# High-risk neuroblastoma

Source: https://nuclide.cc/indications/neuroblastoma-high-risk/  
Nuclide record `neuroblastoma-high-risk` (Indication). Data CC BY-NC 4.0, attribute "Data from Nuclide (nuclide.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: Indication
- 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

## 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. ([COG ANBL1531](https://nuclide.cc/trials/anbl1531/), [131I-MIBG (iobenguane I-131) therapy](https://nuclide.cc/drugs/i131-mibg/), [MIBG imaging and 131I-MIBG therapy](https://nuclide.cc/technologies/mibg-theranostics/))
- Consolidation: Busulfan-melphalan (HR-NBL1) or tandem thiotepa-cyclophosphamide then carboplatin-etoposide-melphalan (ANBL0532) with autologous stem cell rescue.
- Local control: Radiotherapy to the primary site bed and residual MIBG-avid metastases after transplant.
- Post-consolidation: Dinutuximab with GM-CSF and isotretinoin for five cycles (ANBL0032; interleukin-2 dropped after HR-NBL1), then two years of eflornithine maintenance.
- 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. ([Temozolomide](https://nuclide.cc/drugs/temozolomide/), [131I-MIBG (iobenguane I-131) therapy](https://nuclide.cc/drugs/i131-mibg/))
- Survivorship: Hearing, cardiac, renal, endocrine, fertility and second-cancer follow-up for life.

## 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

- isotopes: [Fluorine-18](https://nuclide.cc/isotopes/f-18/), [Iodine-131](https://nuclide.cc/isotopes/i-131/)
- technologies: [MIBG imaging and 131I-MIBG therapy](https://nuclide.cc/technologies/mibg-theranostics/)
- companies: [Y-mAbs Therapeutics](https://nuclide.cc/companies/y-mabs/)
- terms: [MIBG Curie and SIOPEN scores](https://nuclide.cc/terms/curie-siopen-score/)
- drugs: [131I-MIBG (iobenguane I-131) therapy](https://nuclide.cc/drugs/i131-mibg/), [Temozolomide](https://nuclide.cc/drugs/temozolomide/)
- trials: [COG ANBL1531](https://nuclide.cc/trials/anbl1531/)
- ideas: [18F-MFBG PET replacing 123I-MIBG scintigraphy](https://nuclide.cc/ideas/idea-mfbg-pet-replaces-mibg/)
- indications: [Neuroblastoma (paediatric)](https://nuclide.cc/indications/neuroblastoma/)
- targets: [Norepinephrine transporter (NET)](https://nuclide.cc/targets/norepinephrine-transporter/)

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