Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

low-risk disease

1st line – observation ± surgery

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ACUTE
|
low-risk disease
1st line – 

observation ± surgery

Patients with low-risk disease have an excellent prognosis. Estimated 5-year overall survival in this population is 98%; 5-year event-free survival is 91%.[58]

The majority of perinatal tumours are localised, arise from the adrenal gland(s), and are of favourable histology. Multiple prospective studies have shown that tumours <5 cm in size are likely to spontaneously regress.[66][67][68][69]​​​ Therefore, efforts have been made to minimise therapy in this group of patients.

Observation is recommended for: low-risk MS disease that is asymptomatic with favourable biology (these patients have a high rate of spontaneous regression); infants <6 months with L1 disease with a small isolated adrenal mass <5 cm diameter (tumour enlargement in these patients warrants surgery).[37][100][101][102]

Observation is accompanied by serial ultrasound (e.g., at 3-6 week intervals, or as clinically indicated), and should continue at increasing intervals over a 2-year period.

Surgical resection is recommended for all other patients with low-risk stage L1 disease.[37]

Observation should continue at increasing intervals over a 2-year period.

If tumour enlargement is noted during the observation period, surgery should be considered.

Consider – chemotherapy

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ACUTE
|
low-risk disease
Consider – 

chemotherapy

Additional treatment recommended for SOME patients in selected patient group

Chemotherapy may be considered in low-risk patients where: the tumour progresses following surgery; surgery would be more feasible with a smaller tumour size; or the patient is experiencing severe symptoms from mass effect of the tumour (e.g., airway compromise, spinal cord compression, or bowel obstruction).[70][71][72] A common regimen is carboplatin, etoposide, cyclophosphamide, and doxorubicin​ 

Given the excellent prognosis of patients with low-risk disease, efforts have been made in trials to decrease or eliminate chemotherapy for this patient population.

See local specialist protocol for dosing guidelines.

Primary options

carboplatin

and

etoposide

and

cyclophosphamide

and

doxorubicin

intermediate-risk disease

1st line – chemotherapy

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ACUTE
|
intermediate-risk disease
1st line – 

chemotherapy

With a combination of surgery and chemotherapy, 5-year overall-survival and event-free survival is approximately 96% and 85%, respectively, in patients with intermediate-risk disease.[58]

Duration of chemotherapy depends on the biological features of the tumour.[37]​ There is a wide range of biological variability in these patients, and these factors inform choice of chemotherapy regimen.[73]

A common regimen is carboplatin, etoposide, cyclophosphamide, and doxorubicin, usually given for 2-8 cycles.

See local specialist protocol for dosing guidelines.

Primary options

carboplatin

and

etoposide

and

cyclophosphamide

and

doxorubicin

Consider – surgery

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ACUTE
|
intermediate-risk disease
Consider – 

surgery

Additional treatment recommended for SOME patients in selected patient group

An attempt at gross total resection may be recommended after chemotherapy, depending on response to chemotherapy.[37]

The timing of surgery varies, but usually follows a few cycles of chemotherapy.[73][74][75][76]

high-risk disease

1st line – induction: cytoreductive chemotherapy

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ACUTE
|
high-risk disease
1st line – 

induction: cytoreductive chemotherapy

Induction chemotherapy should be started in all patients using an intense induction regimen that is usually given for 5 cycles.[37]

The agents used are similar to those used for patients with low- or intermediate-risk disease (i.e., carboplatin, etoposide, cyclophosphamide, and doxorubicin); however, they are given in higher doses. There is a lack of comparative data; alternative chemotherapy regimens may achieve similar response rates.[37]

Autologous peripheral blood stem cells are collected during the induction phase.

See local specialist protocol for dosing guidelines.

Primary options

carboplatin

and

etoposide

and

cyclophosphamide

and

doxorubicin

Plus – induction: surgical resection of the primary tumour

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ACUTE
|
high-risk disease
Plus – 

induction: surgical resection of the primary tumour

Treatment recommended for ALL patients in selected patient group

Patients typically undergo surgical removal of the primary tumour once chemotherapy has decreased the initial tumour volume.

Total gross resection may result in better survival rates than incomplete resection.[77][78][79][80] Therefore, the goal of surgery is to remove as much tumour as possible, while limiting morbidity.

Plus – consolidation: high-dose chemotherapy + autologous bone marrow transplant

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ACUTE
|
high-risk disease
Plus – 

consolidation: high-dose chemotherapy + autologous bone marrow transplant

Treatment recommended for ALL patients in selected patient group

After induction chemotherapy is completed and the primary tumour is surgically removed, the next phase of therapy is consolidation using high-dose (myeloablative) chemotherapy followed by autologous stem cell transplant.[37] [ Cochrane Clinical Answers logo ] Myeloablative therapy prolongs event-free survival; however, the impact on overall survival rate is less clear.[81][82][83]

Tandem transplantation, comprising two consecutive rounds of high-dose chemotherapy with autologous stem cell transplant, is recommended for most patients with high-risk disease. Specific patients with more favourable high-risk disease can receive a single round of high-dose chemotherapy with autologous stem cell transplant.[37]

Consolidation chemotherapy regimens vary but can include combinations of carboplatin, etoposide, cyclophosphamide, melphalan, busulfan, and thiotepa. Toxicity profiles differ between commonly used regimens including: busulfan plus melphalan (BuMel); carboplatin plus etoposide plus melphalan (CEM); and thiotepa plus cyclophosphamide followed by CEM.[84][85][86]​

See local specialist protocol for dosing guidelines.

Primary options

busulfan

and

melphalan

OR

carboplatin

and

etoposide

and

melphalan

OR

thiotepa

and

cyclophosphamide

and

carboplatin

and

etoposide

and

melphalan

Plus – consolidation: radiotherapy to the primary site

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ACUTE
|
high-risk disease
Plus – 

consolidation: radiotherapy to the primary site

Treatment recommended for ALL patients in selected patient group

Radiotherapy is typically given after autologous bone marrow transplant.[37]

Radiation to the primary tumour site is recommended for local control of the tumour.[37]

Radiation to metastatic sites may also be beneficial and may prevent recurrence.

Plus – post-consolidation: immunotherapy

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ACUTE
|
high-risk disease
Plus – 

post-consolidation: immunotherapy

Treatment recommended for ALL patients in selected patient group

Used to target residual tumour after bone marrow transplant to prevent recurrence.

In the US, post-consolidation immunotherapy consists of dinutuximab (a chimeric anti-glycolipid disialoganglioside [GD2] antibody that binds to the surface of neuroblastoma cells) plus sargramostim (granulocyte-macrophage colony-stimulating factor [GM-CSF]) and isotretinoin.[37]

Post-consolidation regimens may vary between countries, and you should consult your local protocols. Dinutuximab is available as dinutuximab or dinutuximab beta, depending on geographical location (e.g., dinutuximab is available in the US, while dinutuximab beta is available in Europe). They are the same drug with the same pharmacological action; however, the way they are produced is different (dinutuximab beta is produced in Chinese hamster ovary cells instead of murine myeloma cells) and the doses are different. In Europe, dinutuximab beta is used in combination with aldesleukin (interleukin-2) rather than sargramostim. Dinutuximab beta plus isotretinoin but without sargramostim is a commonly used post-consolidation regimen in Europe.[37]

Isotretinoin promotes the differentiation of neuroblastoma cells, thereby attenuating their malignant potential. It is effective in minimal residual disease. Isotretinoin improved outcomes in patients randomised to isotretinoin after chemotherapy and transplant compared with no further therapy.[81]

Compared with isotretinoin alone, dinutuximab‐containing immunotherapy increased overall-survival and event‐free survival in people with high‐risk neuroblastoma pre‐treated with autologous haematopoietic stem cell transplantation.[87][88]

See local specialist protocol for dosing guidelines.

Primary options

dinutuximab

and

sargramostim

and

isotretinoin

OR

dinutuximab beta

and

aldesleukin

and

isotretinoin

Consider – continuation: eflornithine

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ACUTE
|
high-risk disease
Consider – 

continuation: eflornithine

Additional treatment recommended for SOME patients in selected patient group

Eflornithine, an inhibitor of the enzyme ornithine decarboxylase (ODC) that promotes cancer cell survival, is recommended as an option for continuation therapy in patients with high-risk disease. It should be used in patients who have had at least a partial response to prior systemic agents and have completed post-consolidation immunotherapy with an anti-GD2 antibody.[37]

Patients with neuroblastoma that expresses the ODC1 gene have been found to have a worse survival rate compared with patients without ODC1 expression.[89] Early-phase and non-randomised clinical trials have shown eflornithine to be both well tolerated and to improve outcomes.[90][91][92]

See local specialist protocol for dosing guidelines.

Primary options

eflornithine

ONGOING

relapsed or refractory disease

1st line – chemotherapy, radiation, MIBG, and/or immunotherapy

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ONGOING
|
relapsed or refractory disease
1st line – 

chemotherapy, radiation, MIBG, and/or immunotherapy

Relapsed or refractory neuroblastoma is extremely difficult to cure, and there is no standard treatment for these patients. Participation in clinical trials should be encouraged.

Patients with relapsed or refractory disease are commonly treated with chemoimmunotherapy. Combination therapy with dinutuximab (or dinutuximab beta) plus irinotecan and temozolomide in children with relapsed or refractory disease has been found to be superior to irinotecan and temozolomide alone. These responses are seen in soft tissue, bone, and bone marrow relapsed disease and are irrespective of prior dinutuximab exposure.[93]

Naxitamab, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), is indicated in paediatric patients ≥1 year of age with relapsed or refractory high-risk neuroblastoma whose disease is limited to the bone or bone marrow, and who have shown a partial/minor response or stable disease to prior therapy.[94] Approval of naxitamab combined with GM-CSF was based on preliminary data showing overall response rate (ORR; 34 to 45%) in single-arm studies of patients with relapsed/refractory high-risk neuroblastoma.[95][96]

Because of its high affinity for neuroblastoma, efforts have been made to utilise 131-iodine-metaiodobenzylguanidine (MIBG) as a treatment for neuroblastoma.[97][98][99] Thyroid protection with potassium iodide should be given prior to MIBG infusions.

Chemotherapy options for relapsed/refractory neuroblastoma include common regimens such as irinotecan plus temozolomide, and topotecan plus cyclophosphamide.

Primary options

irinotecan

and

temozolomide

OR

topotecan

and

cyclophosphamide

OR

dinutuximab

or

dinutuximab beta

-- AND --

irinotecan

-- AND --

temozolomide

OR

naxitamab

and

sargramostim

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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