Overview
Neuroblastoma is a cancer that originates from the developing sympathetic nervous system and is the most common extracranial solid tumor in children.1,2 It has been estimated that more than 700 patients are diagnosed with neuroblastoma annually in the United States.3 The prevalence is approximately 1 per 7,000 live births.2 The average age of a patient at the time of a neuroblastoma diagnosis is between 1 and 2 years of age.3 The vast majority of individuals are ≤4 years of age at diagnosis.4
Neuroblastoma is a primitive neoplasm of neuroectodermal origin composed of neuroblasts (or immature nerve cells).5 These tumors may occur anywhere in the sympathoadrenal neuroendocrine system including the adrenal gland, connective/soft tissue, retroperitoneum, and mediastinum.5
Due to differences in disease severity, symptoms, and clinical behavior of the tumor, neuroblastoma is considered a complex and heterogeneous disease.1,6 For example, some patients have tumors that spontaneously regress without any treatment, while others are diagnosed with aggressive metastatic disease that requires multimodal intervention.6
In addition to disease burden and treatment-related side effects, some patients with neuroblastoma may face additional challenges. Limited data suggest that health disparities due to race/ethnicity and socioeconomic status exist among patients with neuroblastoma.6–9 For example, a recent study found that the 5-year survival was higher for white (80.7%) or Hispanic (80.8%) patients with neuroblastoma compared with their Black counterparts (72.6%).9
These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroblastoma include up-to-date guidelines for the treatment of patients with neuroblastoma. These guidelines were developed by a multidisciplinary panel of representatives from NCCN Member Institutions with neuroblastoma-focused expertise in the fields of pediatric oncology, surgical oncology, radiation oncology, pathology, and radiology. Treatment recommendations for neuroblastoma in these guidelines will continue to be updated by the NCCN Neuroblastoma Panel annually based on consensus and emerging clinical evidence.
Guidelines Development and Update Methodology
The complete details of the development of the NCCN Guidelines are available at NCCN.org.
Literature Search Criteria
Prior to the development of the NCCN Guidelines for Neuroblastoma, an electronic search of the PubMed database was performed to obtain key literature in neuroblastoma published since 2012, using the search term “neuroblastoma.” The PubMed database was chosen because it remains the most widely used resource for medical literature and indexes peer-reviewed biomedical literature.10 The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types: Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV; Guideline; Randomized Controlled Trials; Meta-Analysis; Systematic Reviews; and Validation Studies. The data from key PubMed articles as well as articles from additional sources deemed as relevant to these guidelines as discussed by the panel have been included in this version of the Discussion section. Recommendations for which high-level evidence is lacking are based on the panel’s review of lower-level evidence and expert opinion.
Sensitive/Inclusive Language
NCCN Guidelines strive to use language that advances the goals of equity, inclusion, and representation.11 NCCN Guidelines endeavor to use language that is person-first; not stigmatizing; antiracist, anticlassist, antimisogynist, antiageist, antiableist, and antiweight-biased; and inclusive of individuals of all sexual orientations and gender identities. NCCN Guidelines incorporate nongendered language, instead focusing on organ-specific recommendations. This language is both more accurate and more inclusive and can help fully address the needs of individuals of all sexual orientations and gender identities. NCCN Guidelines will continue to use the terms men, women, female, and male when citing statistics, recommendations, or data from organizations or sources that do not use inclusive terms. Most studies do not report how sex and gender data are collected and use these terms interchangeably or inconsistently. If sources do not differentiate gender from sex assigned at birth or organs present, the information is presumed to predominantly represent cisgender individuals. NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate language in their future analyses.
Genetic Risk Factors
Although cases of familial neuroblastoma have been reported, they are rare (estimated to be about 1%–2% of all cases).12,13 Among the cases of familial neuroblastoma that do occur, germline gain-of-function ALK mutations and loss-of-function PHOX2B mutations have been identified as causative factors.14–16 Certain genetic syndromes are also associated with neuroblastoma, such as Li-Fraumeni syndrome, and those caused by mutations in RAS pathway genes, including Costello syndrome, Noonan syndrome, and neurofibromatosis.13 Other genetic variants likely contribute to familial neuroblastoma or predispose patients to sporadic neuroblastoma; however, additional validation studies are needed.12,17,18
Clinical Presentation
Symptoms associated with neuroblastoma can vary depending on the location of the tumor.19 Patients with neuroblastoma most commonly present with an abdominal mass or abdominal distension.2,20 Other signs and symptoms of the disease can include loss of appetite, weight loss, irritability, constipation, fever, hypertension, anemia, paralysis, bruising or swelling around the eyes, bone pain, and pancytopenia.
Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a paraneoplastic syndrome associated with neuroblastoma that may also occur in a small subgroup of patients.5,21–24 OMAS is characterized by rapid eye movements, ataxia, irritability, sleep disturbance, and irregular muscle movements.
Workup
The workup for suspected neuroblastoma in a patient outside of the perinatal period as recommended by the NCCN Neuroblastoma Panel includes a combination of tissue sampling for diagnostic evaluation and additional evaluations that involve a complete history and physical (H&P), family history assessment, laboratory tests, and imaging.1,20 Histologic evaluation and molecular characterization of the neuroblastoma tumor on diagnosis are also essential for tumor staging, risk classification, and treatment selection in most (but not all) patients.1,6,25,26
Diagnostic Workup
Based on international consensus, one of the following criteria must be met for a definitive diagnosis of neuroblastoma: (1) an unequivocal pathologic diagnosis made from tumor tissue by light microscopy; or (2) bone marrow aspirate or trephine biopsy containing unequivocal tumor cells (eg, syncytia or immunocytologically positive clumps of cells) and increased levels of urinary catecholamine metabolites.27
A neuroblastoma diagnosis should be made primarily based on tissue sampling (Figure 1). For patients outside of the perinatal period, the NCCN Neuroblastoma Panel recommends that surgical resection should be considered in the setting of localized disease, particularly in the absence of image-defined risk factors (IDRFs; for a description, see the “Principles of Imaging,” available in the full guidelines at NCCN.org). When biopsy rather than upfront resection is indicated, minimally invasive biopsy techniques can be used; however, open biopsy may be preferred in some clinical scenarios in which adequate tissue cannot be obtained by less invasive means.
NEUROB-1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroblastoma, Version 2.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 6; 10.6004/jnccn.2024.0040
Multiple core biopsies may provide adequate tissue; clinicians should consider the amount of tissue needed for full histologic and molecular evaluation. It is crucial that an adequate amount of tissue be obtained to evaluate the status of key prognostic factors needed for risk classification and treatment selection. Once it has been confirmed that sufficient tissue for clinical purposes has been obtained, preservation of additional tissue for research is encouraged when possible. Fine-needle aspiration is not recommended by the panel. It is important that an experienced pathologist review frozen sections to determine the adequacy of the specimen, as some samples may be necrotic at the time of initial biopsy.
Bilateral bone marrow aspirates and trephine biopsies can be used for diagnostic purposes, particularly in rare cases in which marrow is the only source of tumor material. In these situations, every attempt should be made to obtain adequate material for the full complement of molecular testing.
Patients <2 months of age with existing or evolving hepatomegaly28 and infants in whom safety considerations (coagulopathy, impending organ failure) preclude biopsy should not undergo a biopsy until after initiation of therapy and clinical stabilization. In these cases, biopsy should be performed when it is safe to do so to obtain tissue for histologic evaluation and molecular testing. Patients <6 months of age with L1 adrenal tumors with maximum diameter ≤3.1 cm if solid or 5 cm if at least 25% cystic do not require an initial biopsy or resection based on data from a prospective multicenter cooperative group study.29
See the later section on “Pathology” for additional recommendations regarding tissue sampling, histologic classification, and molecular testing considerations.
Additional Workup
The NCCN Neuroblastoma Panel recommends that all patients undergo an H&P, with special attention given to the abdominal examination to evaluate for masses and organomegaly, as well as a thorough neurologic examination (Figure 1). Any family history of neuroblastoma or other childhood cancers should be noted.
Several laboratory tests are considered essential as part of the workup for neuroblastoma. These include a CBC with differential and a comprehensive metabolic panel. Urine catecholamine levels (homovanillic acid [HVA] and vanillylmandelic acid [VMA]) are elevated in the majority of patients with neuroblastoma.19,30 Analysis of urine HVA and VMA levels is required for diagnosis only if bone marrow is the only diagnostic tissue obtained.
Other tests and assessments have been deemed as useful in selected cases by the NCCN panel. Clinicians may consider obtaining the prothrombin/international normalized ratio if the liver is involved or there is a concern for bleeding. Pregnancy tests should be done for all patients of childbearing potential. A referral to fertility specialists should be made for patients with high-risk disease to discuss possible options and timing for fertility preservation.
Analysis of lactate dehydrogenase and ferritin levels can be considered in select cases. High levels of lactate dehydrogenase and ferritin in patients with neuroblastoma have been associated with worse prognosis; however, neither of these are components of the risk classification criteria recommended by the NCCN Neuroblastoma Panel (see “Neuroblastoma Risk Classification” in Figure 2).31,32
NEUROB-2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroblastoma, Version 2.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 6; 10.6004/jnccn.2024.0040
Some assessments are recommended by the panel only if a certain type of treatment is indicated. For example, audiograms, echocardiograms, or electrocardiograms should be done if specific chemotherapy agents are to be administered.
Imaging studies are also an essential component of the workup for neuroblastoma because imaging results will have a profound impact on tumor staging and risk classification, and therefore are important to determine the treatment strategy implemented for each patient (Figure 1). See the later section on “Imaging” and the section on “Principles of Imaging” in the full guidelines, at NCCN.org for additional information about imaging for patients with neuroblastoma.
Pathology
Sampling
Pathology workflows should be designed to facilitate histologic diagnosis with prognostic classification and molecular profiling as required for treatment. The NCCN Neuroblastoma Panel recommends a coordinated diagnostic sampling effort that includes pathologists, oncologists, surgeons, and radiologists.33,34
For the pathology diagnosis of neuroblastoma, considerations for acceptable tissue sampling from either the primary site or a site of metastasis are based on the requirements for risk stratification and treatment. These include surgical resection if clinically indicated, incisional biopsy (>1 cm3), or tissue cores (at least 10 cores, ideally 20–30 mm in length obtained using a 16-gauge needle if possible). Clinicians should be aware that bilateral bone marrow biopsies and clot sections alone may not be sufficient to assess characteristics relevant to the International Neuroblastoma Pathology Classification (INPC) system.35
The tissue quantity requirements specified previously may be challenging to meet. In some cases, open rather than minimally invasive procedures may be necessary to obtain the adequate specimens for all required testing.36 Advanced planning for the required amount and condition of the tissue (eg, formalin-fixed paraffin-embedded, fresh, frozen, touch preparations) will increase the likelihood of completing the required testing. Additional testing may be required for patients enrolled in clinical trials.
Histologic Classification
Neuroblastoma diagnosis should be determined according to the International Collaboration on Cancer Reporting and INPC.25,26 Histologic classification based on the INPC should be done prior to the start of therapy and is typically made based on hematoxylin and eosin staining.
Immunohistochemical stains can be helpful in the setting of small samples, unusual locations, or undifferentiated subtypes. In these situations, the NCCN panel recommends staining for chromogranin and synaptophysin, which are widely used markers for neuroendocrine cells and tumors.37 Staining for the neural crest marker PHOX2B (strongly recommended) and tyrosine hydroxylase are also appropriate for these situations.38
Neuroblastoma is part of a group known as peripheral neuroblastic tumors, which are tumors of the sympathetic nervous system that arise from the embryonic neural crest.39,40 The INPC distinguishes peripheral neuroblastic tumors into 4 categories mainly based on Schwannian stroma development: neuroblastoma (Schwannian stroma-poor); ganglioneuroblastoma, intermixed (Schwannian stroma-rich); ganglioneuroma (Schwannian stroma-dominant); and ganglioneuroblastoma, nodular (composite, Schwannian stroma-rich/stroma-dominant and stroma-poor).25,26 Neuroblastoma is the most common type of neuroblastic tumor.
The INPC classifies peripheral neuroblastic tumors into a favorable histology group or unfavorable histology group. Classification of tumors is based on the grade of neuroblastic differentiation (undifferentiated subtype, poorly differentiated subtype, and differentiating subtype), MKI (Mitosis-Karyorrhexis Index=estimated mitotic and karyorrhectic nuclei per 5,000 neuroblastoma cells; low,<100; intermediate, 100–200; and high, ≥200), and age at diagnosis. Favorable histology tumors include (1) poorly differentiated or differentiating subtype with low or intermediate MKI, ≤547 days of age at diagnosis; and (2) differentiating subtype with low MKI, ≤1,824 days of age at diagnosis. Unfavorable histology tumors include (1) undifferentiated subtype at any age; (2) high MKI at any age; (3) poorly differentiated subtype with any MKI, ≥548 days of age at diagnosis; (4) differentiating subtype with intermediate MKI, ≥548 days of age at diagnosis; and (5) differentiating subtype with any MKI, ≥1,825 days of age at diagnosis.
Tumors in the category of ganglioneuroblastoma, intermixed and ganglioneuroma are usually diagnosed in older children and classified into the favorable histology group. Patients in these 2 categories are expected to have an excellent prognosis. Tumors in the category of ganglioneuroblastoma, nodular are composed of at least 2 distinct histologies: one is neuroblastoma while the other is either ganglioneuroblastoma, intermixed or ganglioneuroma. The neuroblastoma component usually makes discrete nodules and dictates clinical behavior of the tumor in this category.41 To determine the prognostic group (favorable or unfavorable histology group) for tumors categorized as ganglioneuroblastoma, nodular, the same age-dependent criteria of morphologic features (grade of neuroblastic differentiation and MKI) as described in the neuroblastoma category (see previous section) should be applied to the neuroblastoma component.
See “Principles of Pathology” in the guidelines on NCCN.org for more information about the histologic classification of neuroblastoma.
Molecular Genetic Testing Considerations
Risk stratification for the initial treatment of neuroblastoma is heavily dependent on molecular tumor profiling (see “Neuroblastoma Risk Classification” on Figure 2). The key prognostic molecular biomarkers that should be assessed include MYCN amplification status, segmental chromosomal aberration (SCA) status, and tumor cell ploidy.
Amplification of the MYCN oncogene is associated with aggressive disease, and is the strongest independent prognostic risk factor included in the neuroblastoma risk classification system.32,42,43 The NCCN Neuroblastoma Panel recommends the assessment of MYCN amplification status in all neuroblastomas and neuroblastoma nodules of ganglioneuroblastoma nodular tumors.
SCAs, defined as the loss or gain of a portion of a chromosome arm, may also be associated with inferior outcome in patients with neuroblastoma.32,44 The most extensively studied SCAs in neuroblastoma include loss of genetic material from chromosomes 1p and 11q; however, segmental losses involving 3p or 4p and segmental gains involving 17q, 1q, or 2p are also considered when assigning SCA status. The panel recommends that molecular genetic testing include analysis of these 7 SCAs for appropriate risk stratification.
Ploidy status, a measure of the amount of DNA within cells, is another prognostic factor for a small subset of patients.32 In general, a DNA index = 1 is considered less favorable than a DNA index >1, and ploidy has historically been used in risk classification in infants.6,45
New targeted therapies for the treatment of neuroblastoma are emerging.46,47 For example, amplification and sequence variants in the ALK gene predict response to matched targeted agents.1,48–50 Molecular genetic testing requirements will continue to evolve as new targeted therapies become available.
Assay Selection
Multiple approaches using different assays can be used for molecular genetic testing to meet the previously stated recommendations. Next-generation sequencing has become widely available and analysis of formalin-fixed paraffin-embedded tissue with this approach is feasible. Using NGS to simultaneously evaluate for the key neuroblastoma prognostic factors (including the presence of MYCN amplification and SCAs) and aberrations that may guide therapy selection (such as amplification or activating mutations in ALK) is recommended, as long as the approach enables robust assessment of copy number status and can provide coverage of the relevant regions of neuroblastoma-associated genes. Use of a single assay may be beneficial when tissue is limited.
The status of the standard prognostic biomarkers can also be assessed using fluorescence in situ hybridization, microarray, and/or flow cytometry; however, clinicians should be aware that these assays will not identify sequence variants in neuroblastoma-related genes such as ALK.
See the “Principles of Pathology” section in the guidelines on NCCN.org for additional information about molecular genetic testing considerations.
Imaging
A neuroblastic tumor diagnosis is usually suspected based on the patient’s age and the appearance of the tumor on imaging.39 The combination of imaging studies to be used during the initial evaluation of a child with a suspected neuroblastic tumor depends on the symptoms and suspected sites of disease.19,51 Local extension of neuroblastoma mainly consists of vascular encasement, infiltration of adjacent soft tissues and organs (most commonly the kidneys and liver), and infiltration of the foramina and epidural space of the spinal canal when the primary tumor arises from a paraspinal sympathetic chain.
Approximately 50% of patients present with localized or regional disease, and approximately 35% of patients have regional lymph node spread at time of diagnosis.52 The International Neuroblastoma Risk Group (INRG) Task Force developed the INRG Staging System and the INRG Risk Classification System for neuroblastoma, which have profound implications for imaging in this disease.32,40 Moreover, although soft tissue tumor volume was previously used to measure response in the prior International Neuroblastoma Response Criteria (INRC), the revised INRC use RECIST criteria for the measurement of soft tissue disease, using assessment of the single longest dimension of soft tissue lesions.53,54
The primary goals of imaging in a patient with suspected neuroblastoma are to identify features consistent with a neuroblastic tumor,55 assess for the presence of IDRFs to facilitate INRG staging (see next section on “Staging”),40 help estimate the potential surgical risk that would be associated with local tumor excision, assess for the presence and degree of regional and distant metastatic disease, and facilitate posttreatment response assessment and disease surveillance.
The NCCN Neuroblastoma Panel recommends cross-sectional imaging (MRI with/without contrast or CT with contrast) to evaluate soft tissue disease at initial evaluation. MRI of the spine with/without contrast is appropriate in the setting of paraspinal disease or if there are concerns regarding involvement of nerve roots or spinal cord. MRI of the brain with/without contrast or CT skull/orbits with contrast should be done if neurologic symptoms are present or if otherwise clinically indicated.
123Iodine-metaiodobenzylguanidine (123I-MIBG) imaging should be used to assess for metastatic disease due to the high specificity and high sensitivity of this tracer. MIBG, a norepinephrine analogue, is taken up by norepinephrine transporters; uptake has been demonstrated in up to 90% of neuroblastoma tumors. Interpretation of 123I-MIBG imaging is performed by means of semiquantitative scoring of tracer update within body segments. The modified Curie score56 and the International Society of Pediatric Oncology Europe Neuroblastoma (SIOPEN) score57 are the 2 most commonly used systems. In North America, the modified Curie score is used. If available, single-photon emission CT (SPECT) or SPECT/CT should be performed at sites of known or suspected disease to improve sensitivity and anatomic localization of disease sites.58
18F-FDG-PET imaging should be obtained in patients with 123I-MIBG nonavid disease or suspected mixed-avidity disease, with the exception of patients who are <6 months of age with L1 adrenal tumors ≤3.1 cm in diameter if solid or <5 cm if at least 25% cystic component.29 FDG-PET/CT and PET/MRI can also be useful alternative or supplemental diagnostic tools when 123I-MIBG imaging and anatomic imaging do not correlate. See “Principles of Imaging” in these guidelines on NCCN.org for additional information.
Imaging is also an important component of posttreatment response assessment and disease surveillance. See later sections on “Response Assessment” and “Disease Surveillance” for more information.
Staging
The NCCN Neuroblastoma Panel recommends using the neuroblastoma staging system developed by the INRG (see ST-1 in these guidelines on NCCN.org).40 This system was developed to improve the consistency and uniformity of tumor staging for patients with neuroblastoma by ensuring that disease staging could be done before start of treatment. Tumor stage defined by the INRG Staging System is also a key prognostic factor accounted for in the updated Children’s Oncology Group (COG) neuroblastoma risk classification system (see “Neuroblastoma Risk Classification,” Figure 2).32 As risk classification is used to guide neuroblastoma treatment, it is essential for disease staging to be completed before initiation of treatment when possible. Initiation of emergent therapy, if needed, should not be delayed for 123I-MIBG or FDG-PET imaging; however, this imaging should be obtained as soon as possible.
In the INRG Staging System, localized tumors are classified based on the number of IDRFs present. Although the currently used list of IDRFs is derived from a consensus list of risk factors initially developed to guide surgical decision-making, IDRFs are thought to be proxies for tumor biologic features that are not yet well understood. See “Principles of Imaging” in the full guidelines on NCCN.org for a description of IDRFs.
An L1 tumor is defined as a localized tumor that is not involved with vital structures, as defined by the list of IDRFs, and is confined to one body compartment. An L2 tumor is described as a locoregional tumor with the presence of one or more IDRFs. A patient with stage M neuroblastoma has distant metastatic disease, except for the special case of young children with INRG stage MS disease. MS neuroblastoma is diagnosed only in children who are <18 months, with metastases confined to the skin, liver, and/or bone marrow (limited marrow disease).
Risk Classification
The risk classification criteria incorporated into the NCCN Guidelines is adapted from an updated risk classifier published by the COG in 2021.32 The assigned risk group is based on outcomes data generated over recent decades.26,32,59–61 Event-free survival (EFS) and overall survival (OS) outcomes are influenced by key prognostic risk factors, including age at diagnosis, INRG stage (see previous section on “Staging”), tumor MYCN status (ie, presence or absence of MYCN amplification), histopathology (favorable or unfavorable based on INPC), presence or absence of SCAs, and ploidy status (diploid or hyperdiploid).
It should be noted that treatment substantially impacts outcome, and outcomes achieved often reflect the effects of different types of therapy within a given risk group. However, risk classification must occur in practice before the start of therapy. The risk assignments that follow therefore reflect pretreatment decision-making, taking into account treatment administered to prior patients with neuroblastoma over time.
Based on this classification system, patients of any age with L1 disease with tumors that are MYCN nonamplified are included in the low-risk group. Patients with L1 disease and tumor MYCN amplification would only be considered low risk if complete resection is achieved. If residual tumor remains postresection, patients with L1, MYCN-amplified tumors are considered to have high-risk disease. Asymptomatic patients who are <12 months of age with MS disease and favorable histology tumor that is demonstrated to be MYCN nonamplified, hyperdiploid, and without SCAs are also assigned to the low-risk group.
Patients who are between 12 and 18 months of age with M or MS stage disease with tumors that are found to have unfavorable prognostic factors such as unfavorable histology, presence of SCAs, or MYCN amplification are assigned to the high-risk group. Patients who are ≥18 months with M stage disease are also assigned to the high-risk group regardless of any other features. Apart from those with L1 disease and completely resected tumors (who are considered to have low-risk disease despite MYCN status), detection of MYCN amplification leads to assignment to the high-risk group regardless of age or stage.32
The intermediate-risk group generally includes patients whose disease characteristics do not meet the criteria for either the low-risk or high-risk groups. See Figure 2 for the detailed Neuroblastoma Risk Classification table.
For symptomatic infants with INRG stage MS disease who are too ill to undergo biopsy at the time of initial presentation (such as those with coagulopathy or impending organ failure), and especially those with hepatomegaly leading to respiratory compromise,62 therapy is started with a presumptive assignment to the intermediate-risk group. However, if a biopsy undertaken when the patient is clinically stable identifies tumor cells with MYCN amplification, the patient would then be reassigned to the high-risk group.
Clinicians should be aware that there are differences between the COG risk classifier and criteria used by cooperative groups outside of North America.32,63,64 For example, patients with L2, MYCN nonamplified disease who are >18 months of age at diagnosis and have unfavorable histology or whose tumors are undifferentiated/poorly differentiated are classified as high risk by COG criteria, but may be categorized as intermediate risk by other groups.
For the complete criteria for each risk group, see “Neuroblastoma Risk Classification” in Figure 2 and Figure 3 and the “Principles of Risk Classification” section in the full guidelines on NCCN.org.
NEUROB-2A. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroblastoma, Version 2.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 6; 10.6004/jnccn.2024.0040
Treatment for Patients With Newly Diagnosed Neuroblastoma
Due to the complex nature of the disease, it is recommended that a multidisciplinary team be involved in making treatment decisions for patients with neuroblastoma. The team should include at a minimum: diagnostic radiologists, nuclear medicine physicians, interventional radiologists, surgeons, anatomic pathologists, molecular pathologists, radiation oncologists, and pediatric oncologists.
Non–High-Risk Disease
Over the past 2 decades, the staging system, risk classification system, and response criteria definitions for neuroblastoma have evolved. It is important to note that published results from clinical trials for patients with non–high-risk disease used a legacy staging system (International Neuroblastoma Staging System) and older response criteria27 or protocol-specific response criteria.28 These NCCN Guidelines are based on published data from clinical trials of patients with non–high-risk disease, but also bridge the transition to currently used staging, classification, and response criteria systems where applicable.32,53,63
Approximately half of newly diagnosed patients with neuroblastoma have non–high-risk disease.65,66 Patients with low- and intermediate-risk (ie, non–high risk) neuroblastoma have excellent survival rates. Five-year survival rates are >95% for patients with low-risk neuroblastoma and approximately 90%–95% for those with intermediate-risk neuroblastoma.20,32 The goal of therapy for these patients is to cure the disease with minimal toxicity. Recent clinical trials have focused on reduction of therapy for patients with favorable biology and have been successful in maintaining excellent outcomes with these strategies.28,67,68
Treatment for Low-Risk Neuroblastoma
Treatment approaches for patients with low-risk INRG L1 tumors involve surgical resection, with the exception of those who are <6 months old with isolated adrenal masses with maximum diameter ≤3.1 cm if solid, or 5 cm if at least 25% of the mass is cystic. For these patients, observation without biopsy is the recommended approach (Figure 4). If upfront surgery will potentially obviate the need for chemotherapy and can be safely performed with minimal morbidity, a resection should be performed (see “Principles of Surgery” in the full guidelines at NCCN.org). If the resection is incomplete, and MYCN amplification is detected, the patient should be reassigned to the high-risk group. In patients with INRG MS disease who are asymptomatic and have tumors with favorable biology, observation is also the preferred approach. For complete treatment recommendations for low-risk neuroblastoma, see Figure 4.
NEUROB-3. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroblastoma, Version 2.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 6; 10.6004/jnccn.2024.0040
Treatment for Intermediate-Risk Neuroblastoma
Intermediate-risk treatment involves a combination of moderate-intensity multiagent chemotherapy and surgical resection (see “Principles of Systemic Therapy” and “Principles of Surgery” in the full guidelines at NCCN.org).
The North American treatment strategy for patients with intermediate-risk neuroblastoma is based on results of the COG study ANBL0531, which aimed to decrease the number of chemotherapy cycles given to patients with more favorable tumor biology, by allowing for a larger residual primary tumor following chemotherapy with or without surgery, compared with treatment endpoints used on legacy clinical trials.28 Patients were assigned to receive a minimum number of cycles based on age, stage, and tumor biologic features.
The NCCN Neuroblastoma Panel recommends that patients with intermediate-risk neuroblastoma receive 2 to 8 cycles of chemotherapy, with the number of cycles depending on a combination of factors (including disease stage, age, and biologic features; see Figures 5–7). Favorable biologic features include favorable histology, DI>1, and no SCA. If SCA or histology status are unavailable, then clinicians should consider the tumor to have unfavorable biologic features. For infants with stage MS disease who are too unstable to undergo biopsy before starting treatment, the panel recommends initiating chemotherapy and then obtaining a biopsy when it is safe to do so.
NEUROB-4. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroblastoma, Version 2.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 6; 10.6004/jnccn.2024.0040
NEUROB-5. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroblastoma, Version 2.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 6; 10.6004/jnccn.2024.0040
NEUROB-6. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroblastoma, Version 2.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 6; 10.6004/jnccn.2024.0040
In the ANBL0531 clinical trial, protocol-specific criteria for disease response were used, and primary tumor response was assessed based on tumor volume reduction. The goal for groups of patients with localized, favorable biology tumors was to achieve at least a 50% reduction in the primary tumor volume, while patients with localized disease with less favorable tumor biologic features were to continue therapy until a goal of 90% reduction in primary tumor volume (very good partial response) was achieved. The goal treatment endpoint for metastatic disease response for patients with the equivalent of INRG MS disease and those with intermediate-risk INRG stage M disease were also protocol-specific, and not identical to the legacy INRC.27
Since the completion of ANBL0531, the neuroblastoma response criteria have been updated and no longer include very good partial response as a response category. Additionally, in the current system of response assessment, tumors are measured with a single dimension as per Response Evaluation Criteria in Solid Tumors (RECIST), rather than by tumor volume (see “Response Assessment” in the full guidelines at NCCN.org).53 Until additional data become available regarding the use of the revised response criteria in assessment of disease in patients with non–high-risk neuroblastoma, the committee supports utilizing either volume or 1-dimensional assessments of primary tumor response in this group of patients.
After completion of the assigned number of chemotherapy cycles, the NCCN Neuroblastoma Panel recommends surveillance if the targeted tumor reduction goal was achieved (see Figures 5–7). If the targeted tumor reduction goal with the initial course of chemotherapy regimen was not achieved, a multidisciplinary discussion regarding the role of surgery versus additional chemotherapy should be undertaken on an iterative basis, and surveillance should only begin once the target response or reduction in primary tumor size, as noted in the guidelines, is achieved with chemotherapy and/or surgery.
For some patients, surgical resection may be appropriate to reach the targeted treatment endpoint. Surgical resection should be considered if chemotherapy has resulted in <50% reduction in tumor size. The preservation of vital structures and of end-organ function is of utmost importance in the intermediate-risk context, because less than complete response has been shown to be an acceptable endpoint of therapy for patients with localized intermediate-risk tumors. The timing of resection will depend on the response to initial therapy and subsequent assessment of surgical risk. Multidisciplinary discussion regarding the optimal timing of resection should occur.
If surgery cannot be performed safely to achieve the proposed degree of tumor reduction, additional chemotherapy may be given with re-evaluation after every 2 cycles. At these timepoints, the potential risks and benefits of additional chemotherapy or surgery can be further discussed by the multidisciplinary treatment team.
In some circumstances it may be reasonable to consider biopsy of the residual mass to assess for histologic differentiation, which may support observation of a tumor that does not shrink sufficiently with chemotherapy and for which a surgical debulking is considered unsafe. In COG ANBL0531, cyclophosphamide and topotecan were used as additional treatment of patients who did not achieve the target response with 8 cycles of the intermediate-risk therapy regimen outlined in Figure 5.28 SIOPEN treatment regimens can also be considered, as similar outcomes are achieved with the SIOPEN and COG strategies.69
For complete treatment recommendations for intermediate-risk neuroblastoma, see Figures 5 through 7.
High-Risk Disease
Approximately half of newly diagnosed patients with neuroblastoma have high-risk disease.65,66 Patients with newly diagnosed high-risk neuroblastoma have an estimated 5-year EFS rate of 51% from a large analysis reflecting 10 years of data from the COG.32 These outcomes have improved over time as a result of increasingly intensive multimodal therapies divided into induction, consolidation, and postconsolidation phases (see Figure 8 for a high-level overview of treatment of high-risk neuroblastoma). Much of the data summarized subsequently is derived from cooperative group phase III trials and the panel encourages participation in open clinical trials when available. For complete treatment recommendations for patients with high-risk neuroblastoma, see Figures 8 through 12 (see Figure 13 for references).
NEUROB-7. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroblastoma, Version 2.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 6; 10.6004/jnccn.2024.0040
NEUROB-8. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroblastoma, Version 2.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 6; 10.6004/jnccn.2024.0040
NEUROB-9. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroblastoma, Version 2.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 6; 10.6004/jnccn.2024.0040
NEUROB-10. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroblastoma, Version 2.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 6; 10.6004/jnccn.2024.0040
NEUROB-11. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroblastoma, Version 2.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 6; 10.6004/jnccn.2024.0040
NEUROB-12. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Neuroblastoma, Version 2.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 6; 10.6004/jnccn.2024.0040
Induction Therapy
The goal of initial induction therapy is to decrease disease burden and to achieve the best possible response before subsequent phases of therapy. This goal is achieved through a combination of multiagent cytoreductive chemotherapy and surgical resection of the primary tumor and locoregional disease (Figure 9). In addition, autologous peripheral blood stem cells are collected during induction to facilitate subsequent therapy.
There are no contemporary data comparing North American induction regimens that have been evaluated in prospective randomized trials. Instead, a number of induction combinations have evolved over the past several decades, mainly based on cisplatin- and alkylator-intensive regimens developed at Memorial Sloan Kettering Cancer Center.70 Several different regimens have been used in North American cooperative group pilot and phase III trials, each enrolling over 100 patients over the past 2 decades.71
These regimens yield broadly similar end-induction response rates, with approximately 80% of patients having a partial response or better and approximately 9% of patients progressing despite these intensive regimens.71 Given the lack of prospective comparative efficacy data and similar response rates, toxicity considerations have driven the evolution of induction regimens to reduce exposure to nephrotoxic and cardiotoxic agents. The combination of topotecan and cyclophosphamide given as cycles 1 and 2 of induction was studied initially as part of a pilot trial that demonstrated the feasibility and acceptable end-induction response rate (84%) of this approach.72 This regimen was adopted for use in ANBL0532, demonstrating that 39.1% of patients had a partial response or better after the first 2 cycles with topotecan and cyclophosphamide.73
A subsequent trial, ANBL12P1, empirically reduced induction to 5 cycles, with an 80% end-induction response rate.74 Likewise, data from Memorial Sloan Kettering Cancer Center demonstrated comparable end-induction response rates with 5 versus 7 induction cycles.70 Therefore, a 5-cycle induction was included as part of the standard arm of the COG phase III trial, ANBL1531. The ANBL1531 induction regimen was similar to the published ANBL12P1 regimen, with minor adjustments to dosing to align with updated COG chemotherapy standards. Given extensive contemporary experience with a 5-cycle induction regimen, the NCCN Neuroblastoma Panel recommends either ANBL12P1 or ANBL1531 induction as preferred regimens, with a 6-cycle regimen from ANBL0532 as an additional acceptable regimen (see “Principles of Systemic Therapy” in the full guidelines at NCCN.org). However, the NCCN Neuroblastoma Panel acknowledges the lack of comparative data, and notes that other published chemotherapy regimens that achieve a similar end-induction response rate could be considered as reasonable alternatives for individual patients.
Several strategies to improve induction are under investigation at this time, including early addition of ALK inhibitors for patients whose tumors harbor ALK aberrations.75 In addition, interventions such as the early administration of 131I-MIBG or anti-GD2 monoclonal antibody therapy are being evaluated.75 As robust safety and efficacy data are not yet available to support these approaches, the panel does not recommend adoption of these approaches outside the context of clinical trials at this time.
Surgical resection of the primary tumor and associated locoregional adenopathy is another important goal of induction therapy (see “Principles of Surgery” in the full guidelines at NCCN.org for additional information). Given the aggressive nature of these tumors, upfront resection is rarely feasible and the NCCN Neuroblastoma Panel recommends surgical resection after several cycles of initial cytoreductive chemotherapy. Even after initial chemotherapy, resection with negative margins is rarely feasible and is not the recommended surgical goal. Instead, 2 large analyses have demonstrated improved EFS and lower local relapse/progression rates in patients who had >90% resection (North American experience) or a complete macroscopic resection (European experience).76,77 The NCCN panel therefore recommends this degree of resection, broadly considered a gross total resection, as the goal of primary site surgery. When vital organs, major nerves, and/or major blood vessels would be threatened or would require resection to achieve this goal, the panel recommends subtotal resection.
The NCCN Neuroblastoma Panel recommends full disease reassessment at the end of induction. This end-induction evaluation is a critical decision point in the treatment of patients with high-risk neuroblastoma. Prior analyses have demonstrated that patients with poor end-induction response (less than partial response) have inferior outcomes compared with patients with more favorable end-induction response (partial response or better).71 However, analyses of randomized trials evaluating different consolidation strategies support a potential role for modern consolidation therapies even in patients with less than a partial response to induction. For example, the CCG-3891 trial reported higher EFS for patients with less favorable end-induction response who were randomized to transplant (vs continued chemotherapy).78 Likewise, the ANBL0532 trial (see subsequent section) reported a benefit of tandem transplant (vs single transplant) independent of end-induction response.73
The NCCN Neuroblastoma Panel recommends proceeding to consolidation therapy for patients with partial response or better to induction, though the panel acknowledges that bridging therapy to improve response may be appropriate in select patients depending upon the nature of the partial response (Figure 10).79 Patients with progressive disease during or at the end of induction have not typically been candidates to proceed with consolidation therapy, and the panel endorses this approach. Instead, the panel recommends nonmyeloablative therapies for these patients, including a chemoimmunotherapy regimen combining anti-GD2 monoclonal antibody with chemotherapy80 or participation in clinical trials for patients with first relapse.
Patients with end-induction minor response or stable disease require individualized decision-making. For patients with end-induction minor response or stable disease not proceeding to consolidation therapy, the panel recommends a chemoimmunotherapy regimen combining anti-GD2 monoclonal antibody with chemotherapy or participation in clinical trials for patients with refractory disease. Recent retrospective data suggest that proceeding to consolidation therapy may be appropriate for patients with an inadequate response to standard induction therapy whose disease responds to alternative “bridging” therapies.79 Specifically, patients with incomplete response to induction who received bridging therapy and then proceeded to consolidation therapy had superior outcomes compared with patients who received bridging therapy and did not move on to consolidation. Moreover, patients with a complete response to bridging therapy who proceeded to consolidation had favorable outcomes.
Consolidation Therapy
A standard consolidation phase includes both high-dose chemotherapy with autologous stem cell rescue and consolidative radiotherapy to the primary site (Figure 11). In North America, it is also considered standard to administer radiotherapy to sites of residual metastatic disease remaining at the end-induction disease evaluation.
High-dose chemotherapy with autologous stem cell rescue has been a hallmark of high-risk neuroblastoma therapy since a series of randomized trials demonstrated improved outcomes with this approach compared with continued conventional chemotherapy.81 The NCCN Neuroblastoma Panel acknowledges that these randomized trials were conducted in a treatment era that preceded routine use of anti-GD2–directed immunotherapy and that additional work is needed to understand if subgroups of patients might benefit from consolidative approaches that do not rely on high-dose chemotherapy with autologous stem cell rescue. For example, a single-institution retrospective experience suggests that similar OS rates may be achieved with or without high-dose chemotherapy among patients with greater than a partial response in the era of anti-GD2 immunotherapy.82
For patients who are candidates for consolidation therapy, the NCCN Neuroblastoma Panel recommends tandem transplantation with 2 consecutive rounds of high-dose chemotherapy with autologous stem cell rescue for most patients with high-risk disease (a category 1 recommendation). This recommendation is based on data from the COG ANBL0532 randomized phase 3 trial.73 Patients without progressive disease after a 6-cycle induction were eligible for randomization to a single transplant with full-dose carboplatin/etoposide/melphalan (CEM) or to tandem transplant with thiotepa/cyclophosphamide followed 6 to 10 weeks later with dose-reduced CEM. Patients randomized to the tandem transplant arm had significantly improved EFS (3-year EFS, 61.6% vs 48.4% for single transplant).
There are 2 less common subgroups of patients with high-risk disease for whom a single round of high-dose chemotherapy with autologous stem cell rescue may be appropriate: (1) patients with stage L2, ≥18 months at diagnosis, unfavorable histology, AND MYCN nonamplified disease; and (2) patients with stage M, 12 to <18 months at diagnosis, MYCN nonamplified, with any of the following other unfavorable features: unfavorable histology; diploid DNA content; and/or presence of SCAs. Patients in these 2 groups have historically had more favorable outcomes compared with patients with high-risk disease due to MYCN amplification or patients with high-risk disease due to age ≥18 months at time of diagnosis of stage M disease. For example, in a large series from the COG, patients in these 2 groups had 5-year EFS rates of approximately 75% to 80%.32 Patients in these 2 more favorable subgroups were nonrandomly assigned to single transplant with full-dose CEM in ANBL0532, and the panel endorses this approach.
The combination of busulfan and melphalan (BuMel) is a preferred conditioning regimen in Europe based on results of a randomized phase 3 trial that showed superior EFS with BuMel compared with CEM after the European rapid COJEC induction regimen.83 In addition, the BuMel regimen was associated with lower rates of most adverse events, though the risk of sinusoidal obstruction syndrome was higher. The COG conducted a pilot trial, ANBL12P1, that demonstrated the feasibility of this approach,74 but the role of BuMel in the context of North American therapy is not currently defined. Single transplant with BuMel may be an appropriate regimen for patients with a contraindication to tandem transplant or for patients in subgroups for which single transplant is recommended.
Radiation therapy to the primary tumor is typically administered on recovery from high-dose chemotherapy with stem cell rescue. Neuroblastoma is a radiosensitive tumor, and a commonly used dose of 21.6 Gy is recommended. Recent national trials have attempted to improve local control by augmenting radiotherapy.84,85 In COG trial A3973, a subset of patients had primary site radiotherapy fields extended to include uninvolved draining nodal stations. As these patients had similar local relapse/progression rates compared with patients treated without extending the radiotherapy field, this approach is not recommended by the panel.85 In COG trial ANBL0532, patients with gross residual tumor after primary site resection received a boost of 14.4 Gy to gross residual tumor.84 This augmented dose did not improve local relapse/progression or EFS rates compared with the historic controls. Based on these data, the panel does not recommend either strategy.
The NCCN Neuroblastoma Panel recommends radiation to sites of residual metastatic disease remaining by 123I-MIBG or FDG-PET (if MIBG nonavid) at the end-induction disease evaluation, recognizing that not all sites may be feasibly targeted by external beam radiation therapy. This recommendation is based on single-institution data supporting a benefit from this approach,86,87 though this approach has not been adopted internationally. See “Principles of Radiation Therapy” in the full guidelines at NCCN.org for additional information.
Postconsolidation Therapy
The NCCN Neuroblastoma Panel recommends postconsolidation therapy containing an anti-GD2 antibody for those who do not experience disease progression after consolidation therapy, while chemoimmunotherapy or participation in a clinical trial is recommended for those with progressive disease (Figure 12).
Historically, postconsolidation therapy consisted of 6 cycles of isotretinoin administered as a differentiating agent. This approach was adopted based on the landmark CCG-3891 trial that demonstrated improved outcomes in patients randomized to isotretinoin compared with no further therapy.78 Subsequently, the ANBL0032 trial demonstrated a significant improvement in EFS for patients randomized to receive the anti-GD2 monoclonal antibody dinutuximab + cytokines (sargramostim in cycles 1, 3, and 5; interleukin-2 in cycles 2 and 4) + isotretinoin (2-year EFS from randomization at start of postconsolidation therapy of 66%) compared with patients randomized to isotretinoin alone (2-year EFS of 46%).88 Based on these findings, the ANBL0032 immunotherapy regimen became a standard postconsolidation regimen (category 1 recommendation for use of postconsolidation therapy with anti-GD2 antibody) (see “Principles of Systemic Therapy” in the full guidelines at NCCN.org).89
Data from the SIOPEN HR-NBL1 trial called into question the role of interleukin-2 together with anti-GD2 immunotherapy. In this trial, patients were randomized to receive anti-GD2 immunotherapy (dinutuximab beta) with or without subcutaneous interleukin-2.90 Interleukin-2 did not improve outcomes and was associated with increased toxicity. Based on these findings, COG high-risk protocols no longer include interleukin-2, and the panel endorses this approach.
Other anti-GD2 antibodies may be appropriate as postconsolidation therapy. For example, dinutuximab beta given with isotretinoin but without sargramostim is a commonly used postconsolidation regimen in Europe. A nonrandomized comparison showed higher EFS among patients treated with this approach compared with the historic experience with isotretinoin alone.91
Continuation Therapy
Eflornithine [2,5-diamino-2-(difluoromethyl) pentanoic acid hydrochloride hydrate] is an inhibitor of ornithine decarboxylase, a key enzyme required for the synthesis of polyamines that regulate homeostasis and promote survival in cancer cells. This agent was studied as continuation therapy in a multicenter, single-arm, phase II trial (Study 3b; ClinicalTrials.gov identifier: NCT02395666) in children with high-risk neuroblastoma that had responded to frontline therapy that included induction, consolidation, and anti-GD2 directed immunotherapy. Patients who had a partial response or better following standard frontline therapy were eligible to enroll in Study 3b after completion of immunotherapy and received eflornithine 750 mg/m2 ± 250 mg/m2 twice daily for up to 2 years. Reported adverse events included transaminitis and hearing loss.92
Data from 92 patients on Study 3b were compared with an external control arm consisting of 852 patients treated with anti-GD2 immunotherapy, cytokines, and isotretinoin on COG ANBL0032 who did not go on to receive eflornithine continuation therapy.93 Patients on Study 3b had superior outcomes compared with the external control group (EFS hazard ratio [HR], 0.48 [95% CI, 0.27–0.85]; OS HR, 0.32 [95% CI, 0.15–0.70]). Further analyses using propensity score matching and sensitivity analyses also demonstrated higher EFS and OS for patients on Study 3b, though the potential for residual confounding remains in the context of a nonrandomized comparison.
In December 2023, the FDA approved eflornithine for use in the continuation setting for patients with high-risk neuroblastoma who have achieved a partial response or better following completion of anti-GD2 immunotherapy.94 The NCCN Neuroblastoma Panel suggests that clinicians discuss eflornithine as a continuation therapy option with patients and families; this is a category 2B recommendation (Figure 12). Serial monitoring of hearing with audiograms or brainstem auditory evoked response is essential, as most patients with high-risk neuroblastoma are at a critical age for language development.
Disease Evaluations During Frontline Therapy for High-Risk Disease
Following initial staging evaluations before the start of therapy (see the earlier section on “Staging”), patients with high-risk disease undergo anatomic imaging (CT or MRI) of the primary site prior to planned surgical resection. Full disease evaluation (anatomic imaging of the primary site, 123I-MIBG scan [or FDG-PET, if MIBG nonavid disease], and bilateral bone marrow aspirates and biopsies) is recommended at the end of induction, start of postconsolidation, and end of therapy. Patients with more than 5 residual MIBG-avid sites of disease at the end of induction are encouraged to have a repeat 123I-MIBG scan after recovery from high-dose chemotherapy with stem cell rescue to prioritize metastatic sites that might be treated during consolidative radiotherapy. An 123I-MIBG scan (or FDG-PET, if MIBG nonavid disease) is recommended halfway through postconsolidation therapy, with anatomic imaging and bone marrow evaluations reserved for patients with residual disease identified on the disease evaluation at the start of postconsolidation therapy.
Organ Function Evaluations During Frontline Therapy for High-Risk Disease
Therapy for high-risk neuroblastoma is intensive and associated with both acute and long-term toxicities (see the later section on “Monitoring for Late Effects Related to Neuroblastoma Treatment”). During treatment, these patients require frequent laboratory monitoring, including blood counts, chemistry panels, and urinalyses. Detailed evaluation of renal function (often with nuclear medicine measurements of glomerular filtration rate) is essential before consolidation high-dose therapy. Serial monitoring of cardiac function with electrocardiograms and echocardiograms is routine. Serial monitoring of hearing with audiograms or brainstem auditory evoked response is essential, as most patients with high-risk neuroblastoma are at a critical age for language development.
Therapy for Adolescents and Adults With High-Risk Neuroblastoma
Neuroblastoma is largely a disease of young children, though adolescents and adults may occasionally present with high-risk disease. The clinical studies that inform these guidelines, including toxicity data, therefore predominantly included patients <5 years of age at initial diagnosis. The general principles of high-risk therapy should be applied to older patients with high-risk disease, though it is acknowledged that these patients may require a more individualized approach to treatment based upon comorbid conditions and tolerance of planned therapy.
Response Assessment
The disease response criteria recommended by the NCCN Neuroblastoma Panel are based on the INRC, which were revised in 2017 based on the availability of modern imaging modalities and new methods for bone marrow disease assessment.53 Changes in urinary catecholamine levels (HVA and VMA) are no longer considered for response assessment due to the lack of standardization and the influence of diet. See the treatment algorithm for the specific requirements regarding timing of response, as these differ across risk groups.
Response assessment in the primary tumor site or metastatic bone or soft tissue should be based on RECIST criteria and functional imaging (anatomic and MIBG/FDG-PET).53,54 If either primary neuroblastoma tumors or metastatic bone or soft tissue lesions are not MIBG avid, or when MIBG imaging and anatomic imaging do not correlate, FDG-PET imaging is recommended.
Interpretation of MIBG tumor uptake in metastatic bone or soft tissue is performed by means of semiquantitative scoring of body segments. The modified Curie score95 and the SIOPEN score57 are the 2 most commonly used systems. In North America, the modified Curie score is used.
MIBG is considered more sensitive and specific than technetium-99m (99mTc)-based bone scintigraphy, which is no longer recommended for use in response assessment in bone. Novel radiotracers for assessing response are in development. However, the panel notes that at this time there are insufficient data available to incorporate these tracers for routine response assessment.
For bone marrow response assessment, the panel recommends using the approach described by Burchill et al35 and included in the INRC (based on immunocytology and/or immunohistochemistry).
The definition of overall response is based on the combination of primary tumor, metastatic bone or soft tissue, and bone marrow responses.
For the complete neuroblastoma response assessment criteria recommended by the NCCN Neuroblastoma Panel, see “Response Assessment” in the full guidelines at NCCN.org.
Disease Surveillance
Although outcomes have improved for patients with neuroblastoma, approximately half of patients with high-risk disease will still develop relapsed or refractory disease.66 Treatment options for those with relapsed or refractory disease remain limited; recommendations for the treatment of relapsed or refractory neuroblastoma will be addressed by the NCCN Neuroblastoma Panel in a future iteration of the guidelines.
Close surveillance of patients treated for neuroblastoma is essential to detect disease progression and other side effects related to prior treatment. Surveillance recommendations stratified by risk group are detailed subsequently; see “Disease Surveillance/Follow-up After Completion of Treatment” section in the full guidelines at NCCN.org for complete surveillance recommendations.
Low-Risk Disease
For patients with low-risk neuroblastoma who did not receive any treatment (observation only), the use of ultrasound for surveillance is recommended when clinically indicated and appropriate (Figure 4).
For those with low-risk disease whose tumors were surgically resected, the NCCN Neuroblastoma Panel recommends cross-sectional imaging to delineate new baseline disease status at least 1 month postoperatively (Figure 4). This is followed by a transition to ultrasound for surveillance if possible (∼ every 3 months for year 1, every 6 to 12 months for years 2–3, and then as clinically indicated). Cross-sectional imaging for surveillance may be required depending on the location of the primary tumor. Additionally, an interim H&P is recommended every 3 months in year 1, then every 6 months in year 2, followed by every 6 to 12 months in year 3, and then as clinically indicated. In terms of laboratory studies, the panel notes that urine catecholamine levels are no longer included in the revised INRC.53 However, obtaining spot catecholamine testing can be considered during surveillance, if levels were elevated at diagnosis.
Intermediate-Risk Disease
Surveillance recommendations for patients with intermediate-risk disease were adapted from the ANBL0531 and ANBL1232 studies.28,75 For patients who were treated for intermediate-risk disease, the NCCN panel recommends an interim H&P approximately every 3 months for year 1, every 6 months for year 2, and then annually for years 3 through 5. Audiologic assessment should be considered depending on the degree of exposure to ototoxic agents. CBC with differential is recommended at the same frequency as imaging if bone marrow was involved at diagnosis. Creatinine should be assessed every 6 months for year 1, then annually for years 2 and 3, and then as clinically indicated. Thyroid function can also be impacted by neuroblastoma treatment. Thyroid studies including thyroid-stimulating hormone (TSH) are recommended annually through year 3, and then as clinically indicated. The panel recommends including free T4 analysis if TSH is abnormal. Like surveillance in patients with low-risk disease, urine catecholamine levels are no longer recommended as part of INRC.53 However, obtaining spot catecholamine levels can be considered during surveillance if elevated at diagnosis.
If the treatment endpoint has been achieved in patients with intermediate-risk disease, the NCCN Neuroblastoma Panel recommends an MIBG scan as part of the end-of-therapy evaluation. For patients with MIBG-avid tumors and INRG stage M disease at diagnosis, a 123I-MIBG scan with SPECT is recommended, if available, while imaging by FDG-PET is recommended for patients with MIBG nonavid tumors. If either MIBG or FDG-PET scan was positive at diagnosis and at completion of therapy, these studies should be obtained until a negative scan is achieved or the patient is 36 months from completion of therapy. This should be done every 3 to 6 months in year 1, annually in years 2 and 3, and then as clinically indicated.
The panel also recommends CT or MRI cross-sectional imaging of the primary site approximately every 3 months for year 1, then every 6 months for year 2, followed by annually for year 3, and then as clinically indicated.
High-Risk Disease
Surveillance recommendations for high-risk disease were adapted from the ANBL0532 and ANBL1531 studies.73,96 For patients who were treated for high-risk disease, the NCCN Neuroblastoma Panel recommends that H&P be performed approximately every 3 months for year 1, then every 6 months for years 2 through 5. The NCCN panel strongly recommends audiologic assessment annually for 5 years, and then as clinically indicated, as studies have suggested that high rates of severe ototoxicity (requiring hearing aids) are seen in survivors of high-risk neuroblastoma.97 CBC with differential is recommended at the same frequency as imaging. Assessment of electrolytes (including Ca+ +, PO4, and Mg+ +), as well as creatinine, alanine aminotransferase, and bilirubin, are recommended every 3 months for year 1, followed by every 6 months for years 2 and 3, and then annually for years 4 and 5. Thyroid studies including TSH should be done every 6 months for years 1 and 2, and then annually for years 3 through 5. The panel recommends including free T4 analysis if TSH is abnormal.
Depending on total anthracycline dose and radiation dose administered with potential impact to the heart (and if normal at the end of therapy), an echocardiogram should be obtained every 2 to 5 years if normal at the end of therapy, as cardiotoxicity is a known late effect in patients with high-risk neuroblastoma.66,98 See the following section on “Monitoring for Late Effects Related to Neuroblastoma Treatment.” Hemoglobin A1c, ferritin, reproductive health laboratory tests (follicle-stimulating hormone, luteinizing hormone, anti-Müllerian hormone), and pulmonary function tests should be evaluated if clinically indicated. Like surveillance in patients with low-risk and intermediate-risk disease, urine catecholamine levels are no longer recommended as part of INRC.53 However, spot catecholamine levels can be considered during surveillance if elevated at diagnosis.
For patients with MIBG-avid tumors, a 123I-MIBG scan with SPECT is recommended, if available, while imaging by FDG-PET is recommended for those with MIBG nonavid tumors. Imaging should be done every 3 to 6 months in year 1, every 6 months in year 2, followed by annually in year 3, and then as clinically indicated.
The panel also recommends CT or MRI cross-sectional imaging of the primary site approximately every 3 to 6 months for year 1, then every 6 months for year 2, followed by annually for year 3, and then as clinically indicated.
If the bone marrow is no longer involved at the end of therapy, bilaterial bone marrow aspirates and biopsies should be obtained only if clinically indicated.
Monitoring for Late Effects Related to Neuroblastoma Treatment
The therapies used to treat neuroblastoma may result in a wide range of late effects, which are treatment-related complications that can occur months or years after completion of treatment.99 The late effects that may develop in survivors of neuroblastoma are specific to each individual, the age at which neuroblastoma is diagnosed, and the wide range of therapies used to treat it. Monitoring for late effects is becoming increasingly important, especially as survival outcomes for patients with high-risk neuroblastoma who receive multimodality therapy continue to improve.6 Monitoring should be done at each follow-up visit. Typically, monitoring for late effects as a component of survivorship follow-up starts 2 or more years after completion of systemic therapy. The NCCN Neuroblastoma Panel strongly recommends that a personalized survivorship care plan be developed for each patient. Generalized recommendations for screening for late effects in those with neuroblastoma would not be appropriate for many patients.
Patients with high-risk neuroblastoma (especially those treated with myeloablative therapy) are at particularly high risk of hearing impairment, endocrine deficiencies, and growth retardation.66,98,100,101 Additional late effects common to those with high-risk disease include chronic kidney disease, impaired fertility, cardiotoxicity, neurocognitive impairment, and second malignant neoplasms.99,100
An analysis of the retrospective Childhood Cancer Survivor Study found that survivors of high-risk neuroblastoma were at higher risk of late morbidity and mortality compared with those treated for intermediate- or low-risk disease.102 All-cause mortality was higher across all risk groups, and the risk for second malignant neoplasms was higher among survivors of high-risk and intermediate-risk disease. Individuals treated for high-risk neuroblastoma were also at higher risk of grade 3 to 5 chronic health conditions compared with their siblings.
Patients who receive chemotherapy for non–high-risk disease typically receive lower cumulative doses of chemotherapeutic agents and limited or no EBRT; therefore, these patients are at lower risk of long-term toxicities compared with those with high-risk disease. However, patients with non–high-risk disease constitute a heterogeneous group, and there is a wide range of cumulative chemotherapeutic exposures. The NCCN Neuroblastoma Panel recommends consulting the COG Survivorship Guidelines for appropriate screening and counseling related to thyroid, cardiac, pulmonary, renal, bone, reproductive health, second malignant neoplasms (with special attention to thyroid and kidney), and other treatment-associated late effects for patients who received treatment of non–high-risk neuroblastoma.103
It has been reported that many patients with neuroblastoma who receive platinum-based chemotherapy experience ototoxicity.98 Hearing loss is also a reported side effect of eflornithine treatment, with 13% of patients experiencing new or worsening hearing loss after initiation of eflornithine.94 Screening for sensorineural hearing loss in patients who are treated with platinum chemotherapy and eflornithine is of particular importance to minimize delays in speech and language development, which in turn can impact academic performance and social development. Although the COG Survivorship Guidelines outline the minimum recommended frequency for audiologic assessment, the NCCN Neuroblastoma Panel recommends a referral to institutional audiology and/or otolaryngology teams for children with impaired hearing to determine the appropriate schedule for subsequent evaluations.103
Fertility preservation is an option for some patients with high-risk disease. When possible, referral to fertility specialists for further discussion is recommended before the start of chemotherapy.
See “Monitoring for Late Effects” in the full guidelines at NCCN.org for complete recommendations.
Summary
The NCCN Guidelines for Neuroblastoma were developed by a multidisciplinary panel and provide recommendations for the initial diagnosis, risk stratification, and treatment of neuroblastoma based on clinical evidence and consensus. The recommended strategies for treating newly diagnosed neuroblastoma will continue to evolve based on emerging data from clinical trials. The NCCN Guidelines for Neuroblastoma will be updated on an annual basis as relevant data become available. Treatment recommendations for relapsed/refractory neuroblastoma will be addressed in a future iteration.
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NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise indicated.
NCCN CATEGORIES OF PREFERENCE
Preferred intervention: Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.
Other recommended intervention: Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.
Useful in certain circumstances: Other interventions that may be used for selected patient populations (defined with recommendation).
All recommendations are considered appropriate.
Clinical trials: NCCN believes that the best management for any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PLEASE NOTE
The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their application or use in any way.
