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Background: Understanding the landscape of clinical trials for patients with neuroblastoma may inform efforts to improve drug development., Procedure: We evaluated therapeutic trials for patients with neuroblastoma from 2011 to 2020 in our search using clinical trial information from ClinicalTrials.gov, Clinicaltrialregister.eu, PubMed, and American Society of Clinical Oncology (ASCO) annual meeting collection. Trends in trials and treatments over time were evaluated qualitatively., Results: A total of 192 trials met inclusion criteria. A median of 20.5 trials were started per year, which was stable over time. There were 87 (45%) phase 1, 100 (51%) phase 2, and only five (2.6%) phase 3 trials. The median time to completion was 4.9 years for phase 1 and 2 trials (no phase 3 trials reported as completed during the study period). In all, 34% of trials were international, while 20% of trials were intercontinental. Eighty-nine percent of nonmyeloablative trials included at least one novel agent. 48% of these trials studied combination therapies, and 86% of these combinations included conventional chemotherapy. Among 157 trials that included a targeted agent, 78 targets were identified, with GD2 being the primary target under investigation in 16.7% of these trials. Only eight trials were included in regulatory decisions, which led to European Medicines Agency (EMA) or Food and Drug Administration (FDA) approval for neuroblastoma., Conclusions: The large number of trials initiated per year, the range of targets, and the rate of intercontinental collaboration are encouraging. The paucity of late-stage trials, the prolonged trial duration, and relative lack of combination studies are major causes of concern. This work will inform future drug development for neuroblastoma., (© 2022 Wiley Periodicals LLC.)

While considerable efforts and progress in our understanding of the long-term toxicities of surgery, radiation and chemotherapy in children with cancer have been made over the last 5 decades, there continues to be a wide gap in our knowledge of the long-term health impact of most novel targeted and immunotherapy agents. To address this gap, ACCELERATE, a multi-stakeholder collaboration of clinical and translational academics, regulators from the EMA and FDA, patient/family advocates and members spanning small biotechnology through to large pharmaceutical companies have initiated the development of an international long-term follow-up data registry to collect this important information prospectively. Providing critical safety data on the long-term use of these approved and investigational therapies in children will support the regulatory requirements and labeling information. It will also provide the necessary insight to help guide physicians and families on the appropriateness of a targeted or immune therapy for their child and inform survivorship planning., (© 2021 Wiley Periodicals LLC.)

Background: Long-term outcome remains poor for children with high-risk neuroblastoma (five-year overall survival [OS] ∼50%). Our objectives were to (a) identify prognostic biomarkers and apply them in a nomogram to identify the subgroup of ultra-high-risk patients at highest risk of disease progression/death, for whom novel frontline therapy is urgently needed; and (b) validate the nomogram in an independent cohort., Methods: A total of 1820 high-risk patients (≥18 months old with metastatic neuroblastoma), diagnosed 1998-2015, from the International Neuroblastoma Risk Groups (INRG) Data Commons were analyzed in a retrospective cohort study. Using multivariable Cox regression of OS from diagnosis, a nomogram was created from prognostic biomarkers to predict three-year OS. External validation was performed using the SIOPEN HR-NBL1 trial cohort (n = 521), evidenced by receiver operating characteristic curves., Results: The nomogram, including MYCN status (P < 0.0001), lactate dehydrogenase (LDH) (P = 0.0007), and presence of bone marrow metastases (P = 0.004), had robust performance and was validated. Applying the nomogram at diagnosis (a) gives prognosis of an individual patient and (b) identifies patients predicted to have poor outcome (three-year OS was 30% ± 5% for patients with a nomogram score of > 82 points; 58% ± 1% for those ≤82 points). Median follow-up time was 5.5 years (range, 0-14.1)., Conclusions: In high-risk neuroblastoma, a novel, publicly available nomogram using prognostic biomarkers (MYCN status, LDH, presence of bone marrow metastases; https://neuroblastoma.shinyapps.io/High-Risk-Neuroblastoma-Nomogram/) has the flexibility to apply a clinically suitable and context-specific cutoff to identify patients at highest risk of death. This will facilitate testing urgently needed new frontline treatment options to improve outcome for these children., (© 2020 Wiley Periodicals LLC.)

Purpose: Age, MYCN status, stage, and histology have been used as neuroblastoma (NB) risk factors for decades. Serum lactate dehydrogenase (LDH) and serum ferritin are reproducible, easily obtained, and prognostic, though never used in risk stratification, except one German trial. We analyzed the prognostic strength of LDH and ferritin, overall, within high-risk NB, and by era, using the International Neuroblastoma Risk Group Data Commons., Patients and Methods: Children with NB (1990-2016) were categorized into LDH (n = 8867) and ferritin (n = 8575) risk groups using EFS. Cox models compared the prognostic strength of LDH and ferritin to age, MYCN status, and INSS stage., Results: Higher LDH conferred worse EFS, overall (5-year EFS) (100-899 IU/L: 76 ± 0.6%; 0-99 or 900-1399 IU/L: 60 ± 1.2%; ≥1400 IU/L: 36 ± 1.2%; P < .0001), and in high-risk NB post-2009 (3-year EFS) (117-381 IU/L: 67 ± 8.9%; 382-1334 IU/L: 58 ± 4.4%; 0-116 or ≥1335 IU/L: 46 ± 3.9%; P = .003). Higher ferritin conferred worse EFS, overall (5-year EFS) (1-29 ng/mL: 87 ± 0.9%; 0 or 30-89 ng/mL: 74 ± 0.8%; ≥90 ng/mL: 48 ± 0.9%; P < .0001), and in high-risk NB post-2009 (3-year EFS) (1-53 ng/mL: 71 ± 9.3%; 0 or 54-354 ng/mL: 55 ± 4.7%; ≥355 ng/mL: 34 ± 6.1%; P = .0008). In multivariable analyses adjusting for age, MYCN, and stage, LDH and ferritin maintained independent prognostic ability (P < .0001; adjusted HRs (95% CI): 1.7 (1.5-1.9), 2.3 (2.0-2.7), respectively)., Conclusions: LDH and ferritin are strongly prognostic in NB, overall and within high-risk NB patients treated post-2009 with modern therapy. LDH and ferritin show promise for (a) identifying ultra-high-risk; (b) refining risk stratification; and (c) clinical utility in low-/middle-income countries. Routine collection of LDH and ferritin should be reinitiated for evolving NB risk stratification., (© 2020 Wiley Periodicals LLC.)

Background: The European Neuroblastoma Study Group 5 (ENSG5) trial showed that time-intensive "rapid" induction chemotherapy (COJEC) was superior to "standard" 3-weekly chemotherapy for children with high-risk metastatic neuroblastoma. Long-term outcomes of the ENSG5 trial were analysed., Procedure: Patients with metastatic neuroblastoma aged ≥12 months were randomly assigned to "standard" or "rapid" induction, receiving the same chemotherapy drugs and doses. Event-free survival (EFS) and overall survival (OS) were analysed and prognostic factors evaluated. Amongst patients surviving >5 years, a population of children with persistent metastatic disease after the end of treatment was identified and described., Results: Ten-year EFS was 18.2% (95% confidence interval: 12.2-25.2) for the "standard" arm and 26.8% (19.5-34.7) for the "rapid" arm (hazard ratio [HR] 0.85, P = 0.28). Ten-year OS for the "standard" arm was 19.7% (13.4-26.8) and 28.3% (20.8-36.2) for the "rapid arm" (HR 0.83, P = 0.19). There was a trend for worse EFS and OS for patients having MYCN amplification (HR 1.37 and 1.40, respectively) and those with partial and mixed response to induction (HR 1.69 and 1.75 for EFS and 1.66 and 2.00 for OS, respectively). Among 69 patients who survived >5 years, six had persistent metastatic disease after the end of treatment., Conclusion: The benefit of the "rapid" induction regimen seems to be maintained in the long term, although the small number of survivors could justify the lack of statistical significance. MYCN amplification and poor metastatic response to induction could be associated with worse outcomes. A small group of patients with persistent metastatic disease that survived long term has been described., (© 2018 Wiley Periodicals, Inc.)