# High-risk neuroblastoma

Source: https://onco.cc/cancers/neuroblastoma-high-risk/  
OnCo record `neuroblastoma-high-risk` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

High-risk neuroblastoma has spread widely in a child over 18 months old or carries extra copies of the MYCN gene. Treatment lasts about 18 months and uses every tool: chemotherapy, surgery, high-dose chemotherapy with stem cell rescue, radiotherapy, and the anti-GD2 antibody dinutuximab, which raised survival in ANBL0032; eflornithine, given afterwards, was approved in 2023 to lower relapse.

## Summary

High-risk disease is stage M neuroblastoma in a child over 18 months, MYCN-amplified disease at any age and stage, and a few L2 and infant M cases with unfavourable genetics. Treatment runs in blocks. Induction with five or six cycles (cyclophosphamide and topotecan, cisplatin and etoposide, cyclophosphamide with doxorubicin and vincristine in the COG regimen; rapid COJEC in Europe) brings most children to a partial response and clears the marrow; surgery removes the primary; consolidation with myeloablative chemotherapy and autologous stem cell rescue follows; radiotherapy to the primary site and residual metastases; then post-consolidation immunotherapy with an anti-GD2 antibody and isotretinoin for six months. CCG-3891, reported in 1999, established both myeloablative therapy with autologous marrow rescue and 13-cis-retinoic acid maintenance: three-year event-free survival 34 percent against 22 percent with transplant, and 46 percent against 29 percent with retinoic acid.

ANBL0032 randomised 226 children after transplant to isotretinoin alone or with the chimeric anti-GD2 antibody ch14.18 (dinutuximab), GM-CSF and interleukin-2: two-year event-free survival 66 percent against 46 percent and overall survival 86 percent against 75 percent, and dinutuximab was approved in March 2015. SIOPEN HR-NBL1 showed that busulfan and melphalan beat carboplatin, etoposide and melphalan as the myeloablative regimen, three-year event-free survival 50 percent against 38 percent, and that adding interleukin-2 to dinutuximab beta brought toxicity without benefit. COG ANBL0532 showed tandem transplant with thiotepa-cyclophosphamide then carboplatin-etoposide-melphalan beat a single transplant, three-year event-free survival 61.6 percent against 48.4 percent. Eflornithine (DFMO), an ornithine decarboxylase inhibitor that lowers MYCN-driven polyamine synthesis, was approved in December 2023 as two years of maintenance after immunotherapy on the basis of the NMTRC003 and 003B single-arm studies compared with matched ANBL0032 controls, the first approval in neuroblastoma on an external control. Naxitamab, a humanised anti-GD2 antibody given with GM-CSF, was granted accelerated approval in November 2020 for relapsed or refractory disease in bone or marrow.

About half of children still relapse, and relapsed high-risk disease is rarely cured. Irinotecan and temozolomide with dinutuximab (ANBL1221) is the standard relapse chemo-immunotherapy; iodine-131 MIBG delivers targeted radiation to the roughly 90 percent of tumours that take up the tracer and is being tested in induction in ANBL1531, which also gives lorlatinib to the roughly one in ten children whose tumours carry an ALK mutation after the NANT phase 1 showed responses in relapsed ALK-mutant disease. GD2 CAR T-cells produced remissions in relapsed children in the Bambino Gesù phase 1/2 trial reported in 2023, anti-GD2 antibody is being moved into induction alongside chemotherapy, and fluorine-18 MFBG PET may replace MIBG scans. The survivors carry the heaviest late-effect burden in childhood oncology: cisplatin hearing loss in most, infertility, growth failure, cardiac and renal damage, and second cancers.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: INRG high-risk neuroblastoma; Metastatic neuroblastoma; MYCN-amplified neuroblastoma; Stage 4 neuroblastoma
- Tags: subtype-page; paediatric
- Group: paediatric
- Burden: About half of children with neuroblastoma have high-risk disease, metastatic at over 18 months of age or MYCN-amplified at any age; it accounts for around one in eight childhood cancer deaths, and only about half of children are cured despite the most intensive treatment given to any child.
- Subtypes: Stage M neuroblastoma over 18 months without MYCN amplification; MYCN-amplified neuroblastoma at any age or stage (about a fifth of all neuroblastoma); ALK-mutated or ALK-amplified high-risk neuroblastoma (lorlatinib added in ANBL1531); Ultra-high-risk neuroblastoma (poor end-of-induction response, or MYCN amplification with ALK or TERT alterations); Relapsed or refractory high-risk neuroblastoma (MIBG-avid and MIBG-non-avid; bone and marrow versus soft tissue); Adolescent and adult neuroblastoma (indolent, chemotherapy-resistant; ALK and ATRX alterations)
- Biomarkers: MYCN amplification; ALK mutation or amplification; 11q loss, 1p loss and 17q gain; TERT rearrangement and ATRX loss (telomere maintenance); MIBG avidity and Curie or SIOPEN score; End-of-induction response (INRC); Marrow minimal residual disease by GD2 synthase or PHOX2B PCR; Urinary catecholamine metabolites

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/neuroblastoma-high-risk/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/neuroblastoma-high-risk/#overview [3 state-of-the-art points]
- Types and stages (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/neuroblastoma-high-risk/#what-it-is [6 subtypes]
- Symptoms and diagnosis (on the hub): How this cancer shows itself, how the diagnosis is confirmed, and the biomarkers clinicians test for. https://onco.cc/cancers/neuroblastoma-high-risk/#finding-it [8 biomarkers]
- Treatment (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/neuroblastoma-high-risk/#treating-it [6 settings, 6 decisions with options]
- Trials and papers (on the hub): Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/neuroblastoma-high-risk/#evidence [10 trials, 6 key papers, 8 milestones]
- Biology and targets (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/neuroblastoma-high-risk/#science [7 targets]
- Countries and centres (own page): Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes. https://onco.cc/cancers/neuroblastoma-high-risk/where-you-are/ [1 centre]
- Decisions and support (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/neuroblastoma-high-risk/#living-with-it [23 questions, 6 red cards]
- Pipeline and open problems (own page): Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/neuroblastoma-high-risk/coming/ [20 medicines, 10 trials, 2 ideas, 3 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/neuroblastoma-high-risk/data/ [93 connected records]

## Standard of care

- Induction: Five or six cycles of cyclophosphamide-topotecan, cisplatin-etoposide and cyclophosphamide-doxorubicin-vincristine (COG) or rapid COJEC (SIOPEN); iodine-131 MIBG and, for ALK-mutant disease, lorlatinib within ANBL1531; surgery after induction. ([Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/), [Topotecan](https://onco.cc/drugs/topotecan/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [Etoposide](https://onco.cc/drugs/etoposide/), [Doxorubicin](https://onco.cc/drugs/doxorubicin/), [Vincristine](https://onco.cc/drugs/vincristine/), [COG ANBL1531](https://onco.cc/trials/anbl1531/), [131I-MIBG (iobenguane I-131) therapy](https://onco.cc/drugs/i131-mibg/), [Lorlatinib](https://onco.cc/drugs/lorlatinib/), [MIBG imaging and 131I-MIBG therapy](https://onco.cc/technologies/mibg-theranostics/))
- Consolidation: Busulfan-melphalan (HR-NBL1) or tandem thiotepa-cyclophosphamide then carboplatin-etoposide-melphalan (ANBL0532) with autologous stem cell rescue. ([Busulfan](https://onco.cc/drugs/busulfan/), [Melphalan (including hepatic delivery system)](https://onco.cc/drugs/melphalan/), [Thiotepa](https://onco.cc/drugs/thiotepa/), [Carboplatin](https://onco.cc/drugs/carboplatin/), [Etoposide](https://onco.cc/drugs/etoposide/), [Autologous stem cell transplant (high-dose therapy)](https://onco.cc/technologies/autologous-stem-cell-transplant/), [Tandem autologous transplant](https://onco.cc/technologies/tandem-transplant/), [COG ANBL0532](https://onco.cc/trials/anbl0532/), [SIOPEN HR-NBL1](https://onco.cc/trials/hr-nbl1/))
- Local control: Radiotherapy to the primary site bed and residual MIBG-avid metastases after transplant. ([IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [Proton therapy](https://onco.cc/technologies/proton-therapy/))
- Post-consolidation: Dinutuximab with GM-CSF and isotretinoin for five cycles (ANBL0032; interleukin-2 dropped after HR-NBL1), then two years of eflornithine maintenance. ([Dinutuximab (ch14.18) / dinutuximab beta](https://onco.cc/drugs/dinutuximab/), [Sargramostim](https://onco.cc/drugs/sargramostim/), [Aldesleukin (high-dose IL-2)](https://onco.cc/drugs/aldesleukin/), [COG ANBL0032](https://onco.cc/trials/anbl0032/), [Caution: IL-2 added to anti-GD2 therapy](https://onco.cc/pairings/il2-anti-gd2-caution/), [Eflornithine (DFMO)](https://onco.cc/drugs/eflornithine/), [NMTRC003/003B (DFMO maintenance)](https://onco.cc/trials/nmtrc003/))
- Relapsed or refractory: Irinotecan-temozolomide with dinutuximab (ANBL1221) or naxitamab with GM-CSF; iodine-131 MIBG for avid disease; lorlatinib for ALK-mutant disease; GD2 CAR T-cells in trials. ([Dinutuximab (ch14.18) / dinutuximab beta](https://onco.cc/drugs/dinutuximab/), [Irinotecan (and liposomal irinotecan)](https://onco.cc/drugs/irinotecan/), [Temozolomide](https://onco.cc/drugs/temozolomide/), [Anti-GD2 antibody + irinotecan-temozolomide (chemoimmunotherapy)](https://onco.cc/pairings/anti-gd2-plus-chemo-relapse/), [Naxitamab](https://onco.cc/drugs/naxitamab/), [Naxitamab Study 201](https://onco.cc/trials/naxitamab-201/), [131I-MIBG (iobenguane I-131) therapy](https://onco.cc/drugs/i131-mibg/), [Lorlatinib](https://onco.cc/drugs/lorlatinib/), [GD2-CART01 (Bambino Gesù phase 1/2)](https://onco.cc/trials/gd2-cart01/), [ANBL1221](https://onco.cc/trials/anbl1221/))
- Survivorship: Hearing, cardiac, renal, endocrine, fertility and second-cancer follow-up for life. ([Cardio-oncology](https://onco.cc/technologies/cardio-oncology/), [Late effects and survivorship toxicity](https://onco.cc/terms/late-effects/), [Oncofertility and fertility preservation](https://onco.cc/technologies/fertility-preservation/))

## State of the art

- Anti-GD2 immunotherapy after transplant raised two-year event-free survival from 46 to 66 percent in ANBL0032 and is standard worldwide.
- Tandem transplant (ANBL0532) and busulfan-melphalan (HR-NBL1) each beat the older single-transplant regimens.
- Eflornithine maintenance, approved in 2023 on an external-control comparison, and lorlatinib for ALK-mutant disease are the newest additions; GD2 CAR T-cells have produced remissions in relapse.

## Open problems

- About half of children relapse and relapsed disease is rarely cured.
- MYCN has no direct inhibitor; eflornithine and lorlatinib act around it.
- Cisplatin hearing loss, infertility and second cancers in survivors of the most intensive regimen in paediatric oncology.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Neuroblastoma
- Wikipedia: Neuroblastoma: https://en.wikipedia.org/wiki/Neuroblastoma
- NCI PDQ: Neuroblastoma Treatment: https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq

## Connected records

- cancers: [Intermediate-risk neuroblastoma](https://onco.cc/cancers/neuroblastoma-intermediate-risk/), [Low-risk neuroblastoma (INRG very low and low risk, including stage MS)](https://onco.cc/cancers/neuroblastoma-low-risk/), [Neuroblastoma (paediatric)](https://onco.cc/cancers/neuroblastoma/)
- technologies: [Autologous stem cell transplant (high-dose therapy)](https://onco.cc/technologies/autologous-stem-cell-transplant/), [CAR-T cell therapy](https://onco.cc/technologies/car-t/), [Cardio-oncology](https://onco.cc/technologies/cardio-oncology/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [MIBG imaging and 131I-MIBG therapy](https://onco.cc/technologies/mibg-theranostics/), [Monoclonal antibodies](https://onco.cc/technologies/monoclonal-antibody/), [Oncofertility and fertility preservation](https://onco.cc/technologies/fertility-preservation/), [Proton therapy](https://onco.cc/technologies/proton-therapy/), [Tandem autologous transplant](https://onco.cc/technologies/tandem-transplant/)
- targets: [ALK](https://onco.cc/targets/alk/), [GD2 (disialoganglioside)](https://onco.cc/targets/gd2/), [MYCN (N-myc)](https://onco.cc/targets/mycn/)
- drugs: [131I-MIBG (iobenguane I-131) therapy](https://onco.cc/drugs/i131-mibg/), [Aldesleukin (high-dose IL-2)](https://onco.cc/drugs/aldesleukin/), [Busulfan](https://onco.cc/drugs/busulfan/), [Carboplatin](https://onco.cc/drugs/carboplatin/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/), [Dinutuximab (ch14.18) / dinutuximab beta](https://onco.cc/drugs/dinutuximab/), [Doxorubicin](https://onco.cc/drugs/doxorubicin/), [Eflornithine (DFMO)](https://onco.cc/drugs/eflornithine/), [Etoposide](https://onco.cc/drugs/etoposide/), [Irinotecan (and liposomal irinotecan)](https://onco.cc/drugs/irinotecan/), [Isotretinoin](https://onco.cc/drugs/isotretinoin/), [Lorlatinib](https://onco.cc/drugs/lorlatinib/), [Melphalan (including hepatic delivery system)](https://onco.cc/drugs/melphalan/), [Naxitamab](https://onco.cc/drugs/naxitamab/), [Sargramostim](https://onco.cc/drugs/sargramostim/), [Temozolomide](https://onco.cc/drugs/temozolomide/), [Thiotepa](https://onco.cc/drugs/thiotepa/), [Topotecan](https://onco.cc/drugs/topotecan/), [Vincristine](https://onco.cc/drugs/vincristine/)
- companies: [Children's Oncology Group (COG)](https://onco.cc/companies/childrens-oncology-group/), [United Therapeutics](https://onco.cc/companies/united-therapeutics/), [US WorldMeds](https://onco.cc/companies/us-worldmeds/), [Y-mAbs Therapeutics](https://onco.cc/companies/y-mabs/)
- institutions: [SIOP Europe (European Society for Paediatric Oncology)](https://onco.cc/institutions/siop-europe/)
- terms: [ADCC (antibody-dependent cellular cytotoxicity)](https://onco.cc/terms/adcc/), [INRG staging and risk groups](https://onco.cc/terms/inrg-staging/), [Late effects and survivorship toxicity](https://onco.cc/terms/late-effects/), [MIBG Curie and SIOPEN scores](https://onco.cc/terms/curie-siopen-score/), [MYCN amplification](https://onco.cc/terms/mycn-amplification/), [Segmental chromosomal aberrations and ploidy (neuroblastoma)](https://onco.cc/terms/segmental-chromosomal-aberrations/), [Urinary catecholamine metabolites (VMA and HVA)](https://onco.cc/terms/urinary-catecholamines/)
- key papers: [ANBL0532: tandem versus single autologous stem cell transplant for high-risk neuroblastoma](https://onco.cc/key-papers/paper-anbl0532-tandem-transplant-park-jama-2019/), [ANBL1221 expansion: irinotecan, temozolomide and dinutuximab with GM-CSF in refractory or relapsed neuroblastoma](https://onco.cc/key-papers/paper-anbl1221-expansion-dinutuximab-gm-csf-mody-jco-2020/), [ANBL1221: irinotecan-temozolomide with temsirolimus or dinutuximab in relapsed or refractory neuroblastoma](https://onco.cc/key-papers/paper-anbl1221-irinotecan-temozolomide-dinutuximab-mody-lancet-oncol-2017/), [Anti-GD2 antibody with GM-CSF, interleukin-2 and isotretinoin for high-risk neuroblastoma (COG ANBL0032)](https://onco.cc/key-papers/paper-yu-anti-gd2-neuroblastoma-nejm-2010/), [HR-NBL1/SIOPEN: busulfan-melphalan versus carboplatin-etoposide-melphalan high-dose chemotherapy for high-risk neuroblastoma](https://onco.cc/key-papers/paper-hr-nbl1-busulfan-melphalan-ladenstein-lancet-oncol-2017/), [The International Neuroblastoma Risk Group (INRG) classification system](https://onco.cc/key-papers/paper-inrg-cohn-jco-2009/)
- trials: [ANBL1221](https://onco.cc/trials/anbl1221/), [ANBL17P1](https://onco.cc/trials/anbl17p1/), [COG ANBL0032](https://onco.cc/trials/anbl0032/), [COG ANBL0532](https://onco.cc/trials/anbl0532/), [COG ANBL1531](https://onco.cc/trials/anbl1531/), [GD2-CART01 (Bambino Gesù phase 1/2)](https://onco.cc/trials/gd2-cart01/), [High-Risk Neuroblastoma Study 2 of SIOP-Europa-Neuroblastoma (SIOPEN)](https://onco.cc/trials/nct04221035/), [Naxitamab Study 201](https://onco.cc/trials/naxitamab-201/), [NMTRC003/003B (DFMO maintenance)](https://onco.cc/trials/nmtrc003/), [SIOPEN HR-NBL1](https://onco.cc/trials/hr-nbl1/)
- ideas: [18F-MFBG PET replacing 123I-MIBG scintigraphy](https://onco.cc/ideas/idea-mfbg-pet-replaces-mibg/), [GD2 CAR-T as consolidation in high-risk neuroblastoma](https://onco.cc/ideas/idea-gd2-car-t-frontline-consolidation/)
- pairings: [Anti-GD2 antibody + irinotecan-temozolomide (chemoimmunotherapy)](https://onco.cc/pairings/anti-gd2-plus-chemo-relapse/), [Caution: IL-2 added to anti-GD2 therapy](https://onco.cc/pairings/il2-anti-gd2-caution/)
- biomarkers: [MYCN amplification](https://onco.cc/biomarkers/mycn-amp/)

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JSON: https://onco.cc/api/v1/entities/neuroblastoma-high-risk.json