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

Back
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%.[57]

The majority of perinatal tumors are localized, arise from the adrenal gland(s), and are of favorable histology. Multiple prospective studies have shown that tumors <5 cm in size are likely to spontaneously regress.[65][66][67][68] Therefore, efforts have been made to minimize therapy in this group of patients.

Observation is recommended for: low-risk MS disease that is asymptomatic with favorable 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 (tumor enlargement in these patients warrants surgery).[36][99][100][101]

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.[36]

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

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

Consider – chemotherapy

Back
ACUTE
|
low-risk disease
Consider – 

chemotherapy

Treatment recommended for SOME patients in selected patient group

Chemotherapy may be considered in low-risk patients where: the tumor progresses following surgery; surgery would be more feasible with a smaller tumor size; or the patient is experiencing severe symptoms from mass effect of the tumor (e.g., airway compromise, spinal cord compression, or bowel obstruction).[69][70][71] 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

Back
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.[57]

Duration of chemotherapy depends on the biologic features of the tumor.[36]​ There is a wide range of biologic variability in these patients, and these factors inform choice of chemotherapy regimen.[72]

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

Back
ACUTE
|
intermediate-risk disease
Consider – 

surgery

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.[36]

The timing of surgery varies, but usually follows a few cycles of chemotherapy.[72][73][74][75]

high-risk disease

1st line – induction: cytoreductive chemotherapy

Back
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.[36]

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.[36]

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 tumor

Back
ACUTE
|
high-risk disease
Plus – 

induction: surgical resection of the primary tumor

Treatment recommended for ALL patients in selected patient group

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

Total gross resection may result in better survival rates than incomplete resection.[76][77][78][79]​​ Therefore, the goal of surgery is to remove as much tumor as possible, while limiting morbidity.

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

Back
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 tumor is surgically removed, the next phase of therapy is consolidation using high-dose (myeloablative) chemotherapy followed by autologous stem cell transplant.[36] [ Cochrane Clinical Answers logo ] Myeloablative therapy prolongs event-free survival; however, the impact on overall survival rate is less clear.[80][81][82]

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 favorable high-risk disease can receive a single round of high-dose chemotherapy with autologous stem cell transplant.[36]

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.[83][84][85]​​ 

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: radiation therapy to the primary site

Back
ACUTE
|
high-risk disease
Plus – 

consolidation: radiation therapy to the primary site

Treatment recommended for ALL patients in selected patient group

Radiation therapy is typically given after autologous bone marrow transplant.[36]

Radiation to the primary tumor site is recommended for local control of the tumor.[36]

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

Plus – postconsolidation: immunotherapy

Back
ACUTE
|
high-risk disease
Plus – 

postconsolidation: immunotherapy

Treatment recommended for ALL patients in selected patient group

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

Postconsolidation immunotherapy consists of dinutuximab (a chimeric antiglycolipid disialoganglioside [GD2] antibody that binds to the surface of neuroblastoma cells) plus sargramostim (granulocyte-macrophage colony-stimulating factor [GM-CSF]) and isotretinoin.[36]

Isotretinoin promotes the differentiation of neuroblastoma cells, thereby attenuating their malignant potential. It is effective in minimal residual disease. Isotretinoin improved outcomes in patients randomized to isotretinoin after chemotherapy and transplant compared with no further therapy.[80]

Compared with isotretinoin alone, dinutuximab‐containing immunotherapy increased overall-survival and event‐free survival in people with high‐risk neuroblastoma pretreated with autologous hematopoietic stem cell transplantation.[86][87]

See local specialist protocol for dosing guidelines.

Primary options

dinutuximab

and

sargramostim (GM-CSF)

and

isotretinoin

Consider – continuation: eflornithine

Back
ACUTE
|
high-risk disease
Consider – 

continuation: eflornithine

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 postconsolidation immunotherapy with an anti-GD2 antibody.[36]

Patients with neuroblastoma that expresses the ODC1 gene have been found to have a worse survival rate compared with patients without ODC1 expression.[88] Early-phase and nonrandomized clinical trials have shown eflornithine to be both well tolerated and to improve outcomes.[89][90][91]

See local specialist protocol for dosing guidelines.

Primary options

eflornithine

ONGOING

relapsed or refractory disease

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

Back
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 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.[92]

Naxitamab, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), is indicated in pediatric 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.[93] 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.[94][95]

Because of its high affinity for neuroblastoma, efforts have been made to utilize 131-iodine-metaiodobenzylguanidine (MIBG) as a treatment for neuroblastoma.[96][97][98]​ 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

and

irinotecan

and

temozolomide

OR

naxitamab

and

sargramostim (GM-CSF)

back arrow

Choose a patient group to see our recommendations

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

Use of this content is subject to our disclaimer