; EudraCT: 2012-000072-42. Legal entity responsible for the study University of Birmingham. Funding Roche. Disclosure L. Moreno: Honoraria (self), Travel / Accommodation / Expenses: Celgene; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: Mundipharma; Licensing / Royalties, I am member of Siopen Executive Committee, Siopen receives royalties for the sales of dinutuximab beta: Eusa Pharma. D. Valteau-Couanet: Advisory / Consultancy, Travel / Accommodation / Expenses, Licensing / Royalties, Member of Siopen Executive Committee, SIOPEN receives royalties for the sales of dinutuximab beta: Eusa Pharma; Research grant / Funding (institution): Ophelia; Travel / Accommodation / Expenses: Jazz Pharma. K. Nysom: Advisory / Consultancy: Bayer. N. Gerber: Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Novartis. R. Ladenstein: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses, Licensing / Royalties, Royalties to the institution for dinutuximab beta: Apeiron; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses, Licensing / Royalties, Royalties to the institution for dinutuximab beta: Eusa Pharma; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. A.D. Pearson: Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Genentech. All other authors have declared no conflicts of interest.

MAPPYACTS (NCT02613962) is an international prospective precision medicine study recruiting children and adolescents with recurrent/refractory malignancies. Design: Patients < 18 years at diagnosis underwent on-purpose tumor biopsy/surgery of recurrent/refractory malignancies for molecular characterization by WES and whole RNA sequencing. Results were reviewed in a dedicated weekly molecular tumor board (MTB), followed by discussion with the treating physician in a clinical MTB (CMTB). Whenever possible, patients were enrolled subsequently in clinical trials based on CMTB recommendations. In parallel, plasma was collected for cell free DNA (cfDNA) analysis by WES (100x) and capture sequencing (> 2000x) targeting alterations identified by tumor WES. Results: From February 2016 to October 2018, 500 patients have been included in 17 centers in France, Italy and Ireland. Median age at inclusion was 13 years (range, 1-33). 38% had sarcomas, 28% brain tumors, 22% other solid tumors, 12% hematological malignancies with a median of one prior relapse/progression. Eleven patients were excluded (10 screening failures, 1 consent withdrawal). 489 patients underwent 525 interventions: biopsy (57%), surgery (34%), blood/bone marrow (9%), in 55% done to metastatic sites. Molecular profiling was performed in 433 patients (88%) and was contributive for 390 patients. Known pathogenic germline variants were identified in 33 patients (8%). For 271/390 patients (70%), there were at least one genetic alteration that could represent a potential therapeutic target. A total of 548 ”actionable” alterations were identified (311 SNV, 208 focal CNA, 29 gene fusions). Overall 448 treatment recommendations were given, 1 to 5 per patient (median 2) and 8% had alterations considered as “ready for use” for treatment at relapse. Recommendations involved mainly cell cycle checkpoint (n=97), PI3K/AKT/mTOR (n=83) and RAF/MAPK (n=68), cell cycle (n=67), growth factor receptor signaling (n=62) and DNA damage repair (n=33). Follow-up information is available for 197 patients discussed in the CMTB before January 2018. Fifty-six patients (28%) were treated with a matched targeted agent, 48 of them in a clinical trial, mostly in our proof-of-concept AcSé-ESMART trial. CfDNA WES of the first 40 samples revealed at least 1 tumor specific SNV in all cases, with a mean of 38% of SNVs seen in the tumor also displayed in cfDNA (range, 2-89%) and correlation between cfDNA quantity and percentage of tumor SNVs in the cfDNA (p=0.02). Conclusion: MAPPYACTS underlines the role of precision medicine approaches to identify actionable molecular alterations in recurrent pediatric cancer enabling access to innovative treatment through early clinical trials. The impact of surrogate approach based on cfDNA testing to identify targetable genetic alterations is currently under evaluation. Citation Format: Pablo Berlanga, Gudrun Schleiermacher, Ludovic Lacroix, Gaelle Pierron, Tiphaine Adam de Beaumais, Mathieu Chicard, Yasmine Iddir, Jean Yves Scoazec, Paul Freneaux, Mohamed Amine Bayar, Sophie Cotteret, Samuel Abbou, Michela Casanova, Cormac Owens, Stefan Michiels, Olivier Delattre, Gilles Vassal, Birgit Geoerger. Pediatric precision medicine program in recurrent tumors: Results of the first 500 patients included in the European MAPPYACTS molecular profiling trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT081.

10001 Background: BEACON-Neuroblastoma is a randomized Phase II trial to assess the activity of backbone chemotherapy regimens for children with RR-HRNB and to determine if inhibiting angiogenesis with bevacizumab adds to the activity of this chemotherapy. Methods: Patients aged 1-21 years with RR-HRNB with adequate organ function and performance status were randomized in a 2x2 factorial design to: temozolomide (T) versus irinotecan-temozolomide (IT), with or without bevacizumab. Here we report the results of the irinotecan randomization (T vs. IT), which had a probability-based Bayesian design. Primary endpoint was best overall response (complete or partial) during the first 6 courses, by RECIST for measurable disease patients and International Neuroblastoma Response Criteria for evaluable disease patients for which overall response rate (ORR) was calculated. Results: From 2013 to 2018, 61 patients were randomized to treatment with T and 60 to IT. Median age was 5.8 years. 85 and 36 had measurable and evaluable disease respectively; 55 and 66 had refractory and relapsed disease; 22 had MYCN amplification. Baseline characteristics were balanced between the arms. Response data was not yet available for 2 patients on T. Response was not assessable for 17 patients (did not have treatment or stopped early) who were considered non-responders. The ORR was 24% for T and 17% for IT (risk ratio (RR) = 0.70, 95% credible interval 0.32 to 1.44). The probability that the RR for ORR was >1.0 was 17%, meaning that IT did not show greater activity than T. There was no interaction between treatment with/without bevacizumab (heterogeneity test, p=0.7). 27 (44%) T and 35 (58%) IT patients had grade ≥3 toxicities as per CTCAE v4.0. Diarrhea occurred in no patients on T and 7 (12%) on IT; hematological toxicities included anemia (6 T, 4 IT), neutropenia (14 T, 22 IT) and thrombocytopenia (14 T, 11 IT). Conclusions: Irinotecan does not improve the response rate when added to temozolomide in RR-HRNB, but does increase diarrhea. Longer follow-up is needed before assessing whether it impacts progression-free or overall survival. Number of responses by treatment arm. Clinical trial information: NCT02308527. [Table: see text]

10014 Background: We determined the role of scIL-2 combined with long term infusion (LTI) of DB in patients (pts) with high-risk relapsed/refractory neuroblastoma. Methods: 160 pts were enrolled into an open label SIOPEN Phase II clinical trial (EudraCT 2009-018077-31). Pts were randomly assigned to receive up to 5 cycles of 100 mg/m2 DB-LTI (d8-17) and 160 mg/m2 oral isotretinoin (d19-32) (81 pts) with and without 6x106IU/m2 scIL-2 (d1-5; 8-12) (79 pts). Endpoints were toxicity, response rates and 2yrs-event free and -overall survival. Results: Between 07/2014 and 07/2017, 160 pts from 11 countries were randomised. Median follow-up is 2.6 years. Pts were well balanced between arms according to stage, age, MYCN amplification, patients with relapse and remission status. The 2yrs-EFS and -OS for DB (81 pts) vs. DB combined with scIL-2 (79 pts) was 59%±6% vs 65%±6% (p = 0.721) and 79%±5% vs 84%±4% (p = 0.904). In 97 pts with evaluable disease, a response rate of 49% (9% CR, 40% PR) vs 52% (26% CR, 26% PR) after treatment with DB vs DB and scIL-2 was observed. Grade 3&4 fever (16% vs 46%, P = 0.000), allergic reaction (1% vs 14%, P = 0.004), hematological toxicity (46% vs 66%, P = 0.013) and neurotoxicity (0% vs 8%, p = 0.003) were significantly worse in the combination arm, but no difference was seen for capillary leak, gastrointestinal, liver enzyme elevation and pain. Paraplegia possibly related to the treatment was observed in 2 pts in the combination arm, none in the arm without scIL-2, and one resolved to baseline. A subgroup of 34 pts who had a relapse and measurable disease at treatment start, showed a 2yrs-EFS and -OS in DB (17 pts) vs DB combined with scIL-2 (17 pts) of 35%±12% vs 69%±12% (p = 0.116) and 59%±12% vs 81%±10% (p = 0.167). However, this trend was statistically not significant. Pharmacokinetic and HACA response between both arms was not different with overlapping antibody concentration-time curves and a HACA response of 15/81 (19%) (DB) vs 16/79 (20%) (DB and scIL-2). Conclusions: No significant difference in efficacy of DB combined with scIL-2 and increased toxicity in this arm suggests that this schedule of scIL-2 is of no additional benefit. Clinical trial information: 2009-018077-31.

10018 Background: The international prospective precision medicine trial MAPPYACTS (NCT02613962) aims to define the molecular profile in recurrent/refractory malignancies in order to suggest the most adapted salvage treatment. Methods: Patients < 18 years-old at the time of initial diagnosis underwent on-purpose tumor biopsy/surgery of their recurrent/refractory malignancy for molecular characterization by WES and whole RNA sequencing. Results were reviewed in a dedicated weekly molecular tumor board (MTB), followed by discussion with the treating physician in a clinical MTB (CMTB). Whenever possible, patients were enrolled subsequently in clinical trials based on CMTB recommendations. Results: From February 2016 to October 2018, 500 patients have been included in 17 centers in France, Italy and Ireland. Median age at inclusion was 13 years. 38% had sarcomas, 28% brain tumors, 22% other solid tumors, 12% hematological malignancies with a median of one prior relapse/progression. Eleven patients did not undergo intervention procedure (10 screening failures, 1 consent withdrawal). Molecular profiling was performed on samples in 433 patients and was contributive for 390 patients. For 271/390 patients (70%), there was at least one genetic alteration that could represent a potential therapeutic target and 8% had alterations considered as “ready for use” for treatment at relapse. Among them, 19 (7%) died before the CMTB. With follow-up censored in January 2019, 72 patients (27%) were treated with at least one matched targeted agent, 57 of them in a clinical trial, mostly the proof-of concept AcSé-ESMART trial (NCT02813135). Of the 166 patients (61%) that did not receive the matched treatment recommended by CMTB (80 still on follow-up), main reasons were: response/stable disease under previous therapy (50), another treatment (48), rapid disease progression/death (30) and legal representative refusal (12). Conclusions: MAPPYACTS profiling allowed tailored targeted treatment, mainly through early clinical trials, in patients with recurrent pediatric cancer. Since most detected molecular findings are within the investigational or hypothetical evidence level, therapeutic proof-of-concept trials that are exploring targeted therapies in molecularly enriched patient populations are crucial to improve knowledge and potentially outcome. Clinical trial information: NCT02613962.

The Ewing sarcoma family of tumors (ESFT) is defined by cell surface expression of CD99 and a translocation involving EWS and an ETS partner. Cytotoxic chemotherapy remains the benchmark of first- and second-line therapy, and although the majority of patients with localized disease are cured, almost one third of patients relapse or progress from their disease. Moreover, cure remains elusive in most patients who present with distant metastases. In recent years, the ESFT literature has been dominated by reports of attempts at modulating the insulin-like growth factor (IGF) receptor (IGFR). Unfortunately, three phase II studies examining inhibiting antibodies to IGFR-1 published disappointing results. Whether these results were due to failure to modulate the pathway or other limitations in study design and/or patient selection remain unclear. Other novel strategies currently being investigated in ESFT include tyrosine kinase, mammalian target of rapamycin (mTOR), and poly(ADP-ribose) polymerase (PARP) inhibitors.

International audience; Background: The role of tumor molecular profiling in directing targeted therapy utilization remains to be defined for pediatric tumors. We aimed to evaluate the feasibility of a sequencing and molecular biology tumor board (MBB) program, and its clinical impact on children with solid tumors. Procedure: We report on a single-center MBB experience of 60 pediatric patients with a poor prognosis or relapsed/refractory solid tumors screened between October 2014 and November 2015. Tumor molecular profiling was performed with panel-based next-generation sequencing and array comparative genomic hybridization. Results: Mean age was 12 ± 5.7 years (range 0.1–21.5); main tumor types were high-grade gliomas (n = 14), rare sarcomas (n = 9), and neuroblastomas (n = 8). The indication was a poor prognosis tumor at diagnosis for 16 patients and relapsed (n = 26) or refractory disease (n = 18) for the remaining 44 patients. Molecular profiling was feasible in 58 patients. Twenty-three patients (40%) had a potentially actionable finding. Patients with high-grade gliomas had the highest number of targetable alterations (57%). Six of the 23 patients subsequently received a matched targeted therapy for a period ranging from 16 days to 11 months. The main reasons for not receiving targeted therapy were poor general condition (n = 5), pursuit of conventional therapy (n = 6), or lack of pediatric trial (n = 4). Conclusions: Pediatric molecular profiling is feasible, with more than a third of patients being eligible to receive targeted therapy, yet only a small proportion were treated with these therapies. Analysis at diagnosis may be useful for children with very poor prognosis tumsors.

Proton therapy (PT) is a radiotherapy treatment modality that uses protons, rather than conventional photons. PT is often used in paediatric oncology due to its reported capability to reduce acute and late adverse treatment effects. As PT is unavailable in Ireland, patients are referred abroad for treatment. To: (1) produce a descriptive study of Irish children referred abroad for PT, and (2) discuss the case for PT in general. A retrospective review of all children referred for PT before October 2015 was performed. Information was gathered regarding demographics, diagnosis, referral timeline, adverse effects attributable to PT, current status and cost. A review of the relevant literature was performed. Seventeen children treated in Ireland have been referred abroad for PT. The largest number was in the 0–4 year old group. At initial diagnosis the median age was 4.8 years. The average cost per child was €37,312. Two patients suffered disease relapse. Four have encountered PT-related adverse effects. Despite the fact that >100,000 patients worldwide have been treated with PT, the level of published evidence to support superiority over conventional treatment remains low. It is debated that randomised control trials in this area would be inconsistent with the principle of clinical equipoise. In contrast, there is a call for level 1 evidence to justify drastic changes in patient care, particularly in light of recent reports of unexpected toxicities. In time, careful evaluation, follow-up and clinical trials will likely support the preferential use of PT in children.

Neuroblastoma is the most common extra-cranial solid tumor in children. It is a heterogeneous disease, consisting of neural crest-derived tumors with remarkably different clinical behaviors. It can present in a wide variety of ways, including lesions which have the potential to spontaneously regress, or as an extremely aggressive form of metastatic cancer which is resistant to all forms of modern therapy. They can arise anywhere along the sympathetic nervous system. The median age of presentation is approximately 18 months of age. Urinary catecholamines (HVA and VMA) are extremely sensitive and specific tumor markers and are used in diagnosis, treatment response assessment and post-treatment surveillance. The largest national treatment groups from North America, Europe and Japan have formed the International Neuroblastoma Risk Group Task Force (INRG) to identify prognostic factors, to understand the mechanisms of tumorigenesis in this rare disease and to develop multi-modality therapies to improve outcomes and decrease treatment-related toxicities. This international cooperation has resulted in a significant leap in our understanding of the molecular pathogenesis of neuroblastoma. Lower staged disease can be cured if the lesion is resectable. Treatment of unresectable disease (loco-regional and metastatic) is stratified depending on clinical features (age at presentation, staging investigations) and specific tumor biological markers that include histopathological analyses, chromosomal abnormalities and the quantification of expression of an oncogene (MYCN). Modern treatment of high-risk neuroblastoma is the paradigm for the evolution of therapy in pediatric oncology. Outcomes have improved substantially with multi-modality therapy, including chemotherapy, surgery, radiation therapy, myeloablative therapy with stem cell transplant, immunotherapy and differentiation therapy; these comprise the standard of care worldwide. In addition, newer targeted therapies are being tested in phase I/II trials. If successful these agents will be incorporated into mainstream treatment programs.

High-risk neuroblastoma (HR NBL) treatment requires intensive induction chemotherapy. The profoundly emetogenic agents used can compromise nutritional status. Our institution introduced a new antiemetic guideline in 2010 incorporating regular dexamethasone, in addition to ondansetron, for all highly emetogenic protocols.A retrospective comparative review of pediatric patients diagnosed with HR NBL who received rapid COJEC induction chemotherapy as per HR-SIOPEN NBL trial. Prophylactic antiemetics were prescribed regardless of chemotherapy emetogenicity in group A (2004-2010) but for defined time periods considering chemotherapy emetogenicity in group B (2010-2017).Sixty-three children were eligible for inclusion (median age, 31 months; range, 1-88 months). Group A had more episodes of emesis than group B (189 vs. 116, P 0.0001). There was a significant difference in weight-for-age Z score change between the groups by induction end (P = 0.0027). Four children (13%) in group A lost10% body weight versus none in group B. Nutrition support (NS) was utilized by 29 children (94%) in group A and 22 children (69%) in group B. Group A had a median of 3 (range, 1-7) admissions for febrile neutropenia (FN) versus a median of 1.5 (range, 0-4) for group B (P = 0.003) during induction.The review of our guidelines led to reduced emesis frequency for group B. They also required less NS, followed expected growth trajectories more closely and had fewer FN admissions. We propose that this may have occurred due to better emesis control resulting in improved nutritional status and associated enhanced immune function.

10521Background: The effect of complete macroscopic excision (CME) of the primary tumour on event free survival (EFS) in high-risk neuroblastoma remains controversial. We therefore investigated the...

10539Background: Randomization of immunotherapy versus standard was not possible in the HR-NBL1/SIOPEN trial. In order to explore an impact of immunotherapy on outcome, we used trial patients prior...

More than half of children with high-risk neuroblastoma (NB) will experience recurrence. Radiologic imaging is used for initial staging and during therapy to assess response. However, the role of surveillance imaging in the detection of relapse has not been well studied. Surveillance potentially results in high cumulative exposure to ionizing radiation, which may be associated with an increased risk of developing second malignancies.We reviewed NB cases at our institution between 2000 and 2011. We calculated radiation exposure due to imaging (during diagnosis, treatment, and posttherapy surveillance) using cumulative effective dose (CED) estimates and determined whether cross-sectional imaging identified recurrences.Fifty of 183 patients with NB experienced a recurrence. The median time from diagnosis to relapse was 1.20 years (range: 0.18-6.66 years). Most patients had evidence of metastases and only 4 of 50 patients presented with isolated primary tumor site recurrences. The mean CED prior to relapse was 125.2 mSv (range: 24.5-259.7), 64% of which was from computed tomography (CT) scans. Thirty-seven of 50 patients had clinically evident or measurable disease detected by X-ray (XR), ultrasound (US), or urinary catecholamines (UCats), and the addition of metaiodobenzylguanidine (MIBG) scans identified eight additional recurrences. Thus, cross-sectional imaging (CT/MRI, where MRI is magnetic resonance imaging) was only required to identify 10% (5/50) of cases.Relapsed disease was detected in most patients by symptoms/exam, MIBG scan, UCats, and/or XR/US, supporting reduced use of CT imaging in posttherapy surveillance, thereby decreasing cumulative radiation dose. Refinement of surveillance imaging may be further guided by risk stratification, disease sites, and potentially biomolecular markers.

Background/objectivesSeveral centres (Children’s Hospital Philadelphia, Sick Kids Toronto) and organisations (COG) have developed chemotherapy standardisation programmes to reduce risk, increase efficiency and decrease cost associated with the presciption, preparation and administration of chemotherapy in paediatric patients.Most European paediatric chemotherapy protocols use different doses, infusion times, hydration protocols and supportive medicine doses for the same drugs. There is huge variety in how individual patients receive the same drugs. This introduces significant, unnecessary, potential risks and complexity.By 2016 our aim is that all children at our institution should have chemotherapy prescribed, prepared and administered according to a standard institutional protocol.Design/methodsWe set up a multi-disciplinary chemotherapy standardisation group within our department. The project was developed in association with a hospital quality initiative. We reviewed all treatment protocols in use at the current time at OLCH and assessed the variety in chemotherapy administration. We performed staff and parental questionnaires regarding their perceptions of the variety in administration, supportive medicines and discharge times.We held a meeting of all senior departmental management to review and critique the project and multiple staff education sessions to implement the recommended changes.ResultsThere is huge variation in how European protocols mandate that chemotherapy be administered, particularly in protocols using doxorubicin, cisplatin, ifosfamide and cyclophosphamide.We have developed a standard, institutional document which determines how chemotherapy and supportive medicines are administered, limiting variation and risk, increasing staff efficiency and decreasing lengths of hospital admissions.ConclusionThere is unnecessary variation in the way chemotherapy is administered to paediatric patients in Europe. Doses should not be changed, but length of chemotherapy infusion and associated hydration/supportive medicines are extremely varied and there is little evidence to say this is beneficial in terms of patient outcomes. Chemotherapy protocols can be standardised, limiting variation, reducing potential risk and increasing staff and ward efficiencies.

A 5-year-old girl with previously well-controlled partial epilepsy secondary to focal cortical dysplasia (FCD) developed an increase in seizure frequency. Two months later, magnetic resonance showed a substantial alteration in lesion imaging characteristics. The lesion was resected. FCD was confirmed but inflammatory changes were also present. We propose that chronic inflammation was induced by unremitting seizure activity and suggest that inflammation may be implicated as a basis for alteration in the imaging characteristics of FCD.