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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%.[1,2,3] 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 monitoring because 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.)
Incidence and Epidemiology
Neuroblastoma is the most common extracranial solid tumor in childhood. More than 650 cases are diagnosed each year in North America.[4,5] 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. The data on age at diagnosis show that this is a disease of infancy, with the highest rate of diagnosis in the first month of life.[4,5,6]
The incidence of neuroblastoma in black children is slightly lower than that in white children. However, there are also racial differences in tumor biology, with African Americans more likely to have high-risk disease and fatal outcomes.[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]
Epidemiologic studies have shown that environmental or other exposures have not been unequivocally associated with increased or decreased incidence of neuroblastoma.
Neuroblastoma originates in the adrenal medulla and paraspinal or periaortic regions where sympathetic nervous system tissue is present (refer to Figure 1).
Figure 1. Neuroblastoma may be found in the adrenal glands and paraspinal nerve tissue from the neck to the pelvis.
Studies analyzing constitutional DNA in rare cohorts of familial neuroblastoma patients have provided insight into the complex genetic basis for tumor initiation. 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 have multifocal primary neuroblastoma (about 20%).
Several germline mutations have been associated with a genetic predisposition to neuroblastoma, including the following:
Sporadic neuroblastoma may also show a germline contribution, either with modest effect sizes for common polymorphic alleles or with greater effect sizes for rare pathogenic variants. As an example of the latter, rare germline variants of BARD1 have been identified in children with high-risk neuroblastoma.
Genome-wide association studies have identified several common genomic variables (single nucleotide polymorphisms [SNPs]) with modest effect size that are associated with neuroblastoma. A subset of these SNPs is associated with susceptibility to high-risk neuroblastoma, including variants related to the following:
Other SNPs are associated with susceptibility to low-risk neuroblastoma. One example that illustrates a mechanism by which SNPs may contribute to neuroblastoma risk is the polymorphism in the first intron of the oncogene LMO1 that forms a GATA transcription factor-binding site in an enhancer.[21,26,26] This risk allele is associated with high expression of LMO1 in aggressive neuroblastoma. LMO1 protein is necessary for growth of neuroblastoma in vitro and enhances growth of neuroblastoma cell lines with low LMO1 expression.
Genomic and Biologic Features of Neuroblastoma
Neuroblastoma can be subdivided into a biologically defined subset that has a very favorable prognosis (i.e., low-risk neuroblastoma) and another group that has a guarded prognosis (i.e., high-risk neuroblastoma). While neuroblastoma in infants with tumors that have favorable biology is highly curable, only 50% of children with high-risk neuroblastoma are alive at 5 years from diagnosis, at best.
Low-risk neuroblastoma is usually found in children younger than 18 months with limited extent of disease; the tumor has changes, usually increases, in the number of whole chromosomes in the neuroblastoma cell. Low-risk tumors are hyperdiploid when examined by flow cytometry.[27,28] In contrast, high-risk neuroblastoma generally occurs in children older than 18 months, is often metastatic to bone, and usually has segmental chromosome abnormalities. They are near diploid or near tetraploid by flow cytometric measurement.[27,28,29,30,31,32,33] High-risk tumors also show exonic mutations (refer to the Exonic mutations in neuroblastoma section of this summary for more information), but most high-risk tumors lack mutations in genes that are recurrently mutated. Compared with adult cancers, neuroblastomas show a low number of mutations per genome that affect protein sequence (10-20 per genome).
Key genomic characteristics of high-risk neuroblastoma that are discussed below include the following:
Segmental chromosomal aberrations (includingMYCNgene amplification)
Segmental chromosomal aberrations, found most frequently in 1p, 1q, 3p, 11q, 14q, and 17p (and MYCN amplification), are best detected by comparative genomic hybridization and are seen in almost all high-risk and/or stage 4 neuroblastomas.[29,30,31,32,33] Among all patients with neuroblastoma, a higher number of chromosome breakpoints correlated with the following, whether or not MYCN amplification was considered:[29,30,31,32,33][Level of evidence: 3iiD]
In a study of unresectable primary neuroblastomas without metastases in children older than 12 months, segmental chromosomal aberrations were found in most, and older children were more likely to have them and to have more of them per tumor cell. In children aged 12 to 18 months, the presence of segmental chromosomal aberrations had a significant effect on event-free survival (EFS) but not on overall survival (OS). However, in children older than 18 months, there was a significant difference in OS in children with segmental chromosomal aberrations versus children without segmental chromosomal aberrations (67% vs. 100%), regardless of the histologic prognosis.
Segmental chromosomal aberrations are also predictive of recurrence in infants with localized unresectable or metastatic neuroblastoma without MYCN gene amplification.[27,28]
MYCN amplification (defined as more than 10 copies per diploid genome) is one of the most common segmental chromosomal aberrations, detected in 16% to 25% of tumors. For high-risk neuroblastoma, 40% to 50% of cases show MYCN amplification. In all stages of disease, amplification of the MYCN gene strongly predicts a poorer prognosis in both time to tumor progression and OS in almost all multivariate regression analyses of prognostic factors.[27,28] Within the localized MYCN-amplified cohort, ploidy status may further predict outcome. However, patients with hyperdiploid tumors with any segmental chromosomal aberrations do relatively poorly.
In a Children's Oncology Group study of MYCN copy number in 4,672 patients with neuroblastoma, 79% had MYCN-wild-type tumors, 3% had tumors with MYCN gain (defined as a twofold to fourfold increase in signal by fluorescence in situ hybridization), and 18% had MYCN-amplified tumors. When individual clinical/biological features were examined, the percentage of patients with an unfavorable feature was lowest in the MYCN-wild-type category, intermediate in the MYCN-gain category, and highest in the MYCN-amplified category (P < .0001), except for the 11q aberration, for which the highest rates were in the MYCN-gain category. Patients with non-stage 4 disease and patients with non-high-risk disease and MYCN gain had a significantly increased risk of death than did MYCN-wild-type patients.
Most unfavorable clinical and pathobiological features are associated, to some degree, with MYCN amplification; in a multivariable logistic regression analysis of 7,102 International Neuroblastoma Risk Group patients, pooled segmental chromosomal aberrations and gain of 17q were the only poor prognostic features not associated with MYCN amplification. However, segmental chromosomal aberrations at 11q are almost mutually exclusive of diffuse MYCN amplification.
Exonic mutations in neuroblastoma
Multiple reports have documented that a minority of high-risk neuroblastomas have a small number of low-incidence, recurrently mutated genes. The most commonly mutated gene is ALK, which is mutated in approximately 10% of patients (see below). Other genes with even lower frequencies of mutation include ATRX, PTPN11, ARID1A, and ARID1B.[38,39,40,41,42,43,44] As shown in Figure 2, most neuroblastoma cases lack mutations in genes that are altered in a recurrent manner.
Figure 2. Data tracks (rows) facilitate the comparison of clinical and genomic data across cases with neuroblastoma (columns). The data sources and sequencing technology used were whole-exome sequencing (WES) from whole-genome amplification (WGA) (light purple), WES from native DNA (dark purple), Illumina WGS (green), and Complete Genomics WGS (yellow). Striped blocks indicate cases analyzed using two approaches. The clinical variables included were sex (male, blue; female, pink) and age (brown spectrum). Copy number alterations indicates ploidy measured by flow cytometry (with hyperdiploid meaning DNA index >1) and clinically relevant copy number alterations derived from sequence data. Significantly mutated genes are those with statistically significant mutation counts given the background mutation rate, gene size, and expression in neuroblastoma. Germline indicates genes with significant numbers of germline ClinVar variants or loss-of-function cancer gene variants in our cohort. DNA repair indicates genes that may be associated with an increased mutation frequency in two apparently hypermutated tumors. Predicted effects of somatic mutations are color coded according to the legend. Reprinted by permission from Macmillan Publishers Ltd: Nature Genetics (Pugh TJ, Morozova O, Attiyeh EF, et al.: The genetic landscape of high-risk neuroblastoma. Nat Genet 45 (3): 279-84, 2013), copyright (2013).
ALK, the exonic mutation found most commonly in neuroblastoma, is a cell surface receptor tyrosine kinase, expressed at significant levels only in developing embryonic and neonatal brains. Germline mutations in ALK have been identified as the major cause of hereditary neuroblastoma. Somatically acquired ALK-activating mutations are also found as oncogenic drivers in neuroblastoma.
The presence of an ALK mutation correlates with significantly poorer survival in high-risk and intermediate-risk neuroblastoma patients. ALK mutation was examined in 1,596 diagnostic neuroblastoma samples.ALK tyrosine kinase domain mutations occurred in 8% of samples-at three hot spots and 13 minor sites-and correlated significantly with poorer survival in patients with high-risk and intermediate-risk neuroblastoma. ALK mutations were found in 10.9% of MYCN-amplified tumors versus 7.2% of those without MYCN amplification. ALK mutations occurred at the highest frequency (11%) in patients older than 10 years. The frequency of ALK aberrations was 14% in the high-risk neuroblastoma group, 6% in the intermediate-risk neuroblastoma group, and 8% in the low-risk neuroblastoma group.
Small-molecule ALK kinase inhibitors such as crizotinib are being developed and tested in patients with recurrent and refractory neuroblastoma. (Refer to the Treatment Options Under Clinical Evaluation for Recurrent or Refractory Neuroblastoma section in the PDQ summary on Neuroblastoma Treatment for more information about crizotinib clinical trials.)
Genomic evolution of exonic mutations
There are limited data regarding the genomic evolution of exonic mutations from diagnosis to relapse for neuroblastoma. Whole-genome sequencing was applied to 23 paired diagnostic and relapsed neuroblastomas to define somatic genetic alterations associated with relapse, while a second study evaluated 16 paired diagnostic and relapsed specimens. Both studies identified an increased number of mutations in the relapsed samples compared with the samples at diagnosis; this has been confirmed in a study of tumor samples sent for next-generation sequencing.
In addition, three relapse samples showed structural alterations involving MAPK pathway genes consistent with pathway activation, so aberrations in this pathway were detected in 18 of 23 relapse samples (78%). Aberrations were found in ALK (n = 10), NF1 (n = 2), and one each in NRAS, KRAS, HRAS, BRAF, PTPN11, and FGFR1. Even with deep sequencing, 7 of the 18 alterations were not detectable in the primary tumor, highlighting the evolution of mutation presumably leading to relapse and the importance of genomic evaluations of tissues obtained at relapse.
In a study of 276 neuroblastoma samples of all stages and from patients of all ages, very deep (33,000X) sequencing of two amplified ALK mutational hot spots revealed 4.8% clonal mutations and an additional 5% subclonal mutations, suggesting that subclonal mutations are common. Deep sequencing can reveal the presence of mutations in tiny subsets of tumor cells that may be able to survive during treatment and grow to constitute a relapse.
Genomic alterations promoting telomere lengthening
Lengthening of telomeres, the tips of chromosomes, promotes cell survival. Telomeres otherwise shorten with each cell replication, resulting eventually in the lack of a cell's ability to replicate. Low-risk neuroblastomas have little telomere lengthening activity. Aberrant genetic mechanisms for telomere lengthening have been identified for high-risk neuroblastoma.[38,39,49] Thus far, the following three mechanisms, which appear to be mutually exclusive, have been described:
Additional biological factors associated with prognosis
MYC and MYCN expression
Immunostaining for MYC and MYCN proteins on 357 undifferentiated/poorly differentiated neuroblastomas has demonstrated that elevated MYC/MYCN protein expression is prognostically significant. Sixty-eight tumors highly expressed MYCN protein, and 81 were MYCN amplified. Thirty-nine tumors expressed MYC highly and were mutually exclusive of high MYCN expression. Segmental chromosomal aberrations were not examined in this study, except for MYCN amplification.
Most neuroblastomas with MYCN amplification in the International Neuroblastoma Pathology Classification system have unfavorable histology, but about 7% have FH. Of those with MYCN amplification and FH, most do not express MYCN, despite the gene being amplified, and have a more favorable prognosis than those that express MYCN. Segmental chromosomal aberration at 11q is almost mutually exclusive of diffuse MYCN amplification. Rarely, MYCN amplification may be detected by fluorescence in situ hybridization in only a subclone of the tumor cells. In these cases, the clinical outcome reflects the prognostic background (i.e., age, stage, ploidy, and segmental chromosomal aberrations) of the tumor in which the heterogeneous amplification is found.[53,54]
Neurotrophin receptor kinases
Expression of neurotrophin receptor kinases and their ligands vary between high-risk and low-risk tumors. TrkA is found on low-risk tumors, and absence of its ligand NGF is postulated to lead to spontaneous tumor regression. In contrast, TrkB is found in high-risk tumors that also express its ligand, BDNF, which promotes neuroblastoma cell growth and survival.
Immune system inhibition
Anti-GD2 antibodies, along with modulation of the immune system to enhance antineuroblastoma activity, are often used to help treat neuroblastoma. The anti-GD2 antibody (3F8), used for treating neuroblastoma exclusively at one institution, utilizes natural killer cells to kill the neuroblastoma cells. However, the natural killer cells can be inhibited by the interaction of HLA antigens and killer immunoglobulin receptor subtypes. Thus, the patient's immune system genes can help determine response to immunotherapy for neuroblastoma.[56,57] A report on the effects of immune system genes on response to dinutuximab, a commercially available anti-GD2 antibody, awaits publication.
Current data do not support neuroblastoma screening. Screening at the ages of 3 weeks, 6 months, or 1 year did not lead to reduction in the incidence of advanced-stage neuroblastoma with unfavorable biological characteristics in older children, nor did it reduce overall mortality from neuroblastoma.[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 caused by 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, occur rarely in children with neuroblastoma. Opsoclonus/myoclonus syndrome can be 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.[63,64,65]
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.[63,66] The primary tumor is typically diffusely infiltrated with lymphocytes.
Some patients may respond neurologically to removal of the neuroblastoma, but improvement may be slow and partial; symptomatic treatment is often necessary. Adrenocorticotropic hormone or corticosteroid treatment can be effective, but some patients do not respond to corticosteroids.[64,66] Other therapy with various drugs, plasmapheresis, intravenous gamma globulin, and rituximab have been reported to be effective in selected cases.[64,68,69,70] The long-term neurologic outcome may be superior in patients treated with chemotherapy, possibly because of its immunosuppressive effects.[62,68]
Diagnostic evaluation of neuroblastoma includes the following:
Serum catecholamines are not routinely used in the diagnosis of neuroblastoma except in unusual circumstances.
For patients older than 18 months with stage 4 disease, bone marrow with extensive tumor involvement combined with elevated catecholamine metabolites may be adequate for diagnosis and assigning risk/treatment group; however, INPC cannot be determined from tumor metastatic to bone marrow. Testing for MYCN amplification may be successfully performed on involved bone marrow if there is at least 30% tumor involvement.
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. In a COG study of expectant observation of small adrenal masses in neonates, biopsy was not required for infants; 81% of patients avoided undergoing any surgery at all. In a German clinical trial, 25 infants aged 3 months and younger with presumed localized neuroblastoma were observed without biopsy for periods of 1 to 18 months before biopsy or resection. There were no apparent ill effects from 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 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. This single statistic can be misleading because of the extremely heterogeneous prognosis based on the neuroblastoma patient's age, stage, and biology. However, studies demonstrate a significant improvement in survival for high-risk patients diagnosed and treated between 2000 and 2010 compared with those diagnosed from 1990 to 1999. (Refer to Table 1 for more information.)
The prognosis for patients with neuroblastoma is related to the following:[79,80,81,82]
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 for fetal and neonatal neuroblastoma is similar to that for 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.
The effect of patient age on prognosis is strongly influenced by clinical and pathobiological factors, as evidenced by the following:
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.[87,88,89,90]
Survival of patients with 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%),[91,92] with outcome particularly dependent on MYCN status, tumor cell ploidy, and the pattern of chromosomal aberrations (numerical chromosomal aberrations and segmental chromosomal aberrations). Hyperdiploidy and numerical chromosomal aberrations confer a favorable prognosis while diploidy and segmental chromosomal aberrations are associated with early treatment failure.[88,93] 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 EFS of 81% and OS of 93%.[6,86,94,95,96] Infants younger than 12 months with INSS stage 4 disease and MYCN amplification are categorized as high risk and have a 3-year EFS of 10%.
Adolescents and young adults
Neuroblastoma has a worse long-term prognosis in adolescents older than 10 years or adults, regardless of stage or site. The disease is more indolent in older patients than in children.
Although adolescent and young adult patients have infrequent MYCN amplification (9% in patients aged 10-21 years), older children with advanced disease have a poor rate of survival. Tumors from the adolescent and young adult population commonly have segmental chromosomal aberrations, and ALK and ATRX mutations are much more frequent.[19,33,97]
The 5-year EFS rate is 32% for patients between the ages of 10 years and 21 years and the OS rate is 46%; for stage 4 disease, the 10-year EFS rate is 3% and the and OS rate is 5%. Aggressive chemotherapy and surgery have been shown to achieve a minimal disease state in more than 50% of these patients.[61,99,100] 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.[98,99,100]
Site of primary tumor
Clinical and biological features of neuroblastoma differ by primary tumor site. In a study of data on 8,389 patients entered in clinical trials and compiled by the International Risk Group Project, the following results were observed:
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.
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:
High mitosis/karyorrhexis index is considered a prognostically unfavorable histologic characteristic, but its prognostic ability is age dependent.[105,106]
In a COG study (P9641 [NCT00003119]) investigating the effect of histology, among other factors, on outcome, 87% of 915 children with stage 1 and stage 2 neuroblastoma without MYCN amplification were treated with initial surgery and observation. Patients (13%) who had or were at risk of developing symptomatic disease, or who had less than 50% tumor resection at diagnosis, or who had unresectable progressive disease after surgery alone, were treated with chemotherapy and surgery. Those 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%.
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. In the COG P9641 (NCT00003119) low-risk study, stage 2b patients (those with tumor-containing lymph nodes on the same side of the body cavity as the tumor, but not on the opposite side of the cavity), but not stage 1 or 2a patients, had a poorer outcome with unfavorable histology (86% ± 5% vs. 99% ± 1%). The poorer outcome was predominantly in patients older than 18 months.
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.[107,108,109] Similarly, the persistence of MIBG-avid tumor measured as Curie score (refer to the Curie score and SIOPEN score section of this summary for more information about Curie scoring) in two or more sites after completion of induction therapy predicts a poor prognosis. A decrease in mitosis and an increase in histologic differentiation of the primary tumor are also prognostic.
The accuracy of prognostication based on decrease in primary tumor size is less clear. In a study conducted by seven large international centers, 229 high-risk patients were treated in a variety of ways, including surgical removal of the primary tumor, radiation to the tumor bed, and, in most cases, antiGD2 antibody-enhanced immunotherapy. Primary tumor response was measured in three ways: as 30% or greater reduction in the longest dimension, 50% or greater reduction in tumor volume, or 65% or greater reduction in tumor volume (calculated from three tumor dimensions, a conventional radiologic technique). The measurements were performed at diagnosis and after induction chemotherapy before primary tumor resection. None of the methods of measuring primary tumor response at end of induction chemotherapy were predictive of survival.
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,[115,116] 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.[119,120,121]
Evidence (observation [spontaneous regression]):
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:
International Neuroblastoma Pathology Classification (INPC) System
The INPC system involves evaluation of tumor specimens obtained before therapy for the following morphologic features:[2,3,4,5,6]
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 (refer to Table 1).[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 do those that do express MYCN.
International Neuroblastoma Risk Group (INRG) Classification System
The INRG used a survival-tree analysis to compare 35 prognostic factors in more than 8,800 patients with neuroblastoma from a variety of clinical trials. The following INPC (Shimada system) histologic factors were included in the analysis:[9,10]
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.
The INRG histologic subsets are incorporated into the INRG Risk Classification Schema. (Refer to Table 6 in the Treatment Option Overview for Neuroblastoma section of this summary for more information.)
Approximately 70% of patients with neuroblastoma have metastatic disease at diagnosis. A thorough evaluation for metastatic disease is performed before therapy initiation. The studies described below 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. Approximately 90% of neuroblastomas will be MIBG avid. The MIBG scan has a sensitivity and specificity of 90% to 99%, and MIBG avidity is equally distributed between primary and metastatic sites. Although iodine I 123 (123I) has a shorter half-life, it is preferred over 131I because of its lower radiation dose, better quality images, reduced thyroid toxicity, and lower cost. Fluorine F 18-fludeoxyglucose positron emission tomography (PET) scans are used to evaluate extent of disease in patients with tumors that are not MIBG avid.
Imaging with 123I-MIBG is optimal for identifying soft tissue and bony metastases and was shown to be superior to PET-computed tomography (PET-CT) in one prospective comparison. In a retrospective review of 132 children with neuroblastoma, technetium Tc 99m-methylene diphosphonate (99mTc-MDP) bone scintigraphy failed to identify unique sites of metastatic disease that would change the disease stage or clinical management. Bone scans can be omitted in most cases. Baseline MIBG scans performed at diagnosis provide an excellent method for monitoring disease response and performing posttherapy surveillance. A retrospective analysis of paired 123I-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, 123I-MIBG imaging was superior for the detection of bone marrow and bony metastases.
Curie score and SIOPEN score
Multiple groups have investigated a semiquantitative 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 Europe Neuroblastoma (SIOPEN) methods.
Other staging tests and procedures
Other tests and procedures used to stage neuroblastoma include the following:
Lumbar puncture is avoided because central nervous system (CNS) metastasis at diagnosis is rare, and lumbar puncture may be associated with an increased incidence of subsequent development of CNS metastasis.
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 [1,12] and is described in Table 3. This represented the first step in harmonizing disease staging and risk stratification worldwide. The INSS is a surgical staging system that was developed in 1988 and used the extent of 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 limited 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.[1,12,13,14]
The COG Neuroblastoma Risk Grouping that incorporates INSS is described in the Treatment Option Overview for Neuroblastoma section of this summary.
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 (refer to Table 4). 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.
IDRFs include the following:
The INRGSS has incorporated this staging system into a risk grouping system using multiple other parameters at diagnosis. (Refer to Table 6 in the Treatment Option Overview for Neuroblastoma section of this summary for more information.)
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 1 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. The INRG collaboration has also defined techniques for detecting and quantifying neuroblastoma in bone marrow, both at diagnosis and after treatment. Quantification of this disease may result in more accurate assessment of response to treatment, but has not yet been applied to any clinical trials.
By combining the INRGSS, preoperative imaging, and biological factors, each patient is assigned a risk stage that predicts outcome and dictates the appropriate treatment approach. The INRGSS has predictive value for children with INSS stage 1, 2, and 3, with stage L1 having a 5-year EFS of 90% and OS of 96%, versus 79% EFS and 89% OS for L2. However, the INSS stage also discriminates among INRGSS stage L2 patients, with INSS stages 1, 2, and 3 (non-MYCN amplified) having 5-year EFS rates of 94%, 81%, and 76% and 5-year OS rates of 99%, 93%, and 83%, respectively. In the latter study, many children with L2 tumors underwent primary surgery and had an outcome significantly superior to that of children who underwent biopsy only as the initial operative procedure (5-year OS of 93% vs. 83%). Many of the children entered on the latter study underwent primary surgery against protocol in spite of IDRFs and L2 classification, and these children had superior outcome (5-year OS of 95% vs. 83%). However, these children also had a 17% rate of operative complications (vs. 5%). In L1 patients undergoing primary surgery, those with operative complications had a lower OS (92% vs. 97%).
Most international protocols have begun to incorporate the collection and use of IDRFs in risk stratification and assignment of therapy.[22,23] The COG has been collecting and evaluating INRGSS data since 2006. A COG trial that opened in 2014 uses the INRGSS along with input from the surgeon to determine therapy for patients with certain localized disease and for stage 4S patients. Note that the INSS allows patients up to age 12 months to be classified as stage 4S, while the INRGSS allows patients up to age 18 months to be staged as MS. The primary tumor in INSS stage 4S must be INSS stage 1 or 2, while the primary tumor in MS can be INSS stage 3. 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.
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 plan treatment, the treatments described in this summary are based on both the INRG system and the COG risk stratification system. In the INRG system, each child is assigned to a group according to the presence or absence of image-defined risk factors and metastasis. (Refer to the list of image-defined risk factors [IDRFs] in the Stage Information for Neuroblastoma section of this summary for more information.) Ongoing COG clinical trials have incorporated the International Neuroblastoma Risk Group Staging System (INRGSS) in lieu of the International Neuroblastoma Staging System (INSS). In the previous COG risk system, each child was assigned to a low-risk, intermediate-risk, or high-risk group (refer to Tables 7, 10, and 13 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:
Table 5 describes the treatment options for low-risk, intermediate-risk, high-risk, stage 4S, and recurrent neuroblastoma.
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 assigned all patients to a low-, intermediate-, or high-risk group. The COG risk-based treatment plan is no longer in use, as current studies are based on the INRG risk grouping. This risk-based schema was based on the following factors:
Table 7 (in the Treatment of Low-Risk Neuroblastoma section), Table 10 (in the Treatment of Intermediate-Risk Neuroblastoma section), and Table 13 (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.
International Neuroblastoma Risk Grouping
The INRG classifies all neuroblastoma patients into 16 pretreatment risk groups on the basis of INRG stage, age, histologic category, grade of tumor differentiation, MYCN amplification, 11q aberration (a single segmental chromosomal aberration), and ploidy. They assigned four levels of risk according to outcomes among 8,800 patients with high-quality data, as they had been entered on clinical trials (refer to Table 6). In the overall risk grouping, histology is an important risk determinant for all stage L1 and L2 tumors, and grade of differentiation discriminates among neuroblastomas and nodular ganglioneuroblastomas in patients older than 18 months. The goals are to develop shared data from the patients and defined risk groups for future trials.
Controversy exists regarding the previous COG risk grouping system, the INRG Risk Grouping Schema in current use, and the treatment of certain small subsets of patients.[15,16,17] 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 Pediatric Oncology Group and Children's Cancer Group studies suggested that this subgroup of patients could be successfully treated as intermediate risk.[18,19,20] Future versions of the INRG Risk Grouping are expected to contain more tumor genomic criteria to help assign risk.
Description of Revised International Neuroblastoma Response Criteria (INRC)
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.[21,22,23] The revised INRC depend on the use of three-dimensional (3-D) imaging combined with MIBG for primary tumor, bone, and lymph node or soft tissue metastases. PET scans are used instead of MIBG in the 10% of patients with MIBG non-avid tumors; technetium Tc 99m (99mTc) bone scans will no longer be used, as a retrospective study of 132 patients who received both MIBG and 99mTc scans showed no staging benefit.
Response Evaluation Criteria In Solid Tumors (RECIST) criteria are used to measure response of primary tumor. Abnormal, enlarged lymph nodes are measured in the shorter dimension. Bone marrow involvement is quantified using histologic evaluation of four biopsies or trephines; the use of immunohistologic techniques is encouraged. Catecholamine metabolites are not quantified with regard to response.
The response criteria are defined as follows:
Persistent elevation in urinary vanillylmandelic acid/ homovanillic acid (VMA/HVA) with stable disease or an increase in VMA/HVA without clinical or radiographic evidence of progression does not indicate progressive disease, but warrants continued follow-up.
Care should be taken in interpreting the development of metastatic disease in an infant who was initially considered to have stage 1 or 2 disease. If the pattern of metastases in such a patient is consistent with a 4S pattern of disease (skin, liver, bone marrow less than 10% involved), these patients are not classified as having progressive/metastatic disease, which would typically be a criteria for removal from protocol therapy. Instead, these patients are managed as stage 4S.
Controversy exists regarding the necessity of measuring the primary tumor response in all three dimensions or whether the single longest dimension, as in RECIST tumor response determination, is just as useful. The latter has been adopted for use in the INRC.
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 (L1) 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 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.[28,29,30,31,32,33] 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 low-risk or intermediate-risk patients.[36,37,38]
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.[36,37,38] 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, which were severe in about one-half of them. This finding 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, which includes urinary VMA/HVA testing, one of the most reliable imaging tests to detect disease progression or recurrence is the iodine I 123-metaiodobenzylguanidine scan.[41,42] Cross-sectional imaging with computed tomography scans is controversial because of the amount of radiation received and the low proportion of relapses detected with this modality.
Special Considerations for the Treatment of Children With 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. Other types of clinical trials explore or define novel therapies when there is no standard therapy for a cancer diagnosis. Information about ongoing clinical trials is available from the NCI website.
Low-risk neuroblastoma represents nearly one-half of all newly diagnosed patients. The success of previous Children's Oncology Group (COG) clinical trials has contributed to the continued reduction in therapy for select patients with neuroblastoma.
The previously used COG neuroblastoma low-risk group assignment criteria are described in Table 7.
Table 8 shows the International Neuroblastoma Risk Group (INRG) classification for very low-risk or low-risk neuroblastoma in use for current COG studies.
(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) exceeding 90% and overall survival (OS) ranging from 99% to 100%.[2,3]
Treatment options for low-risk neuroblastoma include the following:
Surgery followed by observation
Treatment for patients categorized as low risk (refer to Table 7) may be surgery alone. 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.
Chemotherapy with or without surgery
Chemotherapy with or without surgery is used to treat symptomatic disease, unresectable progressive disease after surgery, or disease with unfavorable histology or diploid disease.
The use of chemotherapy may be restricted to specific cases such as 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 do other low-risk patients.[3,5]
Chemotherapy is also reserved for low-risk patients who are symptomatic (e.g., 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 long-term effects (COG-P9641).
Observation without biopsy
Observation without biopsy has been used to treat perinatal neuroblastoma with small adrenal tumors.
A COG study determined that selected small INSS stage 1 or stage 2 adrenal masses, presumed to be neuroblastoma, detected in infants younger than 6 months by screening or incidental ultrasound may safely be observed without a definitive histologic diagnosis being obtained and without surgical intervention, thus avoiding potential complications of surgery in the newborn. Patients are observed frequently to detect any tumor growth or spread that would indicate a need for intervention. Additional studies, including an expansion of criteria allowing observation without surgery, are underway in the COG ANBL1232 (NCT02176967) study (refer to Table 9).
Evidence (observation without biopsy):
Evidence (observation following biopsy or partial resection):
Treatment Options Under Clinical Evaluation
Information about National Cancer Institute (NCI)-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
The previously used Children's Oncology Group (COG) neuroblastoma intermediate-risk group assignment criteria are described in Table 10.
Table 11 shows the International Neuroblastoma Risk Group (INRG) classification for intermediate-risk neuroblastoma in use for current COG studies.
Treatment Options for Intermediate-Risk Neuroblastoma
Treatment options for intermediate-risk neuroblastoma include the following:
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 long-term effects 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):
This study investigated an overall reduction in treatment compared with previous treatment plans in patients with unresectable, localized, MYCN-nonamplified tumors and infants with stage 4 MYCN -nonamplified disease. The intermediate-risk group received four to eight cycles of moderate-dose neoadjuvant chemotherapy (carboplatin, cyclophosphamide, doxorubicin, and etoposide), additional surgery in some instances, and avoided radiation therapy. Of the 464 patients with intermediate-risk tumors (stages 3, 4, and 4S), 69.6% had favorable features, defined as hyperdiploidy and favorable histology, and were assigned to receive four cycles of chemotherapy.
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 emergency therapy)
Radiation therapy for intermediate-risk patients is emergency therapy reserved for patients with the following:
The previously used Children's Oncology Group (COG) neuroblastoma high-risk group assignment criteria are described in Table 13.
Table 14 shows the International Neuroblastoma Risk Group (INRG) classification for high-risk neuroblastoma in use for current COG studies.
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 after treatment 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.[4,5]
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.
Treatment options for high-risk neuroblastoma typically include the following:
Chemotherapy, surgery, myeloablative therapy and SCT, radiation therapy, and dinutuximab, 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 on the basis of the antineuroblastoma activity seen in relapsed patients. Response to therapy after four cycles of chemotherapy or at the end of induction chemotherapy correlates with EFS at the completion of high-risk therapy.[9,10]
After a response to chemotherapy, resection of the primary tumor is usually attempted. Whether a gross-total resection is beneficial either before or after induction chemotherapy is controversial.
The consolidation phase of high-risk regimens involves myeloablative chemotherapy and SCT, 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 SCT (31% to 47%) versus conventional chemotherapy (22% to 31%).[14,15,16] Previously, total-body irradiation had been used in SCT conditioning regimens. Most current protocols use either carboplatin/etoposide/melphalan or busulfan/melphalan as conditioning for SCT.[Level of evidence: 3iA]
Evidence (myeloablative chemotherapy and stem cell rescue):
(Refer to the Autologous Hematopoietic Cell Transplantation section in the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation.)
Radiation to the primary tumor site (whether or not a complete excision was obtained) and persistently MIBG-positive bony metastatic sites is often performed after myeloablative therapy. The optimal dose of radiation therapy has not been determined. Radiation of metastatic disease sites is determined on an individual 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.
Postconsolidation therapy is designed to treat potential minimal residual disease following SCT. For high-risk patients in remission after SCT, dinutuximab combined with GM-CSF and IL-2 are given in concert with isotretinoin and have been shown to improve EFS.[24,25]
Evidence (all treatments):
Surgery and radiation therapy (local control)
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 after 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.
The previously used Children's Oncology Group (COG) neuroblastoma 4S group assignment criteria are described in Table 15.
Table 16 shows the International Neuroblastoma Risk Group (INRG) classification for stage 4S neuroblastoma in use for current COG studies.
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.[3,4,5] 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
Observation with supportive care is used to treat asymptomatic patients with favorable tumor biology.
The treatment of children with stage 4S disease is dependent on clinical presentation.[3,4] Most patients do not require therapy unless bulk disease is causing organ compromise and risk of death.
Chemotherapy is used to treat 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:
A scoring system to measure signs and symptoms of deterioration or compromise was developed to better assess this group. This scoring system has been evaluated retrospectively, was predictive of the clinical course, and has been applied prospectively. It was also helpful in directing the management of patients with INSS stage 4S disease.[8,9]
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 to avoid toxicity, which contributes to poorer 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 resulting from 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 patients with low-risk and intermediate-risk disease. An analysis of 23 paired MIBG and positron emission tomography (PET) scans in 14 patients with refractory or recurrent high-risk neuroblastoma treated with iodine I 131-MIBG (131I-MIBG) found that the MIBG scan was more sensitive than fluorine F 18-fludeoxyglucose (18F-FDG) PET for detecting metastatic bone lesions, although there was a trend for 18F-FDG PET to be more sensitive for soft tissue lesions.
Subclonal ALK mutations or other MAPK pathway lesions 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.[3,4] Modern comprehensive molecular analysis comparing primary and relapsed neuroblastoma from the same patients revealed extensive clonal enrichment and several newly discovered 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.[5,6]
If neuroblastoma recurs in a child originally diagnosed with high-risk disease, the prognosis is usually poor despite additional intensive therapy.[7,8,9,10] However, it is often possible to gain many additional months of life for these patients with alternative chemotherapy regimens.[11,12] 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 survival-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:
Although the OS after recurrence in children presenting with high-risk neuroblastoma is generally extremely poor, patients with high-risk neuroblastoma at first relapse after complete remission or minimal residual disease in whom relapse was a single site of soft tissue mass (a few children also had bone marrow or bone disease at relapse) had a 5-year OS of 35% in one single-institution study. All patients underwent surgical resection of the soft tissue disease. MYCN amplification and multifocal soft tissue disease were associated with a worse postprogression survival.
The Children's Oncology Group (COG) experience with recurrence in patients with low-risk and intermediate-risk neuroblastoma is that most patients 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.[14,15] 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 myeloablative therapy and 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 long-term effects from the chemotherapy regimen as used in previous 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 they may be offered entry into a clinical trial.
Evidence (surgery followed by observation or 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 previous 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 long-term effects from the chemotherapy regimen, as used in previous 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 is treated as follows:
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 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 1 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 long-term effects from the chemotherapy regimen, as used in a previous COG trial (COG-A3961).
Treatment options for metastatic recurrent neuroblastoma initially classified as intermediate risk include the following:
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 also be considered as part of the patient's treatment plan.
Although the OS after recurrence in children presenting with high-risk neuroblastoma is generally extremely poor, patients with high-risk neuroblastoma at first relapse after complete remission or minimal residual disease in whom relapse was a single site of soft tissue mass (a few children also had bone marrow or bone disease at relapse) had a 5-year OS of 35% in one single-institution study.
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 (chemotherapy with or without autologous SCT):
Evidence (second autologous SCT following additional 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.
Clinical trials of novel therapeutic approaches, such as a vaccine designed to induce host antiganglioside antibodies that can replicate the antineoplastic activities of intravenously administered monoclonal antibodies, are currently under investigation. Patients also receive a beta-glucan treatment, which has a broad range of immunostimulatory effects and synergizes with anti-GD2/GD3 monoclonal antibodies. In a phase I study of 15 children with high-risk neuroblastoma, the therapy was tolerated without any dose-limiting toxicity. Long-term progression-free survival (PFS) has been reported in patients who achieve a second or later complete or very good partial remission followed by consolidation with anti-GD2 immunotherapy and isotretinoin with or without maintenance therapy. This includes patients who had previously received anti-GD2 immunotherapy and isotretinoin.
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.[38,39] 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:
Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).
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.
General Information About Neuroblastoma
Added text about the findings from a Children's Oncology Group study of MYCN copy number in 4,672 patients with neuroblastoma (cited Campbell et al. as reference 37).
Revised text to state that two studies identified an increased number of mutations in the relapsed samples compared with the samples at diagnosis; this has been confirmed in a study of tumor samples sent for next-generation sequencing (cited Padovan-Merhar et al. as reference 47).
Added Padovan-Merhar et al. as reference 4.
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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
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Levels of Evidence
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The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Neuroblastoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389190]
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Last Revised: 2017-09-28
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