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Neuroblastoma Treatment (PDQ®)

Health Professional Version
Last Modified: 08/29/2014
Table of Contents

General Information About Neuroblastoma

Cellular Classification of Neuroblastic Tumors

Stage Information for Neuroblastoma

Treatment Option Overview for Neuroblastoma

Treatment of Low-Risk Neuroblastoma

Treatment of Intermediate-Risk Neuroblastoma

Treatment of High-Risk Neuroblastoma

Treatment of Stage 4S Neuroblastoma

Recurrent Neuroblastoma

Changes to this Summary (08/29/2014)

About This PDQ Summary

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General Information About Neuroblastoma

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] 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:

  • Primary care physician.
  • Pediatric surgical subspecialists.
  • Radiation oncologists.
  • Pediatric medical oncologists/hematologists.
  • Rehabilitation specialists.
  • Pediatric nurse specialists.
  • Social workers.
  • Child life professionals.

(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.[2] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1,3,4] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[1,3,4] Childhood and adolescent cancer survivors require close follow-up since cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Incidence

Neuroblastoma is the most common extracranial solid tumor in childhood. More than 650 cases are diagnosed each year in North America.[5,6] The prevalence is about 1 case per 7,000 live births; the incidence is about 10.54 cases per 1 million per year in children younger than 15 years. About 37% are diagnosed as infants, and 90% are younger than 5 years at diagnosis, with a median age at diagnosis of 19 months.[7]

While there is no racial variation in incidence, there are racial differences in tumor biology, with African Americans more likely to have high-risk disease and fatal outcome.[8,9]

Population-based studies of screening for infants with neuroblastoma have demonstrated that spontaneous regression of neuroblastoma without clinical detection in the first year of life is at least as prevalent as clinically detected neuroblastoma.[10-12]

Anatomy

Neuroblastoma originates in the adrenal medulla or the paraspinal sites where sympathetic nervous system tissue is present.

Enlarge
Drawing shows parts of the body where neuroblastoma may be found, including the paraspinal nerve tissue and the adrenal glands. Also shown are the spine and right and left kidney.
Figure 1. Neuroblastoma may be found in the adrenal glands and paraspinal nerve tissue from the neck to the pelvis.


Risk Factors

Little is known about the events that predispose to the development of neuroblastoma. Parental exposures have not been definitively linked to neuroblastoma.

Germline deletion at the 1p36 or 11q14-23 locus is associated with neuroblastoma, and the same deletions are found somatically in sporadic neuroblastomas.[13,14]

About 1% to 2% of patients with neuroblastoma have a family history of neuroblastoma. These children are on average younger (9 months at diagnosis), and about 20% have multifocal primary neuroblastomas. The primary cause of familial neuroblastoma is a germline mutation in the ALK gene.[15] Familial neuroblastoma is rarely associated with congenital central hypoventilation syndrome (Ondine’s curse), which is caused by a germline mutation of the PHOX2B gene.[16]

Biologic and Molecular Features

Biological subtypes

On the basis of biologic factors and an improved understanding of the molecular development of the neural crest cells that give rise to neuroblastoma, neuroblastic tumors have been categorized into the following three biological types:

  • Type 1: Characterized by gains and losses of whole chromosomes. It expresses the TrkA neurotrophin receptor, is hyperdiploid, and tends to spontaneously regress.[17,18]

  • Type 2A: Characterized by copy number alterations in portions of chromosomes. Type 2A expresses the TrkB neurotrophin receptor and its ligand, has gained an additional copy of chromosome 17q, has loss of heterozygosity of 14q or 11q, and is genomically unstable.[17,18]

  • Type 2B: Generally has the MYCN gene amplified and has a gain of chromosome 17q, loss of chromosome 1p, and expression of the TrkB neurotrophin receptor and its ligand.[17,18]

These specific genetic changes may be combined with traditional clinical factors such as patient age and tumor stage to refine neuroblastoma risk classes.

Children whose tumors have lost a copy of 11q are older at diagnosis, and their tumors contain more segmental chromosome changes in gene copy number compared with children whose tumors show MYCN amplification.[19,20] Moreover, segmental chromosome changes not detected at diagnosis may be found in neuroblastomas at relapse. This suggests that clinically important tumor progression is associated with accumulation of segmental chromosomal alterations.[21]

Molecular features

Approximately 6% to 10% of sporadic neuroblastomas carry somatic ALK-activating mutations, and an additional 3% to 4% have a high frequency of ALK gene amplification. The mutations result in constitutive phosphorylation of ALK, leading to dysregulation of cell signaling and uncontrolled proliferation of the ALK-mutant neuroblasts. Thus, inhibition of ALK kinase is a potential target for treatment of neuroblastoma, especially in children whose tumors harbor an ALK mutation or ALK gene amplification.[22]

Genome-wide association studies in children with neuroblastoma have found common single-nucleotide polymorphisms (SNPs) associated with a modest susceptibility to develop high-risk neuroblastoma.[23,24] Other SNPs are associated with susceptibility to develop low-risk neuroblastoma.[24] SNPs associated with race predict a higher incidence of neuroblastoma and worse outcome.[25]

Large genomic studies have found few recurrent gene mutations in patients with neuroblastoma, including ALK (9.2%), PTPN11 (2.9%), ATRX (2.5%; 7.1% focal deletions), MYCN (1.7%), and NRAS (0.8%).[19,21,26,27] ATRX is involved in epigenetic gene silencing and telomere length. ATRX mutation without MYCN amplification is associated with older age at diagnosis in adolescents and young adults with metastatic neuroblastoma.[28] It is unclear whether an ATRX mutation is an independent prognostic risk factor.

Neuroblastoma Screening

Current data do not support neuroblastoma screening. Screening at the ages of 3 weeks, 6 months, or 1 year caused no reduction in the incidence of advanced-stage neuroblastoma with unfavorable biological characteristics in older children, nor did it reduce the number of deaths from neuroblastoma in infants screened at any age.[11,12] No public health benefits have been shown from screening infants for neuroblastoma at these ages. (Refer to the PDQ summary on Neuroblastoma Screening for more information.)

Evidence (against neuroblastoma screening):

  1. A large population-based North American study, in which most infants in Quebec were screened at the ages of 3 weeks and 6 months, has shown that screening detects many neuroblastomas with favorable characteristics [10,11] that would never have been detected clinically, apparently due to spontaneous regression of the tumors.

  2. Another study of infants screened at the age of 1 year shows similar results.[12]

Clinical Presentation

The most common presentation of neuroblastoma is an abdominal mass. The most frequent signs and symptoms of neuroblastoma are due to tumor mass and metastases. They include the following:

  • Proptosis and periorbital ecchymosis: Common in high-risk patients and arise from retrobulbar metastasis.

  • Abdominal distention: May occur with respiratory compromise in infants due to massive liver metastases.

  • Bone pain: Occurs in association with metastatic disease.

  • Pancytopenia: May result from extensive bone marrow metastasis.

  • Fever, hypertension, and anemia: Occasionally found in patients without metastasis.

  • Paralysis: Because they originate in paraspinal ganglia, neuroblastomas may invade through neural foramina and compress the spinal cord extradurally. Immediate treatment is given for symptomatic spinal cord compression. (Refer to the Treatment of Spinal Cord Compression section of this summary for more information.)

  • Watery diarrhea: On rare occasions, children may have severe, watery diarrhea due to the secretion of vasoactive intestinal peptide by the tumor, or may have protein-losing enteropathy with intestinal lymphangiectasia.[29] Vasoactive intestinal peptide secretion may also occur upon chemotherapeutic treatment, and tumor resection reduces vasoactive intestinal peptide secretion.[30]

  • Presence of Horner syndrome: May be caused by neuroblastoma in the stellate ganglion, and children with Horner syndrome without other apparent cause are also examined for neuroblastoma and other tumors.[31]

  • Subcutaneous skin nodules: Neuroblastoma subcutaneous metastasis often has bluish discoloration in the overlying skin and usually is seen only in infants.

The clinical characteristics of neuroblastoma in adolescents are similar to those observed in children. The only exception is that bone marrow involvement occurs less frequently in adolescents, and there is a greater frequency of metastases in unusual sites such as lung or brain.[32]

Opsoclonus/myoclonus syndrome

Paraneoplastic neurologic findings, including cerebellar ataxia or opsoclonus/myoclonus, are rare in children with neuroblastoma.[33] Opsoclonus/myoclonus syndrome is frequently associated with pervasive and permanent neurologic and cognitive deficits, including psychomotor retardation. Neurologic dysfunction is most often a presenting symptom but may arise long after removal of the tumor.[34-36]

Patients who present with opsoclonus/myoclonus syndrome often have neuroblastomas with favorable biological features and are likely to survive, though tumor-related deaths have been reported.[34]

The opsoclonus/myoclonus syndrome appears to be caused by an immunologic mechanism that is not yet fully defined.[34,37] The primary tumor is typically diffusely infiltrated with lymphocytes.[38]

Some patients may clinically respond to removal of the neuroblastoma, but improvement may be slow and partial; symptomatic treatment is often necessary. Adrenocorticotropic hormone or corticosteroid treatment is thought to be effective, but some patients do not respond to corticosteroids.[35,37] Various drugs, plasmapheresis, intravenous gamma globulin, and rituximab have been reported to be effective in selected cases.[35,39-41] The long-term neurologic outcome may be superior in patients treated with chemotherapy, possibly because of its immunosuppressive effects.[33,39]

Diagnosis

Diagnostic evaluation of neuroblastoma includes the following:

  • Metaiodobenzylguanidine (mIBG) scan.[42,43]

  • Imaging of the primary tumor mass: This is generally accomplished by computed tomography or magnetic resonance imaging (MRI) with contrast. Paraspinal tumors that might threaten spinal cord compression are imaged using MRI.

  • Urine catecholamine metabolites: Urinary excretion of the catecholamine metabolites vanillylmandelic acid (VMA) and homovanillic acid (HVA) per mg of excreted creatinine is measured before therapy. Collection of urine for 24 hours is not needed. If elevated, these markers can be used to determine the persistence of disease.

    Serum catecholamines are not routinely used in the diagnosis of neuroblastoma except in unusual circumstances.

  • Biopsy: Tumor tissue is often needed to obtain all the biological data required for risk-group assignment and subsequent treatment stratification in current Children’s Oncology Group (COG) clinical trials. There is an absolute requirement for tissue biopsy to determine the International Neuroblastoma Pathology Classification (INPC). In the risk/treatment group assignment schema for COG studies, INPC has been used to determine treatment for patients with stage 3 disease, stage 4S disease, and patients aged 18 months or younger with stage 4 disease. Additionally, a significant number of tumor cells are needed to determine MYCN copy number, DNA index, and 11q and 1p loss of heterozygosity. 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 and 1p/11q loss of heterozygosity may be successfully performed on involved bone marrow if there is at least 30% to 40% tumor involvement.

    In rare cases, neuroblastoma can be discovered prenatally by fetal ultrasonography.[44] Management recommendations are evolving with regard to the need for immediate diagnostic biopsy in infants aged 6 months and younger with suspected neuroblastoma tumors that are likely to spontaneously regress. Biopsy was not required for infants entered into a COG study of expectant observation of small adrenal masses in neonates, and 81% avoided undergoing any surgery at all.[45] In a German clinical trial, 25 infants aged 3 months and younger with presumed neuroblastoma were observed without biopsy for periods of 1 to 18 months before biopsy or resection. There were no apparent ill effects of the delay.[46]

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:

  1. An unequivocal pathologic diagnosis made from tumor tissue by light microscopy (with or without immunohistology, electron microscopy, or increased levels of serum catecholamines [dopamine and norepinephrine] or urinary catecholamine metabolites [VMA or HVA]).[47]

  2. The combination of bone marrow aspirate or trephine biopsy containing unequivocal tumor cells (e.g., syncytia or immunocytologically-positive clumps of cells) and increased levels of serum catecholamines or urinary catecholamine metabolites.[47]

Prognostic Factors

Between 1975 and 2002, the 5-year survival rate for neuroblastoma in the United States has remained stable at approximately 87% for children younger than 1 year and has increased from 37% to 65% in children aged 1 to 14 years.[1] The 5-year overall survival (OS) for all infants and children with neuroblastoma has increased from 46% when diagnosed between 1974 and 1989, to 71% when diagnosed between 1999 and 2005;[48] however, this single number can be misleading because of the extremely heterogeneous prognosis based on the neuroblastoma patient's age, stage, and biology. (Refer to the Cellular Classification of Neuroblastic Tumors section of this summary for more information.) Approximately 70% of patients with neuroblastoma have metastatic disease at diagnosis.

The prognosis for patients with neuroblastoma is related to the following:[49-52]

Some of these prognostic factors have been combined to create risk groups to help define treatment. (Refer to the International Neuroblastoma Risk Group Staging System section and the Children’s Oncology Group Neuroblastoma Risk Grouping section of this summary for more information.)

Age at diagnosis

The effect of age at diagnosis on 5-year survival is profound. According to the 1975 to 2006 U.S. Surveillance, Epidemiology, and End Results (SEER) statistics, the 5-year survival stratified by age is as follows:[48]

  • Age younger than 1 year – 90%.
  • Age 1 to 4 years – 68%.
  • Age 5 to 9 years – 52%.
  • Age 10 to 14 years – 66%.

Children of any age with localized neuroblastoma and infants aged 18 months and younger with advanced disease and favorable disease characteristics have a high likelihood of long-term, disease-free survival.[53] The prognosis of fetal and neonatal neuroblastoma are similar to that of older infants with neuroblastoma and similar biological features.[54] Older children with advanced-stage disease, however, have a significantly decreased chance for cure, despite intensive therapy.

Survival of patients with International Neuroblastoma Staging System (INSS) stage 4 disease is strongly dependent on age. Children younger than 18 months at diagnosis have a good chance of long-term survival (i.e., a 5-year disease-free survival rate of 50%–80%),[55,56] with outcome particularly dependent on MYCN amplification and tumor cell ploidy. Hyperdiploidy confers a favorable prognosis while diploidy predicts early treatment failure.[57,58] Infants aged 18 months and younger at diagnosis with INSS stage 4 neuroblastoma who do not have MYCN gene amplification are categorized as intermediate risk and have a 3-year event-free survival (EFS) of 81% and OS of 93%.[7,59-62]

Adolescents and young adults

Neuroblastoma has a worse long-term prognosis in an adolescent older than 12 years or in an adult compared with a child, regardless of stage or site and, in many cases, a more prolonged course when treated with standard doses of chemotherapy. Aggressive chemotherapy and surgery have been shown to achieve a minimal disease state in more than 50% of these patients.[32,63,64] Other modalities, such as local radiation therapy and the use of agents with confirmed activity, may improve the poor prognosis for adolescents and adults.[63,64]

Site of primary tumor

Site of primary tumor is not an independent prognostic factor. Multifocal (multiple primaries) neuroblastoma occurs rarely, usually in infants, and generally has a good prognosis.[65] Familial neuroblastoma and germline ALK gene mutation should be considered in patients with multiple primary neuroblastomas.

Tumor histology

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:

  • Cellular differentiation/maturation. Higher degrees of neuroblastic maturation confer improved prognosis for stage 4 patients with segmental chromosome changes without MYCN amplification. Neuroblastoma tumors containing many differentiating cells, termed ganglioneuroblastoma, can have diffuse differentiation conferring a very favorable prognosis or can have nodules of undifferentiated cells whose histology, along with MYCN amplification, determine prognosis.[66,67]

  • Schwannian stroma.

  • Cystic neuroblastoma. About 25% of reported neuroblastomas diagnosed in the fetus and neonate are cystic; cystic neuroblastomas have lower stages and a higher incidence of favorable biology.[54]

Histologic characteristics considered prognostically unfavorable include the following:

  • Mitosis.
  • Karyorrhexis.

A COG study of children with stage 1 and stage 2 neuroblastoma without MYCN amplification and with favorable histologic features reported a 5-year EFS of 90% to 94% and OS of 99% to 100%, while those with unfavorable histology had an EFS of 80% to 86% and an OS of 89% to 93%.[68] Similar results were found in a European study.[69-71]

Regional lymph node involvement

According to the INSS, the presence of cancer in the regional lymph nodes on the same side of the body as the primary tumor has no effect on prognosis. However, when lymph nodes with metastatic neuroblastoma cross the midline and are on the opposite sides of the body from the primary tumor, the patient is upstaged (refer to the Stage Information for Neuroblastoma section of this summary for more information) and a poorer prognosis is conferred.

Response to treatment

Response to treatment has been associated with outcome. In patients with high-risk disease, the persistence of neuroblastoma cells in bone marrow after induction chemotherapy, for example, is associated with a poor prognosis, which may be assessed by sensitive minimal residual disease techniques.[72-74] The degree of tumor volume reduction predicts response in high-risk patients, as does a decrease in mitosis and an increase in histologic differentiation.[75,76] Similarly, the persistence of mIBG-avid tumor after completion of induction therapy predicts a poor prognosis.[77]

Biological features

A number of biologic variables have been studied in children with this tumor:[78]

  • Biological subtype: These biological types are not used to determine treatment at this time; however, type 1 has a very favorable prognosis, while types 2A and 2B have poor prognoses. (Refer to the Biological subtypes subsection of this summary for more information on subtypes 1, 2A, and 2B.)

  • MYCN amplification: MYCN amplification (defined as greater than 10 copies per diploid genome) is detected in 16% to 25% of tumors.[79] In stage 2, 3, 4, and 4S patients, 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. Amplification of the MYCN gene is associated not only with deletion of chromosome 1p, but also gain of the long arm of chromosome 17 (17q), the latter of which independently predicts a poor prognosis.[80] Within the localized MYCN-amplified cohort, ploidy status may further predict outcome.[81]

    The degree of expression of the MYCN gene in the tumor does not predict prognosis.[82] However, high overall MYCN-dependent gene expression and low expression of sympathetic neuron late differentiation genes both predict a poor outcome of neuroblastomas otherwise considered to be at low or intermediate risk of recurrence.[83]

  • Segmental chromosome changes: Segmental chromosome number changes predict recurrence in infants with localized unresectable or metastatic neuroblastoma without MYCN gene amplification. Among all patients with neuroblastoma, a higher number of chromosome breakpoints correlated with advanced age at diagnosis, advanced stage of disease, higher risk of relapse, and a poorer outcome, whether or not MYCN amplification was considered.[19,21,26,84]

  • Whole chromosome changes: Whole chromosome copy number changes do not predict recurrence and are associated with hyperdiploidy.

Other biological prognostic factors that have been extensively investigated include tumor cell telomere length, telomerase activity, and telomerase ribonucleic acid;[85,86] urinary VMA, HVA, and their ratio;[87] MRP1;[88] GABAergic receptor profile;[89] dopamine; CD44 expression; TrkA gene expression; and serum neuron-specific enolase level, serum lactic dehydrogenase level, and serum ferritin level.[78] These factors are currently not in use for stratification on clinical trials.

Spontaneous Regression of Neuroblastoma

The phenomenon of spontaneous regression has been well described in infants with neuroblastoma, especially in infants with the 4S pattern of metastatic spread.[90] (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:[91]

  • Near triploid number of chromosomes.
  • No MYCN amplification.
  • No loss of chromosome 1p.

Additional features associated with spontaneous regression include the lack of telomerase expression,[92,93] the expression of Ha-ras,[94] and the expression of the neurotrophin receptor TrkA, a nerve growth factor receptor.[95]

Studies have suggested that selected infants who appear to have asymptomatic, small, low-stage adrenal neuroblastoma detected by screening or during prenatal or incidental ultrasound examination, often have tumors that spontaneously regress and may be observed safely without surgical intervention or tissue diagnosis.[96-98]

Evidence (observation):

  1. In a COG study, 83 highly selected infants younger than 6 months with stage 1 small adrenal masses as defined by imaging studies were observed without biopsy. Surgical intervention was reserved for those with growth or progression of the mass or increasing concentrations of urinary catecholamine metabolites.[45]
    • Eighty-one percent were spared surgery and all were alive at 2 years of follow-up (refer to the Surgery subsection of this summary for more information).

  2. In a German clinical trial, spontaneous regression and/or lack of progression occurred in nearly one-half of 93 asymptomatic infants aged 12 months or younger with stage 1, 2, or 3 tumors without MYCN amplification.[46]
    • All were observed after biopsy and partial or no resection.

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  60. Schmidt ML, Lal A, Seeger RC, et al.: Favorable prognosis for patients 12 to 18 months of age with stage 4 nonamplified MYCN neuroblastoma: a Children's Cancer Group Study. J Clin Oncol 23 (27): 6474-80, 2005.  [PUBMED Abstract]

  61. George RE, London WB, Cohn SL, et al.: Hyperdiploidy plus nonamplified MYCN confers a favorable prognosis in children 12 to 18 months old with disseminated neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 23 (27): 6466-73, 2005.  [PUBMED Abstract]

  62. Baker DL, Schmidt ML, Cohn SL, et al.: Outcome after reduced chemotherapy for intermediate-risk neuroblastoma. N Engl J Med 363 (14): 1313-23, 2010.  [PUBMED Abstract]

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  64. Franks LM, Bollen A, Seeger RC, et al.: Neuroblastoma in adults and adolescents: an indolent course with poor survival. Cancer 79 (10): 2028-35, 1997.  [PUBMED Abstract]

  65. Hiyama E, Yokoyama T, Hiyama K, et al.: Multifocal neuroblastoma: biologic behavior and surgical aspects. Cancer 88 (8): 1955-63, 2000.  [PUBMED Abstract]

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  68. Strother DR, London WB, Schmidt ML, et al.: Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children's Oncology Group study P9641. J Clin Oncol 30 (15): 1842-8, 2012.  [PUBMED Abstract]

  69. Matthay KK, Perez C, Seeger RC, et al.: Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children's Cancer Group study. J Clin Oncol 16 (4): 1256-64, 1998.  [PUBMED Abstract]

  70. Perez CA, Matthay KK, Atkinson JB, et al.: Biologic variables in the outcome of stages I and II neuroblastoma treated with surgery as primary therapy: a children's cancer group study. J Clin Oncol 18 (1): 18-26, 2000.  [PUBMED Abstract]

  71. Matthay KK, Sather HN, Seeger RC, et al.: Excellent outcome of stage II neuroblastoma is independent of residual disease and radiation therapy. J Clin Oncol 7 (2): 236-44, 1989.  [PUBMED Abstract]

  72. Burchill SA, Lewis IJ, Abrams KR, et al.: Circulating neuroblastoma cells detected by reverse transcriptase polymerase chain reaction for tyrosine hydroxylase mRNA are an independent poor prognostic indicator in stage 4 neuroblastoma in children over 1 year. J Clin Oncol 19 (6): 1795-801, 2001.  [PUBMED Abstract]

  73. Seeger RC, Reynolds CP, Gallego R, et al.: Quantitative tumor cell content of bone marrow and blood as a predictor of outcome in stage IV neuroblastoma: a Children's Cancer Group Study. J Clin Oncol 18 (24): 4067-76, 2000.  [PUBMED Abstract]

  74. Bochennek K, Esser R, Lehrnbecher T, et al.: Impact of minimal residual disease detection prior to autologous stem cell transplantation for post-transplant outcome in high risk neuroblastoma. Klin Padiatr 224 (3): 139-42, 2012.  [PUBMED Abstract]

  75. Yoo SY, Kim JS, Sung KW, et al.: The degree of tumor volume reduction during the early phase of induction chemotherapy is an independent prognostic factor in patients with high-risk neuroblastoma. Cancer 119 (3): 656-64, 2013.  [PUBMED Abstract]

  76. George RE, Perez-Atayde AR, Yao X, et al.: Tumor histology during induction therapy in patients with high-risk neuroblastoma. Pediatr Blood Cancer 59 (3): 506-10, 2012.  [PUBMED Abstract]

  77. Yanik GA, Parisi MT, Shulkin BL, et al.: Semiquantitative mIBG scoring as a prognostic indicator in patients with stage 4 neuroblastoma: a report from the Children's oncology group. J Nucl Med 54 (4): 541-8, 2013.  [PUBMED Abstract]

  78. Riley RD, Heney D, Jones DR, et al.: A systematic review of molecular and biological tumor markers in neuroblastoma. Clin Cancer Res 10 (1 Pt 1): 4-12, 2004.  [PUBMED Abstract]

  79. Ambros PF, Ambros IM, Brodeur GM, et al.: International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee. Br J Cancer 100 (9): 1471-82, 2009.  [PUBMED Abstract]

  80. Bown N, Cotterill S, Lastowska M, et al.: Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma. N Engl J Med 340 (25): 1954-61, 1999.  [PUBMED Abstract]

  81. Bagatell R, Beck-Popovic M, London WB, et al.: Significance of MYCN amplification in international neuroblastoma staging system stage 1 and 2 neuroblastoma: a report from the International Neuroblastoma Risk Group database. J Clin Oncol 27 (3): 365-70, 2009.  [PUBMED Abstract]

  82. Cohn SL, London WB, Huang D, et al.: MYCN expression is not prognostic of adverse outcome in advanced-stage neuroblastoma with nonamplified MYCN. J Clin Oncol 18 (21): 3604-13, 2000.  [PUBMED Abstract]

  83. Fredlund E, Ringnér M, Maris JM, et al.: High Myc pathway activity and low stage of neuronal differentiation associate with poor outcome in neuroblastoma. Proc Natl Acad Sci U S A 105 (37): 14094-9, 2008.  [PUBMED Abstract]

  84. Schleiermacher G, Michon J, Ribeiro A, et al.: Segmental chromosomal alterations lead to a higher risk of relapse in infants with MYCN-non-amplified localised unresectable/disseminated neuroblastoma (a SIOPEN collaborative study). Br J Cancer 105 (12): 1940-8, 2011.  [PUBMED Abstract]

  85. Poremba C, Hero B, Goertz HG, et al.: Traditional and emerging molecular markers in neuroblastoma prognosis: the good, the bad and the ugly. Klin Padiatr 213 (4): 186-90, 2001 Jul-Aug.  [PUBMED Abstract]

  86. Ohali A, Avigad S, Ash S, et al.: Telomere length is a prognostic factor in neuroblastoma. Cancer 107 (6): 1391-9, 2006.  [PUBMED Abstract]

  87. Strenger V, Kerbl R, Dornbusch HJ, et al.: Diagnostic and prognostic impact of urinary catecholamines in neuroblastoma patients. Pediatr Blood Cancer 48 (5): 504-9, 2007.  [PUBMED Abstract]

  88. Haber M, Smith J, Bordow SB, et al.: Association of high-level MRP1 expression with poor clinical outcome in a large prospective study of primary neuroblastoma. J Clin Oncol 24 (10): 1546-53, 2006.  [PUBMED Abstract]

  89. Roberts SS, Mori M, Pattee P, et al.: GABAergic system gene expression predicts clinical outcome in patients with neuroblastoma. J Clin Oncol 22 (20): 4127-34, 2004.  [PUBMED Abstract]

  90. Nickerson HJ, Matthay KK, Seeger RC, et al.: Favorable biology and outcome of stage IV-S neuroblastoma with supportive care or minimal therapy: a Children's Cancer Group study. J Clin Oncol 18 (3): 477-86, 2000.  [PUBMED Abstract]

  91. Ambros PF, Brodeur GM: Concept of tumorigenesis and regression. In: Brodeur GM, Sawada T, Tsuchida Y: Neuroblastoma. New York, NY: Elsevier Science, 2000, pp 21-32. 

  92. Hiyama E, Hiyama K, Yokoyama T, et al.: Correlating telomerase activity levels with human neuroblastoma outcomes. Nat Med 1 (3): 249-55, 1995.  [PUBMED Abstract]

  93. Hiyama E, Reynolds CP: Telomerase as a biological and prognostic marker in neuroblastoma. In: Brodeur GM, Sawada T, Tsuchida Y: Neuroblastoma. New York, NY: Elsevier Science, 2000, pp 159-174. 

  94. Kitanaka C, Kato K, Ijiri R, et al.: Increased Ras expression and caspase-independent neuroblastoma cell death: possible mechanism of spontaneous neuroblastoma regression. J Natl Cancer Inst 94 (5): 358-68, 2002.  [PUBMED Abstract]

  95. Brodeur GM, Minturn JE, Ho R, et al.: Trk receptor expression and inhibition in neuroblastomas. Clin Cancer Res 15 (10): 3244-50, 2009.  [PUBMED Abstract]

  96. Yamamoto K, Ohta S, Ito E, et al.: Marginal decrease in mortality and marked increase in incidence as a result of neuroblastoma screening at 6 months of age: cohort study in seven prefectures in Japan. J Clin Oncol 20 (5): 1209-14, 2002.  [PUBMED Abstract]

  97. Okazaki T, Kohno S, Mimaya J, et al.: Neuroblastoma detected by mass screening: the Tumor Board's role in its treatment. Pediatr Surg Int 20 (1): 27-32, 2004.  [PUBMED Abstract]

  98. Fritsch P, Kerbl R, Lackner H, et al.: "Wait and see" strategy in localized neuroblastoma in infants: an option not only for cases detected by mass screening. Pediatr Blood Cancer 43 (6): 679-82, 2004.  [PUBMED Abstract]

Cellular Classification of Neuroblastic Tumors

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.[1]

There are two cellular classification systems for neuroblastoma.

  • International Neuroblastoma Pathology Classification (INPC) System: The INPC system involves evaluation of tumor specimens obtained before therapy for the following morphologic features:[2-5]
    • Amount of Schwannian stroma.
    • Degree of neuroblastic maturation.
    • Mitosis-karyorrhexis index of the neuroblastic cells.

    Favorable and unfavorable prognoses are defined on the basis of these histologic parameters and patient age. The prognostic significance of this classification system, and of related systems using similar criteria, has been confirmed in several studies.[2-4]

    In the future, the INPC system is likely to be replaced by a system that does not include patient age as a part of cellular classification.

Table 1. Prognostic Evaluation of Neuroblastic Tumors According to the International Neuroblastoma Pathology Classification (Shimada System)a
International Neuroblastoma Pathology classification Original Shimada classification Prognostic group 
Neuroblastoma(Schwannian stroma-poor)bStroma-poor
FavorableFavorableFavorable
<1.5 yrsPoorly differentiated or differentiating & low or intermediate MKI tumor
1.5–5 yrsDifferentiating & low MKI tumor
UnfavorableUnfavorableUnfavorable
<1.5 yrsa) undifferentiated tumorc
b) high MKI tumor
1.5–5 yrsa) undifferentiated or poorly differentiated tumor
b) intermediate or high MKI tumor
≥5 yrsAll tumors
Ganglioneuroblastoma, intermixed(Schwannian stroma-rich)Stroma-rich Intermixed (favorable)Favorabled
Ganglioneuroma(Schwannian stroma-dominant)
MaturingWell differentiated (favorable)Favorabled
MatureGanglioneuroma
Ganglioneuroblastoma, nodular(composite Schwannian stroma-rich/stroma-dominate and stroma-poor)Stroma-rich nodular (unfavorable)Unfavorabled

MKI: mitosis-karyorrhexis index.
aReprinted with permission. Copyright © 1999 American Cancer Society. All rights reserved.[2] Hiroyuki Shimada, Inge M. Ambros, Louis P. Dehner, Jun-ichi Hata, Vijay V. Joshi, Borghild Roald, Daniel O. Stram, Robert B. Gerbing, John N. Lukens, Katherine K. Matthay, Robert P. Castleberry, The International Neuroblastoma Pathology Classification (the Shimada System), Cancer, volume 86, issue 2, pages 364–72.
bSubtypes of neuroblastoma were described in detail elsewhere.[6]
cRare subtype, especially diagnosed in this age group. Further investigation and analysis required.
dPrognostic grouping for these tumor categories is not related to patient age.

Most neuroblastomas with MYCN amplification in the INPC system also have unfavorable histology, but about 7% have favorable histology. Of those with MYCN amplification and favorable histology, most do not express MYCN, despite the gene being amplified, and have a more favorable prognosis than those who do express MYCN.[7]

  • International Neuroblastoma Risk Group (INRG) Classification System: The INRG used a decision-tree analysis to compare 35 prognostic factors in more than 8,000 patients with neuroblastoma from a variety of clinical trials. The following INPC (Shimada system) histologic factors were included in the analysis:[8,9]
    • Diagnostic category.
    • Grade of differentiation.
    • Mitosis/karyorrhexis index.

    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.

Table 2. Histologic Discrimination of International Neuroblastoma Risk Group Subsets of Neuroblastoma Patientsa
INSS Stage/Histologic Subtype Number of Cases EFS (%)  OS (%) 
INSS stage 1, 2, 3, 4S5,13183 ± 191 ± 1
GN, maturing16297 ± 298 ± 2
GNB, intermixed
NB4,97083 ± 190 ± 1
GNB, nodular
INSS stage 2, 3; age >547 d26069 ± 381 ± 2
11q normal and differentiating1680 ± 16100
11q aberration or undifferentiated4961 ± 1173 ± 11

EFS = event-free survival; GN = ganglioneuroma; GNB = ganglioneuroblastoma; INSS = International Neuroblastoma Staging System; NB = neuroblastoma; OS = overall survival.
aAdapted from Cohn et al.[8]

References
  1. Joshi VV, Silverman JF: Pathology of neuroblastic tumors. Semin Diagn Pathol 11 (2): 107-17, 1994.  [PUBMED Abstract]

  2. Shimada H, Ambros IM, Dehner LP, et al.: The International Neuroblastoma Pathology Classification (the Shimada system). Cancer 86 (2): 364-72, 1999.  [PUBMED Abstract]

  3. Shimada H, Umehara S, Monobe Y, et al.: International neuroblastoma pathology classification for prognostic evaluation of patients with peripheral neuroblastic tumors: a report from the Children's Cancer Group. Cancer 92 (9): 2451-61, 2001.  [PUBMED Abstract]

  4. Goto S, Umehara S, Gerbing RB, et al.: Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors: a report from the Children's Cancer Group. Cancer 92 (10): 2699-708, 2001.  [PUBMED Abstract]

  5. Peuchmaur M, d'Amore ES, Joshi VV, et al.: Revision of the International Neuroblastoma Pathology Classification: confirmation of favorable and unfavorable prognostic subsets in ganglioneuroblastoma, nodular. Cancer 98 (10): 2274-81, 2003.  [PUBMED Abstract]

  6. Shimada H, Ambros IM, Dehner LP, et al.: Terminology and morphologic criteria of neuroblastic tumors: recommendations by the International Neuroblastoma Pathology Committee. Cancer 86 (2): 349-63, 1999.  [PUBMED Abstract]

  7. Suganuma R, Wang LL, Sano H, et al.: Peripheral neuroblastic tumors with genotype-phenotype discordance: a report from the Children's Oncology Group and the International Neuroblastoma Pathology Committee. Pediatr Blood Cancer 60 (3): 363-70, 2013.  [PUBMED Abstract]

  8. Cohn SL, Pearson AD, London WB, et al.: The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol 27 (2): 289-97, 2009.  [PUBMED Abstract]

  9. Okamatsu C, London WB, Naranjo A, et al.: Clinicopathological characteristics of ganglioneuroma and ganglioneuroblastoma: a report from the CCG and COG. Pediatr Blood Cancer 53 (4): 563-9, 2009.  [PUBMED Abstract]

Stage Information for Neuroblastoma



Staging Evaluation

A thorough evaluation for metastatic disease is performed before therapy initiation. The following studies are typically performed:[1]

Metaiodobenzylguanidine (mIBG) scan

The extent of metastatic disease is assessed by mIBG scan, which is applicable to all sites of disease (including soft tissue, bone marrow, and cortical bone involvement). Cortical bone metastases are also evaluated by technetium-99 scan. If all sites of bone metastases are imaged by mIBG scan, then subsequent restaging for assessment of disease response may omit the technetium-99 bone scan.[2,3] Approximately 90% of neuroblastomas will be mIBG avid. It has a sensitivity and specificity of 90% to 99% and is equally distributed between primary and metastatic sites.[4] Although iodine 123 (123I) has a shorter half-life, it is preferred over131I because of its lower radiation dose, better quality images, less 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 18F-fluorodeoxyglucose positron emission tomography–computerized tomography (PET-CT) in one prospective comparison.[5] Baseline mIBG scans performed at diagnosis provide an excellent method for monitoring disease response and performing posttherapy surveillance.[6]

A retrospective analysis of paired mIBG and PET scans in 60 newly diagnosed neuroblastoma patients demonstrated that for International Neuroblastoma Staging System (INSS) stages 1 and 2 patients, PET was superior at determining the extent of primary disease and more sensitive for detection of residual masses. In contrast, for stage 4 disease, 123I-mIBG imaging was superior for the detection of bone marrow and bony metastases.[7]

Curie score and SIOPEN score

Multiple groups have investigated a semi-quantitative scoring method to evaluate disease extent and prognostic value. The most common scoring methods in use for evaluation of disease extent and response are the Curie and the International Society of Paediatric Oncology European Neuroblastoma Group (SIOPEN) methods.

  • Curie score: The Curie score is a semiquantitative scoring system developed to predict the extent and severity of mIBG-avid disease. The use of the Curie scoring system was assessed as a prognostic marker for response and survival with mIBG-avid, stage 4 newly diagnosed high-risk neuroblastoma (N = 280), treated on the Children’s Oncology Group (COG) protocol COG-A3973 (NCT00004188). Patients with a Curie score greater than 2 after induction therapy had a significantly worse event-free survival (EFS) than those with scores less than 2 (3-year EFS, 15.4% ± 5.3% for Curie score >2 vs. 44.9% ± 3.9% for Curie score ≤2; P < .001). A postinduction Curie score greater than 2 identified a cohort of patients at greater risk of an event, independent of other known neuroblastoma factors, including age, MYCN status, ploidy, mitosis-karyorrhexis index, and histologic grade.[8]

  • SIOPEN score: The SIOPEN independently developed an mIBG scan scoring system that divided the body into 12 segments, rather than nine, and assigned six degrees, rather than four, of mIBG uptake in each segment. A retrospective study of 58 stage 4 patients from the German Pediatric Oncology Group compared the prognostic value of the Curie and SIOPEN scoring methods. At diagnosis, a Curie score of 2 or less and a SIOPEN score of 4 or less (best cutoff) at diagnosis were correlated to significantly better EFS and overall survival, compared with higher scores. After four cycles of induction, those with complete response by mIBG had a better outcome than those with residual uptake, but after six cycles, there was no significant difference.[9]

Other staging tests and procedures

Other tests and procedures used to stage neuroblastoma include the following:

  • Bone marrow aspiration and biopsy: Bone marrow is assessed by bilateral iliac crest marrow aspirates and trephine (core) bone marrow biopsies to exclude bone marrow involvement. To be considered adequate, core biopsy specimens must contain at least 1 cm of marrow, excluding cartilage. Bone marrow sampling may not be necessary for tumors that are otherwise stage 1.[10]

  • Lumbar puncture: Lumbar puncture is avoided because central nervous system (CNS) metastasis at diagnosis is rare,[11] and lumbar puncture may be associated with an increased incidence of subsequent development of CNS metastasis.[12]

  • Lymph node assessment: Palpable lymph nodes are clinically examined and histologically confirmed if indicated for staging.[1]

  • CT and magnetic resonance imaging (MRI) scan:
    • Three-dimensional (3-D) imaging of the primary tumor and potential lymph node drainage sites is done using CT scans and/or MRI scans of the chest, abdomen, and pelvis. Ultrasound is generally considered suboptimal for accurate 3-D measurements.

    • Paraspinal tumors may extend through neural foramina to compress the spinal cord. Therefore, MRI of the spine adjacent to any paraspinal tumor is part of the staging evaluation.

    • A brain/orbit CT and/or MRI is performed if clinically indicated by examination and/or uptake on mIBG scan.

International Neuroblastoma Staging Systems

International Neuroblastoma Staging System (INSS)

The INSS combines certain features from each of the previously used Evans and Pediatric Oncology Group (POG) staging systems [1,13] and is described in Table 3. This represented the first step in harmonizing disease staging and risk stratification worldwide. The INSS is a postoperative staging system that was developed in 1988 and used the extent of surgical resection to stage patients. This led to some variability in stage assignments in different countries because of regional differences in surgical strategy and, potentially, because of limitations in access to experienced pediatric surgeons. As a result of further advances in the understanding of neuroblastoma biology and genetics, a risk classification system was developed that incorporates clinical and biological factors in addition to INSS stage to facilitate risk group and treatment assignment for COG studies.[1,13-15]

Table 3. The International Neuroblastoma Staging System (INSS)
Stage/Prognostic Group Description 
mIBG = metaiodobenzylguanidine.
Stage 1Localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for tumor microscopically (i.e., nodes attached to and removed with the primary tumor may be positive).
Stage 2ALocalized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph nodes negative for tumor microscopically.
Stage 2BLocalized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumor. Enlarged contralateral lymph nodes must be negative microscopically
Stage 3Unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph node involvement; or midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement. The midline is defined as the vertebral column. Tumors originating on one side and crossing the midline must infiltrate to or beyond the opposite side of the vertebral column.
Stage 4Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs, except as defined for stage 4S.
Stage 4SLocalized primary tumor, as defined for stage 1, 2A, or 2B, with dissemination limited to skin, liver, and/or bone marrow (by definition limited to infants younger than 12 months).[3] Marrow involvement should be minimal (i.e., <10% of total nucleated cells identified as malignant by bone biopsy or by bone marrow aspirate). More extensive bone marrow involvement would be considered stage 4 disease. The results of the mIBG scan, if performed, should be negative for disease in the bone marrow.

Controversy exists regarding the INSS staging system and the treatment of certain small subsets of patients.[16-18] Risk group assignment and recommended treatment are expected to evolve as additional outcome data are analyzed. For example, the risk group assignment for INSS stage 4 neuroblastoma in patients aged 12 to 18 months changed in 2005 for those whose tumors had single copy MYCN and all favorable biological features; these patients had been previously classified as high risk, but data from both POG and Children's Cancer Group studies suggested that this subgroup of patients could be successfully treated as intermediate risk.[19-21]

International Neuroblastoma Risk Group Staging System (INRGSS)

The INRGSS is a preoperative staging system that was developed specifically for the INRG classification system. The extent of disease is determined by the presence or absence of image-defined risk factors (IDRFs) and/or metastatic tumor at the time of diagnosis, before any treatment or surgery. IDRFs are surgical risk factors, detected by imaging, which could potentially make total tumor excision risky or difficult at the time of diagnosis.

The INRGSS simplifies stages into L1, L2, M or MS (refer to Table 4 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.[22] For example, in the case of spinal cord compression, an IDRF is present when more than one-third of the spinal canal in the axial plane is invaded, when the leptomeningeal spaces are not visible, or when the spinal cord magnetic resonance signal intensity is abnormal. By combining the INRGSS, preoperative imaging and biological factors, each patient has a risk stage defined that predicts outcome and dictates the appropriate treatment approach to be followed. The INRGSS has predictive value for lower stage patients, with stage L1 having a 5-year EFS of 90%, compared with 78% for L2.[22]

Most international protocols have begun to incorporate collection and use of IDRF in risk stratification and assignment of therapy.[23,24] 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.

Table 4. International Neuroblastoma Risk Group Staging Systema
Stage Description 
aAdapted from Monclair et al.[22]
L1 Localized tumor not involving vital structures as defined by the list of image-defined risk factorsa and confined to one body compartment.
L2 Locoregional tumor with presence of one or more image-defined risk factors.a
M Distant metastatic disease (except MS).
MS Metastatic disease in children younger than 18 months with metastases confined to skin, liver, and/or bone marrow.

References
  1. Brodeur GM, Pritchard J, Berthold F, et al.: Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 11 (8): 1466-77, 1993.  [PUBMED Abstract]

  2. Brisse HJ, McCarville MB, Granata C, et al.: Guidelines for imaging and staging of neuroblastic tumors: consensus report from the International Neuroblastoma Risk Group Project. Radiology 261 (1): 243-57, 2011.  [PUBMED Abstract]

  3. Taggart DR, London WB, Schmidt ML, et al.: Prognostic value of the stage 4S metastatic pattern and tumor biology in patients with metastatic neuroblastoma diagnosed between birth and 18 months of age. J Clin Oncol 29 (33): 4358-64, 2011.  [PUBMED Abstract]

  4. Howman-Giles R, Shaw PJ, Uren RF, et al.: Neuroblastoma and other neuroendocrine tumors. Semin Nucl Med 37 (4): 286-302, 2007.  [PUBMED Abstract]

  5. Papathanasiou ND, Gaze MN, Sullivan K, et al.: 18F-FDG PET/CT and 123I-metaiodobenzylguanidine imaging in high-risk neuroblastoma: diagnostic comparison and survival analysis. J Nucl Med 52 (4): 519-25, 2011.  [PUBMED Abstract]

  6. Kushner BH, Kramer K, Modak S, et al.: Sensitivity of surveillance studies for detecting asymptomatic and unsuspected relapse of high-risk neuroblastoma. J Clin Oncol 27 (7): 1041-6, 2009.  [PUBMED Abstract]

  7. Sharp SE, Shulkin BL, Gelfand MJ, et al.: 123I-MIBG scintigraphy and 18F-FDG PET in neuroblastoma. J Nucl Med 50 (8): 1237-43, 2009.  [PUBMED Abstract]

  8. Yanik GA, Parisi MT, Shulkin BL, et al.: Semiquantitative mIBG scoring as a prognostic indicator in patients with stage 4 neuroblastoma: a report from the Children's oncology group. J Nucl Med 54 (4): 541-8, 2013.  [PUBMED Abstract]

  9. Decarolis B, Schneider C, Hero B, et al.: Iodine-123 metaiodobenzylguanidine scintigraphy scoring allows prediction of outcome in patients with stage 4 neuroblastoma: results of the Cologne interscore comparison study. J Clin Oncol 31 (7): 944-51, 2013.  [PUBMED Abstract]

  10. Russell HV, Golding LA, Suell MN, et al.: The role of bone marrow evaluation in the staging of patients with otherwise localized, low-risk neuroblastoma. Pediatr Blood Cancer 45 (7): 916-9, 2005.  [PUBMED Abstract]

  11. DuBois SG, Kalika Y, Lukens JN, et al.: Metastatic sites in stage IV and IVS neuroblastoma correlate with age, tumor biology, and survival. J Pediatr Hematol Oncol 21 (3): 181-9, 1999 May-Jun.  [PUBMED Abstract]

  12. Kramer K, Kushner B, Heller G, et al.: Neuroblastoma metastatic to the central nervous system. The Memorial Sloan-kettering Cancer Center Experience and A Literature Review. Cancer 91 (8): 1510-9, 2001.  [PUBMED Abstract]

  13. Brodeur GM, Seeger RC, Barrett A, et al.: International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma. J Clin Oncol 6 (12): 1874-81, 1988.  [PUBMED Abstract]

  14. Castleberry RP, Shuster JJ, Smith EI: The Pediatric Oncology Group experience with the international staging system criteria for neuroblastoma. Member Institutions of the Pediatric Oncology Group. J Clin Oncol 12 (11): 2378-81, 1994.  [PUBMED Abstract]

  15. Ikeda H, Iehara T, Tsuchida Y, et al.: Experience with International Neuroblastoma Staging System and Pathology Classification. Br J Cancer 86 (7): 1110-6, 2002.  [PUBMED Abstract]

  16. Kushner BH, Cheung NK: Treatment reduction for neuroblastoma. Pediatr Blood Cancer 43 (6): 619-21, 2004.  [PUBMED Abstract]

  17. Kushner BH, Kramer K, LaQuaglia MP, et al.: Liver involvement in neuroblastoma: the Memorial Sloan-Kettering Experience supports treatment reduction in young patients. Pediatr Blood Cancer 46 (3): 278-84, 2006.  [PUBMED Abstract]

  18. Navarro S, Amann G, Beiske K, et al.: Prognostic value of International Neuroblastoma Pathology Classification in localized resectable peripheral neuroblastic tumors: a histopathologic study of localized neuroblastoma European Study Group 94.01 Trial and Protocol. J Clin Oncol 24 (4): 695-9, 2006.  [PUBMED Abstract]

  19. Schmidt ML, Lal A, Seeger RC, et al.: Favorable prognosis for patients 12 to 18 months of age with stage 4 nonamplified MYCN neuroblastoma: a Children's Cancer Group Study. J Clin Oncol 23 (27): 6474-80, 2005.  [PUBMED Abstract]

  20. London WB, Castleberry RP, Matthay KK, et al.: Evidence for an age cutoff greater than 365 days for neuroblastoma risk group stratification in the Children's Oncology Group. J Clin Oncol 23 (27): 6459-65, 2005.  [PUBMED Abstract]

  21. George RE, London WB, Cohn SL, et al.: Hyperdiploidy plus nonamplified MYCN confers a favorable prognosis in children 12 to 18 months old with disseminated neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 23 (27): 6466-73, 2005.  [PUBMED Abstract]

  22. Monclair T, Brodeur GM, Ambros PF, et al.: The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J Clin Oncol 27 (2): 298-303, 2009.  [PUBMED Abstract]

  23. Cecchetto G, Mosseri V, De Bernardi B, et al.: Surgical risk factors in primary surgery for localized neuroblastoma: the LNESG1 study of the European International Society of Pediatric Oncology Neuroblastoma Group. J Clin Oncol 23 (33): 8483-9, 2005.  [PUBMED Abstract]

  24. Simon T, Hero B, Benz-Bohm G, et al.: Review of image defined risk factors in localized neuroblastoma patients: Results of the GPOH NB97 trial. Pediatr Blood Cancer 50 (5): 965-9, 2008.  [PUBMED Abstract]

Treatment Option Overview for Neuroblastoma

Because most children with neuroblastoma in North America are treated according to the Children’s Oncology Group (COG) risk-group assignment, the treatments described in this summary are based on the most recently published COG risk stratification system. Each child is assigned to a low-risk, intermediate-risk, or high-risk group (refer to Tables 6, 7, and 8 for more information) based on the following:[1-6]

  • International Neuroblastoma Staging System (INSS) stage.
  • Age.
  • International Neuroblastoma Pathologic Classification (INPC).
  • Ploidy.
  • Amplification of the MYCN oncogene within tumor tissue.[1-6]

Other biological factors that influence treatment selection include unbalanced 11q loss of heterozygosity and loss of heterozygosity for chromosome 1p.[7,8]

The treatment of neuroblastoma has evolved over the past 60 years. Generally, treatment is based on whether the tumor is low, intermediate, or high risk:

  • For low-risk tumors, the approach is either observation or resection. Five-year overall survival (OS) was 97% in a large COG study.[9]

  • For intermediate-risk tumors, chemotherapy is usually given before definitive resection, with the amount and duration based on clinical and tumor biological risk factors and response to therapy. The 3-year OS rate for intermediate-risk patients was about 96% in a large COG study,[10] and thus, the current trend is to decrease chemotherapy to diminish side effects.

  • For high-risk patients, treatment has intensified to include chemotherapy, surgery, radiation therapy, hematopoietic stem cell transplantation, differentiation therapy, and immunotherapy, resulting in survival rates of 40% to 50%.

Table 5. Treatment Options for Neuroblastoma
Stage (COG Risk-Group Assignment)  Treatment Options 
COG = Children's Oncology Group; GM-CSF = granulocyte-macrophage colony-stimulating factor; 131I-mIBG = iodine 131-metaiodobenzylguanidine; SCT = stem cell transplant.
Low-Risk Neuroblastoma Surgery followed by observation.
Chemotherapy with or without surgery (for symptomatic disease or unresectable progressive disease after surgery).
Observation without biopsy (for perinatal neuroblastoma with small adrenal tumors).
Intermediate-Risk Neuroblastoma Chemotherapy with or without surgery.
Surgery and observation (in infants).
Radiation therapy (only for emergent therapy).
High-Risk Neuroblastoma A regimen of chemotherapy, surgery, SCT, radiation therapy, and anti-GD2 antibody ch14.18, with interleukin-2/GM-CSF and isotretinoin.
Stage 4S Neuroblastoma Observation with supportive care (for asymptomatic patients with favorable tumor biology).
Chemotherapy (for symptomatic patients, very young infants, or those with unfavorable biology).
Recurrent NeuroblastomaLocoregional recurrence in patients initially classified as low riskSurgery followed by observation or chemotherapy.
Chemotherapy that may be followed by surgery.
Metastatic recurrence in patients initially classified as low riskObservation (if metastatic disease is in a 4S pattern in an infant).
Chemotherapy.
Locoregional recurrence in patients initially classified as intermediate riskSurgery (complete resection).
Surgery (incomplete resection) followed by chemotherapy.
Metastatic recurrence in patients initially classified as intermediate riskHigh-risk therapy.
Recurrence in patients initially classified as high riskChemotherapy.
131 I-mIBG alone, in combination with other therapy, or followed by stem cell rescue.
Second autologous SCT after retrieval chemotherapy.
Recurrence in the central nervous systemSurgery and radiation therapy.
Novel therapeutic approaches.

Children’s Oncology Group (COG) Neuroblastoma Risk Grouping

The treatment section of this document is organized to correspond with the COG risk-based treatment plan that assigns all patients to a low-, intermediate-, or high-risk group. This risk-based schema is based on the following factors:

  • Patient age at diagnosis.
  • Certain biological characteristics of the tumor, which include MYCN status, INPC histopathology classification, and tumor DNA index.
  • Stage of the tumor as defined by the INSS.

Table 6 (in the Treatment of Low-Risk Neuroblastoma section), Table 7 (in the Treatment of Intermediate-Risk Neuroblastoma section), and Table 8 (in the Treatment of High-Risk Neuroblastoma section) describe the risk group assignment criteria used to assign treatment in the COG-P9641, COG-A3961, and COG-A3973 studies, respectively.

Assessment of risk for low-stage MYCN-amplified neuroblastoma is controversial because it is so rare. A study of 87 INSS stage 1 and 2 patients pooled from several clinical trial groups demonstrated no effect of age, stage, or initial treatment on outcome. The event-free survival (EFS) rate was 53% and the OS rate was 72%. Survival was superior in patients whose tumors were hyperdiploid, rather than diploid (EFS, 82% ± 20% vs. 37% ± 21%; OS, 94% ± 11% vs. 54% ± 15%).[11] 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.[12] The COG considers infants with stage 4 and stage 4S disease with MYCN amplification to be at high risk.

Description of International Neuroblastoma Response Criteria

Before therapy can be stopped after the initially planned number of cycles, certain response criteria, depending on risk group and treatment assignment, must be met. These criteria are defined as follows:[13,14]

  • Complete Response: Total disappearance of tumor, with no evidence of disease. Vanillylmandelic acid (VMA) and homovanillic acid (HVA) are normal.

  • Very Good Partial Response: Primary tumor has decreased by 90% to 99%, and no evidence of metastatic disease. Urine VMA/HVA are normal. Residual bone scan changes are allowed.

  • Partial Response: 50% to 90% decrease in the size of all measurable lesions; the number of bone scan–positive sites is decreased by greater than 50% and no new lesions are present; no more than one positive bone marrow site allowed if this represents a reduction in the number of sites originally positive for tumor at diagnosis.

  • Mixed Response: No new lesions, 50% to 90% reduction of any measurable lesion (primary or metastatic) with less than 50% reduction in other lesions and less than 25% increase in any lesion.

  • No Response or Stable Disease: No new lesions; less than 50% reduction and less than 25% increase in any lesion.

  • Progressive Disease: Any new lesion; increase in any measurable lesion by greater than 25%; previous negative bone marrow now positive for tumor. Persistent elevation in urinary VMA/HVA with stable disease or an increase in VMA/HVA without clinical or radiographic evidence of progression does not indicate progressive disease, but warrants continued follow-up. Care should be taken in interpreting the development of metastatic disease in an infant who was initially considered to have stage 1 or 2 disease. If the pattern of metastases in such a patient is consistent with a 4S pattern of disease (skin, liver, bone marrow less than 10% involved), these patients are not classified as progressive/metastatic disease, which would typically be a criteria for removal from protocol therapy. Instead, these patients are managed as stage 4S.

Surgery

In patients without metastatic disease, the standard of care is to perform an initial surgery to accomplish the following:

  • Establish the diagnosis.
  • Resect as much of the primary tumor as is safely possible.
  • Accurately stage disease through sampling of regional lymph nodes that are not adherent to the tumor.
  • Obtain adequate tissue for biological studies.

The COG reported that expectant observation in infants younger than 6 months with small adrenal masses resulted in an excellent EFS and OS while avoiding surgical intervention in a large majority of patients.[15]

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.[16-19]

Radiation Therapy

In the completed COG treatment plan, radiation therapy for patients with low-risk or intermediate-risk neuroblastoma was reserved for symptomatic life-threatening or organ-threatening tumor bulk that did not respond rapidly enough to chemotherapy. Common situations in which radiation therapy is used in these patients include the following:

  • Infants aged 60 days and younger with stage 4S and marked respiratory compromise from liver metastases that has not responded to chemotherapy.
  • Symptomatic spinal cord compression that has not responded to initial chemotherapy and/or surgical decompression.
Treatment of Spinal Cord Compression

Spinal cord compression is considered a medical emergency. Immediate treatment is given because neurologic recovery is more likely when symptoms are present for a relatively short period of time before diagnosis and treatment. Recovery also depends on the severity of neurologic defects (weakness vs. paralysis). Neurologic outcome appears to be similar whether cord compression is treated with chemotherapy, radiation therapy, or surgery, although radiation therapy is used less frequently than in the past.

The completed COG low-risk and intermediate-risk neuroblastoma clinical trials recommended immediate chemotherapy for cord compression in patients grouped as low risk or intermediate risk.[20-22]

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.[20-22] It was thought that osteoplastic laminotomy, a procedure that does not remove bone, would result in less spinal deformity. Osteoplastic laminotomy may be associated with a lower incidence of progressive spinal deformity requiring fusion but there is no evidence that functional deficit is improved with laminoplasty.[23] In a series of 34 infants with symptomatic epidural spinal cord compression, both surgery and chemotherapy provided unsatisfactory results once paraplegia had been established. The frequency of grade 3 motor deficits and bowel dysfunction increased with a longer symptom duration interval. Most infants with symptomatic epidural spinal cord compression developed sequelae and it was severe in about one-half of them. This supports the need for greater awareness and timely intervention in these infants.[24]

Surveillance During and After Treatment

Surveillance studies during and after treatment are able to detect asymptomatic and unsuspected relapse in a substantial portion of patients. In an overall surveillance plan, one of the most reliable tests to detect disease progression or recurrence is the 123I-metaiodobenzylguanidine scan.[25,26]

References
  1. Cotterill SJ, Pearson AD, Pritchard J, et al.: Clinical prognostic factors in 1277 patients with neuroblastoma: results of The European Neuroblastoma Study Group 'Survey' 1982-1992. Eur J Cancer 36 (7): 901-8, 2000.  [PUBMED Abstract]

  2. Moroz V, Machin D, Faldum A, et al.: Changes over three decades in outcome and the prognostic influence of age-at-diagnosis in young patients with neuroblastoma: a report from the International Neuroblastoma Risk Group Project. Eur J Cancer 47 (4): 561-71, 2011.  [PUBMED Abstract]

  3. Look AT, Hayes FA, Shuster JJ, et al.: Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 9 (4): 581-91, 1991.  [PUBMED Abstract]

  4. Schmidt ML, Lukens JN, Seeger RC, et al.: Biologic factors determine prognosis in infants with stage IV neuroblastoma: A prospective Children's Cancer Group study. J Clin Oncol 18 (6): 1260-8, 2000.  [PUBMED Abstract]

  5. Berthold F, Trechow R, Utsch S, et al.: Prognostic factors in metastatic neuroblastoma. A multivariate analysis of 182 cases. Am J Pediatr Hematol Oncol 14 (3): 207-15, 1992.  [PUBMED Abstract]

  6. Matthay KK, Perez C, Seeger RC, et al.: Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children's Cancer Group study. J Clin Oncol 16 (4): 1256-64, 1998.  [PUBMED Abstract]

  7. Attiyeh EF, London WB, Mossé YP, et al.: Chromosome 1p and 11q deletions and outcome in neuroblastoma. N Engl J Med 353 (21): 2243-53, 2005.  [PUBMED Abstract]

  8. Spitz R, Hero B, Simon T, et al.: Loss in chromosome 11q identifies tumors with increased risk for metastatic relapses in localized and 4S neuroblastoma. Clin Cancer Res 12 (11 Pt 1): 3368-73, 2006.  [PUBMED Abstract]

  9. Strother DR, London WB, Schmidt ML, et al.: Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children's Oncology Group study P9641. J Clin Oncol 30 (15): 1842-8, 2012.  [PUBMED Abstract]

  10. Baker DL, Schmidt ML, Cohn SL, et al.: Outcome after reduced chemotherapy for intermediate-risk neuroblastoma. N Engl J Med 363 (14): 1313-23, 2010.  [PUBMED Abstract]

  11. Bagatell R, Beck-Popovic M, London WB, et al.: Significance of MYCN amplification in international neuroblastoma staging system stage 1 and 2 neuroblastoma: a report from the International Neuroblastoma Risk Group database. J Clin Oncol 27 (3): 365-70, 2009.  [PUBMED Abstract]

  12. Canete A, Gerrard M, Rubie H, et al.: Poor survival for infants with MYCN-amplified metastatic neuroblastoma despite intensified treatment: the International Society of Paediatric Oncology European Neuroblastoma Experience. J Clin Oncol 27 (7): 1014-9, 2009.  [PUBMED Abstract]

  13. Brodeur GM, Pritchard J, Berthold F, et al.: Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 11 (8): 1466-77, 1993.  [PUBMED Abstract]

  14. Brodeur GM, Seeger RC, Barrett A, et al.: International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma. J Clin Oncol 6 (12): 1874-81, 1988.  [PUBMED Abstract]

  15. Nuchtern JG, London WB, Barnewolt CE, et al.: A prospective study of expectant observation as primary therapy for neuroblastoma in young infants: a Children's Oncology Group study. Ann Surg 256 (4): 573-80, 2012.  [PUBMED Abstract]

  16. Adkins ES, Sawin R, Gerbing RB, et al.: Efficacy of complete resection for high-risk neuroblastoma: a Children's Cancer Group study. J Pediatr Surg 39 (6): 931-6, 2004.  [PUBMED Abstract]

  17. Castel V, Tovar JA, Costa E, et al.: The role of surgery in stage IV neuroblastoma. J Pediatr Surg 37 (11): 1574-8, 2002.  [PUBMED Abstract]

  18. La Quaglia MP, Kushner BH, Su W, et al.: The impact of gross total resection on local control and survival in high-risk neuroblastoma. J Pediatr Surg 39 (3): 412-7; discussion 412-7, 2004.  [PUBMED Abstract]

  19. Simon T, Häberle B, Hero B, et al.: Role of surgery in the treatment of patients with stage 4 neuroblastoma age 18 months or older at diagnosis. J Clin Oncol 31 (6): 752-8, 2013.  [PUBMED Abstract]

  20. Katzenstein HM, Kent PM, London WB, et al.: Treatment and outcome of 83 children with intraspinal neuroblastoma: the Pediatric Oncology Group experience. J Clin Oncol 19 (4): 1047-55, 2001.  [PUBMED Abstract]

  21. De Bernardi B, Pianca C, Pistamiglio P, et al.: Neuroblastoma with symptomatic spinal cord compression at diagnosis: treatment and results with 76 cases. J Clin Oncol 19 (1): 183-90, 2001.  [PUBMED Abstract]

  22. Simon T, Niemann CA, Hero B, et al.: Short- and long-term outcome of patients with symptoms of spinal cord compression by neuroblastoma. Dev Med Child Neurol 54 (4): 347-52, 2012.  [PUBMED Abstract]

  23. McGirt MJ, Chaichana KL, Atiba A, et al.: Incidence of spinal deformity after resection of intramedullary spinal cord tumors in children who underwent laminectomy compared with laminoplasty. J Neurosurg Pediatr 1 (1): 57-62, 2008.  [PUBMED Abstract]

  24. De Bernardi B, Quaglietta L, Haupt R, et al.: Neuroblastoma with symptomatic epidural compression in the infant: the AIEOP experience. Pediatr Blood Cancer 61 (8): 1369-75, 2014.  [PUBMED Abstract]

  25. Papathanasiou ND, Gaze MN, Sullivan K, et al.: 18F-FDG PET/CT and 123I-metaiodobenzylguanidine imaging in high-risk neuroblastoma: diagnostic comparison and survival analysis. J Nucl Med 52 (4): 519-25, 2011.  [PUBMED Abstract]

  26. Kushner BH, Kramer K, Modak S, et al.: Sensitivity of surveillance studies for detecting asymptomatic and unsuspected relapse of high-risk neuroblastoma. J Clin Oncol 27 (7): 1041-6, 2009.  [PUBMED Abstract]

Treatment of Low-Risk Neuroblastoma

Low-risk neuroblastoma represents nearly one-half of all newly diagnosed patients. The success of prior Children's Oncology Group (COG) clinical trials has contributed to the continued reduction in therapy for select patients with neuroblastoma.

The COG low-risk group assignment criteria are described in Table 6.

Table 6. Children’s Oncology Group (COG) Neuroblastoma Low-Risk Group Assignment Schema Used for COG Studiesa
INSS Stage  Age  MYCN Status  INPC Classification  DNA Ploidyb 
10–21 yAnyAnyAny
2A/2Bc<365 dAnyAnyAny
≥365 d–21 yNonamplifiedAny-
≥365 d–21 yAmplifiedFavorable-
4Sd<365 dNonamplifiedFavorable>1

INPC = International Neuroblastoma Pathologic Classification; INSS = International Neuroblastoma Staging System.
aThe COG-P9641 (low risk) and COG-A3961 (intermediate risk) trials established the current standard of care for neuroblastoma patients in terms of risk group assignment and treatment strategies.
bDNA Ploidy: DNA Index (DI) > 1 is favorable, = 1 is unfavorable; hypodiploid tumors (with DI < 1) will be treated as a tumor with a DI > 1 (DI < 1 [hypodiploid] to be considered favorable ploidy).
cINSS stage 2A/2B symptomatic patients with spinal cord compression, neurologic deficits, or other symptoms are treated with immediate chemotherapy for four cycles.
dINSS stage 4S infants with favorable biology and clinical symptoms are treated with immediate chemotherapy until asymptomatic (2–4 cycles). Clinical symptoms include the following: respiratory distress with or without hepatomegaly or cord compression and neurologic deficit or inferior vena cava compression and renal ischemia; or genitourinary obstruction; or gastrointestinal obstruction and vomiting; or coagulopathy with significant clinical hemorrhage unresponsive to replacement therapy.

(Refer to the Treatment of Stage 4S Neuroblastoma section of this summary for more information about the treatment of stage 4S neuroblastoma.)

Treatment Options for Low-Risk Neuroblastoma

For patients with localized disease that appears to be resectable (either based on the absence of image-defined risk factors [L1] or on the surgeon's expertise), the tumor should be resected by an experienced surgeon. If the biology is confirmed to be favorable, residual disease is not considered a risk factor for relapse. Several studies have shown that patients with favorable biology and residual disease have excellent outcomes with event-free survival (EFS) in excess of 90% and overall survival (OS) of 99% to 100%.[1,2]

Treatment options for low-risk neuroblastoma include the following:

  1. Surgery followed by observation.
  2. Chemotherapy with or without surgery (for symptomatic disease or unresectable progressive disease after surgery).
  3. Observation without biopsy (for perinatal neuroblastoma with small adrenal tumors). Not considered standard treatment.
Surgery followed by observation

Treatment for patients categorized as low risk (refer to Table 6) may be surgery alone, which is curative for most patients with low-risk neuroblastoma. Patients need not undergo complete resection of disease to be cured by surgery alone.[2]

There is controversy about the need to attempt resection, whether at the time of diagnosis or later, in asymptomatic infants aged 12 months or younger with apparent stage 2B and 3 MYCN-nonamplified and favorable biology disease. In a German clinical trial, some of these patients were observed after biopsy or partial resection without chemotherapy or radiation, and many did not progress locally and never received additional resection.[3]

Chemotherapy with or without surgery (for symptomatic disease or unresectable progressive disease after surgery)

Results from the COG-P9641 study showed that surgery alone, even without complete resection, can cure nearly all patients with stage 1 neuroblastoma, and the vast majority of patients with asymptomatic, favorable biology, INSS stage 2A and 2B disease.[2] The use of chemotherapy may be restricted to specific situations (e.g., children with MYCN-amplified stage 1 and 2 neuroblastoma and children with MYCN-nonamplified stage 2B neuroblastoma who are older than 18 months or who have unfavorable histology or diploid disease). These children have a less favorable outcome than other low-risk patients.[2,4]

Chemotherapy is also reserved for low-risk patients who are symptomatic, such as from spinal cord compression or, in stage 4S, respiratory compromise secondary to hepatic infiltration. The chemotherapy consists of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative chemotherapy dose of each agent is kept low to minimize permanent injury (COG-P9641).[2]

Evidence (chemotherapy):

  1. The COG-P9641 study was one of the first COG studies to test risk stratification based on consensus-derived factors. In this phase III nonrandomized trial, 915 patients underwent an initial operation to obtain tissue for diagnosis and biology studies and for maximal safe primary tumor resection. Chemotherapy was reserved for patients with, or at risk of, symptomatic disease, with less than 50% tumor resection at diagnosis or with unresectable progressive disease after surgery alone.[2]
    • Stage 1: Patients with stage 1 disease achieved 5-year EFS of 93% and 5-year OS of 99%.

    • Stage 2A and 2B: Asymptomatic patients with stage 2A and 2B disease (n = 306) who were observed after initial operation had a 5-year EFS of 87% and OS rate of 96%. EFS was significantly better for patients with stage 2A than for patients with 2B neuroblastoma (92% vs. 85%; P = .0321), but OS did not differ significantly (98% and 96%; P = .2867). The primary study objective (to achieve a 3-year OS of 95% for asymptomatic patients with stage 2A and 2B disease) was met. 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. Outcome for patients with stage 2B, diploid tumors, and unfavorable histology was particularly poor (EFS, 54%; OS, 70%), with no survivors in the few patients with additional 1p loss of heterozygosity and all deaths occurring in children older than 18 months.

    • Asymptomatic patients at diagnosis who were observed after initial operation: Of the initial 915 patients, 800 were asymptomatic at diagnosis and observed after their initial operations. Within this group, 11% experienced recurrent or progressive disease. Of the 115 patients who received immediate chemotherapy (median, four cycles; range, one to eight), 81% of the patients had a very good partial response or better. After chemotherapy, 10% of the patients had disease recurrence or progression. For patients treated with surgery alone, the 5-year EFS rate was 89% and the overall survival estimate was 97% and for patients treated with surgery and immediate chemotherapy, the 5-year EFS rate was 91% and the overall survival estimate was 98%.

    • MYCN amplification: The impact of MYCN-amplified tumors was analyzed in stage I disease. For patients with MYCN-nonamplified tumors the 5-year EFS was 93% and the OS was 99% and for MYCN-amplified tumors the 5-year EFS was 70% (P = .0042) and OS was 80% (P < .001).

Observation without biopsy (for perinatal neuroblastoma with small adrenal tumors)

Studies suggest that selected small adrenal masses, presumed to be neuroblastoma, detected in infants younger than 6 months by screening or incidental ultrasound may safely be observed without obtaining a definitive histologic diagnosis and without surgical intervention, thus avoiding potential complications of surgery in the newborn.[5] Additional studies are necessary to confirm this finding before it can be considered standard treatment.

Evidence (observation without biopsy):

  1. COG-ANBL00P2 reported that expectant observation is safe, with 81% of patients demonstrating spontaneous regression while avoiding surgical intervention.[5]
    • Eighty-three of 87 eligible patients were observed without biopsy or resection and only 16 (19%) ultimately underwent surgery.
    • Three-year EFS (for a neuroblastoma event) was 97.7% and OS was 100%.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with neuroblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References
  1. Matthay KK, Perez C, Seeger RC, et al.: Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children's Cancer Group study. J Clin Oncol 16 (4): 1256-64, 1998.  [PUBMED Abstract]

  2. Strother DR, London WB, Schmidt ML, et al.: Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children's Oncology Group study P9641. J Clin Oncol 30 (15): 1842-8, 2012.  [PUBMED Abstract]

  3. Hero B, Simon T, Spitz R, et al.: Localized infant neuroblastomas often show spontaneous regression: results of the prospective trials NB95-S and NB97. J Clin Oncol 26 (9): 1504-10, 2008.  [PUBMED Abstract]

  4. Bagatell R, Beck-Popovic M, London WB, et al.: Significance of MYCN amplification in international neuroblastoma staging system stage 1 and 2 neuroblastoma: a report from the International Neuroblastoma Risk Group database. J Clin Oncol 27 (3): 365-70, 2009.  [PUBMED Abstract]

  5. Nuchtern JG, London WB, Barnewolt CE, et al.: A prospective study of expectant observation as primary therapy for neuroblastoma in young infants: a Children's Oncology Group study. Ann Surg 256 (4): 573-80, 2012.  [PUBMED Abstract]

Treatment of Intermediate-Risk Neuroblastoma

The Children's Oncology Group (COG) intermediate-risk group assignment criteria are described in Table 7.

Table 7. Children’s Oncology Group (COG) Neuroblastoma Intermediate-Risk Group Assignment Schema Used for the COG-A3961 Studya
INSS Stage  Age  MYCN Status  INPC Classification  DNA Ploidyb 
3c<365 dNonamplifiedAnyAny
≥365 d–21 yNonamplifiedFavorable-
4c<548 d [1-3]NonamplifiedAnyAny
4Sd<365 dNonamplifiedAny=1
<365 dNonamplifiedUnfavorableAny

INPC = International Neuroblastoma Pathologic Classification; INSS = International Neuroblastoma Staging System.
aThe COG-P9641 (low risk) and COG-A3961 (intermediate risk) trials established the current standard of care for non–high-risk neuroblastoma patients in terms of risk group assignment and treatment strategies.
bDNA Ploidy: DNA Index (DI) > 1 is favorable, DI = 1 is unfavorable; hypodiploid tumors (with DI < 1) will be treated as a tumor with a DI > 1 (DI < 1 [hypodiploid] to be considered favorable ploidy).
cINSS stage 3 or stage 4 patients with clinical symptoms as listed above receive immediate chemotherapy.
dINSS stage 4S infants with favorable biology and clinical symptoms are treated with immediate chemotherapy until asymptomatic (2–4 cycles). Clinical symptoms include the following: respiratory distress with or without hepatomegaly or cord compression and neurologic deficit or inferior vena cava compression and renal ischemia; or genitourinary obstruction; or gastrointestinal obstruction and vomiting; or coagulopathy with significant clinical hemorrhage unresponsive to replacement therapy.

(Refer to the Treatment of Stage 4S Neuroblastoma section of this summary for more information about the treatment of stage 4S neuroblastoma.)

Treatment Options for Intermediate-Risk Neuroblastoma

Treatment options for intermediate-risk neuroblastoma include the following:

  1. Chemotherapy with or without surgery.
  2. Surgery and observation (in infants).
  3. Radiation therapy (only for emergent therapy).
Chemotherapy with or without surgery

Patients categorized as intermediate risk have been successfully treated with surgery and four to eight cycles of chemotherapy (carboplatin, cyclophosphamide, doxorubicin, and etoposide; the cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen) (COG-A3961). As a rule, patients whose tumors had unfavorable biology received eight cycles of chemotherapy, compared with four cycles for patients whose tumors had favorable biology. The COG-A3961 phase III trial demonstrated that therapy could be significantly reduced for patients with intermediate-risk neuroblastoma while maintaining outstanding survival.[4]

Whether initial chemotherapy is indicated for all intermediate-risk infants with localized neuroblastoma requires further study.

Evidence (chemotherapy with or without surgery):

  1. In North America, the COG (COG-A3961) investigated a risk-based neuroblastoma treatment plan that assigned all patients to a low-, intermediate-, or high-risk group based on age, International Neuroblastoma Staging System (INSS) stage, and tumor biology (i.e., MYCN gene amplification, International Neuroblastoma Pathology Classification system, and DNA ploidy). This study investigated an overall reduction in treatment compared with prior 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 intermediate-risk tumors (stages 3, 4, and 4S), 69.6% of them had favorable features, defined as hyperdiploidy and favorable histology, and were assigned to receive four cycles of chemotherapy.[4]
    • The administration of neoadjuvant chemotherapy facilitated at least a partial resection of 99.6% of the previously unresectable tumors. No significant difference was noted in overall survival (OS) according to the degree of resection (complete vs. incomplete, P = .37).

    • Only 2.5% of the 479 patients received local radiation therapy. The 3-year event-free survival (EFS) was 88% and OS was 95%.

    • The 3-year EFS was 92% for patients with stage 3 disease (n = 269), 90% for patients with stage 4S disease (n = 31), and 81% for patients with stage 4 disease (n = 176) (P < .001 for stages 3 and 4S vs. stage 4); the 3-year OS estimates were 98% for stage 3 disease, 97% for stage 4S disease, and 93% for stage 4 disease (P = .002 for stages 3 and 4S vs. stage 4).

    • There was no difference in OS in patients with favorable biologic features between those who received eight cycles of chemotherapy (100%) compared with those who received four cycles (96%).

    • There was no unexpected toxicity.

  2. A German prospective clinical trial enrolled 340 infants aged 1 year or younger whose tumors were stage 1, 2, or 3, histologically verified, and lacked MYCN amplification. Chemotherapy was given at diagnosis to 57 infants with organs threatened by tumor. The tumor was completely resected or nearly so in 190 infants who underwent low-risk surgery. A total of 93 infants whose tumors were not resectable without high-risk surgery, due to age or organ involvement, were observed without chemotherapy.[5]
    • Three-year OS was excellent (95%) for infants receiving chemotherapy.

    • Further surgery was avoided in 33 infants and chemotherapy was avoided in 72 infants.

    • The 3-year OS rate for the infants who were observed without treatment was 99%. The metastases-free survival rate was 94% for infants with unresected tumors and was not different from infants treated with surgery or chemotherapy (median follow-up, 58 months).

    • Forty-four of 93 infants with unresected tumors experienced spontaneous regression (17 were complete regressions) and 39 infants experienced progression.

    • The investigators suggested that a wait-and-see strategy is appropriate for infants with localized neuroblastoma because regressions have been observed after the first year of life.

  3. Moderate-dose chemotherapy has been shown to be effective in the prospective Infant Neuroblastoma European Study (EURO-INF-NB-STUDY-1999-99.1); about one-half of the infants with unresectable, nonmetastatic neuroblastoma and no MYCN amplification underwent a safe surgical resection and avoided long-term adverse effects.[6][Level of evidence: 3iiA]
    • The 5-year OS rate was 99% and the EFS rate was 90% (median follow-up, 6 years).

    • In this study, infants undergoing surgical resection had a better EFS than those who did not have surgery.

  4. A prospective SIOPEN trial treated children with stage 2 or stage 3 unresectable neuroblastoma and those aged 12 to 18 months, with favorable International Neuroblastoma Pathology Classification.[7][Level of evidence: 3iiD]
    • The EFS was 98% with conventional chemotherapy.
    • These results are similar to the COG (COG-A3961) trial.

  5. In two European prospective trials of infants with disseminated neuroblastoma without MYCN gene amplification, infants with INSS stage 3 primary or positive skeletal scintigraphy were not started on chemotherapy unless life-threatening or organ-threatening symptoms developed. Chemotherapy when given consisted of short-dose and standard-dose chemotherapy.[8]
    • The OS was 100% in the 41 patients who did not have INSS stage 4S regardless of initial chemotherapy.

    • In infants with overt metastases to the skeleton, lung, and central nervous system, the 2-year OS was 96% (n = 45).

    • No patients died of surgery-related or chemotherapy-related complications on either protocol.

In cases of abdominal neuroblastoma thought to involve the kidney, nephrectomy is not undertaken before a trial of chemotherapy has been given.[9]

Surgery and observation (in infants)

The need for chemotherapy in all asymptomatic infants with stage 3 or 4 disease is somewhat controversial, as some European studies have shown favorable outcomes with surgery and observation as described below.[8]

Evidence (surgery and observation in infants):

  1. Infants classified as stage 4 (from 4S) due to a primary tumor infiltrating across the midline (INSS 3) or positive bone scintigraphy not associated with changes in the cortical bone documented on plain radiographs and/or computed tomography were reported to have a better outcome compared to other stage 4 infants (EFS, 90% vs. 27%).[10]

  2. International Society of Paediatric Oncology European Neuroblastoma Group (SIOPEN) conducted a prospective trial of 125 infants (n = 41 with INSS 3 primary tumors or positive scintigraphy) with disseminated neuroblastoma without MYCN amplification to see if these patients could be observed in the absence of symptoms. However, treating physicians did not always follow the wait-and-see strategy.[8]
    • There was no significant difference in 2-year OS in patients with unresectable primary tumors and patients with resectable primary tumors (97% vs. 100%) and patients with negative or with positive skeletal scintigraphy without radiologic abnormalities (100% vs. 97%).

  3. A German prospective clinical trial enrolled 340 infants aged 1 year or younger whose tumors were stage 1, 2, or 3, verified histologically, and lacked MYCN amplification. Of the 190 infants undergoing resection, there were eight infants with stage 3 disease. A total of 93 infants whose tumors were not resectable without high-risk surgery, due to age or organ involvement, were observed without chemotherapy, which included 21 stage 3 patients. Fifty-seven infants, including 41 stage 3 patients, were treated with chemotherapy to control threatening symptoms.[5]
    • Three-year OS was excellent for the entire group of infants with unresected tumors (99%), infants receiving chemotherapy (95%), and infants with resected tumors (98%) (P = .45).

Radiation therapy (only for emergent therapy)

Radiation therapy is reserved for patients with the following:

  • Symptomatic life-threatening or organ-threatening tumor that does not respond rapidly enough to chemotherapy and/or surgery and/or;
  • Progressive disease.
Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with neuroblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References
  1. Schmidt ML, Lal A, Seeger RC, et al.: Favorable prognosis for patients 12 to 18 months of age with stage 4 nonamplified MYCN neuroblastoma: a Children's Cancer Group Study. J Clin Oncol 23 (27): 6474-80, 2005.  [PUBMED Abstract]

  2. London WB, Castleberry RP, Matthay KK, et al.: Evidence for an age cutoff greater than 365 days for neuroblastoma risk group stratification in the Children's Oncology Group. J Clin Oncol 23 (27): 6459-65, 2005.  [PUBMED Abstract]

  3. George RE, London WB, Cohn SL, et al.: Hyperdiploidy plus nonamplified MYCN confers a favorable prognosis in children 12 to 18 months old with disseminated neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 23 (27): 6466-73, 2005.  [PUBMED Abstract]

  4. Baker DL, Schmidt ML, Cohn SL, et al.: Outcome after reduced chemotherapy for intermediate-risk neuroblastoma. N Engl J Med 363 (14): 1313-23, 2010.  [PUBMED Abstract]

  5. Hero B, Simon T, Spitz R, et al.: Localized infant neuroblastomas often show spontaneous regression: results of the prospective trials NB95-S and NB97. J Clin Oncol 26 (9): 1504-10, 2008.  [PUBMED Abstract]

  6. Rubie H, De Bernardi B, Gerrard M, et al.: Excellent outcome with reduced treatment in infants with nonmetastatic and unresectable neuroblastoma without MYCN amplification: results of the prospective INES 99.1. J Clin Oncol 29 (4): 449-55, 2011.  [PUBMED Abstract]

  7. Kohler JA, Rubie H, Castel V, et al.: Treatment of children over the age of one year with unresectable localised neuroblastoma without MYCN amplification: results of the SIOPEN study. Eur J Cancer 49 (17): 3671-9, 2013.  [PUBMED Abstract]

  8. De Bernardi B, Gerrard M, Boni L, et al.: Excellent outcome with reduced treatment for infants with disseminated neuroblastoma without MYCN gene amplification. J Clin Oncol 27 (7): 1034-40, 2009.  [PUBMED Abstract]

  9. Shamberger RC, Smith EI, Joshi VV, et al.: The risk of nephrectomy during local control in abdominal neuroblastoma. J Pediatr Surg 33 (2): 161-4, 1998.  [PUBMED Abstract]

  10. Minard V, Hartmann O, Peyroulet MC, et al.: Adverse outcome of infants with metastatic neuroblastoma, MYCN amplification and/or bone lesions: results of the French society of pediatric oncology. Br J Cancer 83 (8): 973-9, 2000.  [PUBMED Abstract]

Treatment of High-Risk Neuroblastoma

The Children's Oncology Group (COG) high-risk group assignment criteria are described in Table 8.

Table 8. Children’s Oncology Group (COG) Neuroblastoma High-Risk Group Assignment Schema
INSS Stage  Age  MYCN Status  INPC Classification  DNA Ploidya 
2A/2Bb≥365 d–21 yAmplifiedUnfavorable-
3c<365 dAmplifiedAnyAny
≥365 d–21 yNonamplifiedUnfavorable-
≥365 d–21 yAmplifiedAny-
4c<365 dAmplifiedAnyAny
≥548 d–21 yAnyAny-
4S<365 dAmplifiedAnyAny

INPC = International Neuroblastoma Pathologic Classification; INSS = International Neuroblastoma Staging System.
aDNA Ploidy: DNA Index (DI) > 1 is favorable, DI = 1 is unfavorable; hypodiploid tumors (with DI < 1) will be treated as a tumor with a DI > 1 (DI < 1 [hypodiploid] to be considered favorable ploidy).
bINSS stage 2A/2B symptomatic patients with spinal cord compression, neurologic deficits, or other symptoms are treated with immediate chemotherapy for four cycles.
cINSS stage 3 or stage 4 patients with clinical symptoms as listed above receive immediate chemotherapy.

Approximately 8% to 10% of infants with stage 4S disease will have MYCN-amplified tumors and are usually treated on high-risk protocols. The overall event-free survival (EFS) and overall survival (OS) for infants with stage 4 and 4S disease and MYCN-amplification were only 30% at 2 to 5 years posttreatment in a European study.[1]

For children with high-risk neuroblastoma, long-term survival with current treatments is about 54%.[2] Children with aggressively treated, high-risk neuroblastoma may develop late recurrences, some more than 5 years after completion of therapy.[3,4]

Treatment Options for High-Risk Neuroblastoma

Outcomes for patients with high-risk neuroblastoma remain poor despite recent improvements in survival in randomized trials.

A treatment option for high-risk neuroblastoma is the following:

  1. A regimen of chemotherapy, surgery, stem cell transplant (SCT), radiation therapy, and anti-GD2 antibody ch14.18 with interleukin-2/granulocyte-macrophage colony-stimulating factor (GM-CSF) and isotretinoin.
Chemotherapy, surgery, SCT, radiation therapy, and anti-GD2 antibody ch14.18, with interleukin-2/GM-CSF and isotretinoin

Treatment for patients with high-risk disease is generally divided into the following three phases:

  • Induction (includes chemotherapy and surgical resection).
  • Consolidation (hematopoietic stem cell rescue/transplantation [HSCT] and radiation therapy to the site of the primary tumor).
  • Maintenance (immunotherapy and retinoid).
Induction phase

The backbone of the most commonly used induction therapy includes dose-intensive cycles of cisplatin and etoposide alternating with vincristine, cyclophosphamide, and doxorubicin.[5] Topotecan was added to this regimen based on the anti-neuroblastoma activity seen in relapsed patients.[6] Response to therapy at the end of induction chemotherapy correlates with EFS at the completion of high-risk therapy.[7] After a response to chemotherapy, resection of the primary tumor is usually attempted.

Consolidation phase

The consolidation phase of high-risk regimens involves myeloablative chemotherapy and HSCT, which attempts to eradicate minimal residual disease using lethal doses of chemotherapy and autologous stem cells collected during induction chemotherapy to repopulate the bone marrow. Several large randomized controlled studies have shown an improvement in 3-year EFS for HSCT (31% to 47%) versus conventional chemotherapy (22% to 31%).[8-10] Previously, total-body irradiation had been used in HSCT conditioning regimens. Most current protocols use either carboplatin/etoposide/melphalan or busulfan/melphalan as conditioning for HSCT. Two or more sequential cycles of myeloablative chemotherapy and stem cell rescue given in a tandem fashion has been shown to be feasible for patients with high-risk neuroblastoma.[11,12]

A randomized clinical study (COG-ANBL0532) testing the efficacy of two cycles versus one cycle of myeloablative chemotherapy with stem cell rescue has been completed. (Refer to the Autologous Hematopoietic Cell Transplantation section in the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation.)

Tandem consolidation using 131I-mIBG, vincristine, and irinotecan with autologous SCT followed by busulfan/melphalan with autologous SCT has been studied in refractory patients.[13]

Radiation to the primary tumor site (whether or not a complete excision was obtained) and persistently metaiodobenzylguanidine-positive bony metastatic sites is often performed before, during, or after myeloablative therapy. The optimal dose of radiation therapy has not been determined. Radiation of metastatic disease sites is determined on an individual case basis or according to protocol guidelines for patients enrolled in studies.

Preliminary outcomes for proton radiation therapy of high-risk neuroblastoma primary tumors have been published.[14]

Maintenance phase

Differentiation therapy is used to treat potential minimal residual disease following HSCT.[15] After recovery from myeloablative chemotherapy and stem cell rescue, patients are treated with the differentiating agent oral isotretinoin for 6 months. Immunotherapy is given along with differentiated therapy in the post-HSCT differentiation therapy regimen. Antibodies developed to target GD2, present on the surface of neuroblastoma cells, are used. For high risk-patients in remission following HSCT, chimeric anti-GD2 antibody ch14.18 combined with GM-CSF and interleukin-2 are given in concert with isotretinoin and have been shown to improve EFS.[16,17]

Evidence (all treatments):

  1. A randomized study was performed comparing high-dose therapy with purged autologous bone marrow transplant (ABMT) versus three cycles of intensive consolidation chemotherapy. In addition, patients on this study were subsequently randomly assigned to stop therapy or to receive 6 months of isotretinoin.[8]; [15][Level of evidence: 1iiA]
    • The 5-year EFS was significantly better in the ABMT arm (30%), compared with the consolidation chemotherapy arm (19%; P = .04). There was no significant difference in 5-year OS (39% vs. 30%; P = .39). However, in patients who survived more than 3 years, a significant benefit is seen in OS with ABMT.[15]

    • Patients who received isotretinoin had a higher 5-year EFS than patients who received no maintenance therapy (42% vs. 31%), although the difference was not significant. For patients who participated in both random assignments, the 5-year OS from the time of the second randomization for patients assigned ABMT and isotretinoin was 59% and 41% for patients assigned to ABMT without isotretinoin. Patients assigned to consolidation chemotherapy and isotretinoin showed a 5-year survival of 38% and 36% for patients receiving consolidation chemotherapy and no isotretinoin.[15] However, these patients were selected for having completed ABMT without developing progressive disease.

  2. In a separate prospective, randomized study, there was no advantage to purging harvested stem cells of neuroblastoma cells before transplantation.[18]

  3. In a COG phase III trial after HSCT, patients were randomly assigned to receive anti-GD2 monoclonal antibody (ch14.18) administered with GM-CSF and interleukin-2 in conjunction with isotretinoin, versus isotretinoin alone.[16]
    • Immunotherapy together with isotretinoin (EFS, 66%) was superior to standard isotretinoin maintenance therapy (EFS, 46%). As a result, immunotherapy post-HSCT is considered the standard of care in COG trials for high-risk disease.

Local control (surgery and radiation therapy)

The potential benefit of aggressive surgical approaches in high-risk patients with metastatic disease to achieve complete tumor resection, either at the time of diagnosis or following chemotherapy, has not been unequivocally demonstrated.

  • 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.[19-24]

  • Radiation therapy to consolidate local control after surgical resection is often given.[25]; [26][Level of evidence: 3iiA]

  • In stage 4 patients older than 18 months, it is controversial as to whether there is any advantage to gross-total resection of the primary tumor mass after chemotherapy.[21-24]

Treatment Options Under Clinical Evaluation

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

  • COG-ANBL12P1 (NCT01798004) (Busulfan, Melphalan, and SCT After Chemotherapy in Treating Patients With Newly Diagnosed High-Risk Neuroblastoma): Because busulfan/melphalan has not been used with the COG induction regimen, the primary objective of this study is to examine the toxicity profile of busulfan/melphalan in the context of COG therapy, with specific focus on the incidence and severity of pulmonary and hepatic toxicity. The outcome of this trial will influence the choice of preparative regimens used in the upcoming COG high-risk neuroblastoma trials.

  • COG-ANBL09P1 (NCT01175356) (Induction Therapy Including 131I-Metaiodobenzylguanidine [mIBG] and Chemotherapy in Treating Patients With Newly Diagnosed High-Risk Neuroblastoma Undergoing SCT, Radiation Therapy, and Maintenance Therapy With Isotretinoin): This pilot study will evaluate the tolerability and feasibility of an induction chemotherapy regimen containing five cycles of multiagent chemotherapy and a block of 131I-mIBG followed by a consolidation regimen of busulfan/melphalan with autologous stem cell rescue and external-beam radiation therapy. The study has been amended to omit vincristine and irinotecan as radiation sensitizers, and the period from transplant to the start of radiation was extended to 42 days because of toxicity.

  • COG-ANBL0032 (Isotretinoin With Monoclonal Antibody, Interleukin-2, and Sargramostim Following SCT in Treating Patients With Neuroblastoma): The COG is studying, now in a nonrandomized fashion, the use of monoclonal antibody therapy with GM-CSF and interleukin-2 combined with isotretinoin following chemotherapy.[16]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with neuroblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References
  1. Canete A, Gerrard M, Rubie H, et al.: Poor survival for infants with MYCN-amplified metastatic neuroblastoma despite intensified treatment: the International Society of Paediatric Oncology European Neuroblastoma Experience. J Clin Oncol 27 (7): 1014-9, 2009.  [PUBMED Abstract]

  2. Maris JM: Recent advances in neuroblastoma. N Engl J Med 362 (23): 2202-11, 2010.  [PUBMED Abstract]

  3. Cotterill SJ, Pearson AD, Pritchard J, et al.: Late relapse and prognosis for neuroblastoma patients surviving 5 years or more: a report from the European Neuroblastoma Study Group "Survey". Med Pediatr Oncol 36 (1): 235-8, 2001.  [PUBMED Abstract]

  4. Mertens AC, Yasui Y, Neglia JP, et al.: Late mortality experience in five-year survivors of childhood and adolescent cancer: the Childhood Cancer Survivor Study. J Clin Oncol 19 (13): 3163-72, 2001.  [PUBMED Abstract]

  5. Kushner BH, LaQuaglia MP, Bonilla MA, et al.: Highly effective induction therapy for stage 4 neuroblastoma in children over 1 year of age. J Clin Oncol 12 (12): 2607-13, 1994.  [PUBMED Abstract]

  6. Park JR, Scott JR, Stewart CF, et al.: Pilot induction regimen incorporating pharmacokinetically guided topotecan for treatment of newly diagnosed high-risk neuroblastoma: a Children's Oncology Group study. J Clin Oncol 29 (33): 4351-7, 2011.  [PUBMED Abstract]

  7. Cheung NK, Heller G, Kushner BH, et al.: Stage IV neuroblastoma more than 1 year of age at diagnosis: major response to chemotherapy and survival durations correlated strongly with dose intensity. Prog Clin Biol Res 366: 567-73, 1991.  [PUBMED Abstract]

  8. Matthay KK, Villablanca JG, Seeger RC, et al.: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group. N Engl J Med 341 (16): 1165-73, 1999.  [PUBMED Abstract]

  9. Berthold F, Boos J, Burdach S, et al.: Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial. Lancet Oncol 6 (9): 649-58, 2005.  [PUBMED Abstract]

  10. Pritchard J, Cotterill SJ, Germond SM, et al.: High dose melphalan in the treatment of advanced neuroblastoma: results of a randomised trial (ENSG-1) by the European Neuroblastoma Study Group. Pediatr Blood Cancer 44 (4): 348-57, 2005.  [PUBMED Abstract]

  11. Granger M, Grupp SA, Kletzel M, et al.: Feasibility of a tandem autologous peripheral blood stem cell transplant regimen for high risk neuroblastoma in a cooperative group setting: a Pediatric Oncology Group study: a report from the Children's Oncology Group. Pediatr Blood Cancer 59 (5): 902-7, 2012.  [PUBMED Abstract]

  12. Seif AE, Naranjo A, Baker DL, et al.: A pilot study of tandem high-dose chemotherapy with stem cell rescue as consolidation for high-risk neuroblastoma: Children's Oncology Group study ANBL00P1. Bone Marrow Transplant 48 (7): 947-52, 2013.  [PUBMED Abstract]

  13. French S, DuBois SG, Horn B, et al.: 131I-MIBG followed by consolidation with busulfan, melphalan and autologous stem cell transplantation for refractory neuroblastoma. Pediatr Blood Cancer 60 (5): 879-84, 2013.  [PUBMED Abstract]

  14. Hattangadi JA, Rombi B, Yock TI, et al.: Proton radiotherapy for high-risk pediatric neuroblastoma: early outcomes and dose comparison. Int J Radiat Oncol Biol Phys 83 (3): 1015-22, 2012.  [PUBMED Abstract]

  15. Matthay KK, Reynolds CP, Seeger RC, et al.: Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children's oncology group study. J Clin Oncol 27 (7): 1007-13, 2009.  [PUBMED Abstract]

  16. Yu AL, Gilman AL, Ozkaynak MF, et al.: Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med 363 (14): 1324-34, 2010.  [PUBMED Abstract]

  17. Cheung NK, Cheung IY, Kushner BH, et al.: Murine anti-GD2 monoclonal antibody 3F8 combined with granulocyte-macrophage colony-stimulating factor and 13-cis-retinoic acid in high-risk patients with stage 4 neuroblastoma in first remission. J Clin Oncol 30 (26): 3264-70, 2012.  [PUBMED Abstract]

  18. Kreissman SG, Seeger RC, Matthay KK, et al.: Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial. Lancet Oncol 14 (10): 999-1008, 2013.  [PUBMED Abstract]

  19. George RE, Li S, Medeiros-Nancarrow C, et al.: High-risk neuroblastoma treated with tandem autologous peripheral-blood stem cell-supported transplantation: long-term survival update. J Clin Oncol 24 (18): 2891-6, 2006.  [PUBMED Abstract]

  20. DeCou JM, Bowman LC, Rao BN, et al.: Infants with metastatic neuroblastoma have improved survival with resection of the primary tumor. J Pediatr Surg 30 (7): 937-40; discussion 940-1, 1995.  [PUBMED Abstract]

  21. Adkins ES, Sawin R, Gerbing RB, et al.: Efficacy of complete resection for high-risk neuroblastoma: a Children's Cancer Group study. J Pediatr Surg 39 (6): 931-6, 2004.  [PUBMED Abstract]

  22. Castel V, Tovar JA, Costa E, et al.: The role of surgery in stage IV neuroblastoma. J Pediatr Surg 37 (11): 1574-8, 2002.  [PUBMED Abstract]

  23. La Quaglia MP, Kushner BH, Su W, et al.: The impact of gross total resection on local control and survival in high-risk neuroblastoma. J Pediatr Surg 39 (3): 412-7; discussion 412-7, 2004.  [PUBMED Abstract]

  24. Simon T, Häberle B, Hero B, et al.: Role of surgery in the treatment of patients with stage 4 neuroblastoma age 18 months or older at diagnosis. J Clin Oncol 31 (6): 752-8, 2013.  [PUBMED Abstract]

  25. Haas-Kogan DA, Swift PS, Selch M, et al.: Impact of radiotherapy for high-risk neuroblastoma: a Children's Cancer Group study. Int J Radiat Oncol Biol Phys 56 (1): 28-39, 2003.  [PUBMED Abstract]

  26. Gatcombe HG, Marcus RB Jr, Katzenstein HM, et al.: Excellent local control from radiation therapy for high-risk neuroblastoma. Int J Radiat Oncol Biol Phys 74 (5): 1549-54, 2009.  [PUBMED Abstract]

Treatment of Stage 4S Neuroblastoma

Many patients with stage 4S neuroblastoma do not require therapy. However, tumors with unfavorable biology or patients who are symptomatic due to evolving hepatomegaly and organ compromise are at increased risk of death and are treated with low-dose to moderate-dose chemotherapy. Eight percent to 10% of these patients will have MYCN amplification and are treated with high-risk protocols.[1] (Refer to the Treatment of High-Risk Neuroblastoma section of this summary for more information about the treatment of stage 4S high-risk neuroblastoma.)

Table 9. Children’s Oncology Group (COG) Neuroblastoma Stage 4S Group Assignment Schema Used for COG-P9641, COG-A3961, and COG-A3973 Studiesa
INSS Stage  Age  MYCN Status  INPC Classification  DNA Ploidyb Risk Group 
4Sc<365 dNonamplifiedFavorable>1Low
<365 dNonamplifiedAny=1Intermediate
<365 dNonamplifiedUnfavorableAnyIntermediate
<365 dAmplifiedAnyAnyHigh

INPC = International Neuroblastoma Pathologic Classification; INSS = International Neuroblastoma Staging System.
aThe COG-P9641, COG-A3961, and COG-A3973 trials established the current standard of care for neuroblastoma patients in terms of risk group assignment and treatment strategies.
bDNA Ploidy: DNA Index (DI) > 1 is favorable, = 1 is unfavorable; hypodiploid tumors (with DI < 1) will be treated as a tumor with a DI > 1 (DI < 1 [hypodiploid] to be considered favorable ploidy).
cINSS stage 4S infants with favorable biology and clinical symptoms are treated with immediate chemotherapy until asymptomatic or according to protocol guidelines. Clinical symptoms include the following: respiratory distress with or without hepatomegaly or cord compression and neurologic deficit or inferior vena cava compression and renal ischemia; or genitourinary obstruction; or gastrointestinal obstruction and vomiting; or coagulopathy with significant clinical hemorrhage unresponsive to replacement therapy.

Treatment Options for Stage 4S Neuroblastoma

There is no standard approach to the treatment of stage 4S neuroblastoma.

Treatment options for stage 4S neuroblastoma include the following:

  1. Observation with supportive care (for asymptomatic patients with favorable tumor biology).
  2. Chemotherapy (for symptomatic patients, very young infants, or those with unfavorable biology).

Resection of primary tumor is not associated with improved outcome.[2-4] Rarely, infants with massive hepatic 4S neuroblastoma develop cirrhosis from the chemotherapy and/or radiation therapy that is used to control the disease and may benefit from orthotopic liver transplantation.[5]

Observation with supportive care (asymptomatic patients with favorable tumor biology)

The treatment of children with stage 4S disease is dependent on clinical presentation.[2,3] Most patients do not require therapy unless bulk disease is causing organ compromise and risk of death.

Chemotherapy (symptomatic patients, very young infants, or those with unfavorable biology)

Infants diagnosed with International Neuroblastoma Staging System (INSS) stage 4S neuroblastoma, particularly those with hepatomegaly or those younger than 2 months, have the potential for rapid clinical deterioration and may benefit from early initiation of therapy. It has been difficult to identify infants with stage 4S disease who will benefit from chemotherapy. Several clinical trials have evaluated the presence of symptoms in patients with 4S disease, including the following:

  • In 45 patients with stage 4S neuroblastoma diagnosed in the first month of life, 16 patients developed dyspnea caused by massive liver enlargement; one-half of them did not survive.[6]

  • A review of 35 patients with INSS stage 4S disease described 13 patients younger than 4 weeks, all of whom had liver involvement. Of the seven who died, all presented with hepatomegaly at birth and all deaths were due to hepatomegaly or related complications. Of the infants who were aged 1 month to 12 months (n = 22), 21 had hepatomegaly, and there were three deaths (14%). Deaths were due to infection, disseminated intravascular coagulation, and radiation nephritis. One death was related to hepatomegaly. A scoring system to measure signs and symptoms of deterioration or compromise was developed to better assess this group.[7] This scoring system has been evaluated retrospectively and was predictive of the clinical course and has been applied prospectively. It was also helpful in directing the management of patients with INSS 4S disease.[7,8]

Various chemotherapy regimens (cyclophosphamide alone, carboplatin/etoposide, cyclophosphamide/doxorubicin/vincristine) have been used to treat symptomatic patients. The approach is to administer the chemotherapy only as long as symptoms persist in order to avoid toxicity, which contributes to lower survival. Additionally, lower doses of chemotherapy are often recommended for very young or low-weight infants along with granulocyte colony-stimulating factors after each cycle of chemotherapy.

Evidence (chemotherapy for symptomatic patients, very young infants, or those with unfavorable biology):

  1. Eighty stage 4S patients were enrolled on COG-P9641.[9]
    • Overall, the 5-year event-free survival (EFS) was 77% and the overall survival (OS) was 91%.

    • The 5-year EFS was 63% and OS was 84% for the 41 patients with asymptomatic stage 4S neuroblastoma treated with surgery alone, and the EFS was 95% and OS was 97% for the 39 patients treated with surgery and chemotherapy (EFS P = .0016; OS P = .1302). Previously, chemotherapy toxicity was thought to be responsible for the lower survival of patients with stage 4S disease; however, the use of chemotherapy on COG-P9641 was restricted to specific clinical situations with a recommended number of cycles.

  2. Also, on COG-P9641, asymptomatic infants with biologically favorable (MYCN-nonamplified) INSS stage 4S disease did not receive chemotherapy until the development of progressive disease or clinical symptoms.[9]
    • Infants who became symptomatic had disease-related organ failure and infectious complications resulting in an inferior OS compared with those who received immediate chemotherapy (4–8 cycles of therapy). The 3-year OS for infants who did not receive chemotherapy was 84% versus 97% for infants who received chemotherapy (P = .1321).

  3. On COG-ANBL0531, the 2-year OS rate for INSS stage 4S patients was 81%, which is lower than reported on COG-P9641 and thought to reflect the expanded eligibility allowing enrollment of patients who were too ill to undergo diagnostic biopsy. These patients would have been excluded from prior COG trials.[10]

  4. A prospective study was performed in 125 infants with stage 4S MYCN-nonamplified tumors or INSS stage 3 primary tumors and/or positive bone scintigraphy not associated with changes in the cortical bone documented on plain radiographs and/or CT. A pretreatment symptom score was used to determine initial treatment; observation was recommended for infants with low symptom scores (n = 86) and chemotherapy for infants with high symptom scores (n = 37). The chemotherapy recommended for patients with high symptom scores included two to four 3-day courses of carboplatin and etoposide, and 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.[8]
    • There was no difference in the 2-year EFS and OS between asymptomatic and symptomatic patients (EFS, 87% vs. 88%; OS, 98% vs. 97%), although many of the investigators preferred to give chemotherapy in the presence of a low symptom score.

    • For infants with low symptom scores, there was no difference between the outcome in the initially untreated infants (n = 56; OS, 93%) and treated infants (n = 30; OS, 86%).

    • The OS was 90% for infants presenting with high symptom scores.

    • There was no significant difference in 2-year OS in patients with unresectable primary tumors and patients with resectable primary tumors (97% vs. 100%) and patients with negative or with positive skeletal scintigraphy without radiologic abnormalities (100% vs. 97%).

References
  1. Canete A, Gerrard M, Rubie H, et al.: Poor survival for infants with MYCN-amplified metastatic neuroblastoma despite intensified treatment: the International Society of Paediatric Oncology European Neuroblastoma Experience. J Clin Oncol 27 (7): 1014-9, 2009.  [PUBMED Abstract]

  2. Guglielmi M, De Bernardi B, Rizzo A, et al.: Resection of primary tumor at diagnosis in stage IV-S neuroblastoma: does it affect the clinical course? J Clin Oncol 14 (5): 1537-44, 1996.  [PUBMED Abstract]

  3. Katzenstein HM, Bowman LC, Brodeur GM, et al.: Prognostic significance of age, MYCN oncogene amplification, tumor cell ploidy, and histology in 110 infants with stage D(S) neuroblastoma: the pediatric oncology group experience--a pediatric oncology group study. J Clin Oncol 16 (6): 2007-17, 1998.  [PUBMED Abstract]

  4. Nickerson HJ, Matthay KK, Seeger RC, et al.: Favorable biology and outcome of stage IV-S neuroblastoma with supportive care or minimal therapy: a Children's Cancer Group study. J Clin Oncol 18 (3): 477-86, 2000.  [PUBMED Abstract]

  5. Steele M, Jones NL, Ng V, et al.: Successful liver transplantation in an infant with stage 4S(M) neuroblastoma. Pediatr Blood Cancer 60 (3): 515-7, 2013.  [PUBMED Abstract]

  6. Gigliotti AR, Di Cataldo A, Sorrentino S, et al.: Neuroblastoma in the newborn. A study of the Italian Neuroblastoma Registry. Eur J Cancer 45 (18): 3220-7, 2009.  [PUBMED Abstract]

  7. Hsu LL, Evans AE, D'Angio GJ: Hepatomegaly in neuroblastoma stage 4s: criteria for treatment of the vulnerable neonate. Med Pediatr Oncol 27 (6): 521-8, 1996.  [PUBMED Abstract]

  8. De Bernardi B, Gerrard M, Boni L, et al.: Excellent outcome with reduced treatment for infants with disseminated neuroblastoma without MYCN gene amplification. J Clin Oncol 27 (7): 1034-40, 2009.  [PUBMED Abstract]

  9. Strother DR, London WB, Schmidt ML, et al.: Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children's Oncology Group study P9641. J Clin Oncol 30 (15): 1842-8, 2012.  [PUBMED Abstract]

  10. Park JR, Bagatell R, London WB, et al.: Children's Oncology Group's 2013 blueprint for research: neuroblastoma. Pediatr Blood Cancer 60 (6): 985-93, 2013.  [PUBMED Abstract]

Recurrent Neuroblastoma

Tumor growth due to maturation should be differentiated from tumor progression by performing a biopsy and reviewing histology. Patients may have persistent maturing disease with metaiodobenzylguanidine (mIBG) uptake that does not affect outcome, particularly in patients with low-risk and intermediate-risk disease.[1] When neuroblastoma recurs in a child originally diagnosed with high-risk disease, the prognosis is usually poor despite additional intensive therapy.[2-5] However, it is often possible to gain many additional months of life for these patients with alternative chemotherapy regimens.[6,7] Clinical trials are appropriate for these patients and may be offered. Information about ongoing clinical trials is available from the NCI Web site.

Prognostic Factors for Recurrent Neuroblastoma

The International Neuroblastoma Risk Group Project performed a decision-tree analysis of clinical and biological characteristics (defined at diagnosis) associated with survival after relapse in 2,266 patients with neuroblastoma entered on large clinical trials in well-established clinical trials groups around the world.[2]

  • Overall survival (OS) in the entire relapse population was 20%.

  • Among patients with all stages of disease at diagnosis, MYCN amplification predicted a poorer prognosis, measured as 5-year OS.

  • Among patients diagnosed with International Neuroblastoma Staging System (INSS) stage 4 without amplification, age older than18 months and high lactate dehydrogenase (LDH) level predicted poor prognosis.

  • Among patients with MYCN amplification, stages 1 and 2 have a better prognosis than stages 3 and 4.

  • Among patients with MYCN-nonamplified who are not stage 4, patients with hyperdiploidy had a better prognosis than patients with diploidy in those younger than 18 months, while among those older than 18 months, differentiating tumors did much better than undifferentiated and poorly differentiated tumors.

Significant prognostic factors determined at diagnosis for postrelapse survival include the following:[2]

  • Age.
  • INSS stage.
  • MYCN status.
  • Time from diagnosis to first relapse.
  • LDH level, ploidy, and histologic grade of tumor differentiation (to a lesser extent).

The Children’s Oncology Group (COG) experience with recurrence in low-risk and intermediate-risk neuroblastoma is that the majority of recurrences can be salvaged. The COG reported a 3-year event free survival (EFS) of 88% and an OS of 96% in intermediate-risk patients and a 5-year EFS of 89% and OS of 97% in low-risk patients.[8,9] Moreover, in most patients originally diagnosed with low-risk or intermediate-risk disease, local recurrence or recurrence in the 4S pattern may be treated successfully with surgery and/or with moderate dose chemotherapy, without hematopoietic stem cell transplantation.

Recurrent Neuroblastoma in Patients Initially Classified as Low Risk

Locoregional recurrence

Treatment options for locoregional recurrent neuroblastoma initially classified as low risk include the following:

  1. Surgery followed by observation or chemotherapy.
  2. Chemotherapy that may be followed by surgery.

Local or regional recurrent cancer is resected if possible.

Those with favorable biology and regional recurrence more than 3 months after completion of planned treatment are observed if resection of the recurrence is total or near total (≥90% resection). Those with favorable biology and a less than near-total resection are treated with chemotherapy.

Infants younger than 1 year at the time of locoregional recurrence whose tumors have any unfavorable biologic properties are observed if resection is total or near total. If the resection is less than near total, these same infants are treated with chemotherapy. Chemotherapy may consist of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide, or cyclophosphamide and topotecan. The cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen as used in prior COG trials (COG-P9641 and COG-A3961).

Older children with local recurrence with either unfavorable International Neuroblastoma Pathology Classification at diagnosis or MYCN gene amplification have a poor prognosis and may be treated with surgery, aggressive combination chemotherapy, or offered entry into a clinical trial.

Evidence (surgery and chemotherapy):

  1. A COG study of treatment of low-risk patients with stage 1, 2A, 2B, and 4S neuroblastoma enrolled 915 patients, 800 of whom were asymptomatic and were treated with surgery alone followed by observation. The others received chemotherapy with or without surgery.[9]
    • About 10% of patients developed progressive or recurrent tumor. Most recurrences were treated on study with surgery alone or moderate chemotherapy with or without surgery, and most were salvaged as demonstrated by the EFS (89%) and OS (97%) rates at 5 years.
Metastatic recurrence

Treatment options for metastatic recurrent neuroblastoma initially classified as low risk include the following:

  1. Observation (if metastatic disease is in a 4S pattern in an infant).
  2. Chemotherapy.

Metastatic recurrent or progressive neuroblastoma in an infant initially categorized as low risk and younger than 1 year at recurrence may be treated according to tumor biology as defined in the prior COG trials (COG-P9641 and COG-A3961):

  1. If the biology is completely favorable, metastasis is in a 4S pattern, and the recurrence or progression is within 3 months of diagnosis, the patient is observed systematically.

  2. If the metastatic progression or recurrence occurs more than 3 months after diagnosis or not in a 4S pattern, then the primary tumor is resected if possible and chemotherapy is given.

    Chemotherapy may consist of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen, as used in prior COG trials (COG-P9641 and COG-A3961).

Any child initially categorized as low risk who is older than 1 year at the time of metastatic recurrent or progressive disease and whose recurrence is not in the stage 4S pattern usually has a poor prognosis and should be considered for high-risk therapy.

  1. Treatment may consist of an aggressive regimen of combination chemotherapy.
Recurrent Neuroblastoma in Patients Initially Classified as Intermediate Risk

The treatment options for locoregional and metastatic recurrence in patients with intermediate-risk neuroblastoma are derived from the results of the COG-A3961 trial. Among 479 patients with intermediate-risk neuroblastoma treated on the COG-A3961 clinical trial, 42 patients developed disease progression. The rate was 10% of those with favorable biology and 17% of those with unfavorable biology. Thirty patients had locoregional recurrence, 11 had metastatic recurrence, and one had both types of recurrent disease. Six of the 42 patients died of disease, while 36 patients were salvaged. Thus, most patients with intermediate-risk neuroblastoma and disease progression may be salvaged.[8]

Locoregional recurrence

Treatment options for locoregional recurrent neuroblastoma initially classified as intermediate risk include the following:

  1. Surgery (complete resection).
  2. Surgery (incomplete resection) followed by chemotherapy.

The current standard of care is based on the experience from the COG Intermediate-Risk treatment plan (COG-A3961). Locoregional recurrence of neuroblastoma with favorable biology that occurs more than 3 months after completion of chemotherapy may be treated surgically. If resection is less than near total, then additional chemotherapy may be given. Chemotherapy may consist of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen, as used in a prior COG trial (COG-A3961).

Metastatic recurrence

Treatment options for metastatic recurrent neuroblastoma initially classified as intermediate risk include the following:

  1. High-risk therapy.

Patients with metastatic recurrent neuroblastoma are treated like patients with newly diagnosed high-risk neuroblastoma. (Refer to the Treatment Options for High-Risk Neuroblastoma section of this summary for more information.)

Recurrent Neuroblastoma in Patients Initially Classified as High Risk

Any recurrence in patients initially classified as high risk signifies a very poor prognosis.[2] Clinical trials may be considered. Palliative care should be considered as part of the patient's treatment plan.

Treatment options for recurrent or refractory neuroblastoma in patients initially classified as high risk include the following:

  1. Chemotherapy.
    • Topotecan in combination with cyclophosphamide or etoposide.[10]
    • Temozolomide with irinotecan.

  2. Iodine 131-mIBG (131I-mIBG) alone, in combination with other therapy, or followed by stem cell rescue.

  3. Second autologous stem cell transplantation (SCT) after retrieval chemotherapy. (Refer to the Autologous Hematopoietic Cell Transplantation section in the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation.)

It is not known whether one therapeutic approach is superior to another.

Evidence (chemotherapy):

  1. Topotecan in combination with cyclophosphamide or etoposide has been used in patients with recurrent disease who did not receive topotecan initially.[11,12]; [10][Level of evidence: 1A]

  2. The combination of irinotecan and temozolomide had a 15% response rate in one study.[13][Level of evidence: 2A]

  3. High-dose carboplatin, irinotecan, and/or temozolomide has been used in patients resistant or refractory to regimens containing topotecan.[12]

  4. A retrospective study reported on 74 patients who received 92 cycles of ifosfamide, carboplatin, and etoposide, included 37 patients who received peripheral blood stem cell rescue following response to this drug combination.[14]
    • Disease regressions (major and minor responses) were achieved by 14 of 17 patients (82%) with a new relapse, 13 of 26 patients (50%) with refractory neuroblastoma, and 12 of 34 patients (35%) who were treated for progressive disease during chemotherapy (P = .005).

    • Grade 3 toxicities were rare.

Evidence (131I-mIBG):

  1. For children with recurrent or refractory neuroblastoma, 131I-mIBG is an effective palliative agent and may be considered alone or in combination with chemotherapy (with stem cell rescue) in a clinical research trial.[15-19]; [20,21][Level of evidence: 3iiiA]

Evidence (second autologous SCT following retrieval chemotherapy):

  1. Second autologous stem cell transplantation (SCT) after retrieval chemotherapy may be considered, particularly in the setting of a clinical trial. (Refer to the Autologous Hematopoietic Cell Transplantation section in the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation.)
  2. Data from three consecutive German high-risk neuroblastoma trials described 253 children relapsing after intensive chemotherapy with autologous SCT who had a 5-year OS rate of less than 10%. Only 23 of the 253 patients eventually proceeded to a second autologous SCT following retrieval chemotherapy.[22][Level of evidence: 3iiiA]
    • Among these patients, the 3-year OS rate was 43%, but the 5-year OS rate was less than 20%.
    • This shows that intensive second-line therapy is feasible, although even with intensive therapy and second autologous SCT, only a small minority of relapsed high-risk neuroblastoma patients may benefit.
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.[23,24] 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:

  1. Surgery and radiation therapy.
  2. Novel therapeutic approaches.

Current treatment approaches generally include eradicating bulky and microscopic residual disease in the CNS and minimal residual systemic disease that may herald further relapses. Neurosurgical interventions serve to decrease edema, control hemorrhage, and remove bulky tumor before starting therapy. Compartmental radioimmunotherapy using intrathecal radioiodinated monoclonal antibodies has been tested in patients with recurrent metastatic CNS neuroblastoma after surgery, craniospinal radiation therapy, and chemotherapy.[7]

Treatment Options Under Clinical Evaluation for Recurrent or Refractory Neuroblastoma

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

  • COG-ANBL1221 (NCT01767194) (A Phase II Randomized Trial of Irinotecan/Temozolomide with Temsirolimus or Chimeric 14.18 Antibody [ch14.18] in Children with Refractory, Relapsed, or Progressive Neuroblastoma): This “Pick the Winner” phase II study is designed to compare the response rates and progression-free survival for patients with refractory, relapsed, or progressive neuroblastoma receiving temsirolimus or ch14.18 in combination with irinotecan and temozolomide. Patients more than 365 days of age who have progressed from INSS stage 1, 2, or 4S and have received no chemotherapy or only one cycle of chemotherapy are eligible for this trial.

  • NANT N2011-04 (NCT01711554) (Lenalidomide and Monoclonal Antibody With or Without Isotretinoin in Treating Younger Patients With Refractory or Recurrent Neuroblastoma): This study is to determine the maximum tolerated dose and/or recommended phase II dose of lenalidomide in combination with fixed doses of ch14.18 given intravenously for 4 days (days 8–11) and isotretinoin given twice each day orally for 14 days (days 15–28) and repeated every 28 days to children with refractory or recurrent neuroblastoma.

  • NCT00911560 (Bivalent Vaccine With Escalating Doses of the Immunological Adjuvant OPT-821, in Combination With Oral Beta-Glucan for High-Risk Neuroblastoma): The purpose of this study is to test the safety of a vaccine against neuroblastoma and its effect on cancer.

  • Studies with the ALK inhibitor crizotinib include the following: COG-ADVL0912 (NCT00939770), a phase I and II study of PF-02341066, an oral small molecule inhibitor of anaplastic lymphoma kinase (ALK) and C-met, in children with relapsed/refractory solid tumors and anaplastic large cell lymphoma; and ADVL1212 (NCT01606878), a phase I study of crizotinib in combination with conventional chemotherapy for relapsed or refractory solid tumors or anaplastic large cell lymphoma.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent neuroblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References
  1. Marachelian A, Shimada H, Sano H, et al.: The significance of serial histopathology in a residual mass for outcome of intermediate risk stage 3 neuroblastoma. Pediatr Blood Cancer 58 (5): 675-81, 2012.  [PUBMED Abstract]

  2. London WB, Castel V, Monclair T, et al.: Clinical and biologic features predictive of survival after relapse of neuroblastoma: a report from the International Neuroblastoma Risk Group project. J Clin Oncol 29 (24): 3286-92, 2011.  [PUBMED Abstract]

  3. Pole JG, Casper J, Elfenbein G, et al.: High-dose chemoradiotherapy supported by marrow infusions for advanced neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 9 (1): 152-8, 1991.  [PUBMED Abstract]

  4. Castel V, Cañete A, Melero C, et al.: Results of the cooperative protocol (N-III-95) for metastatic relapses and refractory neuroblastoma. Med Pediatr Oncol 35 (6): 724-6, 2000.  [PUBMED Abstract]

  5. Lau L, Tai D, Weitzman S, et al.: Factors influencing survival in children with recurrent neuroblastoma. J Pediatr Hematol Oncol 26 (4): 227-32, 2004.  [PUBMED Abstract]

  6. Saylors RL 3rd, Stine KC, Sullivan J, et al.: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 19 (15): 3463-9, 2001.  [PUBMED Abstract]

  7. Kramer K, Kushner BH, Modak S, et al.: Compartmental intrathecal radioimmunotherapy: results for treatment for metastatic CNS neuroblastoma. J Neurooncol 97 (3): 409-18, 2010.  [PUBMED Abstract]

  8. Baker DL, Schmidt ML, Cohn SL, et al.: Outcome after reduced chemotherapy for intermediate-risk neuroblastoma. N Engl J Med 363 (14): 1313-23, 2010.  [PUBMED Abstract]

  9. Strother DR, London WB, Schmidt ML, et al.: Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children's Oncology Group study P9641. J Clin Oncol 30 (15): 1842-8, 2012.  [PUBMED Abstract]

  10. London WB, Frantz CN, Campbell LA, et al.: Phase II randomized comparison of topotecan plus cyclophosphamide versus topotecan alone in children with recurrent or refractory neuroblastoma: a Children's Oncology Group study. J Clin Oncol 28 (24): 3808-15, 2010.  [PUBMED Abstract]

  11. Simon T, Längler A, Harnischmacher U, et al.: Topotecan, cyclophosphamide, and etoposide (TCE) in the treatment of high-risk neuroblastoma. Results of a phase-II trial. J Cancer Res Clin Oncol 133 (9): 653-61, 2007.  [PUBMED Abstract]

  12. Kushner BH, Kramer K, Modak S, et al.: Differential impact of high-dose cyclophosphamide, topotecan, and vincristine in clinical subsets of patients with chemoresistant neuroblastoma. Cancer 116 (12): 3054-60, 2010.  [PUBMED Abstract]

  13. Bagatell R, London WB, Wagner LM, et al.: Phase II study of irinotecan and temozolomide in children with relapsed or refractory neuroblastoma: a Children's Oncology Group study. J Clin Oncol 29 (2): 208-13, 2011.  [PUBMED Abstract]

  14. Kushner BH, Modak S, Kramer K, et al.: Ifosfamide, carboplatin, and etoposide for neuroblastoma: a high-dose salvage regimen and review of the literature. Cancer 119 (3): 665-71, 2013.  [PUBMED Abstract]

  15. Polishchuk AL, Dubois SG, Haas-Kogan D, et al.: Response, survival, and toxicity after iodine-131-metaiodobenzylguanidine therapy for neuroblastoma in preadolescents, adolescents, and adults. Cancer 117 (18): 4286-93, 2011.  [PUBMED Abstract]

  16. Matthay KK, Yanik G, Messina J, et al.: Phase II study on the effect of disease sites, age, and prior therapy on response to iodine-131-metaiodobenzylguanidine therapy in refractory neuroblastoma. J Clin Oncol 25 (9): 1054-60, 2007.  [PUBMED Abstract]

  17. Matthay KK, Tan JC, Villablanca JG, et al.: Phase I dose escalation of iodine-131-metaiodobenzylguanidine with myeloablative chemotherapy and autologous stem-cell transplantation in refractory neuroblastoma: a new approaches to Neuroblastoma Therapy Consortium Study. J Clin Oncol 24 (3): 500-6, 2006.  [PUBMED Abstract]

  18. Matthay KK, Quach A, Huberty J, et al.: Iodine-131--metaiodobenzylguanidine double infusion with autologous stem-cell rescue for neuroblastoma: a new approaches to neuroblastoma therapy phase I study. J Clin Oncol 27 (7): 1020-5, 2009.  [PUBMED Abstract]

  19. DuBois SG, Chesler L, Groshen S, et al.: Phase I study of vincristine, irinotecan, and ¹³¹I-metaiodobenzylguanidine for patients with relapsed or refractory neuroblastoma: a new approaches to neuroblastoma therapy trial. Clin Cancer Res 18 (9): 2679-86, 2012.  [PUBMED Abstract]

  20. Johnson K, McGlynn B, Saggio J, et al.: Safety and efficacy of tandem 131I-metaiodobenzylguanidine infusions in relapsed/refractory neuroblastoma. Pediatr Blood Cancer 57 (7): 1124-9, 2011.  [PUBMED Abstract]

  21. French S, DuBois SG, Horn B, et al.: 131I-MIBG followed by consolidation with busulfan, melphalan and autologous stem cell transplantation for refractory neuroblastoma. Pediatr Blood Cancer 60 (5): 879-84, 2013.  [PUBMED Abstract]

  22. Simon T, Berthold F, Borkhardt A, et al.: Treatment and outcomes of patients with relapsed, high-risk neuroblastoma: results of German trials. Pediatr Blood Cancer 56 (4): 578-83, 2011.  [PUBMED Abstract]

  23. Kramer K, Kushner B, Heller G, et al.: Neuroblastoma metastatic to the central nervous system. The Memorial Sloan-kettering Cancer Center Experience and A Literature Review. Cancer 91 (8): 1510-9, 2001.  [PUBMED Abstract]

  24. Matthay KK, Brisse H, Couanet D, et al.: Central nervous system metastases in neuroblastoma: radiologic, clinical, and biologic features in 23 patients. Cancer 98 (1): 155-65, 2003.  [PUBMED Abstract]

Changes to this Summary (08/29/2014)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

General Information About Neuroblastoma

Added Figure 1 to illustrate that neuroblastoma may be found in the adrenal glands and paraspinal nerve tissue from the neck to the pelvis.

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.

About This PDQ Summary



Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of neuroblastoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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The lead reviewers for Neuroblastoma Treatment are:

  • Christopher N. Frantz, MD (Alfred I. duPont Hospital for Children)
  • Michael P. LaQuaglia, MD (Memorial Sloan-Kettering Cancer Center)
  • Karen J. Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Nita Louise Seibel, MD (National Cancer Institute)
  • Stephen J. Shochat, MD (St. Jude Children's Research Hospital)

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For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 8:00 a.m. to 8:00 p.m., Eastern Time. A trained Cancer Information Specialist is available to answer your questions.

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The NCI's LiveHelp® online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 8:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer.

Write to us

For more information from the NCI, please write to this address:

NCI Public Inquiries Office
9609 Medical Center Dr.
Room 2E532 MSC 9760
Bethesda, MD 20892-9760

Search the NCI Web site

The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use the search box in the upper right corner of each Web page. The results for a wide range of search terms will include a list of "Best Bets," editorially chosen Web pages that are most closely related to the search term entered.

There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.

Find Publications

The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237).