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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.
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 the United States.[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% of patients 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 the incidence in White children. However, there are also racial differences in tumor biology, with African American patients 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 incidences 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.
Neuroblastoma Screening (Genetic Predisposition and Familial Neuroblastoma)
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 about 20% have multifocal primary neuroblastoma.
Germline mutations. Several germline mutations have been associated with a genetic predisposition to neuroblastoma, including the following:
Other cancer predisposition syndromes. Children with gene aberrations associated with other cancer predisposition syndromes can be at increased risk of developing neuroblastoma and other malignancies. The following syndromes primarily involve genes in the canonical RAS pathway:
In addition, neuroblastoma has been described in patients with the following syndromes:
Sporadic neuroblastoma may also have an increased incidence resulting from less potent germline predispositions. Genome-wide association studies have identified several common genomic variables (single nucleotide polymorphisms [SNPs]) with modest effect size that are associated with increased risks of developing neuroblastoma. Most of these genomic risk variables are significantly associated with distinct neuroblastoma phenotypes (i.e., high-risk vs. low-risk disease).
Neuroblastoma predisposition and surveillance
Screening recommendations from the American Association for Cancer Research (AACR) emerged from the 2016 Childhood Cancer Predisposition Workshop. The AACR recommends that the following individuals undergo biochemical and radiographic surveillance for early detection of tumors in the first 10 years of life:
Surveillance consists of the following:
Surveillance begins at birth or at diagnosis of neuroblastoma predisposition and continues every 3 months until age 6 years and then continues every 6 months until age 10 years. Patients with Costello syndrome may have elevated urinary catecholamines in the absence of a catecholamine-secreting tumor, so only very high levels or significantly rising levels should prompt further investigation beyond the ultrasonography and chest x-ray. Patients with Li-Fraumeni syndrome should not undergo chest x-rays.
About 5% of children with Beckwith-Wiedemann syndrome have the molecular etiology of mutations causing decreased activity of CDKN1C. A review of all large studies of genetically subtyped Beckwith-Wiedemann syndrome found 70 children with the CDKN1C mutation, 4.6% of whom developed neuroblastoma; there were no cases of Wilms tumor or hepatoblastoma. There is little experience with screening these children for neuroblastoma, so there are no generally accepted guidelines, although the authors of the study suggest screening with urinary VMA/HVA every 4 to 6 months. Other genetic subtypes of Beckwith-Wiedemann syndrome have a prevalence of neuroblastoma of less than 1%, and no neuroblastic tumors were found among 123 children with the genotype gain of methylation at imprinting control region 1.
Neuroblastoma Screening (General Population)
Current data do not support neuroblastoma screening in the general public. 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):
Genomic and Biologic Features of Neuroblastoma
Molecular features of neuroblastoma
Children with neuroblastoma can be subdivided into subsets with different predicted risks of relapse on the basis of clinical factors and biological markers at the time of diagnosis.
Genomic analyses of localized, resectable non-MYC amplified neuroblastoma cases from two consecutive European studies and a North American cohort revealed a different prognostic impact of tumor genomics depending on patient age (<18 months or >18 months). Patients were treated with surgery alone regardless of a tumor residuum.[Level of evidence: 3iii]
Key genomic characteristics of high-risk neuroblastoma that are discussed below include the following:
Segmental chromosomal aberrations
Segmental chromosomal aberrations, found most frequently in 1p, 1q, 3p, 11q, 14q, and 17p, are best detected by comparative genomic hybridization and are seen in most high-risk and/or stage 4 neuroblastoma tumors.[33,34,35,36,37] Among all patients with neuroblastoma, a higher number of chromosome breakpoints (i.e., a higher number of segmental chromosome aberrations) correlated with the following:[33,34,35,36,37][Level of evidence: 3iiD]
An international collaboration studied 556 patients with high-risk neuroblastoma and identified two types of segmental copy number aberrations that are associated with extremely poor outcome. Distal 6q losses were found in 6% of patients and were associated with a 10-year survival rate of only 3.4%; amplifications of regions not encompassing the MYCN locus, in addition to MYCN amplification, were detected in 18% of the patients and were associated with a 10-year survival rate of 5.8%.
In a study of children older than 12 months who had unresectable primary neuroblastomas without metastases, 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 EFS but not on OS. However, in children older than 18 months, there was a significant difference in OS between children with segmental chromosomal aberrations (67%) and children without segmental chromosomal aberrations (100%), regardless of tumor histology.
Segmental chromosomal aberrations are also predictive of recurrence in infants with localized unresectable or metastatic neuroblastoma without MYCN gene amplification.[30,31]
MYCN amplification is detected in 16% to 25% of neuroblastoma tumors. Among patients with 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.[30,31] Within the localized-tumor MYCN-amplified cohort, patients with hyperdiploid tumors have better outcomes than do patients with diploid tumors. However, patients with hyperdiploid tumors with MYCN amplification or any segmental chromosomal aberrations do relatively poorly compared with patients with hyperdiploid tumors without MYCN amplification.
In a Children's Oncology Group study of MYCN copy number in 4,672 patients with neuroblastoma, the following results were reported:
Most unfavorable clinical and pathobiological features are associated, to some degree, with MYCN amplification; in a multivariable logistic regression analysis of 7,102 patients in the International Neuroblastoma Risk Group (INRG) study, pooled segmental chromosomal aberrations and gains of 17q were poor prognostic features even when not associated with MYCN amplification. However, another poor prognostic feature, segmental chromosomal aberrations at 11q, are almost entirely mutually exclusive of MYCN amplification.[44,45]
In a cohort of 6,223 patients from the INRG database with known MYCN status, the OS hazard ratio (HR) associated with MYCN amplification was 6.3 (95% confidence interval [CI], 5.7–7.0; P < .001). The greatest adverse prognostic impact of MYCN amplification for OS was in the youngest patients (<18 months: HR, 19.6; ≥18 months: HR, 3.0). Patients whose outcome was most impacted by MYCN status were those with otherwise favorable features, including age younger than 18 months, high mitosis karrhyohexis index, and low ferritin.[Level of evidence: 3iiiA]
Intratumoral heterogeneous MYCN amplification (hetMNA) refers to the coexistence of MYCN-amplified cells as a cluster or as single scattered cells and non-MYCN–amplified tumor cells. HetMNA has been reported infrequently and can occur spatially within the tumor as well as between the tumor and the metastasis at the same time or temporally during the disease course. The International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) biology group investigated the prognostic significance of this neuroblastoma subtype. Tumor tissue from 99 patients identified as having hetMNA and diagnosed between 1991 and 2015 was analyzed to elucidate the prognostic significance of MYCN-amplified clones in otherwise non-MYCN–amplified neuroblastomas. Patients younger than 18 months showed a better outcome in all stages compared with older patients. The genomic background correlated significantly with relapse frequency and OS. No relapses occurred in cases of only numerical chromosomal aberrations. This study suggests that hetMNA tumors have to be evaluated in the context of the genomic tumor background in combination with the clinical pattern, including the patient's age and disease stage. Future studies are needed in patients younger than 18 months who have localized disease with hetMNA.
Exonic mutations in neuroblastoma
Multiple reports have documented that a minority of high-risk neuroblastomas have a low incidence of 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 mutations include ATRX, PTPN11, ARID1A, and ARID1B.[48,49,50,51,52,53,54] 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).
The ALK gene provides instructions for making a cell surface receptor tyrosine kinase, expressed at significant levels only in developing embryonic and neonatal brains; ALK is the exonic mutation found most commonly in neuroblastoma. Germline mutations in ALK have been identified as the major cause of hereditary neuroblastoma. Somatically acquired ALK-activating exonic 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 mutations were examined in 1,596 diagnostic neuroblastoma samples and the following results were observed:
In a study that compared the genomic data of primary diagnostic neuroblastomas originating in the adrenal gland (n = 646) with that of neuroblastomas originating in the thoracic sympathetic ganglia (n = 118), 16% of thoracic tumors harbored ALK mutations.
Small-molecule ALK kinase inhibitors such as crizotinib (added to conventional therapy) are being tested in patients with newly diagnosed high-risk neuroblastoma and activated ALK (COG ANBL1531).
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 neuroblastoma tumor samples 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 neuroblastoma 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 (78%) relapse samples. 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 mutations presumably leading to relapse and the importance of genomic evaluations of tissues obtained at relapse.
In a deep-sequencing study, 276 neuroblastoma samples (comprised of all stages and from patients of all ages at diagnosis) underwent very deep (33,000X) sequencing of just two amplified ALK mutational hot spots, which revealed 4.8% clonal mutations and an additional 5% subclonal mutations, suggesting that subclonal ALK gene mutations are common. Thus, deep sequencing can reveal the presence of mutations in tiny subsets of neuroblastoma 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 neuroblastoma tumors have little telomere lengthening activity. Aberrant genetic mechanisms for telomere lengthening have been identified in high-risk neuroblastoma tumors.[48,49,60] 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 a restricted subset of 357 undifferentiated/poorly differentiated neuroblastoma tumors demonstrated that elevated MYC/MYCN protein expression is prognostically significant. Sixty-eight tumors (19%) highly expressed the MYCN protein, and 81 were MYCN amplified. Thirty-nine tumors (10.9%) expressed MYC highly and were mutually exclusive of high MYCN expression; in the MYC-expressing tumors, MYC or MYCN gene amplification was not seen. Segmental chromosomal aberrations were not examined in this study.
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 the antibody's antineuroblastoma activity, are often used to help treat neuroblastoma. The clinical effectiveness of one such antibody led to U.S. Food and Drug Administration approval of dinutuximab. The patient response to immunotherapy may, in part, be caused by variation in immune function among patients. One anti-GD2 antibody, termed 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 (KIR) subtypes.[64,65] This finding was confirmed and expanded by an analysis of outcomes for patients treated on the national randomized COG-ANBL0032 (NCT00026312) study with the anti-GD2 antibody dinutuximab combined with granulocyte-macrophage colony-stimulating factor and interleukin-2. The study found that certain KIR/KIR-ligand genotypes were associated with better outcomes for patients who were treated with immunotherapy.[Level of evidence: 1A] The presence of inhibitory KIR/KIR ligands was associated with a decreased effect of immunotherapy. Thus, the patient's immune system genes help determine response to immunotherapy for neuroblastoma. Additional studies are needed to determine whether this immune system genotyping can guide patient selection for certain immunotherapies.
The most frequent signs and symptoms of neuroblastoma are caused by tumor mass and metastases and include the following:
The clinical presentation of neuroblastoma in adolescents is similar to the clinical presentation 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. Of young children presenting with opsoclonus/myoclonus syndrome, about one-half are found to have neuroblastoma.[72,73] The incidence in the United Kingdom is estimated at 0.18 cases of opsoclonus/myoclonus per 1 million children per year and the average age at diagnosis is 1.5 to 2 years.
The usual presentation is the onset of progressive neurologic dysfunction over a few days before a neuroblastoma is discovered, but, occasionally, neurologic symptoms arise long after removal of the primary tumor.[72,75,76] Neuroblastoma patients who present with opsoclonus/myoclonus syndrome often have neuroblastoma with favorable biological features and have excellent survival rates, although tumor-related deaths have been reported.
Genomic copy number profiles were analyzed in 44 cases of neuroblastoma associated with opsoclonus/myoclonus syndrome. Because there were no tumor relapses or disease-related deaths, the overall genomic profile was not of prognostic significance.
The opsoclonus/myoclonus syndrome appears to be caused by an immunologic mechanism that is not yet fully characterized. The primary tumor is typically diffusely infiltrated with lymphocytes. Cerebrospinal fluid shows increased number of B cells, and oligoclonal immunoglobulin bands are often seen. Steroid-responsive elevations of B-cell–related cytokines are also often seen.
Some patients may rapidly respond neurologically to immune interventions or simply to removal of the neuroblastoma, but in many cases, improvement may be slow and partial. The improvement in acutely presenting motor deficits and ataxia seen with immunological therapy is not clearly associated with improvement in long-term neuropsychological disability, which primarily consists of cognitive and behavioral deficits. The long-term benefits of rapid improvement resulting from treatment, whether of symptoms or of the underlying neuroblastoma, are unclear, but rapid improvement appears to be worthwhile.[76,80]
Treatment with adrenocorticotropic hormones or corticosteroids can be effective for acute symptoms, but some patients do not respond to corticosteroids.[75,81] Other therapy with various immunomodulatory drugs, plasmapheresis, intravenous gamma globulin, and rituximab have been reported to be effective in select cases.[75,82,83,84,85] Combination immunosuppressive therapy has been explored, with improved short-term results. The short-term neurologic outcomes may be superior in patients treated with chemotherapy, possibly because of its immunosuppressive effects.
The first randomized, open-label, phase III study of patients with opsoclonus/myoclonus ataxia syndrome has been completed by the Children's Oncology Group (COG). Patients with newly diagnosed neuroblastoma and opsoclonus/myoclonus ataxia syndrome who were younger than 8 years were randomly assigned to receive either intravenous immunoglobulin (IVIG) or no IVIG in addition to prednisone and risk-adapted treatment of the tumor. Of the 53 patients who participated, 21 of 26 patients (81%) in the IVIG group had an opsoclonus/myoclonus ataxia syndrome response over a period of weeks to months, compared with 11 of 27 patients (41%) in the non-IVIG group (odds ratio [OR], 6.1; P = .0029). This study demonstrates that short-term neurologic response is improved in patients treated with chemotherapy, corticosteroids, and immunoglobulin, compared with patients treated with chemotherapy and corticosteroid without immunoglobulin. Additional follow-up is needed to assess long-term neurodevelopment and learning problems in this population.
Diagnostic evaluation of neuroblastoma includes the following:
Metaiodobenzylguanidine (MIBG) scanning is a critical part of the standard diagnostic evaluation of neuroblastoma, for both the primary tumor and sites of metastases.[88,89] MIBG scanning is also critical to assess response to therapy. About 90% of neuroblastoma cases are MIBG avid; 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. (Refer to the Stage Information for Neuroblastoma section of this summary for more information about imaging of neuroblastoma.)
In contrast to urine, 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. However, every attempt should be made to obtain an adequate biopsy from the primary tumor.
Diagnosis of fetal/neonatal neuroblastoma. In rare cases, neuroblastoma may be discovered prenatally by fetal ultrasonography. Management recommendations are evolving regarding 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 of 3.1 cm or less 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. Therefore, prenatally identified adrenal masses approximately 3.1 cm or less can be safely observed if no metastatic disease is identified and there is no involvement of large vessels or organs.
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:
The prognosis for patients with neuroblastoma is related to the following:
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.)
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 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 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 patients diagnosed from 1990 to 1999. (Refer to Table 1 for more information.) Similarly, the COG ANBL0531 (NCT00499616) study found equivalent outcomes for many subsets of intermediate-risk children who were treated with substantially reduced chemotherapy, when compared with the earlier COG-A3961 (NCT00003093) study.
Age at diagnosis
Infants and children
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:
The effect of patient age on prognosis is strongly influenced by clinical and pathobiological factors, as evidenced by the following:
Adolescents and young adults
Adolescents and adults rarely develop neuroblastoma, accounting for less than 5% of all cases. When neuroblastoma occurs in this age range, it shows a more indolent clinical course than does neuroblastoma in younger patients, and it shows de novo chemotherapy resistance. Neuroblastoma in adolescents and young adults may also exhibit unusual clinicopathologic characteristics such as large tumors, bilateral adrenal disease, and pheochromocytoma-like features.[Level of evidence: 3iii] Neuroblastoma has a worse long-term prognosis in adolescents older than 10 years or in adults, regardless of stage or site.
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.[37,38,102] In adolescents, approximately 40% of the tumors will have loss-of-function mutations in ATRX, compared with less than 20% in younger children and 0% in infants younger than 1 year. Complex DNA microarray findings and novel mutations have been reported in some patients.[Level of evidence: 3iii]
The 5-year OS rate for adolescent and young adult patients (aged 15–39 years) is 38%.[Level of evidence: 3iA] 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 OS rate is 5%. Aggressive chemotherapy and surgery have been shown to achieve a minimal disease state in more than 50% of these patients.[70,105] 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.[104,105]
The biology of adult-onset neuroblastoma appears to differ from the biology of pediatric or adolescent neuroblastoma based on a single-institution series of 44 patients (aged 18–71 years). Genetic abnormalities in adult patients included somatic ATRX (58%) and ALK mutations (42%) but no MYCN amplification. Germline testing was performed in four patients, two of whom had aberrations (one patient with a BRCA1 mutation, the other patient with TP53 and NF1 mutations). In the 11 patients with locoregional disease, 10-year progression-free survival (PFS) was 35%, and OS was 61%. Among 33 adults with stage 4 neuroblastoma, 7 (21%) patients achieved a complete response (CR) after induction chemotherapy and/or surgery. In patients with stage 4 disease at diagnosis, the 5-year PFS was 10% and most patients who were alive with disease at 5 years died of neuroblastoma over the next 5 years; 10-year OS was 19%. CR after induction was the only prognostic factor for PFS and OS. Anti-GD2 immunotherapy (m3F8 or hu3F8) was well tolerated in adults.
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 and undifferentiated tumor cells are considered prognostically unfavorable histologic characteristics, but the prognostic value is age dependent.[110,111]
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%.
(Refer to the Genomic and Biologic Features of Neuroblastoma section of this summary for more information.)
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, confirming much smaller, previous studies with less complete clinical and biological data:
Using the Therapeutically Applicable Research to Generate Effect Treatments (TARGET) and genome-wide association study datasets, a study compared the genomic and epigenomic data of primary diagnostic neuroblastomas originating in the adrenal gland (n = 646) with that of neuroblastomas originating in the thoracic sympathetic ganglia (n = 118). Neuroblastomas arising in the adrenal gland were more likely to harbor structural DNA aberrations such as MYCN amplification, whereas thoracic tumors showed defects in mitotic checkpoints resulting in hyperdiploidy. Thoracic tumors were more likely to harbor gain-of-function ALK aberrations than were adrenal tumors among all cases (OR, 1.89; P = .04), and among cases without MYCN amplification (OR, 2.86; P = .003). Because 16% of thoracic tumors harbor ALK mutations, routine sequencing for these mutations in this setting should be considered.
In the TARGET cohort, 70% of patients with adrenal primary tumors and 51% of patients with thoracic primary tumors were stage 4; in the genome-wide association study without MYCN amplification, 43% of patients with adrenal primary tumors and 17% of patients with thoracic primary tumors were stage 4. By multivariate analysis, adrenal site was an independent predictor of worse outcome in the genome-wide association study cohort but not in the TARGET cohort after adjusting for MYCN amplification status, disease stage, and age of at least 18 months. Adrenal neuroblastoma was not an independent predictor of worse EFS by similar multivariable analysis for either the genome-wide association study or TARGET cohorts.
It is not clear whether the effect of primary neuroblastoma tumor site on prognosis is entirely dependent on the differences in tumor biology associated with tumor site.
Multifocal 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.
Stage of disease
Several imaged-based and surgery-based systems were used for assigning disease stage before the 1990s. In an effort to facilitate comparison of results obtained throughout the world, a surgical pathologic staging system, termed the International Neuroblastoma Staging System (INSS), was developed. The INSS predicted outcome on the basis of stage at diagnosis, although important interactions with biological variables were also found.[2,3,4,7,42,43,94,98,99] However, because surgical approaches differ from one institution to another, INSS stage for patients with locoregional disease may also vary considerably. More recently, to define extent of disease at diagnosis in a uniform manner, a presurgical International Neuroblastoma Risk Group staging system (INRGSS) was developed for the International Neuroblastoma Risk Group Classification System.[30,114] The INRGSS is currently used in North American and European cooperative group studies. Unlike the INSS, the INRGSS stage is not affected by locoregional lymph node involvement.
Refer to the following sections of this summary for more information:
Response to treatment
Response to treatment has been associated with outcome. In patients with intermediate-risk disease who had a poor response to initial therapy in the COG ANBL0531 (NCT00499616) study, 6 of 20 patients subsequently developed progressive or recurrent disease, and one patient died. 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.[115,116,117] Similarly, the persistence of MIBG-avid tumor measured as Curie score greater than 2 (refer to the Curie score and SIOPEN score section of this summary for more information about Curie scoring) after completion of induction therapy predicts a poor prognosis for patients with MYCN-nonamplified high-risk tumors. A Curie score greater than 0 after induction therapy is associated with a worse outcome for high-risk patients with MYCN-amplified disease.[118,119]
Treatment-associated decrease in mitosis and increase in histologic differentiation of the primary tumor are also prognostic of response.
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 chemotherapy, surgical removal of the primary tumor, radiation to the tumor bed, high-dose myeloablative therapy plus stem cell transplant, and, in most cases, isotretinoin and anti-GD2 antibody immunotherapy enhanced by cytokines. Primary tumor response was measured after induction chemotherapy 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.
Levels of LDH and ferritin
Higher serum LDH and ferritin values conferred worse 5-year EFS and OS rates in a large international cohort of patients diagnosed with neuroblastoma (n > 8,575) from 1990 to 2016. Higher serum values for LDH and ferritin also conferred worse 3-year EFS and OS rates in patients with high-risk neuroblastoma after 2009. In a multivariate analysis that adjusted for age at diagnosis, MYCN status, and INSS stage IV disease, LDH and ferritin maintained independent prognostic ability (P < .0001).[Level of evidence: 3iii]
Although not critically evaluated in the original INRG classification system, subsequent analysis of the INRG Data Commons has clearly demonstrated independent statistical significance of the levels of serum ferritin and LDH on prognosis in all patients and in high-risk patients, including in the time period between 2010 and 2016. Therefore, it was suggested that these two easily obtainable lab values be incorporated into the prognostic classification system of the INRG.
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,[125,126] the expression of the H-Ras protein, 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 ultrasonography often have tumors that spontaneously regress and may be observed safely without surgical intervention or tissue diagnosis.[129,130,131]
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 was derived from the experience with the original Shimada classification, and the two systems are compared in Table 1. The INPC 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]
Most neuroblastomas with MYCN amplification in the INPC system also have unfavorable histology, but about 7% have favorable histology. Of neuroblastoma tumors with MYCN amplification and favorable histology, most do not express MYCN, despite the gene being amplified, and these patients have a more favorable prognosis than do patients whose tumors do express MYCN.
Data from the INRG Data Commons (18,865 patients) were analyzed to validate the independent prognostic ability of age at diagnosis, histologic category, MKI, and grade of differentiation. Four histologic prognostic groups of patients were identified (aged <18 months with low vs. high MKI; aged >18 months with differentiating vs. undifferentiating/poorly differentiating tumors). By using a risk schema devoid of the confounding of age and INPC, this analysis identified a novel and unfavorable subgroup of patients older than 547 days with stage 1 or 2, MYCN-nonamplified, intermediate or high MKI diploid tumors who had a very poor event-free survival (EFS) rate (EFS rate, 46%).[Level of evidence: 3iii]
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:[10,11]
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.
Imaging with 123I-MIBG is optimal for identifying soft tissue and bony metastases and was shown to be superior to positron emission tomography–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 determined using 123I-MIBG or PET scanning. It was concluded that 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 patients with newly diagnosed neuroblastoma demonstrated that for International Neuroblastoma Staging System (INSS) stage 1 and stage 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 and SIOPEN scoring methods
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.
The prognostic significance of postinduction Curie scores has been validated in an independent cohort of patients. A retrospective study of Curie scoring of 123I-MIBG scans obtained from high-risk patients who had been prospectively enrolled in the SIOPEN/HR-NBL1 (NCT00030719) trial was performed. Scans of ten anatomic regions were evaluated, with each region being scored 0 to 3 on the basis of disease extent, and a cumulative Curie score generated. The optimal prognostic cut point for Curie score at diagnosis was 12 in SIOPEN/HR-NBL1, with a significant outcome difference by Curie score noted (5-year event-free survival [EFS] rate, 43.0% ± 5.7% [Curie score ≤12] vs. 21.4% ± 3.6% [Curie score >12], P < .0001). The optimal Curie score cut point after induction chemotherapy was 2 in SIOPEN/HR-NBL1, with a postinduction Curie score of greater than 2 being associated with an inferior outcome (5-year EFS rate, 39.2% ± 4.7% [Curie score ≤2] vs. 16.4% ± 4.2% [Curie score >2], P < .0001). The postinduction Curie score maintained independent statistical significance in Cox models when adjusted for the covariates of age and MYCN gene copy number.
The German Pediatric Oncology Group compared the prognostic value of the Curie and SIOPEN scoring methods in a retrospective study of 58 patients with stage 4 neuroblastoma who were older than 1 year. They demonstrated very similar results. At diagnosis, a Curie score of 2 or lower and a SIOPEN score of 4 or lower (best cutoff) at diagnosis correlated with significantly better EFS and overall survival (OS) rates, compared with higher scores. After four cycles of induction chemotherapy, patients with a complete response by SIOPEN and Curie scoring had a better outcome than did patients with residual uptake in metastases; however, subsequent resolution of MIBG-positive metastases occurring between the fourth and sixth cycles of chemotherapy did not affect prognosis.
The cited clinical trials did not include postinduction-phase assessments of Curie or SIOPEN scores after transplant and immunotherapy, and cutoffs and outcomes associated with those assessments may differ from the preinduction and postinduction scores.
Positron emission tomography (PET) scan
Fluorine F 18-fludeoxyglucose PET scans are used to evaluate extent of disease in patients with tumors that are not MIBG avid.
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 staging systems [1,15] and is described in Table 3. This system 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 is used to assess the extent of resection in staging 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.[1,15,16,17]
The COG Neuroblastoma Risk Grouping that incorporates INSS is described in Table 6 found in the Treatment Option Overview for Neuroblastoma section of this summary.
A study from the INRG database identified 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 final use of the INSS by the COG was for the intermediate-risk ANBL0531 (NCT00499616) study, which was closed in 2014. Subsequent studies have used the INRGSS. The INRGSS is a preoperative staging system that was developed specifically for the INRG classification system (refer to Table 4). This staging system has replaced the INSS in active COG and SIOPEN clinical trials. The extent of disease is determined by the presence or absence of 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, as defined in the original literature, include the following:[20,22]
COG IDRFs, using an anatomic localization approach, include the following:[21,23]; [Level of evidence: 3iiiC]
Assessment of surgical resectability should include IDRFs. The more IDRFs present, the higher the morbidity of the operation and the lower the chance of complete resection.
Neoadjuvant chemotherapy is not always effective in eliminating IDRFs, as seen in a retrospective study in the European Unresectable Neuroblastoma trial from 2001 to 2006 that examined data from 143 patients with INSS stage 3 neuroblastoma who were older than 1 year without MYCN amplification. All patients had surgical risk factors that deemed the tumors unresectable. In a centrally reviewed subset, unfavorable histology by International Neuroblastoma Pathology Classification was found in 53% of patients. At diagnosis, 228 IDRFs were identified.; [Level of evidence: 3iiA]
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 lists of IDRFs [original IDRFs and COG 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. The INRG collaboration has also defined techniques for detecting and quantifying neuroblastoma in bone marrow, both at diagnosis and after treatment. Quantification of bone marrow metastatic disease may result in more accurate assessment of response to treatment, but has not yet been applied to any clinical trials.
The decision by the INRG Task Force to replace the category of 4S disease with that of the new MS definition was based on reports in which small numbers of infants with L2 primary tumors and 4S metastatic patterns, including those aged 12 to 18 months, had favorable outcomes.[18,20] A subsequent study of the actual INRG data found that a number of biological characteristics predicted poor outcome of MS patients (aged 12 to 18 months), and that only those infants with favorable biology had long-term outcomes similar to those with the traditional 4S diagnosis.
By combining the INRGSS, preoperative IDRFs, and biological factors, each patient is assigned a risk stage that predicts outcome and dictates the appropriate treatment approach. The validity of the INRGSS was explored in the following retrospective studies of localized neuroblastoma with previously defined INSS stage without MYCN amplification:
Most international protocols have begun to incorporate the collection and use of IDRFs in risk stratification and assignment of therapy.[28,29] 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 subsets of patients not at high risk, including those with L1, L2, and MS disease (ANBL1232 [NCT02176967]). 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. In August 2018, a COG study for subsets of high-risk patients was opened (ANBL1531 [NCT03126916]). Eligible patients include those with stage M disease older than 547 days, stage M patients younger than 547 days with MYCN amplification, and patients of any age with stage L2 or MS disease with MYCN amplification. 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.
Most children with neuroblastoma in North America have been treated according to the Children's Oncology Group (COG) risk-group assignment, even if they were not enrolled in a COG study. In contrast, in the ongoing COG studies, the International Neuroblastoma Risk Group (INRG) risk grouping is 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 risk grouping using the International Neuroblastoma Risk Group Staging System (INRGSS) and the 2007 COG risk stratification system that uses the International Neuroblastoma Staging System (INSS), as described in the COG biology study ANBL00B1 (NCT00904241). The COG is in the process of revising the COG risk stratification schema and the next version will be based on the INRGSS.
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) on the basis of the following factors:[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. This does not correspond to the INRGSS, which only includes 11q abnormalities; however, the criteria may change in future versions.
Generally, treatment is based on whether the tumor is classified as low, intermediate, or high risk, as follows:
Table 5 describes the treatment options for low-risk, intermediate-risk, high-risk, stage 4S, and recurrent neuroblastoma by INSS-based risk group.
Children's Oncology Group (COG) Neuroblastoma Risk Grouping
The treatment sections of this summary are 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 in use for the ongoing ANBL1232 (NCT02176967) COG study, while the ANBL1531 (NCT03126916) study of high-risk neuroblastoma is 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 low-risk COG-P9641 trial, the intermediate-risk COG-A3961 and ANBL0531 (NCT00499616) trials, and the high-risk COG-A3973 and ANBL0532 (NCT00567567) studies.
Assessment of risk for low-stage MYCN-amplified neuroblastoma is controversial because it is so rare. A study of 87 patients with INSS stage 1 and stage 2 neuroblastoma pooled from several clinical trial groups demonstrated no effect of age, stage, or initial treatment on outcome. The 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 classification schema assigns neuroblastoma patients to one of 16 pretreatment risk groups on the basis of INRG stage, age, histologic category, grade of tumor differentiation, MYCN amplification, 11q aberration (the only segmental chromosomal aberration studied), and ploidy. Four levels of risk were defined according to outcomes among 8,800 patients with high-quality data, as they had been entered in 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 of the INRG are to develop shared data from the patients in clinical trials and to define risk groups for future trials.
Controversy exists regarding the current COG risk grouping system, the INRG Risk Grouping Schema, and the treatment of certain small subsets of patients.[17,18,19] Risk group definitions of very low-, low-, intermediate-, and high-risk subsets and the recommended treatments are expected to evolve as new biomarkers are identified and 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.[20,21,22] Future versions of the INRG are expected to contain more tumor genomic criteria to help assign risk.
Revised International Neuroblastoma Response Criteria (INRC)
In COG clinical trials, 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.[23,24,25] The revised INRC depend on the use of three-dimensional (3-D) imaging combined with the following:
Technetium Tc 99m (99mTc) bone scans are no longer used because a retrospective study of 132 patients who received both MIBG and 99mTc scans showed no staging benefit.
Overall response in the revised INRC integrates tumor response of the primary tumor, bone marrow, and soft tissue and bone metastases. Primary and metastatic soft tissue sites are assessed using Response Evaluation Criteria in Solid Tumors (RECIST) and iodine I 123 (123I)-MIBG scans or fluorine F 18-fludeoxyglucose (18F-FDG) PET scans if the tumor is MIBG non-avid. Bone marrow is assessed by histology, immunohistochemistry and cytology, or immunocytology with the help of immunorecognition tools. Bone marrow with less than 5% tumor involvement is classified as minimal disease. Urinary catecholamine levels are not included in response assessment.
The overall INRC response criteria are defined as follows:[23,24]
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 (involvement of skin, liver, and/or bone marrow, the latter less than 10% involved), these patients are not classified as having progressive/metastatic disease, which would typically be a criterion for removal from protocol therapy. Instead, these patients are managed as stage 4S patients.
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 equally 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, on the basis of the stage and the risk group, to accomplish the following:
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.
In patients with L1 tumors (defined as having no image-defined surgical risk factors), the tumors are resectable and resection is less likely to result in surgical complications. L2 tumors, which have at least one image-defined surgical risk factor, are 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.
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.[31,32,33,34,35,36] A meta-analysis of stage 3 versus stage 4 neuroblastoma patients, at all ages combined, found an advantage for gross-total resection (>90%) 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 image-defined risk factors remaining. When an experienced surgeon performed the procedure, a 90% or greater resection of the primary tumor in stage 4 neuroblastoma resulted in a higher local control rate, but did not have a statistically significant impact on OS.
In the current treatment paradigm, 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:
Radiation therapy has become part of the standard of care for patients with high-risk disease and is usually delivered after high-dose chemotherapy and stem cell rescue. The basis for this approach initially came from a single-institution report that demonstrated only a 10% primary site relapse with administration of 21 Gy of radiation therapy. Subsequent cooperative group trials have incorporated posttransplant primary tumor bed irradiation, although the optimal dose remains uncertain.
Treatment of Spinal Cord Compression
Spinal cord compression is considered a medical emergency. Patients receive immediate treatment because neurologic recovery is more likely when symptoms are present for a relatively short 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.[41,43,44] In a single study in this setting looking at the effect of glucocorticoids on neurological outcome, it was associated with improved early symptom relief. However, glucocorticoids did not prevent late residual impairment.
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.[41,43,44] 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 neurologic deficit is improved with laminoplasty.
The burden of long-term health problems in survivors of neuroblastoma with intraspinal extension is high. In a systematic review of 28 studies of treatment and outcome of patients with intraspinal extension, the severity of the symptoms at diagnosis and the treatment modalities were most associated with the presence of long-term health problems. In particular, the severity of neurological motor deficit was most likely to predict neurological outcome. The severity of motor deficit at diagnosis is associated with spinal deformity and sphincter dysfunction at the end of follow-up, while sphincter dysfunction at diagnosis was correlated with long-term sphincter problems. This supports the initiation of treatment before symptoms have deteriorated to complete loss of neurological function.
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 patients.
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 vanillylmandelic acid and homovanillic acid testing, one of the most reliable imaging tests to detect disease progression or recurrence is the 123I-MIBG scan.[49,50]
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
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 schema for very low-risk or low-risk neuroblastoma used in current COG studies, including the ANBL1232 (NCT02176967) study for low-risk and intermediate-risk patients.
(Refer to the Treatment of Stage 4S Neuroblastoma section of this summary for more information about the treatment of patients with 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 after surgery is not considered a risk factor for relapse and chemotherapy is not indicated. 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] Some patients with presumed neuroblastoma have been observed without biopsy; this strategy is being studied further by the COG in the ANBL1232 (NCT02176967) trial.[4,5]
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.
Evidence (surgery followed by observation):
Chemotherapy with or without surgery
Chemotherapy with or without surgery is used to treat the following:
Patients with stage 2B disease had a lower EFS and OS for those with unfavorable histology (EFS, 72%; OS, 86%) or diploid tumors (EFS, 75%; OS, 84%) or for patients older than 18 months. Outcomes for patients with stage 2B, diploid tumors, and unfavorable histology were particularly poor (EFS, 54%; OS, 70%), with no survivors among the few patients who had additional 1p loss of heterozygosity, and all of the deaths occurred in children older than 18 months.
For patients treated with surgery alone, the 5-year EFS rate was 89%, and the OS estimate was 97%; for patients treated with surgery and immediate chemotherapy, the 5-year EFS rate was 91%, and the OS estimate was 98%.
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 ultrasonography 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 under way in the COG ANBL1232 (NCT02176967) study (refer to Table 9).
Evidence (observation without biopsy):
Controversy exists 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 stage 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 therapy, and many patients did not progress locally and never underwent an additional resection. This cohort is also being evaluated in the COG ANBL1232 (NCT02176967) study (refer to the Treatment Options Under Clinical Evaluation section of this summary for more information). Infants younger than 18 months who have L2 tumors with favorable biology are being observed after tumor biopsy.
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. They are mostly derived from the COG-A3961 (NCT00003093) study and were used in the COG ANBL0531 (NCT00499616) study.
The COG-A3961 (NCT00003093) intermediate-risk study results, associated with results from European studies, were used to redefine the intermediate-risk groupings used in the ANBL0531 (NCT00499616) trial. Modifications of the ANBL0531 risk grouping for the ongoing ANBL00B1 (NCT00904241) biology study are shown in Table 10.
Table 11 shows the International Neuroblastoma Risk Group (INRG) classification for intermediate-risk neuroblastoma used in ongoing 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 neoadjuvant 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, ANBL0531 [NCT00499616]). 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. The COG ANBL0531 (NCT00499616) study successfully further reduced the duration and intensity of chemotherapy for multiple subsets of children with intermediate-risk tumors.
In cases of abdominal neuroblastoma thought to involve the kidney, nephrectomy is not undertaken before a course of chemotherapy has been given.
Whether initial chemotherapy is indicated for all intermediate-risk infants with localized neuroblastoma requires further study.
Evidence (chemotherapy with or without surgery):
The A3961 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.
The ANBL0531 (NCT00499616) study treated a similar MYCN-nonamplified, age- and stage-defined group of 404 children and reduced the duration and intensity of chemotherapy for several subsets of patients. The study added stage 4 patients with favorable biology who were aged 12 to 18 months.
Surgery and observation (in infants)
The need for chemotherapy in all asymptomatic infants with stage 3 or stage 4 disease is controversial, as some European studies have shown favorable outcomes with surgery and observation.
Evidence (surgery and observation in infants):
Radiation therapy for children with intermediate-risk disease is reserved for patients with progressive disease during treatment with chemotherapy or progressive unresectable disease after treatment with chemotherapy.
In a prospective randomized COG trial that tested reduced-intensity chemotherapy for patients with intermediate-risk neuroblastoma, only 12 of 479 patients (2.5%) received local radiation therapy (21 Gy). One patient had stage 4S disease, five patients had stage 3 disease, and six patients had stage 4 disease. Radiation therapy was administered for clinical deterioration despite initial therapy (eight patients), residual macroscopic disease and unfavorable biologic features (three patients), or relapse after therapy (one patient).[1,11,12]
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 used in ongoing COG studies, including ANBL1531 (NCT03126916).
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, the 5-year OS with current treatments is about 50% for patients diagnosed between 2005 and 2010.[1,3] 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 INRG 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, tandem cycles of 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 and cyclophosphamide were 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.[9,10,11] In a multivariable analysis of 407 patients from four consecutive COG high-risk trials, 11q loss of heterozygosity was shown to be a significant predictor of progressive disease and lack of 11q loss of heterozygosity was associated with both higher rates of end-induction complete response and end-induction partial response.[Level of evidence: 3iii]
A European prospective randomized controlled trial investigated extended induction therapy in patients with newly diagnosed high-risk neuroblastoma. Patients were randomly assigned to receive either standard induction chemotherapy with six chemotherapy courses or experimental induction chemotherapy that began with two additional courses of topotecan, cyclophosphamide, and etoposide followed by standard induction chemotherapy. In the 422 randomized patients, the 3-year EFS rate was 34% for patients who received the experimental induction regimen and 32% for patients who received the standard induction regimen. The addition of two topotecan-containing chemotherapy courses did not improve the EFS of patients with high-risk neuroblastoma and resulted in more toxicity per patient.[Level of evidence: 1iiDiv]
In a separate study, the addition of dinutuximab anti-GD2 treatment with GM-CSF and low-dose IL-2, given with each induction chemotherapy course, had encouraging outcomes in 42 children with newly diagnosed stage IV disease. This induction therapy, followed by standard consolidation and postconsolidation therapy, produced early partial responses or better in most patients, reduced tumor volumes, and improved Curie scores at the end of induction.
After a response to induction chemotherapy, resection of the primary tumor is usually attempted. Whether a gross-total resection is beneficial either before or after induction chemotherapy is controversial.
Evidence (resection of the primary tumor before or after chemotherapy):
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. Several studies have reported that complete resection of the primary tumor at diagnosis improved survival; however, the outcome in these patients may be more dependent on the biology of the tumor, which itself may determine resectability, than on the extent of surgical resection.[17,18,19] In stage 4 patients older than 18 months, controversy exists about whether there is any advantage to gross-total resection of the primary tumor after chemotherapy.[15,18,19,20] However, in some studies, patients who underwent incomplete resections fared less well than those who underwent complete resections; these outcomes could have resulted from either the biology of unresectable tumors or reduction of tumor bulk.[Level of evidence: 1iiDii]
The consolidation phase of high-risk regimens involves myeloablative chemotherapy and SCT, which attempts to eradicate minimal residual disease (MRD) using otherwise lethal doses of ablative chemotherapy rescued by 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 treatment with SCT (31% to 47%) versus conventional chemotherapy (22% to 31%).[22,23,24] Previously, total-body irradiation had been used in SCT conditioning regimens. Most current protocols use tandem chemotherapy and SCT or 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) is indicated after myeloablative therapy. Boost radiation therapy for gross-residual disease was not shown to improve local control when studied prospectively in the ANBL0532 (NCT00567567) trial.[Level of evidence: 3iiiA]
Evidence (radiation therapy with a boost vs. radiation therapy without a boost for incomplete resection):
Treatment of persistently metaiodobenzylguanidine (MIBG)-positive metastatic sites after induction therapy 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 often 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 by MIBG uptake after induction chemotherapy in high-risk patients. In cases where diffuse bone metastases remain after induction chemotherapy, high-dose chemotherapy is followed by reassessment before consolidative radiation therapy. Irradiation of more than 50% of the bone marrow is not advised.
Preliminary outcomes of proton radiation therapy to treat high-risk neuroblastoma primary tumors have been published, demonstrating acceptable efficacy and toxicity.
Postconsolidation therapy is designed to treat potential MRD after SCT. Radiation therapy has been used to treat the primary site and sometimes to areas of incompletely resolved metastases. 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.[35,36]
Evidence (all treatments):
Radiation therapy to consolidate local control after surgical resection of the primary tumor (whether or not a complete excision was obtained) and myeloablative therapy is often given.[42,43]; [Level of evidence: 3iiA] The optimal dose of radiation therapy has not been determined. Extensive lymph node irradiation, regardless of the extent of surgical resection preceding SCT did not provide a benefit to patients for local progression or OS.[Level of evidence: 3iii]
Treatment of bony metastatic disease is also considered to maximize disease control, delivered at the time of primary tumor bed irradiation. Radiation therapy to metastatic disease sites is determined on an individual basis or according to protocol guidelines for patients enrolled in studies. Many children present with widespread bony metastases. Because it is not feasible to irradiate all initial sites, the current practice is to treat the sites that have not responded, as assessed by MIBG before SCT.[31,46,47] 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 by MIBG uptake after induction chemotherapy in high-risk patients. Irradiation of more than 50% of the bone marrow is not advised.
In cases where diffuse bone metastases remain after induction chemotherapy, high-dose chemotherapy is followed by reassessment before deciding on consolidative radiation therapy.
Preliminary outcomes of proton radiation therapy to treat patients with high-risk neuroblastoma primary tumors have been published, demonstrating acceptable efficacy and toxicity.
Radioactive MIBG therapy has been used to treat recurrent neuroblastoma with some success, and some trials that are incorporating it into the complex therapy for newly diagnosed high-risk neuroblastoma are under way. A Netherlands trial found that although the administration of 131I-MIBG before other chemotherapy was feasible, it resulted in the loss of stem cells in the bone marrow (collected after 131I-MIBG was given) after thawing, which delayed platelet engraftment after autologous SCT.[Level of evidence: 3iii]
A multi-institution phase II clinical trial of children with high-risk neuroblastoma explored maintenance therapy using difluoromethylornithine (DFMO), an ornithine decarboxylase inhibitor. Although the study claimed that survival was improved compared with a subset of patients who were previously treated in the ANBL0032 (NCT00026312) trial, the historical comparison and the potential patient selection bias limit the validity of this finding. In the absence of randomized data, the value of the addition of DFMO to the multidisciplinary treatment of children with neuroblastoma cannot be ascertained. Further studies of DFMO therapy for patients with neuroblastoma are planned, and some trials are under way.
Patients with the ALK gene mutation or ALK amplification will receive nonrandomized COG current standard induction chemotherapy with the ALK inhibitor crizotinib added, followed by further therapy on the standard COG treatment plan.
Patients with MIBG nonavid, ALK nonaberrant tumors will receive standard current chemotherapy as in arm A above.
The classification for the ANBL1531 trial is based on the INRG staging system.
Boost radiation was discontinued in this trial because no clear benefit over historical controls was apparent.
International Neuroblastoma Staging System (INSS) stage 4S patients are younger than 12 months and have an INSS stage 1 or stage 2 primary tumor, whereas International Neuroblastoma Risk Group (INRG) stage MS patients are younger than 18 months with any stage of primary tumor. Both staging systems have the same definition of limited pattern of metastases.
The decision by the INRG Task Force to replace the category of 4S disease with that of the new MS definition was based on reports in which small numbers of infants with L2 primary tumors and 4S metastatic patterns, including patients aged 12 to 18 months, had favorable outcomes.[1,2] A subsequent study of the actual INRG data found that a number of biological characteristics predicted poor outcome of patients aged 12 to 18 months with stage MS disease, and that only those infants with favorable biology had long-term outcomes similar to those with the traditional 4S diagnosis.
Many patients with stage 4S/MS neuroblastoma do not require therapy. However, tumors with unfavorable biology or patients who are symptomatic because of 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 INRG classification for stage MS neuroblastoma used in ongoing COG studies.
Treatment Options for Stage 4S/MS Neuroblastoma
There is no standard approach to the treatment of stage 4S/MS neuroblastoma.
Treatment options for stage 4S/MS neuroblastoma include the following:
Resection of primary tumor is not associated with improved outcome.[5,6,7] Rarely, infants with massive hepatic 4S/MS neuroblastoma develop cirrhosis from the chemotherapy and/or radiation therapy that is used to control the disease and may benefit from orthotopic liver transplant.
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/MS disease is dependent on clinical presentation.[5,6] Most patients do not require therapy unless bulky disease is causing organ compromise and risk of death.
Chemotherapy is used to treat symptomatic patients, very young infants (diagnosed before age 2 months), or patients with unfavorable biology. Patients with evidence of rapid tumor growth in the first several weeks of life require immediate intervention with chemotherapy to avoid potentially irreversible abdominal compartment syndrome and hepatic and/or renal failure.
Infants diagnosed with INSS stage 4S/MS neuroblastoma, particularly those with hepatomegaly or those younger than 3 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.
A scoring system to measure signs and symptoms of deterioration or compromise was developed to better assess this group of stage 4S patients. This scoring system has been evaluated retrospectively, was predictive of the clinical course, and has been applied prospectively to guide the management of patients with INSS stage 4S disease.[10,11] The scoring system has been modified on the basis of the ANBL0531 (NCT00499616) results in the youngest infants discussed above to guide chemotherapeutic intervention for 4S/MS in infants.
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 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 4S/MS disease):
Emergent surgical abdominal decompression can be used to avoid respiratory deterioration and improve ventilation.[12,13]
Previously, chemotherapy toxicity was thought to be responsible for the poorer survival of patients with stage 4S disease; however, the use of chemotherapy on the COG-P9641 trial was restricted to specific clinical situations with a recommended number of cycles.
The chemotherapy for patients with high symptom scores included two to four 3-day courses of carboplatin and etoposide; if symptoms persisted or progressive disease developed, up to four 5-day courses of cyclophosphamide, doxorubicin, and vincristine were administered. One-half of the patients underwent complete or partial resection of the primary tumor.
Radiation therapy (for patients with symptoms related to hepatomegaly from metastatic disease)
In rare cases of marked hepatomegaly in symptomatic MS (4S) infants with neuroblastoma who were unresponsive to chemotherapy, very low-dose radiation therapy has been used. In a series of 41 symptomatic infants with MS disease, radiation therapy was administered to five infants, three of whom died.
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 potentially 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] (Refer to the Genomic and Biologic Features of Neuroblastoma section of this summary for more information).
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. The survival-tree analysis revealed the following:
Significant prognostic factors determined at diagnosis for postrelapse survival include the following:
The Children's Oncology Group (COG) experience with recurrence in patients with low-risk and intermediate-risk neuroblastoma showed 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.[13,14] 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 observation alone, surgery alone, or with moderate-dose chemotherapy, without myeloablative therapy and stem cell transplant.
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 (MRD) 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. 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.
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.
Patients 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.[13,14]
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).[13,14]
Evidence (surgery followed by observation or chemotherapy):
Metastatic recurrence or disease refractory to standard treatment
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 COG ANBL0531 (NCT00499616) study treated patients with newly diagnosed intermediate-risk neuroblastoma with chemotherapy consisting of carboplatin, etoposide, cyclophosphamide, and doxorubicin. Retrieval therapy was included in the protocol for patients who developed progressive nonmetastatic disease within 3 years of study enrollment. Up to six cycles of cyclophosphamide and topotecan could be given to patients. Of 27 patients who received cyclophosphamide and topotecan, 18 patients remained event free, 9 patients experienced relapse, and 2 patients died. Twenty patients who experienced an inadequate initial response to eight cycles of chemotherapy were treated with cyclophosphamide and topotecan. Of those 20 patients, 9 patients achieved a very good partial response or better; however, 6 patients developed progressive disease or experienced relapse, and 1 patient died. This suggests that more aggressive therapy is needed for patients who do not achieve the defined treatment endpoint after eight cycles of chemotherapy.
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 patients had metastatic recurrence, and 1 patient had both types of recurrent disease. Six of the 42 patients died of disease, while 36 patients responded to therapy. 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:
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 should be selected on the basis of previous chemotherapy received.
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.
An analysis of several trials included 383 patients with neuroblastoma whose tumor recurred or progressed on COG modern-era early-phase trials. The 1-year progression-free survival (PFS) rate was 21%, and the 4-year PFS rate was 6%, while the OS rates were 57% at 1 year and 20% at 4 years. Less than 10% of patients experienced no subsequent recurrence or progression. MYCN amplification predicted worse PFS and OS rates. 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 MRD 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:
Chemotherapy combined with immunotherapy produces the best response rate and response duration of treatments for high-risk patients with disease progression.
Evidence (chemotherapy combined with immunotherapy):
Allogeneic transplant 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 no 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 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.[40,41] 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.
A single institution had some success while testing intraventricular compartmental radioimmunotherapy using intrathecal radioiodinated anti-GD2 monoclonal antibodies combined with 18 Gy or 21 Gy of craniospinal irradiation with boosts to gross CNS disease in patients with recurrent metastatic CNS neuroblastoma. The posttreatment 5-year CNS disease-free survival rate was about 69%, and the 5-year OS rate was about 45%.[Level of evidence: 3iiiDii]
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 NCI website and ClinicalTrials.gov website.
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.
Treatment of High-Risk Neuroblastoma
Added text about the results of a European prospective randomized controlled trial that investigated extended induction therapy in patients with newly diagnosed high-risk neuroblastoma (cited Berthold et al. as reference 12 and level of evidence 1iiDiv).
Added text to state that in one study, the addition of dinutuximab anti-GD2 treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF) and low-dose interleukin-2 (IL-2), given with each induction chemotherapy course, had encouraging outcomes in 42 children with newly diagnosed stage IV disease. This induction therapy, followed by standard consolidation and postconsolidation therapy, produced early partial responses or better in most patients, reduced tumor volumes, and improved Curie scores at the end of induction (cited Furman et al. as reference 13).
Added text to state that in some studies, patients who underwent incomplete resections fared less well than those who underwent complete resections; these outcomes could have resulted from either the biology of unresectable tumors or reduction of tumor bulk (cited Holmes et al. as reference 21 and level of evidence 1iiDii).
Treatment of Recurrent Neuroblastoma
Added immunotherapy as a treatment option for recurrent or refractory neuroblastoma in patients initially classified as high risk. Also added text to state that novel anti-GD2 drugs have been evaluated in patients with recurrent or refractory neuroblastoma. Hu14.18 anti-GD2 has been chemically linked with IL-2 and combined with GM-CSF, and a phase II trial of this regimen reported a few durable responses (cited Shusterman et al. as reference 21).
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
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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.
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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:
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: 2021-06-04
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