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Neuroblastoma Treatment (PDQ®)

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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)
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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:

(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] [11] [12]

Anatomy

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

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:

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:

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] [35] [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] [40] [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:

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] [50] [51] [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]

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] [60] [61] [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:

Histologic characteristics considered prognostically unfavorable include the following:

A COG study of children with stage 1 and stage 2 neuroblastoma without MYCN amplification and with favorable histologic features reported a 5-year EFS of 90% to 94% and OS of 99% to 100%, while those with unfavorable histology had an EFS of 80% to 86% and an OS of 89% to 93%. [68] Similar results were found in a European study. [69] [70] [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] [73] [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]

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]

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] [97] [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]

  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]

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  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  86. Ohali A, Avigad S, Ash S, et al.: Telomere length is a prognostic factor in neuroblastoma. Cancer 107 (6): 1391-9, 2006.
  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.
  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.
  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.
  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.
  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.
  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.
  95. Brodeur GM, Minturn JE, Ho R, et al.: Trk receptor expression and inhibition in neuroblastomas. Clin Cancer Res 15 (10): 3244-50, 2009.
  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.
  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.
  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.

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.

Table 1. Prognostic Evaluation of Neuroblastic Tumors According to the International Neuroblastoma Pathology Classification (Shimada System)a

International Neuroblastoma Pathology classificationOriginal Shimada classificationPrognostic group
Neuroblastoma (Schwannian stroma-poor)b Stroma-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)  
 Maturing  Well differentiated (favorable) Favorabled
 Mature  Ganglioneuroma 
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]

Table 2. Histologic Discrimination of International Neuroblastoma Risk Group Subsets of Neuroblastoma Patientsa

INSS Stage/Histologic SubtypeNumber of Cases EFS (%) OS (%)
INSS stage 1, 2, 3, 4S 5,131 83 ± 1 91 ± 1
 GN, maturing 162 97 ± 2 98 ± 2
GNB, intermixed     
NB 4,970 83 ± 1 90 ± 1 
GNB, nodular    
INSS stage 2, 3; age >547 d 260 69 ± 3 81 ± 2
 11q normal and differentiating 16 80 ± 16100
11q aberration or undifferentiated 49 61 ± 11 73 ± 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.
  2. Shimada H, Ambros IM, Dehner LP, et al.: The International Neuroblastoma Pathology Classification (the Shimada system). Cancer 86 (2): 364-72, 1999.
  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.
  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.
  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.
  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.
  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.
  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.
  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.

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.

Other staging tests and procedures

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

International Neuroblastoma Staging Systems

International Neuroblastoma Staging System (INSS)

The INSS combines certain features from each of the previously used Evans and Pediatric Oncology Group (POG) staging systems [1] [13] and is described in Table 3. This represented the first step in harmonizing disease staging and risk stratification worldwide. The INSS is a postoperative staging system that was developed in 1988 and used the extent of surgical resection to stage patients. This led to some variability in stage assignments in different countries because of regional differences in surgical strategy and, potentially, because of limitations in access to experienced pediatric surgeons. As a result of further advances in the understanding of neuroblastoma biology and genetics, a risk classification system was developed that incorporates clinical and biological factors in addition to INSS stage to facilitate risk group and treatment assignment for COG studies. [1] [13] [14] [15]

Table 3. The International Neuroblastoma Staging System (INSS)

Stage/Prognostic GroupDescription
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 2A Localized 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 3 Unresectable 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.
mIBG = metaiodobenzylguanidine.

Controversy exists regarding the INSS staging system and the treatment of certain small subsets of patients. [16] [17] [18] Risk group assignment and recommended treatment are expected to evolve as additional outcome data are analyzed. For example, the risk group assignment for INSS stage 4 neuroblastoma in patients aged 12 to 18 months changed in 2005 for those whose tumors had single copy MYCN and all favorable biological features; these patients had been previously classified as high risk, but data from both POG and Children's Cancer Group studies suggested that this subgroup of patients could be successfully treated as intermediate risk. [19] [20] [21]

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

StageDescription
L1Localized tumor not involving vital structures as defined by the list of image-defined risk factorsa and confined to one body compartment.
L2Locoregional tumor with presence of one or more image-defined risk factors.a
M Distant metastatic disease (except MS).
MSMetastatic disease in children younger than 18 months with metastases confined to skin, liver, and/or bone marrow.
aAdapted from Monclair et al. [22]

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.
  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.
  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.
  4. Howman-Giles R, Shaw PJ, Uren RF, et al.: Neuroblastoma and other neuroendocrine tumors. Semin Nucl Med 37 (4): 286-302, 2007.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  16. Kushner BH, Cheung NK: Treatment reduction for neuroblastoma. Pediatr Blood Cancer 43 (6): 619-21, 2004.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.

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] [2] [3] [4] [5] [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:

Table 5. Treatment Options for Neuroblastoma

Stage (COG Risk-Group Assignment) Treatment Options
Low-Risk NeuroblastomaSurgery 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 NeuroblastomaChemotherapy with or without surgery.
Surgery and observation (in infants).   
Radiation therapy (only for emergent therapy).  
High-Risk NeuroblastomaA regimen of chemotherapy, surgery, SCT, radiation therapy, and anti-GD2 antibody ch14.18, with interleukin-2/GM-CSF and isotretinoin.
Stage 4S NeuroblastomaObservation 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 risk Chemotherapy. 
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.  
COG = Children's Oncology Group; GM-CSF = granulocyte-macrophage colony-stimulating factor; 131I-mIBG = iodine 131-metaiodobenzylguanidine; SCT = stem cell transplant.

Children’s Oncology Group (COG) Neuroblastoma Risk Grouping

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

Table 6 (in the Treatment of Low-Risk Neuroblastoma section), Table 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]

Surgery

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

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] [17] [18] [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:

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] [21] [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] [21] [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:

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  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.

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 y AnyAnyAny
2A/2Bc<365 d Any AnyAny
≥365 d–21 y NonamplifiedAny- 
≥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]

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]

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.
  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.
  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.
  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.
  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.

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 dNonamplified AnyAny
≥365 d–21 y Nonamplified Favorable- 
4c<548 d [1] [2] [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]

  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]

  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]

  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]

  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]

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]

  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]

Radiation therapy (only for emergent therapy)

Radiation therapy is reserved for patients with the following:

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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.

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 y Amplified Unfavorable-
3c<365 dAmplifiedAnyAny
≥365 d–21 y Nonamplified Unfavorable- 
≥365 d–21 y AmplifiedAny- 
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 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] [9] [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]

  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]

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.

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.

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

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 d Nonamplified Favorable >1 Low
<365 d Nonamplified Any =1Intermediate 
<365 d Nonamplified Unfavorable Any Intermediate 
<365 d Amplified Any Any High 
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] [3] [4] Rarely, infants with massive hepatic 4S neuroblastoma develop cirrhosis from the chemotherapy and/or radiation therapy that is used to control the disease and may benefit from orthotopic liver transplantation. [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:

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]

  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]

  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]

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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.

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] [3] [4] [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]

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

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]

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.

  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]

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] [16] [17] [18] [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]

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.

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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.

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).

Board members review recently published articles each month to determine whether an article should:

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Neuroblastoma Treatment are:

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Neuroblastoma Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/neuroblastoma/HealthProfessional. Accessed <MM/DD/YYYY>.

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