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This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. Children and adolescents with cancer are usually referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will enable them to achieve optimal survival and quality of life:
(Refer to the PDQ summaries on Supportive and Palliative Care for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[1,3,4] For neuroblastoma, the 5-year survival rate increased over the same time, from 86% to 95% for children younger than 1 year and from 34% to 68% for children aged 1 to 14 years. Childhood and adolescent cancer survivors require close follow-up since cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Neuroblastoma is the most common extracranial solid tumor in childhood. More than 650 cases are diagnosed each year in North America.[5,6] The prevalence is about 1 case per 7,000 live births; the incidence is about 10.54 cases per 1 million per year in children younger than 15 years. About 37% are diagnosed as infants, and 90% are younger than 5 years at diagnosis, with a median age at diagnosis of 19 months.
While there is no racial variation in incidence, there are racial differences in tumor biology, with African Americans more likely to have high-risk disease and fatal outcome.[8,9]
Population-based studies of screening for infants with neuroblastoma have demonstrated that spontaneous regression of neuroblastoma without clinical detection in the first year of life is at least as prevalent as clinically detected neuroblastoma.[10,11,12]
Neuroblastoma originates in the adrenal medulla or the paraspinal sites where sympathetic nervous system tissue is present.
Figure 1. Neuroblastoma may be found in the adrenal glands and paraspinal nerve tissue from the neck to the pelvis.
Little is known about the events that predispose to the development of neuroblastoma. Parental exposures have not been definitively linked to neuroblastoma.
Germline deletion at the 1p36 or 11q14-23 locus is associated with neuroblastoma, and the same deletions are found somatically in sporadic neuroblastomas.[13,14]
About 1% to 2% of patients with neuroblastoma have a family history of neuroblastoma. These children are on average younger (9 months at diagnosis), and about 20% have multifocal primary neuroblastomas. The primary cause of familial neuroblastoma is a germline mutation in the ALK gene. Familial neuroblastoma is rarely associated with congenital central hypoventilation syndrome (Ondine's curse), which is caused by a germline mutation of the PHOX2B gene.
Biologic and Molecular Features
On the basis of biologic factors and an improved understanding of the molecular development of the neural crest cells that give rise to neuroblastoma, neuroblastic tumors have been categorized into the following three biological types:
These specific genetic changes may be combined with traditional clinical factors such as patient age and tumor stage to refine neuroblastoma risk classes.
Children whose tumors have lost a copy of 11q are older at diagnosis, and their tumors contain more segmental chromosome changes in gene copy number compared with children whose tumors show MYCN amplification.[19,20] Moreover, segmental chromosome changes not detected at diagnosis may be found in neuroblastomas at relapse. This suggests that clinically important tumor progression is associated with accumulation of segmental chromosomal alterations.
Approximately 6% to 10% of sporadic neuroblastomas carry somatic ALK-activating mutations, and an additional 3% to 4% have a high frequency of ALK gene amplification. The mutations result in constitutive phosphorylation of ALK, leading to dysregulation of cell signaling and uncontrolled proliferation of the ALK-mutant neuroblasts. Thus, inhibition of ALK kinase is a potential target for treatment of neuroblastoma, especially in children whose tumors harbor an ALK mutation or ALK gene amplification.
Genome-wide association studies in children with neuroblastoma have found common single-nucleotide polymorphisms (SNPs) associated with a modest susceptibility to develop high-risk neuroblastoma.[23,24] Other SNPs are associated with susceptibility to develop low-risk neuroblastoma. SNPs associated with race predict a higher incidence of neuroblastoma and worse outcome.
Large genomic studies have found few recurrent gene mutations in patients with neuroblastoma, including ALK (9.2%), PTPN11 (2.9%), ATRX (2.5%; 7.1% focal deletions), MYCN (1.7%), and NRAS (0.8%).[19,21,26,27]ATRX is involved in epigenetic gene silencing and telomere length. ATRX mutation without MYCN amplification is associated with older age at diagnosis in adolescents and young adults with metastatic neuroblastoma. It is unclear whether an ATRX mutation is an independent prognostic risk factor.
Although most neuroblastoma tumors are initially sensitive to chemotherapy, many relapse in local and/or metastatic sites. Modern genetic analysis, including deep whole-genome sequencing of primary and relapsed neuroblastomas from the same patients, revealed many new mutations and complex clonal evolution of pre-existing minor subclones. The most common new mutations found were in the RAS-MAPK pathway.[29,30]
Current data do not support neuroblastoma screening. Screening at the ages of 3 weeks, 6 months, or 1 year caused no reduction in the incidence of advanced-stage neuroblastoma with unfavorable biological characteristics in older children, nor did it reduce the number of deaths from neuroblastoma in infants screened at any age.[11,12] No public health benefits have been shown from screening infants for neuroblastoma at these ages. (Refer to the PDQ summary on Neuroblastoma Screening for more information.)
Evidence (against neuroblastoma screening):
The most common presentation of neuroblastoma is an abdominal mass. The most frequent signs and symptoms of neuroblastoma are due to tumor mass and metastases. They include the following:
The clinical characteristics of neuroblastoma in adolescents are similar to those observed in children. The only exception is that bone marrow involvement occurs less frequently in adolescents, and there is a greater frequency of metastases in unusual sites such as lung or brain.
Paraneoplastic neurologic findings, including cerebellar ataxia or opsoclonus/myoclonus, are rare in children with neuroblastoma. Opsoclonus/myoclonus syndrome is frequently associated with pervasive and permanent neurologic and cognitive deficits, including psychomotor retardation. Neurologic dysfunction is most often a presenting symptom but may arise long after removal of the tumor.[36,37,38]
Patients who present with opsoclonus/myoclonus syndrome often have neuroblastomas with favorable biological features and are likely to survive, though tumor-related deaths have been reported.
The opsoclonus/myoclonus syndrome appears to be caused by an immunologic mechanism that is not yet fully defined.[36,39] The primary tumor is typically diffusely infiltrated with lymphocytes.
Some patients may clinically respond to removal of the neuroblastoma, but improvement may be slow and partial; symptomatic treatment is often necessary. Adrenocorticotropic hormone or corticosteroid treatment is thought to be effective, but some patients do not respond to corticosteroids.[37,39] Various drugs, plasmapheresis, intravenous gamma globulin, and rituximab have been reported to be effective in selected cases.[37,41,42,43] The long-term neurologic outcome may be superior in patients treated with chemotherapy, possibly because of its immunosuppressive effects.[35,41]
Diagnostic evaluation of neuroblastoma includes the following:
Serum catecholamines are not routinely used in the diagnosis of neuroblastoma except in unusual circumstances.
In rare cases, neuroblastoma may be discovered prenatally by fetal ultrasonography. Management recommendations are evolving with regard to the need for immediate diagnostic biopsy in infants aged 6 months and younger with suspected neuroblastoma tumors that are likely to spontaneously regress. Biopsy was not required for infants entered into a COG study of expectant observation of small adrenal masses in neonates, and 81% avoided undergoing any surgery at all. In a German clinical trial, 25 infants aged 3 months and younger with presumed neuroblastoma were observed without biopsy for periods of 1 to 18 months before biopsy or resection. There were no apparent ill effects of the delay.
The diagnosis of neuroblastoma requires the involvement of pathologists who are familiar with childhood tumors. Some neuroblastomas cannot be differentiated morphologically, via conventional light microscopy with hematoxylin and eosin staining alone, from other small round blue cell tumors of childhood, such as lymphomas, primitive neuroectodermal tumors, and rhabdomyosarcomas. In such cases, immunohistochemical and cytogenetic analysis may be needed to diagnose a specific small round blue cell tumor.
The minimum criterion for a diagnosis of neuroblastoma, as established by international agreement, is that diagnosis must be based on one of the following:
Between 1975 and 2010, the 5-year survival rate for neuroblastoma in the United States increased from 86% to 95% for children younger than 1 year and increased from 34% to 68% for children aged 1 to 14 years. The 5-year overall survival (OS) for all infants and children with neuroblastoma has increased from 46% when diagnosed between 1974 and 1989, to 71% when diagnosed between 1999 and 2005; however, this single number can be misleading because of the extremely heterogeneous prognosis based on the neuroblastoma patient's age, stage, and biology. (Refer to Table 1 for more information.) Approximately 70% of patients with neuroblastoma have metastatic disease at diagnosis.
The prognosis for patients with neuroblastoma is related to the following:[51,52,53,54]
Some of these prognostic factors have been combined to create risk groups to help define treatment. (Refer to the International Neuroblastoma Risk Group Staging System section and the Children's Oncology Group Neuroblastoma Risk Grouping section of this summary for more information.)
Age at diagnosis
The effect of age at diagnosis on 5-year survival is profound. According to the 1975 to 2006 U.S. Surveillance, Epidemiology, and End Results (SEER) statistics, the 5-year survival stratified by age is as follows:
Children of any age with localized neuroblastoma and infants aged 18 months and younger with advanced disease and favorable disease characteristics have a high likelihood of long-term, disease-free survival (DFS). The prognosis of fetal and neonatal neuroblastoma are similar to that of older infants with neuroblastoma and similar biological features. Older children with advanced-stage disease, however, have a significantly decreased chance for cure, despite intensive therapy.
In North American clinical trials reported in the 1990s, infants aged 1 year and younger had a cure rate higher than 80%, while older children had a cure rate of 50% to 70% with then-current, relatively intensive therapy.[57,58,59,60]
Survival of patients with International Neuroblastoma Staging System (INSS) stage 4 disease is strongly dependent on age. Children younger than 18 months at diagnosis have a good chance of long-term survival (i.e., a 5-year DFS rate of 50%–80%),[61,62] with outcome particularly dependent on MYCN amplification and tumor cell ploidy. Hyperdiploidy confers a favorable prognosis while diploidy predicts early treatment failure.[58,63] Infants aged 18 months and younger at diagnosis with INSS stage 4 neuroblastoma who do not have MYCN gene amplification are categorized as intermediate risk and have a 3-year event-free survival (EFS) of 81% and OS of 93%.[7,64,65,66,67]
Adolescents and young adults
Neuroblastoma has a worse long-term prognosis in an adolescent older than 10 years or in an adult than in a child, regardless of stage or site; and, in many cases, it has a more prolonged course when treated with standard doses of chemotherapy.
Although these patients may have a more indolent course and infrequent MYCN amplification (9% in patients aged 10–21 years), older children with advanced disease have a poor rate of survival. In the adolescent and young adult population, it is common to find multiple segmental chromosome changes and the ALK mutation frequency is about 16%.[68,69]
The 5-year EFS and OS for patients between the ages of 10 and 21 years are 32% and 46%, respectively; for stage IV disease, the 10-year EFS and OS are 3% and 5%, respectively. Aggressive chemotherapy and surgery have been shown to achieve a minimal disease state in more than 50% of these patients.[34,71,72] Other modalities, such as local radiation therapy, autologous stem cell transplant, and the use of agents with confirmed activity, may improve the poor prognosis for adolescents and adults.[70,71,72]
Site of primary tumor
Site of primary tumor is not an independent prognostic factor. Multifocal (multiple primaries) neuroblastoma occurs rarely, usually in infants, and generally has a good prognosis. Familial neuroblastoma and germline ALK gene mutation should be considered in patients with multiple primary neuroblastomas.
Clinical and biological features differ by site. Adrenal primary tumors are more likely than nonadrenal primary tumors and nonthoracic primary tumors are more likely than thoracic tumors to be associated with unfavorable prognostic features, including MYCN amplification, even after controlling for age, stage, and histologic grade. Adrenal, nonthoracic primary-site neuroblastoma was also associated with a higher incidence of stage 4 tumors, segmental chromosome aberrations, and elevated levels of lactate dehydrogenase (LDH) and ferritin.
Neuroblastoma tumor histology has a significant impact on prognosis and risk group assignment (refer to the Cellular Classification of Neuroblastic Tumors section and Table 4 of this summary for more information).
Histologic characteristics considered prognostically favorable include the following:
Histologic characteristics considered prognostically unfavorable include the following:
A COG study of children with stage 1 and stage 2 neuroblastoma without MYCN amplification and with favorable histologic features reported a 5-year EFS of 90% to 94% and OS of 99% to 100%, while those with unfavorable histology had an EFS of 80% to 86% and an OS of 89% to 93%. Similar results were found in a European study.[78,79,80]
Regional lymph node involvement
According to the INSS, the presence of cancer in the regional lymph nodes on the same side of the body as the primary tumor has no effect on prognosis. However, when lymph nodes with metastatic neuroblastoma cross the midline and are on the opposite sides of the body from the primary tumor, the patient is upstaged (refer to the Stage Information for Neuroblastoma section of this summary for more information) and a poorer prognosis is conferred.
Response to treatment
Response to treatment has been associated with outcome. In patients with high-risk disease, the persistence of neuroblastoma cells in bone marrow after induction chemotherapy, for example, is associated with a poor prognosis, which may be assessed by sensitive minimal residual disease techniques.[81,82,83] The degree of tumor volume reduction predicts response in high-risk patients, as does a decrease in mitosis and an increase in histologic differentiation.[84,85] Similarly, the persistence of mIBG-avid tumor after completion of induction therapy predicts a poor prognosis.
A number of biologic variables have been studied in children with this tumor:
The degree of expression of the MYCN gene in the tumor does not predict prognosis. However, high overall MYCN-dependent gene expression and low expression of sympathetic neuron late differentiation genes both predict a poor outcome of neuroblastomas otherwise considered to be at low or intermediate risk of recurrence.
Other biological prognostic factors that have been extensively investigated include tumor cell telomere length, telomerase activity, and telomerase ribonucleic acid;[94,95] urinary VMA, HVA, and their ratio;MRP1; GABAergic receptor profile; dopamine; CD44 expression; TrkA gene expression; and serum neuron-specific enolase level, serum LDH level, and serum ferritin level. These factors are currently not in use for stratification on clinical trials.
Spontaneous Regression of Neuroblastoma
The phenomenon of spontaneous regression has been well described in infants with neuroblastoma, especially in infants with the 4S pattern of metastatic spread. (Refer to the Stage Information for Neuroblastoma section of this summary for more information.)
Spontaneous regression generally occurs only in tumors with the following features:
Additional features associated with spontaneous regression include the lack of telomerase expression,[101,102] the expression of Ha-ras, and the expression of the neurotrophin receptor TrkA, a nerve growth factor receptor.
Studies have suggested that selected infants who appear to have asymptomatic, small, low-stage adrenal neuroblastoma detected by screening or during prenatal or incidental ultrasound examination, often have tumors that spontaneously regress and may be observed safely without surgical intervention or tissue diagnosis.[105,106,107]
Neuroblastomas are classified as one of the small, round, blue cell tumors of childhood. They are a heterogenous group of tumors composed of cellular aggregates with different degrees of differentiation, from mature ganglioneuromas to less mature ganglioneuroblastomas to immature neuroblastomas, reflecting the varying malignant potential of these tumors.
There are two cellular classification systems for neuroblastoma.
Favorable and unfavorable prognoses are defined on the basis of these histologic parameters and patient age. The prognostic significance of this classification system, and of related systems using similar criteria, has been confirmed in several studies.[2,3,4,6]
In the future, the INPC system is likely to be replaced by a system that does not include patient age as a part of cellular classification.
Most neuroblastomas with MYCN amplification in the INPC system also have unfavorable histology, but about 7% have favorable histology. Of those with MYCN amplification and favorable histology, most do not express MYCN, despite the gene being amplified, and have a more favorable prognosis than those who do express MYCN.
Because patient age is used in all risk stratification systems, a cellular classification system that did not employ patient age was desirable, and underlying histologic criteria, rather than INPC or Shimada Classification, was used in the final decision tree. Histologic findings discriminated prognostic groups most clearly in two subsets of patients, as shown in Table 2.
A thorough evaluation for metastatic disease is performed before therapy initiation. The following studies are typically performed:
Metaiodobenzylguanidine (mIBG) scan
The extent of metastatic disease is assessed by mIBG scan, which is applicable to all sites of disease (including soft tissue, bone marrow, and cortical bone involvement). Cortical bone metastases are also evaluated by technetium-99 scan. If all sites of bone metastases are imaged by mIBG scan, then subsequent restaging for assessment of disease response may omit the technetium-99 bone scan.[2,3] Approximately 90% of neuroblastomas will be mIBG avid. It has a sensitivity and specificity of 90% to 99% and is equally distributed between primary and metastatic sites. Although iodine 123 (123 I) has a shorter half-life, it is preferred over131 I because of its lower radiation dose, better quality images, less thyroid toxicity, and lower cost.
Imaging with 123 I-mIBG is optimal for identifying soft tissue and bony metastases and was shown to be superior to 18F-fluorodeoxyglucose positron emission tomography–computerized tomography (PET-CT) in one prospective comparison. Baseline mIBG scans performed at diagnosis provide an excellent method for monitoring disease response and performing posttherapy surveillance.
A retrospective analysis of paired mIBG and PET scans in 60 newly diagnosed neuroblastoma patients demonstrated that for International Neuroblastoma Staging System (INSS) stages 1 and 2 patients, PET was superior at determining the extent of primary disease and more sensitive for detection of residual masses. In contrast, for stage 4 disease, 123 I-mIBG imaging was superior for the detection of bone marrow and bony metastases.
Curie score and SIOPEN score
Multiple groups have investigated a semi-quantitative scoring method to evaluate disease extent and prognostic value. The most common scoring methods in use for evaluation of disease extent and response are the Curie and the International Society of Paediatric Oncology European Neuroblastoma Group (SIOPEN) methods.
Other staging tests and procedures
Other tests and procedures used to stage neuroblastoma include the following:
International Neuroblastoma Staging Systems
International Neuroblastoma Staging System (INSS)
The INSS combines certain features from each of the previously used Evans and Pediatric Oncology Group (POG) staging systems [1,13] and is described in Table 3. This represented the first step in harmonizing disease staging and risk stratification worldwide. The INSS is a postoperative staging system that was developed in 1988 and used the extent of surgical resection to stage patients. This led to some variability in stage assignments in different countries because of regional differences in surgical strategy and, potentially, because of limitations in access to experienced pediatric surgeons. As a result of further advances in the understanding of neuroblastoma biology and genetics, a risk classification system was developed that incorporates clinical and biological factors in addition to INSS stage to facilitate risk group and treatment assignment for COG studies.[1,13,14,15]
Controversy exists regarding the INSS staging system and the treatment of certain small subsets of patients.[16,17,18] Risk group assignment and recommended treatment are expected to evolve as additional outcome data are analyzed. For example, the risk group assignment for INSS stage 4 neuroblastoma in patients aged 12 to 18 months changed in 2005 for those whose tumors had single copy MYCN and all favorable biological features; these patients had been previously classified as high risk, but data from both POG and Children's Cancer Group studies suggested that this subgroup of patients could be successfully treated as intermediate risk.[19,20,21]
A study from the International Neuroblastoma Risk Group database found 146 patients with distant metastases limited to lymph nodes, termed stage 4N, who tended to have favorable-biology disease and a good outcome (5-year OS, 85%), which suggests that less-intensive therapy might be considered.
International Neuroblastoma Risk Group Staging System (INRGSS)
The INRGSS is a preoperative staging system that was developed specifically for the INRG classification system. The extent of disease is determined by the presence or absence of image-defined risk factors (IDRFs) and/or metastatic tumor at the time of diagnosis, before any treatment or surgery. IDRFs are surgical risk factors, detected by imaging, which could potentially make total tumor excision risky or difficult at the time of diagnosis and increase the risk of surgical complications.
The INRGSS simplifies stages into L1, L2, M or MS (refer to Table 4 and the list of IDRFs for more information). Localized tumors are classified as stage L1 or L2 disease on the basis of whether one or more of the 20 IDRFs are present. For example, in the case of spinal cord compression, an IDRF is present when more than one-third of the spinal canal in the axial plane is invaded, when the leptomeningeal spaces are not visible, or when the spinal cord magnetic resonance signal intensity is abnormal. By combining the INRGSS, preoperative imaging and biological factors, each patient has a risk stage defined that predicts outcome and dictates the appropriate treatment approach to be followed. The INRGSS has predictive value for patients with lower-stage disease, with a 5-year EFS of 90% and OS of 98% for stage L1 patients, compared with an EFS of 79% and OS of 89% for stage L2 patients. Among INRG stage L2 children, INSS stage 2 patients do significantly better than do INSS stage 3 patients in 5-year OS.
Most international protocols have begun to incorporate collection and use of IDRF in risk stratification and assignment of therapy.[25,26] The COG has been collecting and evaluating INRGSS data since 2006. A COG trial that opened in 2014 uses the INRGSS to determine therapy for patients with certain localized disease and stage 4S patients. Note that the INSS allows patients up to age 12 months in stage 4S, while the INRGSS allows patients up to age 18 months in stage MS. It is anticipated that the use of standardized nomenclature will contribute substantially to more uniform staging and thereby facilitate comparisons of clinical trials conducted in different parts of the world.
IDRFs include the following:
Previously, most children with neuroblastoma in North America were treated according to the Children's Oncology Group (COG) risk-group assignment, even if they were not enrolled in a COG study. In the most recent COG study, the International Neuroblastoma Risk Group (INRG) system was used to assign treatment. Because the older system is still being used by some physicians to assign treatments, the treatments described in this summary are based on both the INRG system and the most recently published COG risk stratification system. In the INRG system, each child is assigned to a group on the basis of image-defined potential surgical risk, age, and the presence or absence of metastasis. (Refer to the list of image-defined risk factors [IDRFs] for more information.) In the previous COG risk system, each child was assigned to a low-risk, intermediate-risk, or high-risk group (refer to Tables 6, 8, and 10 for more information) based on the following:[1,2,3,4,5,6]
Other biological factors that influenced treatment selection in previous COG studies included unbalanced 11q loss of heterozygosity and loss of heterozygosity for chromosome 1p.[7,8] However, in 2012, the COG Neuroblastoma Committee defined favorable genomics, for purposes of risk assignment, as hyperdiploid neuroblastoma cells without segmental copy number aberrations, including no loss of copy number at 1p, 3p, 4p, or 11q and no gain of copy number at 1q, 2p, or 17q.
The treatment of neuroblastoma has evolved over the past 60 years. Generally, treatment is based on whether the tumor is low, intermediate, or high risk:
Children's Oncology Group (COG) Neuroblastoma Risk Grouping
The treatment section of this document is organized to correspond with the COG risk-based treatment plan that assigns all patients to a low-, intermediate-, or high-risk group. This risk-based schema is based on the following factors:
Table 6 (in the Treatment of Low-Risk Neuroblastoma section), Table 8 (in the Treatment of Intermediate-Risk Neuroblastoma section), and Table 10 (in the Treatment of High-Risk Neuroblastoma section) describe the risk group assignment criteria used to assign treatment in the COG-P9641, COG-A3961, and COG-A3973 studies, respectively.
Assessment of risk for low-stage MYCN-amplified neuroblastoma is controversial because it is so rare. A study of 87 INSS stage 1 and 2 patients pooled from several clinical trial groups demonstrated no effect of age, stage, or initial treatment on outcome. The event-free survival (EFS) rate was 53% and the OS rate was 72%. Survival was superior in patients whose tumors were hyperdiploid, rather than diploid (EFS, 82% ± 20% vs. 37% ± 21%; OS, 94% ± 11% vs. 54% ± 15%). The overall EFS and OS for infants with stage 4 and 4S disease and MYCN-amplification was only 30% at 2 to 5 years after treatment in a European study. The COG considers infants with stage 4 and stage 4S disease with MYCN amplification to be at high risk.
Description of International Neuroblastoma Response Criteria
Before therapy can be stopped after the initially planned number of cycles, certain response criteria, depending on risk group and treatment assignment, must be met. These criteria are defined as follows:[13,14]
In patients without metastatic disease, the standard of care is to perform an initial surgery to accomplish the following:
In patients with L1 tumors (defined as having no image-defined surgical risk factors), resection is less likely to result in surgical complications and, generally, the tumors have been resected. L2 tumors, which have at least one image-defined surgical risk factor, have been treated with chemotherapy when deemed too risky to attempt resection, followed by surgery when the tumors have responded. Recent German studies of selected groups of patients have biopsied tissue and observed infants with both L1 and L2 tumors without MYCN amplification, avoiding additional surgery and chemotherapy in most patients.
The COG reported that expectant observation in infants younger than 6 months with small adrenal masses resulted in an excellent EFS and OS while avoiding surgical intervention in a large majority of patients. According to the surgical guidelines described in the recent intermediate-risk neuroblastoma clinical trial (ANBL0531 [NCT00499616]), the primary tumor is not routinely resected in patients with 4S neuroblastoma.
Whether there is any advantage to gross-total resection of the primary tumor mass after chemotherapy in stage 4 patients older than 18 months remains controversial.[17,18,19,20] A meta-analysis of stage 3 versus stage 4 neuroblastoma patients, at all ages combined, found an advantage for gross-total resection over subtotal resection in stage 3 neuroblastoma only, not stage 4. Also, a small study suggested that after neoadjuvant chemotherapy, completeness of resection was affected by the number of IDRFs remaining.
In the completed COG treatment plan, radiation therapy for patients with low-risk or intermediate-risk neuroblastoma was reserved for symptomatic life-threatening or organ-threatening tumor bulk that did not respond rapidly enough to chemotherapy. Common situations in which radiation therapy is used in these patients include the following:
Treatment of Spinal Cord Compression
Spinal cord compression is considered a medical emergency. Immediate treatment is given because neurologic recovery is more likely when symptoms are present for a relatively short period of time before diagnosis and treatment. Recovery also depends on the severity of neurologic defects (weakness vs. paralysis). Neurologic outcome appears to be similar whether cord compression is treated with chemotherapy, radiation therapy, or surgery, although radiation therapy is used less frequently than in the past.
The completed COG low-risk and intermediate-risk neuroblastoma clinical trials recommended immediate chemotherapy for cord compression in patients grouped as low risk or intermediate risk.[23,24,25]
Children with severe spinal cord compression that does not promptly improve or those with worsening symptoms may benefit from neurosurgical intervention. Laminectomy may result in later kyphoscoliosis and may not eliminate the need for chemotherapy.[23,24,25] It was thought that osteoplastic laminotomy, a procedure that does not remove bone, would result in less spinal deformity. Osteoplastic laminotomy may be associated with a lower incidence of progressive spinal deformity requiring fusion but there is no evidence that functional deficit is improved with laminoplasty. In a series of 34 infants with symptomatic epidural spinal cord compression, both surgery and chemotherapy provided unsatisfactory results once paraplegia had been established. The frequency of grade 3 motor deficits and bowel dysfunction increased with a longer symptom duration interval. Most infants with symptomatic epidural spinal cord compression developed sequelae and it was severe in about one-half of them. This supports the need for greater awareness and timely intervention in these infants.
Surveillance During and After Treatment
Surveillance studies during and after treatment are able to detect asymptomatic and unsuspected relapse in a substantial portion of patients. In an overall surveillance plan, one of the most reliable tests to detect disease progression or recurrence is the 123 I-metaiodobenzylguanidine scan.[28,29]
Low-risk neuroblastoma represents nearly one-half of all newly diagnosed patients. The success of prior Children's Oncology Group (COG) clinical trials has contributed to the continued reduction in therapy for select patients with neuroblastoma.
The COG neuroblastoma low-risk group assignment criteria are described in Table 6.
(Refer to the Treatment of Stage 4S Neuroblastoma section of this summary for more information about the treatment of stage 4S neuroblastoma.)
Treatment Options for Low-Risk Neuroblastoma
For patients with localized disease that appears to be resectable (either based on the absence of image-defined risk factors [L1] or on the surgeon's expertise), the tumor should be resected by an experienced surgeon. If the biology is confirmed to be favorable, residual disease is not considered a risk factor for relapse. Several studies have shown that patients with favorable biology and residual disease have excellent outcomes with event-free survival (EFS) in excess of 90% and overall survival (OS) of 99% to 100%.[1,2]
Treatment options for low-risk neuroblastoma include the following:
Surgery followed by observation
Treatment for patients categorized as low risk (refer to Table 6) may be surgery alone, which is curative for most patients with low-risk neuroblastoma. Patients need not undergo complete resection of disease to be cured by surgery alone.
There is controversy about the need to attempt resection, whether at the time of diagnosis or later, in asymptomatic infants aged 12 months or younger with apparent stage 2B and 3 MYCN-nonamplified and favorable-biology disease. In a German clinical trial, some of these patients were observed after biopsy or partial resection without chemotherapy or radiation, and many did not progress locally and never received additional resection.
Chemotherapy with or without surgery (for symptomatic disease or unresectable progressive disease after surgery)
Results from the COG-P9641 study showed that surgery alone, even without complete resection, can cure nearly all patients with stage 1 neuroblastoma, and the vast majority of patients with asymptomatic, favorable biology, INSS stage 2A and 2B disease. Similar outcomes were seen in a nonrandomized clinical trial in Japan. The use of chemotherapy may be restricted to specific situations (e.g., children with MYCN-amplified stage 1 and 2 neuroblastoma and children with MYCN-nonamplified stage 2B neuroblastoma who are older than 18 months or who have unfavorable histology or diploid disease). These children have a less favorable outcome than other low-risk patients.[2,5]
Chemotherapy is also reserved for low-risk patients who are symptomatic, such as from spinal cord compression or, in stage 4S, respiratory compromise secondary to hepatic infiltration. The chemotherapy consists of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative chemotherapy dose of each agent is kept low to minimize permanent injury (COG-P9641).
Observation without biopsy (for perinatal neuroblastoma with small adrenal tumors)
Studies suggest that selected small adrenal masses, presumed to be neuroblastoma, detected in infants younger than 6 months by screening or incidental ultrasound may safely be observed without obtaining a definitive histologic diagnosis and without surgical intervention, thus avoiding potential complications of surgery in the newborn. Additional studies are necessary to confirm this finding before it can be considered standard treatment.
Evidence (observation without biopsy):
Treatment Options Under Clinical Evaluation
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI website.
Current Clinical Trials
Check the list of NCI-supported cancer clinical trials that are now accepting patients with neuroblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI website.
The Children's Oncology Group (COG) neuroblastoma intermediate-risk group assignment criteria are described in Table 8.
Treatment Options for Intermediate-Risk Neuroblastoma
Treatment options for intermediate-risk neuroblastoma include the following:
Chemotherapy with or without surgery
Patients categorized as intermediate risk have been successfully treated with surgery and four to eight cycles of chemotherapy (carboplatin, cyclophosphamide, doxorubicin, and etoposide; the cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen) (COG-A3961). As a rule, patients whose tumors had unfavorable biology received eight cycles of chemotherapy, compared with four cycles for patients whose tumors had favorable biology. The COG-A3961 phase III trial demonstrated that therapy could be significantly reduced for patients with intermediate-risk neuroblastoma while maintaining outstanding survival. A nonrandomized clinical trial in Japan also reported excellent outcomes for infants with stage 3 neuroblastoma without MYCN amplification.
Whether initial chemotherapy is indicated for all intermediate-risk infants with localized neuroblastoma requires further study.
Evidence (chemotherapy with or without surgery):
In cases of abdominal neuroblastoma thought to involve the kidney, nephrectomy is not undertaken before a trial of chemotherapy has been given.
Surgery and observation (in infants)
The need for chemotherapy in all asymptomatic infants with stage 3 or 4 disease is somewhat controversial, as some European studies have shown favorable outcomes with surgery and observation as described below.
Evidence (surgery and observation in infants):
Radiation therapy (only for emergent therapy)
Radiation therapy is reserved for patients with the following:
The Children's Oncology Group (COG) neuroblastoma high-risk group assignment criteria are described in Table 10.
Approximately 8% to 10% of infants with stage 4S disease will have MYCN-amplified tumors and are usually treated on high-risk protocols. The overall event-free survival (EFS) and overall survival (OS) for infants with stage 4 and 4S disease and MYCN-amplification were only 30% at 2 to 5 years posttreatment in a European study.
For children with high-risk neuroblastoma, long-term survival with current treatments is about 54%. Children with aggressively treated, high-risk neuroblastoma may develop late recurrences, some more than 5 years after completion of therapy.[3,4]
A study from the International Neuroblastoma Risk Group database found 146 patients with distant metastases limited to lymph nodes, termed stage 4N, who tended to have favorable-biology disease and a good outcome (5-year OS, 85%), which suggests that for this special subgroup of high-risk, stage 4 patients, less-intensive therapy might be considered.
Treatment Options for High-Risk Neuroblastoma
Outcomes for patients with high-risk neuroblastoma remain poor despite recent improvements in survival in randomized trials.
A treatment option for high-risk neuroblastoma is the following:
Chemotherapy, surgery, SCT, radiation therapy, and anti-GD2 antibody ch14.18, with IL-2/GM-CSF and isotretinoin
Treatment for patients with high-risk disease is generally divided into the following three phases:
The backbone of the most commonly used induction therapy includes dose-intensive cycles of cisplatin and etoposide alternating with vincristine, cyclophosphamide, and doxorubicin. Topotecan was added to this regimen based on the anti-neuroblastoma activity seen in relapsed patients. Response to therapy at the end of induction chemotherapy correlates with EFS at the completion of high-risk therapy. After a response to chemotherapy, resection of the primary tumor is usually attempted.
The consolidation phase of high-risk regimens involves myeloablative chemotherapy and HSCT, which attempts to eradicate minimal residual disease using lethal doses of chemotherapy and autologous stem cells collected during induction chemotherapy to repopulate the bone marrow. Several large randomized controlled studies have shown an improvement in 3-year EFS for HSCT (31% to 47%) versus conventional chemotherapy (22% to 31%).[9,10,11] Previously, total-body irradiation had been used in HSCT conditioning regimens. Most current protocols use either carboplatin/etoposide/melphalan or busulfan/melphalan as conditioning for HSCT. Two or more sequential cycles of myeloablative chemotherapy and stem cell rescue given in a tandem fashion has been shown to be feasible for patients with high-risk neuroblastoma.[12,13]
A randomized clinical study (COG-ANBL0532) testing the efficacy of two cycles versus one cycle of myeloablative chemotherapy with stem cell rescue has been completed. (Refer to the Autologous Hematopoietic Cell Transplantation section in the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation.)
Tandem consolidation using iodine-131 metaiodobenzylguanidine (131 I-mIBG), vincristine, and irinotecan with autologous SCT followed by busulfan/melphalan with autologous SCT has been studied in refractory patients.
Radiation to the primary tumor site (whether or not a complete excision was obtained) and persistently mIBG-positive bony metastatic sites is often performed before, during, or after myeloablative therapy. The optimal dose of radiation therapy has not been determined. Radiation of metastatic disease sites is determined on an individual-case basis or according to protocol guidelines for patients enrolled in studies.
Metastatic bone relapse in neuroblastoma usually occurs at anatomic sites of previous disease. Metastatic sites identified at diagnosis that did not receive radiation during frontline therapy appeared to have a higher risk of involvement at first relapse relative to previously irradiated metastatic sites. These observations support the current paradigm of irradiating metastases that persist after induction chemotherapy in high-risk patients.
Preliminary outcomes for proton radiation therapy of high-risk neuroblastoma primary tumors have been published.
Differentiation therapy is used to treat potential minimal residual disease following HSCT. After recovery from myeloablative chemotherapy and stem cell rescue, patients are treated with the differentiating agent oral isotretinoin for 6 months. Immunotherapy is given along with differentiated therapy in the post-HSCT differentiation therapy regimen. Antibodies developed to target GD2, present on the surface of neuroblastoma cells, are used. For high risk-patients in remission following HSCT, chimeric anti-GD2 antibody ch14.18 combined with GM-CSF and IL-2 are given in concert with isotretinoin and have been shown to improve EFS.[18,19]
Evidence (all treatments):
Local control (surgery and radiation therapy)
The potential benefit of aggressive surgical approaches in high-risk patients with metastatic disease to achieve complete tumor resection, either at the time of diagnosis or following chemotherapy, has not been unequivocally demonstrated.
Many patients with stage 4S neuroblastoma do not require therapy. However, tumors with unfavorable biology or patients who are symptomatic due to evolving hepatomegaly and organ compromise are at increased risk of death and are treated with low-dose to moderate-dose chemotherapy. Eight percent to 10% of these patients will have MYCN amplification and are treated with high-risk protocols. (Refer to the Treatment of High-Risk Neuroblastoma section of this summary for more information about the treatment of stage 4S high-risk neuroblastoma.)
Treatment Options for Stage 4S Neuroblastoma
There is no standard approach to the treatment of stage 4S neuroblastoma.
Treatment options for stage 4S neuroblastoma include the following:
Resection of primary tumor is not associated with improved outcome.[2,3,4] Rarely, infants with massive hepatic 4S neuroblastoma develop cirrhosis from the chemotherapy and/or radiation therapy that is used to control the disease and may benefit from orthotopic liver transplantation.
Observation with supportive care (asymptomatic patients with favorable tumor biology)
The treatment of children with stage 4S disease is dependent on clinical presentation.[2,3] Most patients do not require therapy unless bulk disease is causing organ compromise and risk of death.
Chemotherapy (symptomatic patients, very young infants, or those with unfavorable biology)
Infants diagnosed with International Neuroblastoma Staging System (INSS) stage 4S neuroblastoma, particularly those with hepatomegaly or those younger than 2 months, have the potential for rapid clinical deterioration and may benefit from early initiation of therapy. It has been difficult to identify infants with stage 4S disease who will benefit from chemotherapy. Several clinical trials have evaluated the presence of symptoms in patients with 4S disease, including the following:
Various chemotherapy regimens (cyclophosphamide alone, carboplatin/etoposide, cyclophosphamide/doxorubicin/vincristine) have been used to treat symptomatic patients. The approach is to administer the chemotherapy only as long as symptoms persist in order to avoid toxicity, which contributes to lower survival. Additionally, lower doses of chemotherapy are often recommended for very young or low-weight infants along with granulocyte colony-stimulating factors after each cycle of chemotherapy.
Evidence (chemotherapy for symptomatic patients, very young infants, or those with unfavorable biology):
Patients with INRG MS tumors that have unfavorable histology or unfavorable genomic features with or without symptoms are treated according to a response-based algorithm to determine length of treatment. For INRG MS patients under observation without chemotherapy, an objective scoring system is used to monitor them for clinical changes and initiate therapy. For patients with complete resolution of symptoms and at least a 50% reduction in primary tumor volume (partial response), chemotherapy is discontinued, and observation continues for 3 years after completion of therapy. If the disease progresses, the patient leaves this study.
Tumor growth due to maturation should be differentiated from tumor progression by performing a biopsy and reviewing histology. Patients may have persistent maturing disease with metaiodobenzylguanidine (mIBG) uptake that does not affect outcome, particularly in patients with low-risk and intermediate-risk disease. In neuroblastoma, subclonal ALK mutations may be present at diagnosis, with subsequent clonal expansion at relapse. Consequently, serial sampling of progressive tumors may lead to the identification of potential actionable mutations. Modern comprehensive molecular analysis comparing primary and relapsed neuroblastoma from the same patients revealed extensive clonal enrichment and several new mutations, with many tumors showing new or clonal-enriched mutations in the RAS-MAPK pathway. This was true for patients with both high-risk and low-risk tumors at diagnosis.[3,4]
If neuroblastoma recurs in a child originally diagnosed with high-risk disease, the prognosis is usually poor despite additional intensive therapy.[5,6,7,8] However, it is often possible to gain many additional months of life for these patients with alternative chemotherapy regimens.[9,10] Clinical trials are appropriate for these patients and may be offered. Information about ongoing clinical trials is available from the NCI website.
Prognostic Factors for Recurrent Neuroblastoma
The International Neuroblastoma Risk Group Project performed a decision-tree analysis of clinical and biological characteristics (defined at diagnosis) associated with survival after relapse in 2,266 patients with neuroblastoma entered on large clinical trials in well-established clinical trials groups around the world.
Significant prognostic factors determined at diagnosis for postrelapse survival include the following:
The Children's Oncology Group (COG) experience with recurrence in low-risk and intermediate-risk neuroblastoma is that the majority of recurrences can be salvaged. The COG reported a 3-year event free survival (EFS) of 88% and an OS of 96% in intermediate-risk patients and a 5-year EFS of 89% and OS of 97% in low-risk patients.[11,12] Moreover, in most patients originally diagnosed with low-risk or intermediate-risk disease, local recurrence or recurrence in the 4S pattern may be treated successfully with surgery and/or with moderate dose chemotherapy, without hematopoietic stem cell transplantation.
Recurrent Neuroblastoma in Patients Initially Classified as Low Risk
Treatment options for locoregional recurrent neuroblastoma initially classified as low risk include the following:
Local or regional recurrent cancer is resected if possible.
Those with favorable biology and regional recurrence more than 3 months after completion of planned treatment are observed if resection of the recurrence is total or near total (≥90% resection). Those with favorable biology and a less than near-total resection are treated with chemotherapy.
Infants younger than 1 year at the time of locoregional recurrence whose tumors have any unfavorable biologic properties are observed if resection is total or near total. If the resection is less than near total, these same infants are treated with chemotherapy. Chemotherapy may consist of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide, or cyclophosphamide and topotecan. The cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen as used in prior COG trials (COG-P9641 and COG-A3961).
Older children with local recurrence with either unfavorable International Neuroblastoma Pathology Classification at diagnosis or MYCN gene amplification have a poor prognosis and may be treated with surgery, aggressive combination chemotherapy, or offered entry into a clinical trial.
Evidence (surgery and chemotherapy):
Treatment options for metastatic recurrent neuroblastoma initially classified as low risk include the following:
Metastatic recurrent or progressive neuroblastoma in an infant initially categorized as low risk and younger than 1 year at recurrence may be treated according to tumor biology as defined in the prior COG trials (COG-P9641 and COG-A3961):
Chemotherapy may consist of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen, as used in prior COG trials (COG-P9641 and COG-A3961).
Any child initially categorized as low risk who is older than 1 year at the time of metastatic recurrent or progressive disease and whose recurrence is not in the stage 4S pattern usually has a poor prognosis and should be considered for high-risk therapy.
Recurrent Neuroblastoma in Patients Initially Classified as Intermediate Risk
The treatment options for locoregional and metastatic recurrence in patients with intermediate-risk neuroblastoma are derived from the results of the COG-A3961 trial. Among 479 patients with intermediate-risk neuroblastoma treated on the COG-A3961 clinical trial, 42 patients developed disease progression. The rate was 10% of those with favorable biology and 17% of those with unfavorable biology. Thirty patients had locoregional recurrence, 11 had metastatic recurrence, and one had both types of recurrent disease. Six of the 42 patients died of disease, while 36 patients were salvaged. Thus, most patients with intermediate-risk neuroblastoma and disease progression may be salvaged.
Treatment options for locoregional recurrent neuroblastoma initially classified as intermediate risk include the following:
The current standard of care is based on the experience from the COG Intermediate-Risk treatment plan (COG-A3961). Locoregional recurrence of neuroblastoma with favorable biology that occurs more than 3 months after completion of chemotherapy may be treated surgically. If resection is less than near total, then additional chemotherapy may be given. Chemotherapy may consist of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen, as used in a prior COG trial (COG-A3961).
Treatment options for metastatic recurrent neuroblastoma initially classified as intermediate risk include the following:
Patients with metastatic recurrent neuroblastoma are treated like patients with newly diagnosed high-risk neuroblastoma. (Refer to the Treatment Options for High-Risk Neuroblastoma section of this summary for more information.)
Recurrent Neuroblastoma in Patients Initially Classified as High Risk
Any recurrence in patients initially classified as high risk signifies a very poor prognosis. Clinical trials may be considered. Palliative care should be considered as part of the patient's treatment plan.
Treatment options for recurrent or refractory neuroblastoma in patients initially classified as high risk include the following:
It is not known whether one therapeutic approach is superior to another.
Evidence (131 I-mIBG):
Evidence (second autologous SCT following retrieval chemotherapy):
Allogeneic transplantation has a historically low success rate in recurrent or progressive neuroblastoma. In a retrospective registry study, allogeneic SCT after a previous autologous SCT appeared to offer minimal benefit. Disease recurrence remains the most common cause of treatment failure.
Recurrent Neuroblastoma in the Central Nervous System
Central nervous system (CNS) involvement, although rare at initial presentation, may occur in 5% to 10% of patients with recurrent neuroblastoma. Because upfront treatment for newly diagnosed patients does not adequately treat the CNS, the CNS has emerged as a sanctuary site leading to relapse.[27,28] CNS relapses are almost always fatal, with a median time to death of 6 months.
Treatment options for recurrent neuroblastoma in the CNS include the following:
Current treatment approaches generally include eradicating bulky and microscopic residual disease in the CNS and minimal residual systemic disease that may herald further relapses. Neurosurgical interventions serve to decrease edema, control hemorrhage, and remove bulky tumor before starting therapy. Compartmental radioimmunotherapy using intrathecal radioiodinated monoclonal antibodies has been tested in patients with recurrent metastatic CNS neuroblastoma after surgery, craniospinal radiation therapy, and chemotherapy.
Treatment Options Under Clinical Evaluation for Recurrent or Refractory Neuroblastoma
The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI website.
Check the list of NCI-supported cancer clinical trials that are now accepting patients with recurrent neuroblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Editorial changes were made to this summary.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of neuroblastoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Neuroblastoma Treatment are:
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Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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The preferred citation for this PDQ summary is:
National Cancer Institute: PDQ® Neuroblastoma Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq. Accessed <MM/DD/YYYY>.
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Last Revised: 2016-01-14
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