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Introduction: Despite poor survival for patients with relapsed or refractory neuroblastoma, only 10-16% of patients are reported to be included in early phase trials. This study aimed to explore the impact of molecular profiling within the prospective precision cancer medicine trial MAPPYACTS (NCT02613962) on subsequent early phase trial recruitment and treatment by matched targeted therapies in this population., Methods and Materials: Clinical data from all French patients with relapsed/refractory neuroblastoma enrolled in MAPPYACTS were analyzed for subsequent matched/non-matched targeted treatment based on clinical tumor board (CMTB) recommendations., Results: From 93 patients with neuroblastoma included in French centers, 78 (84%) underwent whole exome and RNA sequencing and were discussed in the CMTB. Higher rate of successful sequencing analysis was observed in patients with relapsed disease compared to those with refractory disease (p = 0.0002). Among the 50 patients that presented with a new disease relapse/progression after the CMTB recommendations, 35 patients (70%) had at least one actionable alteration identified on the tumor at the time of relapse. Eighteen patients (36%) were included in an early phase clinical trial, 11 of these with a matched agent, 7 with a non-matched treatment; 13 patients were included in the AcSé ESMART trial. Five patients (10%) received a matched targeted therapy outside a clinical trial., Conclusion: Patients with neuroblastoma in the European MAPPYACTS trial were more likely to be included in early phase trials compared to previous reports. Early deep sequencing at first treatment failure, comprehensive therapeutic discussions in molecular tumor boards and innovative trials like AcSé -ESMART improve access to innovative therapies for patients with relapsed/refractory neuroblastoma., Clinical Trial Registration: NCT02613962., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: This multicenter Phase I study (NCT03585465) evaluated nivolumab in combination with 3 metronomic chemotherapy (MC) regimens in children with refractory/relapsing solid tumors., Objectives: To evaluate the feasibility and safety of the three regimens METHODS: Patients aged < 18 years were enrolled. Nivolumab was combined with cyclophosphamide and vinblastine (arm A), capecitabine (arm B), or cyclophosphamide, vinblastine and capecitabine (arm C). Arm A and B were allocated sequentially. Arm C opened only if A and B were deemed safe. Dose-limiting toxicities (DLTs) were evaluated over the first two cycles. Patients were evaluable if they received > 2 cycles and > 70% of the planned dose., Population: Sixteen patients were enrolled, 3 in arm A, 6 in arm B, and 7 in arm C. Median age was 11.5 years (range, 5-19). Patients previously received a median of 3.5 (range, 1-4) lines of systemic treatment, 14 patients had surgery and 11 had radiotherapy., Results: Median number of cycles was 2 (1-24), median treatment duration was 56 days (18-714). In arm C, median number of cycles was 4 with median treatment duration of 95 days. No DLT was observed. Grade 3 adverse events (AE) and serious AE were observed in 8 patients (50%) and 1 patient (6%), respectively, over the first 2 cycles. No grade 4 AE occurred. The 6-month PFS and OS were 12% and 44%, respectively, in the whole population. Prolonged stable disease was observed in a high-grade glioma and an atypical teratoid rhabdoid tumor., Conclusion: Arm C appears safe. A randomized phase II trial evaluating the addition of nivolumab to the triple MC is ongoing., Competing Interests: Declaration of Competing Interest Nivolumab and funding has been provided by BMS. NA has had an advisory role for Bayer and Partners Therapeutics and receives grants (institution) from Bristol Myers Squibb and drugs for a trial from Bristol Myers Squibb, Pierre Fabre, Merck, Pfizer, travel support from Roche; Speaker's Honoraria for Alection, he further has IDMC roles for Accord Healthcare. IA receives speaker’s honoraria from Alection. BG has had an advisory role for AstraZeneca and IDMC roles for trials sponsored by Roche and Novartis. Speaker's Honoraria - Bayer. PC speaker’s honoraria from Alection. NEW receives drug for a trial from Novartis, speaker’s honoraria from Alection, Eusapharma & Novartis. PL receives drug from BMS for a trial and speaker’s honoraria from Alection. MCLD, CL, AP, LW, CFC, GRV, VM and AB declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The optimal therapeutic strategy for relapsing intracranial germ cell tumours (IGCTs) has not been clearly established., Methods: Relapses of IGCTs, occurring from 01/01/1990 to 31/12/2014, were retrieved from the Societe Française d'Oncologie Pediatrique-TGM 90, 92 and GCT 96 protocols, and from the National Childhood Solid Tumour Registry. Refractory IGCTs were excluded., Results: Forty-four relapsing IGCTs were identified: 14 were initially treated for histologically proven germinomas (germinoma group), 5 for non-histologically proven germinomas (putative germinoma group) and 25 for non-germinomatous germ cell tumours (NGGCTs) (NGGCT group). In the germinoma group, the 5-year event-free survival (EFS) and overall survival (OS) were 79% (95% confidence interval [CI]: 47-93) and 86% (95% CI: 54-96), respectively. Only one of the 11 patients treated with reirradiation experienced a further relapse. A trend of better EFS was observed for relapses at sites that were not initially involved: 5-year EFS of 100% versus 67% (95% CI: 28-88), p = 0.09. In the putative germinoma group, 4 of 5 patients experienced a further event, leading to 2 deaths. In the NGGCT group, the 5-year EFS and OS were 56% (95% CI: 35-73) and 60% (95% CI: 38-76), respectively. A significant improvement in outcomes after high-dose chemotherapy (HDC) was observed: 5-year OS of 72% (95% CI: 46-87) versus 29% (95% CI: 4-61), p = 0.006., Conclusion: Relapsing germinomas are highly curable; reirradiation appears to play a key role. Histological proof at initial diagnosis if markers are negative is crucial. Despite inferior outcomes relapsing, NGGCTs can be cured in a significant proportion of cases provided intensive treatment including HDC is applied., Competing Interests: Conflict of interest statement None declared., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: We evaluated the role of bevacizumab as part of the multi-modality treatment of children and adolescents with metastatic rhabdomyosarcoma (RMS) or non-rhabdomyosarcoma soft tissue sarcoma (NRSTS)., Patients and Methods: Eligible patients aged ≥6 months to <18 years were randomised to receive induction chemotherapy (four cycles of IVADo + five cycles of IVA, ±bevacizumab), surgery and/or radiotherapy, followed by maintenance chemotherapy (12 cycles of low-dose cyclophosphamide + vinorelbine, ±bevacizumab). The primary objective was event-free survival (EFS) evaluated by an independent radiological review committee., Results: One hundred and fifty-four patients were randomised to receive chemotherapy alone (n = 80) or with bevacizumab (n = 74). At the data cut-off for the primary efficacy analysis, median EFS was 14.9 months (95% confidence interval [CI]: 10.8-35.9) with chemotherapy and 20.6 months (95% CI: 15.2-24.9) with bevacizumab plus chemotherapy (stratified hazard ratio [HR] = 0.93; 95% CI: 0.61-1.41; P = 0.72). The HR for EFS in patients with RMS (n = 103) was 1.24 (95% CI: 0.73-2.09) versus 0.64 (95% CI: 0.32-1.26) for those with NRSTS (n = 49). Objective response rate was 36.0% (95% CI: 25.2-47.9) with chemotherapy and 54.0% (95% CI: 40.9-66.6) with bevacizumab plus chemotherapy (difference of 18.0%; 95% CI: 0.6-35.3). There were no treatment-related deaths and no increased incidence of grade 3/4 toxicities with bevacizumab., Conclusion: The addition of bevacizumab to chemotherapy appeared tolerable in children and adolescents with metastatic RMS/NRSTS, but the primary end-point of EFS did not show statistically significant improvement., Trial Registration: ClinicalTrials.gov, NCT00643565., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: The aim is to study statural growth in a large cohort of children with chronic myeloid leukaemia (CML) treated with front-line imatinib., Methods: Retrospective data from 81 children less than 18 years of age with CML identified in the French pediatric registry were analysed. Height was expressed as standard deviation score (SDS)., Results: A gradual decrease in height SDS was observed over time since starting imatinib. The height SDS was significantly lower 12 months and 24 months after the start of imatinib overall (p < 10(-4)) irrespective of gender and pubertal age. The height SDS was significantly (p < 10(-4)) lower 12 months after the start of imatinib in boys and girls, and in the prepubertal age group as well as in the postpubertal age group, respectively. A similar finding was observed in the subgroups of boys and girls starting imatinib at a prepubertal or postpubertal age. Loss in height SDS 12 months after the start of imatinib was of the same range in boys when compared to girls and in patients who started imatinib at a prepubertal age compared to those who started at a postpubertal age., Conclusion: Growth velocity was altered during the first years of imatinib treatment in boys as well as in girls and in prepubertal age patients as well as in adolescents.

Purpose: To assess objective response rate (ORR) after two cycles of temozolomide in combination with topotecan (TOTEM) in children with refractory or relapsed neuroblastoma., Patients and Methods: This multicenter, non-randomised, phase II study included children with neuroblastoma according to a two-stage Simon design. Eligibility criteria included relapsed or refractory, measurable or metaiodobenzylguanidine (mIBG) evaluable disease, no more than two lines of prior treatment. Temozolomide was administered orally at 150mg/m(2) followed by topotecan at 0.75mg/m(2) intravenously for five consecutive days every 28days. Tumour response was assessed every two cycles according to International Neuroblastoma Response Criteria (INRC), and reviewed independently., Results: Thirty-eight patients were enroled and treated in 15 European centres with a median age of 5.4years. Partial tumour response after two cycles was observed in 7 out of 38 evaluable patients [ORR 18%, 95% confidence interval (CI) 8-34%]. The best ORR whatever the time of evaluation was 24% (95% CI, 11-40%) with a median response duration of 8.5months. Tumour control rate (complete response (CR)+partial response (PR)+mixed response (MR)+stable disease (SD)) was 68% (95% CI, 63-90%). The 12-months Progression-Free and Overall Survival were 42% and 58% respectively. Among 213 treatment cycles (median 4, range 1-12 per patient) the most common treatment-related toxicities were haematologic. Grade 3/4 neutropenia occurred in 62% of courses in 89% of patients, grade 3/4 thrombocytopenia in 47% of courses in 71% of patients; three patients (8%) had febrile neutropenia., Conclusion: Temozolomide-Topotecan combination results in very encouraging ORR and tumour control in children with heavily pretreated recurrent and refractory neuroblastoma with favourable toxicity profile., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate maximum tolerated dose and recommended dose (RD) for phase II studies of topotecan (TPT) combined with temozolomide (TMZ) (TOTEM) in children and adolescents with relapsed or refractory solid malignancies., Patients and Methods: Multicentre, phase I study with a standard '3+3' design in five dose increments. Eligible patients: aged 6 months to 21 years, diagnosis of a solid malignancy failed at least 2 previous lines of therapy. TMZ was administered orally, starting at 100 mg/m(2)/d, and TPT intravenously over 30 min, starting at 0.75 mg/m(2)/d over 5 consecutive days every 28 d. A pharmacokinetics analysis was performed on Day 1 and Day 5 of cycle 1., Results: Between February and October 2007, 16 patients were treated. The median age was 8.5 years (range, 3-19 years). Dose-limiting toxicity (grade 4 neutropenia and/or thrombocytopenia lasting more than 7 d) during the first cycle occurred in 2 of 3 patients at level 3 (TMZ 150 mg/m(2)/d and TPT 1.0 mg/m(2)/d) and was always manageable. Confirmed complete and partial responses were observed in 4 patients (25%), three with metastatic neuroblastoma and one with high-grade glioma. Seven patients had a stable disease. Pharmacokinetic data show a wide inter-individual variability. No significant differences were observed between plasma TMZ and TPT concentrations on Day 1 and Day 5 indicating the absence of pharmacokinetic interaction between the drugs., Conclusions: The RD for the combination is TMZ 150 mg/m(2)/d and TPT 0.75 mg/m(2)/d with dose-limiting haematological toxicity. The observed activity deserves further evaluation in paediatric malignancies., (Copyright © 2010. Published by Elsevier Ltd.)

The aim of this study was to evaluate a chemotherapy strategy that avoids radiotherapy in first-line treatment of young children with high-grade glioma. A total of 21 children under 5 years of age received the BBSFOP protocol, comprising seven cycles of three drug pairs (carboplatin/procarbazine, cisplatin/etoposide and vincristine/cyclophosphamide) administered over a 16 month period. Radiotherapy was performed in case of recurrence/progression. Median age at diagnosis was 23 months. Histology was classified as World Health Organisation (WHO) grade III in 13 and grade IV in 8. Of the 13 children with a residual tumour, chemotherapy induced 2 partial responses (PR), 1 minor response (MR) and 1 stable disease (SD) with no recurrent disease. Five-year progression-free survival was 35% and 5-year overall survival was 59%, with a median follow-up of 5.2 years. At the last update, 12 children were alive (10 without radiotherapy). In conclusion, this study shows that an adjuvant chemotherapy first approach is safe and allows radiotherapy to be avoided in selected children.

Aim: Improvement of EFS of children older than 3 years with high risk medulloblastoma., Methods: Between 1993 and 1999, 115 patients (3-18 years, mean 8 years) with high risk medulloblastoma were included. After surgery treatment consisted of chemotherapy ('8in1' and etoposide/carboplatin) before and after craniospinal radiotherapy., Results: Patients were staged using Chang-criteria (PF residue only, M1 and M2/M3) by local investigator as well as by central review panel (82.4% concordance). Chemotherapy was well tolerated without major delays in radiotherapy. With a mean follow up of 81 months (9-119), 5-year EFS was 49.8% and OS 60.1%. In detail according to subgroups EFS was 68.8% for PF residue only, 58.8% for M1 disease and 43.1% for M2/M3., Conclusion: M1 patients are legitimate high risk patients. Survival rates are still very low for high risk medulloblastoma patients and future trials should therefore focus on more intensive (chemotherapy/radiotherapy) treatment.

The aim of this study was to assess the efficacy and adverse effects of 2-chlorodeoxyadenosine (2-CdA) and cytosine arabinoside (Ara-C) in children with refractory Langerhans cell histiocytosis (LCH) and haematopoietic dysfunction. Ten patients, with a median age at diagnosis of 0.5 years, were enrolled in this study. Treatment comprised at least two courses of Ara-C (1000 mg/m(2)/d) and 2-CdA (9 mg/m(2)/d) administered for 5d every 4 weeks; subsequent median follow-up was 2.8 years (range 0.03-6.4 years). Among the 7 patients who received at least two courses of therapy, disease activity decreased in 6 patients, and control of disease was achieved in all patients after a median delay of 5.5 months. All patients suffered World Health Organisation (WHO) grade 4 haematological toxicity. Two septic deaths occurred shortly after administration of the first course of 2-CdA/Ara-C; a third patient was withdrawn from the trial after the first course and subsequently died following haematopoietic stem cell transplantation. This series is small, but we conclude that 2-CdA and Ara-C combined chemotherapy probably has major activity in childhood refractory Langerhans cell histiocytosis.

Individual dosing of carboplatin based on drug monitoring was performed within a multi-centric phase I study based on high AUC-levels in children. Twelve patients (aged 3-17 years old) have been included: 3, 5, and 4 patients at the overall target ultrafilterable carboplatin AUC of 20, 25, or 30 mg/ml x min, respectively. Carboplatin was administered as a daily 60-min infusion, repeated on five consecutive days. The initial daily dose corresponding to the three first days was calculated according to the carboplatin clearance (CL) predicted from patients' characteristics (body weight, serum creatinine and nephrectomy status). Three blood samples were taken per patient. The individual CL were estimated by MAP (maximum a posteriori approach) Bayesian method implemented in the MP-K program. The doses for day 4 and 5 was adjusted in order to obtain the overall target AUC. Drug monitoring led to a change in the carboplatin dose (overall administered dose versus overall dose planned) ranging from -41% to +45%. Pharmacokinetics were performed at day 5 for 7/12 children: mean relative change between day 1 and day 5 was -11% showing a statistically significant, but limited, decrease of CL from day 1 to day 5. The percentage of difference between the observed and target overall AUC ranged between -7% and +14%. Three patients (one at each AUC level) who were previously treated with cisplatin experienced dose-limiting hearing loss. In conclusion, drug monitoring and dose adjustment is needed for the control of carboplatin plasma exposure when administering high doses of carboplatin in children.

Childhood malignant brain stem tumours have a very poor prognosis with a median survival of 9 months despite radiotherapy. No chemotherapy has improved survival. However, carboplatin has been reported to have activity in glial tumours as well as antitumour synergy with radiation. Our aims were to test the response rate of these tumours to carboplatin alone and to evaluate the efficacy on survival of carboplatin alone followed by concurrent carboplatin and radiotherapy. Patients younger than 16 years with typical clinical and radiological presentation of infiltrating brain stem tumour, as well as histologically-documented cases in the atypical forms, were eligible. Two courses of carboplatin (1050 mg/m2 over 3 days) were administered initially. This treatment was followed by a chemoradiotherapy phase including five weekly carboplatin courses (200 mg/m2) and conventional radiotherapy. 38 eligible patients were included. No tumour response was observed after the initial phase. This schedule of first-line carboplatin followed by concurrent carboplatin and radiotherapy did not improve survival.

Contrary to major advances in cure rates observed for almost all childhood cancers, progress in reducing brain tumour survival rates remains very limited. Although new drug development in oncology is founded on principles outlined in the organised methodology of phase I, II, and III trials, based on rigorous study design using standardised criteria, this approach has been applied very slowly in the field of neuro-oncology. There are multiple explanations for the paucity of well-conducted prospective clinical trials, such as the rarity and the heterogeneity of these tumours, and the reluctance of some investigators to enroll their patients in constraining trials. Data from the past two decades shows that several methodological problems preclude the drawing of any definite conclusions for the majority of drugs assessed. Among them, the necessity of a central neuropathological and neuroradiological review has been highlighted in, at least, two multicentric studies. Changes in histological diagnosis and grade have been reported in a proportion as high as 20%, and changes in response rate in 14% of the cases. This review of phase II trials for brain tumours reveals a wide array of sometimes arbitrary response definitions, that is if response is defined at all, and most series have enrolled small numbers of patients. We report on the different problems encountered in childhood brain tumours in these phase II trials, and their impact on phase III trials.

Between March 1990 and December 1994, 316 consecutive children with localised neuroblastoma were registered in the French NBL 90 study. In addition to the assessment of a new chemotherapy regimen in unresectable neuroblastoma, we evaluated the prognostic significance of MYCN amplification and loss of the short arm of chromosome 1 (LOH1p). MYCN was found in 22/225 children (10%) and associated with unfavourable clinical features such as age at diagnosis > 1 year and large and unresectable tumours. LOH1p was observed in 9/91 patients (10%), of whom some had favourable prognostic factors such as age at diagnosis < 1 year (n = 4), INSS stage 1 or 2 (n = 3) and no MYCN amplification (n = 4). Overall survival (OS) and event-free survival (EFS) were, respectively, 56% and 22% (median follow-up: 36 months) for children with LOH1p compared with 97% and 94% for those without (log-rank = 10(-8)). All except 1 of the 5 children with MYCN amplification and LOH1p relapsed and ultimately died of the disease. Among the 4 with LOH1p and no MYCN amplification, recurrence occurred in 3 (2 local, 1 metastatic), all alive in second remission after salvage therapy (12-19 months after the relapse). In multivariate analysis, LOH1p was the strongest prognostic indicator for subsequent relapse. LOH1p appears more discriminant than MYCN amplification for predicting the risk of recurrence in children with localised neuroblastoma. However, its analysis was possible in only 30% of our patients and its final impact on survival should be confirmed in larger, prospective studies in order to stratify subsequent treatment.