# Intermediate-risk neuroblastoma

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

## TL;DR

Intermediate-risk neuroblastoma sits between the tumours that go away on their own and the high-risk disease that needs everything. A few cycles of moderate chemotherapy followed by surgery cure most children, and trials have spent twenty years showing how few cycles are enough.

## Summary

The intermediate-risk group takes in L2 tumours in children with unfavourable histology or 11q aberration, L2 tumours in children over 18 months, metastatic stage M disease in infants under 18 months, and stage MS with unfavourable biology, all without MYCN amplification. These tumours will not regress reliably and cannot be removed safely at diagnosis, but they respond to chemotherapy and rarely relapse after it. The question the trials have asked is not which drug but how little: each cycle of carboplatin, etoposide, cyclophosphamide and doxorubicin adds hearing loss, infertility and cardiac risk to a child who will live for seventy years.

COG A3961, reported in the New England Journal of Medicine in 2010, gave 479 children four or eight cycles of that four-drug chemotherapy according to histology and ploidy and operated when the tumour became resectable: three-year overall survival was 96 percent and event-free survival 88 percent, establishing a biology-based reduction of therapy. ANBL0531 then cut further, giving two cycles to the most favourable subset and adding response-based escalation for the rest, with three-year event-free survival 83.2 percent and overall survival 94.9 percent; infants with stage M disease and children with 11q loss or unfavourable histology needed the longer course. SIOPEN's LINES trial applies the same approach in Europe, and infants with stage MS disease who need treatment for a bulky liver receive the same drugs briefly.

Radiotherapy is used only for life-threatening disease that does not respond, and the residual mass after chemotherapy is often left in place when resection would risk the kidney or a nerve root. Children with 11q aberration or unfavourable histology, and infants with stage M disease and diploid tumours, are the ones who still relapse and the ones whose therapy the next trials will not shorten. Telomere maintenance mechanisms (ATRX, TERT) and ALK mutations are being tested as additions to the classification, and long-term follow-up of hearing, kidney function and fertility is what tells the groups whether the reductions were worth it.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: INRG intermediate-risk neuroblastoma; Unresectable localised neuroblastoma; Stage M neuroblastoma in infants
- Tags: subtype-page; paediatric
- Group: paediatric
- Burden: About one neuroblastoma in ten is intermediate risk: unresectable localised disease or metastatic disease in infants, without MYCN amplification, cured in about nine in ten children with a few cycles of moderate chemotherapy.
- Subtypes: L2 neuroblastoma over 18 months, or with unfavourable histology or 11q aberration, without MYCN amplification; Stage M neuroblastoma in infants under 18 months without MYCN amplification; Stage MS neuroblastoma with 11q aberration or unfavourable biology; Intermediate-risk neuroblastoma with favourable biology (two to four cycles); Intermediate-risk neuroblastoma with unfavourable biology (up to eight cycles)
- Biomarkers: INRG stage (L2, M in infants, MS); MYCN amplification (must be absent); 11q aberration; DNA ploidy; INPC histology; ALK mutation; 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-intermediate-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-intermediate-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-intermediate-risk/#what-it-is [5 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-intermediate-risk/#finding-it [7 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-intermediate-risk/#treating-it [4 settings, 3 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-intermediate-risk/#evidence [1 trial, 3 key papers, 3 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-intermediate-risk/#science [1 target]
- 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-intermediate-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-intermediate-risk/#living-with-it [15 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-intermediate-risk/coming/ [4 medicines, 1 trial, 1 idea, 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-intermediate-risk/data/ [31 connected records]

## Standard of care

- Chemotherapy: Two to eight cycles of carboplatin, etoposide, cyclophosphamide and doxorubicin by biology and response (A3961, ANBL0531), then surgery when resectable. ([Carboplatin](https://onco.cc/drugs/carboplatin/), [Etoposide](https://onco.cc/drugs/etoposide/), [Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/), [Doxorubicin](https://onco.cc/drugs/doxorubicin/), [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/), [INRG staging and risk groups](https://onco.cc/terms/inrg-staging/), [ANBL0531](https://onco.cc/trials/anbl0531/))
- Response assessment and surgery: MRI or CT and MIBG scan after chemotherapy; resection of the residual primary where safe, otherwise observation of the residual mass. ([MRI](https://onco.cc/technologies/mri/), [MIBG imaging and 131I-MIBG therapy](https://onco.cc/technologies/mibg-theranostics/), [INRG staging and risk groups](https://onco.cc/terms/inrg-staging/))
- Non-responding or life-threatening disease: Radiotherapy to the primary or to a compressing lesion; escalation to high-risk therapy if biology proves unfavourable. ([IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [Radiotherapy](https://onco.cc/terms/radiotherapy/))
- Follow-up: Hearing, kidney, cardiac and fertility follow-up for the chemotherapy given. ([Late effects and survivorship toxicity](https://onco.cc/terms/late-effects/), [Cardio-oncology](https://onco.cc/technologies/cardio-oncology/), [Oncofertility and fertility preservation](https://onco.cc/technologies/fertility-preservation/))

## State of the art

- Four to eight cycles of moderate chemotherapy gave 96 percent three-year survival in A3961, and ANBL0531 cut therapy to two cycles for the most favourable children.
- Biology (11q, ploidy, histology) sets the number of cycles; response allows escalation.
- Radiotherapy and high-dose therapy are avoided altogether.

## Open problems

- Children with 11q aberration or unfavourable histology still relapse and cannot have therapy shortened.
- Whether telomere maintenance and ALK status should change risk assignment.
- Measuring the late effects of even moderate chemotherapy over decades.

## 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: [High-risk neuroblastoma](https://onco.cc/cancers/neuroblastoma-high-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: [Cardio-oncology](https://onco.cc/technologies/cardio-oncology/), [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [MIBG imaging and 131I-MIBG therapy](https://onco.cc/technologies/mibg-theranostics/), [MRI](https://onco.cc/technologies/mri/), [Oncofertility and fertility preservation](https://onco.cc/technologies/fertility-preservation/)
- companies: [Children's Oncology Group (COG)](https://onco.cc/companies/childrens-oncology-group/)
- institutions: [SIOP Europe (European Society for Paediatric Oncology)](https://onco.cc/institutions/siop-europe/)
- terms: [INRG staging and risk groups](https://onco.cc/terms/inrg-staging/), [Late effects and survivorship toxicity](https://onco.cc/terms/late-effects/), [MYCN amplification](https://onco.cc/terms/mycn-amplification/), [Radiotherapy](https://onco.cc/terms/radiotherapy/), [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: [A3961: outcome after reduced chemotherapy for intermediate-risk neuroblastoma](https://onco.cc/key-papers/paper-a3961-intermediate-risk-neuroblastoma-baker-nejm-2010/), [ANBL0531: response- and biology-based therapy for intermediate-risk neuroblastoma](https://onco.cc/key-papers/paper-anbl0531-twist-jco-2019/), [The International Neuroblastoma Risk Group (INRG) classification system](https://onco.cc/key-papers/paper-inrg-cohn-jco-2009/)
- drugs: [Carboplatin](https://onco.cc/drugs/carboplatin/), [Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/), [Doxorubicin](https://onco.cc/drugs/doxorubicin/), [Etoposide](https://onco.cc/drugs/etoposide/)
- ideas: [18F-MFBG PET replacing 123I-MIBG scintigraphy](https://onco.cc/ideas/idea-mfbg-pet-replaces-mibg/)
- trials: [ANBL0531](https://onco.cc/trials/anbl0531/)
- biomarkers: [MYCN amplification](https://onco.cc/biomarkers/mycn-amp/)

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