Neuroblastoma

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Initial management of neuroblastoma is dependent on the patient's risk of relapse (risk stratification).

Management varies from observation in patients with low-risk disease, to intense multimodal therapy in patients with high-risk disease.

Despite the number of treatment options, many patients with high-risk disease will relapse or be refractory to primary treatment.

Management necessitates a multidisciplinary team of specialists including a paediatric oncologist, cancer surgeon, and radiation oncologist.

Risk stratification

Surgical biopsy is required at the time of diagnosis in order to risk-stratify patients based on tumour biology and chromosomal alterations.

Risk stratification is complex and multifaceted and based on factors including:[4][58][61][62]

Patient age at diagnosis
Disease stage (International Neuroblastoma Risk Group Staging System [INRGSS])
Presence or absence of MYCN (v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog) amplification
Tumour cell ploidy (diploid or hyperdiploid)
Presence or absence of chromosomal aberrations
Histopathological appearance of the tumour

Age is an important component of risk stratification because younger children have better survival rates.[63][64][65]

The revised Children’s Oncology Group (COG) Neuroblastoma Risk Classification System (version 2) stratifies risk (low, intermediate, or high) premised on age, resection status, biomarkers, and INRGSS stage:[58]

Low risk

Stage L1 disease, unless in patients with incomplete resection of tumour and MYCN amplification.
Stage MS disease in patients aged <12 months with no MS tumour-related symptoms, no MYCN amplification, and all favourable biology.

Intermediate risk

Stage L2 disease in patients with no MYCN amplification and either aged <18 months, aged 18 months to <5 years with favourable histology, or aged ≥5 years with International Neuroblastoma Pathology Classification (INPC) differentiating type.
Stage M disease in patients with no MYCN amplification and either aged <12 months or aged 12 to <18 months with all favourable biology.
Stage MS disease in patients aged <12 months with either MS symptoms or no MS symptoms with no MYCN amplification and any unfavourable biology, or in patients aged 12 to <18 months with no MYCN amplification and all favourable biology.

High risk

Stage L1 disease in patients with incomplete resection and MYCN amplification.
Stage L2 disease in patients with MYCN amplification, or in patients with no MYCN amplification and either aged 18 months to <5 years with unfavourable histology or aged ≥5 years with INPC undifferentiated or poorly differentiated type.
Stage M disease in any patient aged ≥18 months, patients aged <18 months with MYCN amplification, or patients aged 12 to <18 months with no MYCN amplification and any unfavourable biology.
Stage MS disease in patients aged <12 months with no MS tumour-related symptoms and MYCN amplification, or in patients aged 12 to <18 months with either MYCN amplification or no MYCN amplification with any unfavourable biology.

This risk classification system has been adopted to prospectively define COG clinical trial eligibility and treatment assignment.[58]

Low-risk disease

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:[37]

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

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]

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.

Intermediate-risk disease

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.

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

High-risk disease can be difficult to cure, and a large proportion of these patients experience disease recurrence. Therefore, patients with high-risk disease are treated aggressively with multimodal therapy including chemotherapy, surgery, autologous bone marrow transplant, radiation, post-consolidation therapy (dinutuximab plus isotretinoin), and continuation therapy (eflornithine).[37]

Induction (cytoreductive) 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.

Surgical resection of the primary tumour:

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.

Consolidation (myeloablative) chemotherapy with autologous stem cell transplant

Patients with complete or partial response following initial cytoreductive chemotherapy are candidates for consolidation using high-dose chemotherapy with autologous stem cell transplant.[37] [ ] 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]

Radiotherapy to the primary site:

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.

Post-consolidation immunotherapy:

Used to target residual tumour after bone marrow transplant to prevent recurrence.
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]) plus isotretinoin.[37] Immunotherapy is used to target residual tumour after bone marrow transplant to prevent recurrence.
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]
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]

Continuation therapy:

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]

Relapsed or refractory disease

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 plus 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 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 utilize 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.

Assessment of disease response to treatment

Accurate assessment of disease response can be challenging because response to specific components (i.e., primary and metastatic soft tissue disease, metastatic bone marrow disease, and metastatic bone disease) need to be taken into account.

The revised International Neuroblastoma Response Criteria (INRC) can be used to assess and categorise disease response.[38] The INRC categorises overall disease response as complete response, partial response, minor response, stable disease, or progressive disease, based on the combined assessment and response of each individual component (soft tissue, bone marrow, and bone disease).

Urinary catecholamine levels are no longer recommended for the assessment of treatment response (due to influence of diet and lack of standardisation).[37][38]

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