Neuroblastoma Treatment (PDQ®) - NCI

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Neuroblastoma Treatment (PDQ)

Health Professional Version
Last Modified: 03/29/2012
Table of Contents
General Information
Predisposition to Neuroblastoma
Presentation of Neuroblastoma
Opsoclonus/myoclonus syndrome
Diagnosis
Prognosis
Age
Biologic factors
Unique Aspects of Neuroblastoma
Biologically discrete types of neuroblastoma
Neuroblastoma screening
Spontaneous regression of neuroblastoma
Cellular Classification
Stage Information
International Neuroblastoma Staging System
Childrens Oncology Group Neuroblastoma Risk Grouping
Treatment Option Overview

Low-Risk Neuroblastoma
Observation without surgery for localized, suspected adrenal neuroblastoma in infants
Intermediate-Risk Neuroblastoma
High-Risk Neuroblastoma
Radiation Therapy
Chemotherapy
Description of International Neuroblastoma Response Criteria
Surveillance for Recurrence of High-Risk Neuroblastoma
Treatment of Low-Risk Neuroblastoma

Standard Treatment Options
Current Clinical Trials
Treatment of Intermediate-Risk Neuroblastoma

Treatment of High-Risk Neuroblastoma

Treatment Options Under Clinical Evaluation
Recurrent Neuroblastoma
Recurrent Neuroblastoma in Patients Initially Classified as Low Risk
Local/regional recurrence
Metastatic recurrence
Recurrent Neuroblastoma in Patients Initially Classified as Intermediate Risk
Recurrent or Refractory Neuroblastoma in Patients Initially Classified as High Risk
Treatment options under clinical evaluation
Changes to this Summary (03/29/2012)
About This PDQ Summary

Purpose of This Summary
Reviewers and Updates
Levels of Evidence
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General Information
The National Cancer Institute (NCI) provides the PDQ pediatric cancer treatment information summaries as a
public service to increase the availability of evidence-based cancer information to health professionals, patients,
and the public.
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 should be 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 primary care
physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists,
rehabilitation specialists, pediatric nurse specialists, social workers, 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 1 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 2.
Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between
1975 and 2002, childhood cancer mortality has decreased by more than 50%. For neuroblastoma, the 5-year
survival rate 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] 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 3 for specific information about
the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors).
Neuroblastoma is predominantly a tumor of early childhood, with two-thirds of the cases presenting in children
aged 5 years or younger. Neuroblastoma originates in the adrenal medulla or the paraspinal sites where
sympathetic nervous system tissue is present. These tumors can be divided into low-, intermediate-, and high-risk
groups as illustrated in the Stage Information 4 section of this summary. Low- and intermediate-risk patients
usually have localized disease or are infants aged 18 months or younger. In rare cases, neuroblastoma can be
discovered prenatally by fetal ultrasonography.[3]
Predisposition to Neuroblastoma
Little is known about the events that predispose to the development of neuroblastoma. Parental exposures have
not been definitively linked. In a genome-wide association study of 1,032 patients with neuroblastoma, a significant
association was observed between a common genetic variation (polymorphism) at chromosome 6p22 and
neuroblastoma. Tumors that arose in patients with this polymorphism tended to be clinically aggressive.[4]
Germline deletion at the 1p36 or 11q14-23 locus are associated with the development of neuroblastoma and the
same deletions are found somatically in sporadic neuroblastomas.[5,6]
About 1% to 2% of patients with neuroblastoma have a family history of neuroblastoma, and these children are on
average younger (9 months); about 20% have multifocal primary neuroblastomas. The primary cause of familial
neuroblastoma is germline mutation in the ALK gene.[7] Similar somatic mutations and amplification of the ALK
gene are found in 8% to12% of sporadic neuroblastomas. The mutations result in constitutive phosphorylation of
ALK, which is critical for cell growth 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.[8] Familial neuroblastoma is rarely associated with Ondines curse (congenital central
hypoventilation syndrome) with germline mutation of the PHOX2B gene.[9]
Presentation of Neuroblastoma
The most common presentation of neuroblastoma is an abdominal mass. The most common symptoms in high-risk
patients are due to a tumor mass or to bone pain from metastases. Proptosis and periorbital ecchymosis are
common in these high-risk patients and arise from retrobulbar metastasis. Extensive bone marrow metastasis may
result in pancytopenia. Abdominal distention with respiratory compromise due to massive liver metastases may
occur in infants. Because they originate in paraspinal ganglia, neuroblastomas may invade through neural foramina
and compress the spinal cord extradurally, causing paralysis. Horner syndrome may be caused by neuroblastoma
in the stellate ganglion, and children with Horner syndrome without apparent cause should be examined for
neuroblastoma and other tumors.[10] Fever, anemia, and hypertension are occasionally found. Multifocal (multiple
primaries) neuroblastoma occurs rarely, usually in infants, and generally has a good prognosis.[11] On rare
occasions, children may have severe, watery diarrhea due to the secretion of vasoactive intestinal peptide (VIP)
by the tumor, or may have protein-losing enteropathy with intestinal lymphangiectasia.[12] VIP secretion may also
occur upon chemotherapeutic treatment, and tumor resection reduces VIP secretion.[13]
Opsoclonus/myoclonus syndrome
Children with neuroblastoma rarely present with paraneoplastic neurologic findings, including cerebellar ataxia or
opsoclonus/myoclonus.[14] Neurologic dysfunction is most often a presenting symptom but may arise long after
removal of the tumor. Opsoclonus/myoclonus syndrome is frequently associated with pervasive and permanent
neurologic and cognitive deficits, including psychomotor retardation.[15-17]
The opsoclonus/myoclonus syndrome appears to be caused by an immunologic mechanism that is not yet fully
defined.[15,18] Unlike most other neuroblastomas, the primary tumor is typically diffusely infiltrated with
lymphocytes.[19] Patients who present with this syndrome often have neuroblastomas with favorable biological
features and are likely to survive, though tumor-related deaths have been reported.[15]
Some patients may clinically respond to removal of the neuroblastoma, but improvement may be slow and partial;
symptomatic treatment is often necessary. Adrenocorticotropic hormone (ACTH) treatment is thought to be
effective, but some patients do not respond to ACTH.[16,18] Various drugs, plasmapheresis, intravenous gamma-
globulin (IVIG), and rituximab have been reported to be effective in selected cases.[16,20-22] The long-term
neurologic outcome may be superior in patients treated with chemotherapy, possibly because of its
immunosuppressive effects.[14,20] The use of immunosuppressive therapy with and without IVIG in the treatment
of patients with neuroblastoma and opsoclonus/myoclonus syndrome is under study by the Children's Oncology
Group (COG) (COG-ANBL00P3 5).
Diagnosis
The diagnosis of neuroblastoma requires the involvement of pathologists who are familiar with childhood tumors.
Some neuroblastomas cannot be differentiated, via conventional light microscopy, from other small round blue cell
tumors of childhood, such as lymphomas, primitive neuroectodermal tumors, and rhabdomyosarcomas. Evidence
for sympathetic neuronal differentiation may be demonstrated by immunohistochemistry, electron microscopy, or
by finding elevated levels of serum catecholamines (e.g., dopamine and norepinephrine) or urine catecholamine
metabolites, such as vanillylmandelic acid (VMA) or homovanillic acid (HVA). The minimum criterion for a
diagnosis of neuroblastoma, as has been established by international agreement, is that it 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 or urinary
catecholamine metabolites).[23]
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, as described above.[23]
However, primary tumor tissue is often needed to obtain all the biological data that may be used to determine
treatment in current COG clinical trials. There is an absolute requirement for tissue biopsy to determine the
International Neuroblastoma Pathology Classification (INPC) (see Cellular Classification 6 section for more
information). The INPC was used to determine treatment in the COG risk assignment schema for prior COG
studies in patients with stage 2, 3, and 4S tumors. In the risk/treatment group assignment schema for the current
COG studies, INPC is used to determine treatment for stage 3 and 4S patients as well as for stage 4 patients aged
18 months or younger. Additionally, a significant number of tumor cells are needed to determine MYCN copy
number DNA index and 11q and 1p loss of heterozygosity (LOH). For older stage 4 patients, bone marrow with
extensive tumor involvement combined with elevated catecholamine metabolites is adequate for study entry.
Prognosis
Approximately 70% of patients with neuroblastoma have metastatic disease at diagnosis. The prognosis for
patients with neuroblastoma is related to their age at diagnosis, clinical stage of disease, site of the primary tumor,
tumor histology, and, in patients older than 1 year, regional lymph node involvement. Biological prognostic variables
are also used to help determine treatment (see below 7).[24-27] The 5-year overall survival 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;[28] however, this single number can be misleading due to the extremely
heterogeneous prognosis based on the neuroblastoma patient's age, stage, and biology. (Refer to the Cellular
Classification 6 section of this summary for more information.)
Age
The effect of age at diagnosis on 5-year survival is profoundage younger than 1 year is associated with 90%
survival, 1 to 4 years is 68%, 5 to 9 years is 52%, and 10 to 14 years is 66%.[28] 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.[29] The prognosis of fetal and neonatal
neuroblastoma are similar to that of older infants with neuroblastoma and similar biological features.[30] Older
children with advanced-stage disease, however, have a significantly decreased chance for cure, despite intensive
therapy. For children aged 18 months and older with stage 4 neuroblastoma, who receive aggressive treatment
with surgery and radiation therapy to the primary tumor mass, as well as aggressive chemotherapy with
hematopoietic stem cell rescue followed by cis-retinoic acid, long-term survival is approximately 30% to 50%.[31]
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, and there is a greater frequency of metastases
in unusual sites such as lung or brain.[32] Neuroblastoma has a worse long-term prognosis in an adolescent or
adult compared to 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.[32-34] Other modalities, such as local radiation therapy
and the use of agents with confirmed activity, may improve the poor prognosis.[33,34] However, the overall
prognosis for older patients is dismal.
Biologic factors
A number of biologic variables have been studied in children with this tumor.[35] Treatment decisions are usually
based on important factors such as the INPC (refer to the Cellular Classification 6 section of this summary for
information about the INPC system), ploidy, amplification of the MYCN oncogene within tumor tissue, unbalanced
11q LOH, and LOH for chromosome 1p.[27,36-42] In the future, MYCN amplification, 11q23 alleles, and ploidy
(along with standardized procedures for evaluation) are expected to be the standard factors used for evaluation of
treatment programs, as established by the International Consensus for Neuroblastoma Molecular Diagnostics.[43]
An open biopsy is often needed to obtain adequate tissue for determination of these biological characteristics.
Many biological characteristics of tumors are not currently used in determining therapy; however, as clinical
research matures, these characteristics may be found useful as therapeutic targets or as clinically important
prognostic factors. Amplification of the MYCN gene is associated not only with deletion of chromosome 1p, but
also gain of the long arm of chromosome 17 (17q), the latter of which independently predicts a poor prognosis.[44]
In contrast to MYCN gene amplification, the degree of expression of the MYCN gene in the tumor does not predict
prognosis.[45] However, high overall MYCN-dependent gene expression and low expression of sympathetic
neuron late differentiation genes both predict a poor outcome of neuroblastomas otherwise considered to be at low
or intermediate risk of recurrence.[46] Other biological prognostic factors that have been extensively investigated
include tumor cell telomere length, telomerase activity, and telomerase ribonucleic acid;[47,48] urinary VMA,
HVA, and their ratio;[49] dopamine; CD44 expression; TrkA gene expression; serum neuron-specific enolase
level, serum lactic dehydrogenase level, and serum ferritin level.[35] High-level expression of the MRP1 drug
resistance gene is an independent indicator of decreased survival.[50] The profile of GABAergic receptors
expressed in neuroblastoma is predictive of prognosis regardless of age, stage, and MYCN gene amplification.[51]
Gene expression profiling may prove useful for prognosis prediction.[52] Whole chromosome copy number
changes do not predict recurrence, while segmental chromosome number changes do.[53] In addition, response to
treatment has been associated with outcome. The persistence of neuroblastoma cells in bone marrow during or
after chemotherapy, for example, is associated with a poor prognosis.[54,55]
Unique Aspects of Neuroblastoma
Biologically discrete types of neuroblastoma
Based on biologic factors and an improved understanding of the molecular development of the neural crest cells
that give rise to neuroblastoma, the tumors have been categorized into three biological types. These types are not
used to determine treatment at this time; however, type 1 has a very favorable prognosis, while types 2 and 3 have
poor prognoses.
Type 1: Expresses the TrkA neurotrophin receptor, is hyperdiploid, and tends to spontaneously regress.
[56,57]
Type 2: Expresses the TrkB neurotrophin receptor and its ligand, has gained an additional copy of
chromosome 17q, has LOH of 14q or 11q, and is genomically unstable.[56,57]
Type 3: Has a gain of chromosome 17q, loss of chromosome 1p, and the MYCN gene becomes amplified.
[56,57]
Children whose tumors have lost a copy of 11q are older at diagnosis, and their tumors contain more segmental
changes in gene copy number compared with children whose tumors show MYCN amplification.[58,59] 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.[60]
Neuroblastoma screening
Current data do not support neuroblastoma screening. Screening infants for neuroblastoma by assay of urinary
catecholamine metabolites was initiated in Japan.[61] 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 [62,63] that would never have been detected clinically,
apparently due to spontaneous regression of the tumors. Another study of infants screened at the age of 1 year
shows similar results.[64] 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.[63,64] No public health benefits
have been shown from screening infants for neuroblastoma at these ages. (Refer to the PDQ summary
Neuroblastoma Screening 8 for more information.)
Spontaneous regression of neuroblastoma
This phenomenon has been well described in infants, especially in those with the 4S pattern of metastatic spread.
[65] (Refer to the Stage Information 4 section of this summary for more information.) In a German clinical trial,
spontaneous regression and/or lack of progression occurred in nearly half of 93 asymptomatic infants aged 12
months or younger with stage 1, 2, or 3 tumors without MYCN amplification; all were observed after partial or no
resection.[66] Regression generally occurs only in tumors with a near triploid number of chromosomes, no MYCN
amplification, and no loss of chromosome 1p. Additional features associated with spontaneous regression [67,68]
include the lack of telomerase expression,[69,70] the expression of Ha-ras,[71] and the expression of the
neurotrophin receptor TrkA, a nerve growth factor receptor.
Studies have suggested that selected infants who appear to have asymptomatic, small, low-stage adrenal
neuroblastoma detected by screening or during prenatal or incidental ultrasound examination, often have tumors
that spontaneously regress and may be observed safely without surgical intervention or tissue diagnosis.[72-74]
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55. 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):
56. Maris JM, Matthay KK: Molecular biology of neuroblastoma. J Clin Oncol 17 (7): 2264-79, 1999. [PUBMED
Abstract]
57. Lastowska M, Cullinane C, Variend S, et al.: Comprehensive genetic and histopathologic study reveals
three types of neuroblastoma tumors. J Clin Oncol 19 (12): 3080-90, 2001. [PUBMED Abstract]
58. Carn H, Kryh H, Nethander M, et al.: High-risk neuroblastoma tumors with 11q-deletion display a poor
prognostic, chromosome instability phenotype with later onset. Proc Natl Acad Sci U S A 107 (9): 4323-8,
59. Castel V, Villamn E, Caete A, et al.: Neuroblastoma in adolescents: genetic and clinical characterisation.
Clin Transl Oncol 12 (1): 49-54, 2010. [PUBMED Abstract]
60. Schleiermacher G, Janoueix-Lerosey I, Ribeiro A, et al.: Accumulation of segmental alterations determines

progression in neuroblastoma. J Clin Oncol 28 (19): 3122-30, 2010. [PUBMED Abstract]
61. Sawada T: Past and future of neuroblastoma screening in Japan. Am J Pediatr Hematol Oncol 14 (4): 320-
6, 1992. [PUBMED Abstract]
62. Takeuchi LA, Hachitanda Y, Woods WG, et al.: Screening for neuroblastoma in North America.
Preliminary results of a pathology review from the Quebec Project. Cancer 76 (11): 2363-71, 1995.
[PUBMED Abstract]
63. Woods WG, Gao RN, Shuster JJ, et al.: Screening of infants and mortality due to neuroblastoma. N Engl J
Med 346 (14): 1041-6, 2002. [PUBMED Abstract]
64. Schilling FH, Spix C, Berthold F, et al.: Neuroblastoma screening at one year of age. N Engl J Med 346
(14): 1047-53, 2002. [PUBMED Abstract]
65. Nickerson HJ, Matthay KK, Seeger RC, et al.: Favorable biology and outcome of stage IV-S
neuroblastoma with supportive care or minimal therapy: a Children's Cancer Group study. J Clin Oncol 18
(3): 477-86, 2000. [PUBMED Abstract]
66. Hero B, Simon T, Spitz R, et al.: Localized infant neuroblastomas often show spontaneous regression:
results of the prospective trials NB95-S and NB97. J Clin Oncol 26 (9): 1504-10, 2008. [PUBMED Abstract]
67. Reynolds CP: Ras and Seppuku in neuroblastoma. J Natl Cancer Inst 94 (5): 319-21, 2002. [PUBMED Abstract]
68. 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.
69. Hiyama E, Hiyama K, Yokoyama T, et al.: Correlating telomerase activity levels with human
neuroblastoma outcomes. Nat Med 1 (3): 249-55, 1995. [PUBMED Abstract]
70. 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.
71. 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,
72. 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
73. Okazaki T, Kohno S, Mimaya J, et al.: Neuroblastoma detected by mass screening: the Tumor Board's role
in its treatment. Pediatr Surg Int 20 (1): 27-32, 2004. [PUBMED Abstract]
74. Fritsch P, Kerbl R, Lackner H, et al.: "Wait and see" strategy in localized neuroblastoma in infants: an
option not only for cases detected by mass screening. Pediatr Blood Cancer 43 (6): 679-82, 2004. [PUBMED
Abstract]
Cellular Classification
The International Neuroblastoma Pathologic Classification (INPC) system involves evaluation of tumor specimens
obtained prior to therapy for the amount of stromal development, the degree of neuroblastic maturation, and the
mitosis-karyorrhexis index of the neuroblastic cells.[1-4] Favorable and unfavorable prognoses are defined on the
bases of these histologic parameters. The prognostic significance of this classification system, and of related
systems using similar criteria, has been confirmed in several studies.[1-3] Neuroblastoma containing many
differentiating cells, termed ganglioneuroblastoma, can have nodules of undifferentiated cells whose histology,
along with MYCN amplification, determines prognosis.[4,5] About 25% of reported neuroblastomas diagnosed in
the fetus and neonate are cystic; cystic neuroblastomas have lower stages and a higher incidence of favorable
biology.[6]
References
1. Shimada H, Ambros IM, Dehner LP, et al.: The International Neuroblastoma Pathology Classification (the
Shimada system). Cancer 86 (2): 364-72, 1999. [PUBMED Abstract]
2. Shimada H, Umehara S, Monobe Y, et al.: International neuroblastoma pathology classification for

prognostic evaluation of patients with peripheral neuroblastic tumors: a report from the Children's Cancer
Group. Cancer 92 (9): 2451-61, 2001. [PUBMED Abstract]
3. Goto S, Umehara S, Gerbing RB, et al.: Histopathology (International Neuroblastoma Pathology

Classification) and MYCN status in patients with peripheral neuroblastic tumors: a report from the
Children's Cancer Group. Cancer 92 (10): 2699-708, 2001. [PUBMED Abstract]
4. Peuchmaur M, d'Amore ES, Joshi VV, et al.: Revision of the International Neuroblastoma Pathology
Classification: confirmation of favorable and unfavorable prognostic subsets in ganglioneuroblastoma,
nodular. Cancer 98 (10): 2274-81, 2003. [PUBMED Abstract]
5. Kubota M, Suita S, Tajiri T, et al.: Analysis of the prognostic factors relating to better clinical outcome in
ganglioneuroblastoma. J Pediatr Surg 35 (1): 92-5, 2000. [PUBMED Abstract]
6. Isaacs H Jr: Fetal and neonatal neuroblastoma: retrospective review of 271 cases. Fetal Pediatr Pathol 26
(4): 177-84, 2007 Jul-Aug. [PUBMED Abstract]
Stage Information
The treatment section of this document is organized to correspond with the Childrens Oncology Group (COG)
risk-based schema for the treatment of neuroblastoma. This schema is based on three factors: patient age at
diagnosis, certain biological characteristics of the patients neuroblastoma tumor, and the stage of the tumor as
defined by the International Neuroblastoma Staging System (INSS). The INSS has replaced the previously used
Childrens Cancer Group (CCG) and Pediatric Oncology Group (POG) staging systems. The INSS is described
below, and the COG risk-based treatment schema is described in Table 1 10 in this section.
A thorough evaluation for metastatic disease should be performed prior to therapy initiation. The following
investigations are recommended:[1]
1. Bone marrow should be assessed by bilateral posterior iliac crest marrow aspirates and trephine (core)
bone marrow biopsies to exclude bone marrow involvement. To be considered adequate, core biopsy
specimens must contain at least 1 cm of marrow, excluding cartilage. Bone marrow sampling may not be
necessary for tumors that are otherwise stage 1.[2]
2. Bone should be assessed by metaiodobenzylguanidine (MIBG) scan, which is applicable to all sites of
disease, and by technetium 99 scan if the results of the MIBG scan are negative or unavailable.[3] Imaging
with 123I-MIBG is optimal for identifying soft tissue and bony metastases and is superior to 18F-FDG
positron emission tomography/computerized tomography (PET/CT) in a prospective comparison.[4] Plain
radiographs of positive lesions are recommended.
3. Palpable lymph nodes should be clinically examined and histologically confirmed if indicated for staging.[1]
4. The abdomen and liver should be assessed by CT scan and/or magnetic resonance imaging (MRI).
Ultrasound is considered suboptimal for accurate 3D measurements. If extension of abdominal disease or
pulmonary metastasis is suspected, the chest should be examined by CT scan.
5. Lumbar puncture should be avoided as central nervous system (CNS) metastasis at diagnosis is rare,[5]
and lumbar puncture may be associated with an increased incidence of subsequent development of CNS
metastasis.[6]
6. Paraspinal tumors may extend through neural foramina to compress the spinal cord. Therefore, MRI of the
spine adjacent to any paraspinal tumor is recommended.
International Neuroblastoma Staging System

INSS combines certain features of the previously used POG and CCG systems [1,7] and has identified distinct
prognostic groups.[1,7-9]
Stage 1: Localized 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 2B: Localized 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 4: Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin,
and/or other organs, except as defined for stage 4S.
Stage 4S: Localized primary tumor, as defined for stage 1, 2A, or 2B, with dissemination limited to skin,
liver, and/or bone marrow (limited to infants younger than 1 year). 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.
Childrens Oncology Group Neuroblastoma Risk Grouping

In North America, the COG investigated a risk-based neuroblastoma treatment plan that assigned all patients to a
low-, intermediate-, or high-risk group based on age, INSS stage, and tumor biology. The relevant biological
attributes of the tumor included MYCN status, International Neuroblastoma Pathologic Classification (INPC)
histopathology classification, and tumor DNA index. The low-risk group was observed without further treatment
unless the patient had life- or organ-threatening tumors. The intermediate-risk group received limited
chemotherapy, additional surgery in some instances, and avoided radiation therapy. This study involved an overall
reduction in treatment compared to prior treatment plans.[10] The high-risk group was treated with aggressive
chemotherapy, second-look surgery, high-dose chemotherapy with stem cell rescue, radiation therapy, and cis-
retinoic acid. The outcome for the low- and intermediate-risk groups combined was an event-free survival and
overall 3-year survival of 88% and 96%, respectively. There was no unexpected toxicity.[10] These studies
(COG-P9641 11 and COG-A3961 12) have established a new standard of care for children in North America with
neuroblastoma.
Some controversies exist regarding the treatment of several small subsets of patients and the INSS staging
system;[11-13] risk group assignment and recommended treatment are expected to mature as additional outcome
data are analyzed. For example, the risk group for INSS stage 4, including patients aged 12 to 18 months was
changed for patients with MYCN-nonamplified status in 2005.[14-16] Table 1 describes the risk group assignment
criteria used to assign treatment in these studies.
Table 1. Childrens Oncology Group (COG) Neuroblastoma Low-, Intermediate-, and High-Risk
Group Assignment Schema Used for COG-9641 and COG-A3961 Studies a
Enlarge 13
INSS Stage Age MYCN Status INPC Classif ication DNA Ploidyb Risk G roup
1 021 y Any Any Any Low
2A/2Bc <365 d Any Any Any Low
365 d21 y Nonamplified Any - Low
365 d21 y Amplified Favorable - Low
365 d21 y Amplified Unfavorable - High
3d <365 d Nonamplified Any Any Intermediate
<365 d Amplified Any Any High
365 d21 y Nonamplified Favorable - Intermediate
365 d21 y Nonamplified Unfavorable - High
365 d21 y Amplified Any - High
4d <548 d [14-16] Nonamplified Any Any Intermediate
548 d21 y Any Any - High
4Se <365 d Nonamplified Favorable >1 Low
<365 d Nonamplified Any =1 Intermediate
<365 d Nonamplified Unfavorable Any Intermediate
INPC = International Neuroblastoma Pathologic Classification; INSS = International Neuroblastoma Staging System.
aThe COG-9641 and COG-A3961 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).
c INSS stage 2A/2B symptomatic patients with spinal cord compression, neurologic deficits, or other symptoms should be treated with immediate chemotherapy for four
cycles.
dINSS stage 3 or stage 4 patients with clinical symptoms as listed above should receive immediate chemotherapy.
e INSS stage 4S infants with favorable biology and clinical symptoms should be treated with immediate chemotherapy until asymptomatic ( 24 cycles). Clinical symptoms
include: 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.
References
2. Russell HV, Golding LA, Suell MN, et al.: The role of bone marrow evaluation in the staging of patients
with otherwise localized, low-risk neuroblastoma. Pediatr Blood Cancer 45 (7): 916-9, 2005. [PUBMED Abstract]
3. 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,
4. 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,
5. DuBois SG, Kalika Y, Lukens JN, et al.: Metastatic sites in stage IV and IVS neuroblastoma correlate with
age, tumor biology, and survival. J Pediatr Hematol Oncol 21 (3): 181-9, 1999 May-Jun. [PUBMED Abstract]
6. 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,
7. Brodeur GM, Seeger RC, Barrett A, et al.: International criteria for diagnosis, staging, and response to
treatment in patients with neuroblastoma. J Clin Oncol 6 (12): 1874-81, 1988. [PUBMED Abstract]
8. 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
9. Ikeda H, Iehara T, Tsuchida Y, et al.: Experience with International Neuroblastoma Staging System and
Pathology Classification. Br J Cancer 86 (7): 1110-6, 2002. [PUBMED Abstract]
10. Baker DL, Schmidt ML, Cohn SL, et al.: Outcome after reduced chemotherapy for intermediate-risk
11. Kushner BH, Cheung NK: Treatment reduction for neuroblastoma. Pediatr Blood Cancer 43 (6): 619-21,
12. 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,
13. Navarro S, Amann G, Beiske K, et al.: Prognostic value of International Neuroblastoma Pathology
Classification in localized resectable peripheral neuroblastic tumors: a histopathologic study of localized
neuroblastoma European Study Group 94.01 Trial and Protocol. J Clin Oncol 24 (4): 695-9, 2006. [PUBMED
Abstract]
14. 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,
15. 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,
16. George RE, London WB, Cohn SL, et al.: Hyperdiploidy plus nonamplified MYCN confers a favorable
prognosis in children 12 to 18 months old with disseminated neuroblastoma: a Pediatric Oncology Group
study. J Clin Oncol 23 (27): 6466-73, 2005. [PUBMED Abstract]
Treatment Option Overview
The treatments described in this summary are based on the Childrens Oncology Group (COG) group assignment,
which is described in the Stage Information 4 section of this summary. Treatment information is presented in this
format because most children with neuroblastoma in North America are treated according to the COG schema.
The prior COG risk-based neuroblastoma studies established the standard of care. They assigned each patient to a
low-, intermediate-, or high-risk group and the basis of the assignment is described in Table 1 10.
In patients without metastatic disease, the standard of care is to perform an initial surgery to establish the
diagnosis, to resect as much of the primary tumor as is safely possible, to accurately stage disease through
sampling of regional lymph nodes that are not adherent to the tumor, and to obtain adequate tissue for biological
studies. Accurate determination of biological characteristics, such as INPC system, usually requires an open
biopsy. The accuracy of diagnosis and staging is increased by performing a metaiodobenzylguanidine (MIBG)
scan.[1] Urinary excretion of the catecholamine metabolites vanillylmandelic acid (VMA) and homovanillic acid
(HVA) per mg of excreted creatinine should be measured prior to therapy. If elevated, these markers can be used
to determine the persistence of disease.
There is controversy about the need for immediate diagnostic biopsy in infants aged 3 months and younger with
suspected neuroblastoma tumors that are likely to spontaneously regress. Biopsy is not required for infants entered
into a COG study of expectant observation of adrenal masses in neonates. In a German clinical trial, 25 infants
aged 3 months and younger with presumed neuroblastoma were observed without biopsy for periods of 1 to 18
months prior to biopsy or resection. There were no apparent ill effects of the delay.[2]
There is also controversy about the need for attempted 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 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.[2]
Low-Risk Neuroblastoma
Treatment for patients categorized as low risk (refer to Table 1 10 in the Stage Information section of this
summary) may be surgery alone, but surgery may be combined with chemotherapy in some cases. Chemotherapy
is reserved for 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 dose of each agent is kept low to minimize permanent injury from the
chemotherapy regimen (COG-P9641 11).
Observation without surgery for localized, suspected adrenal neuroblastoma in infants
Studies suggest that selected presumed neuroblastomas detected in infants 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.[3-5] The experience with tumors detected by mass
urinary catecholamine metabolite screening in Japan appears to be applicable to tumors detected by prenatal or
perinatal ultrasound in the United States.[3] The COG is investigating systematic observation without surgery for
infants with presumed small Evans stage I adrenal neuroblastoma detected by prenatal or perinatal ultrasound.
Intermediate-Risk Neuroblastoma
Patients categorized as intermediate risk (refer to Table 1 10 in the Stage Information section of this summary)
have been successfully treated with surgery and 12 to 24 weeks of the same chemotherapy regimen described
above (COG-A3961 12). As a rule, patients whose tumors have unfavorable biology receive twice as many cycles
of chemotherapy as those with favorable biology.
Whether initial chemotherapy is indicated for all intermediate-risk infants with localized neuroblastoma is
controversial. 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. Forty-four of 93 infants with unresected
tumors experienced spontaneous regression (17 were complete regressions) and 39 infants experienced
progression. The 3-year overall survival (OS) rate was 99%, and the metastases-free survival rate was 94% for
infants with unresected tumors and was not different from infants treated with surgery or chemotherapy (median
follow-up, 58 months). The investigators suggested that a wait-and-see strategy is appropriate for infants with
localized neuroblastoma because regressions have been observed after the first year of life.[2]
Moderate-dose chemotherapy has been shown to be effective in the prospective Infant Neuroblastoma European
Study (INES 99.1 [EURO-INF-NB-STUDY-1999-99.1 14]), where about half of the infants with unresectable,
nonmetastatic neuroblastoma and no MYCN amplification underwent a safe surgical resection and avoided long-
term adverse effects. The 5-year OS rate was 99% and the event-free survival (EFS) rate was 90% (median
follow-up, 6 years). In this study, infants undergoing surgical resection had a better EFS than those who did not
have surgery.[6][Level of evidence: 3iiA]
High-Risk Neuroblastoma
In contrast, patients categorized as high risk (refer to Table 1 10 of the Stage Information section of the summary)
are generally treated with dose-intensive multiagent chemotherapy consisting of very high doses of the drugs listed
above but often also including ifosfamide and high-dose cisplatin. After a response to chemotherapy, resection of
the primary tumor should be attempted, followed by myeloablative chemotherapy and autologous stem cell
transplantation. Radiation of residual tumor and original sites of metastases is often performed before, during, or
after myeloablative therapy. After recovery, patients are treated with oral 13-cis-retinoic acid for 6 months. Both
myeloablative therapy and retinoic acid improve outcome in patients categorized as high risk.[7,8]; [9][Level of
evidence: 1iiA] Compared to retinoic acid alone, chimeric anti-GD2 antibody ch14.18 combined with granulocyte
macrophage-colony stimulating factor and interleukin-2 and given in concert with retinoic acid improves event-free
survival for high-risk neuroblastoma patients in remission after stem cell transplant.[10]
Radiation Therapy
Radiation therapy (RT) for patients with low- or intermediate-risk neuroblastoma in the completed COG treatment
plan was reserved for symptomatic life-threatening or organ-threatening tumor bulk that did not respond rapidly
enough to chemotherapy. The common situations where radiation is used in these patients include: 1) infants aged
60 days and younger with stage 4S and marked respiratory compromise from liver metastases that has not
responded to chemotherapy, or 2) for symptomatic spinal cord compression that has not responded to initial
chemotherapy and/or surgical decompression. In contrast, radiation therapy to the primary site is often
recommended for high-risk patients even in cases of complete resection.
Chemotherapy
Immediate treatment should be given for symptomatic spinal cord compression. Neurologic recovery is more likely
the less the severity of compromise and the shorter the duration of symptoms. Neurologic outcome appears to be
similar whether cord compression is treated with chemotherapy, radiation therapy, or laminectomy. Laminectomy,
however, may result in later scoliosis, and chemotherapy is often needed whether or not surgery or radiation is
used.[11-13] The completed COG neuroblastoma treatment plans recommended immediate chemotherapy for
cord compression in patients classified as low or intermediate risk. Children with neuroblastoma whose spinal cord
compression worsens on medical therapy may benefit from surgical intervention.[14]
Description of International Neuroblastoma Response Criteria

In order to stop therapy after the initially planned number of cycles, certain response criteria, depending on
treatment group, must be met. These criteria are defined below:[15,16]
Complete Response (CR): Total disappearance of tumor, with no evidence of disease. VMA/HVA are
normal.
Very Good Partial Response (VGPR): Primary tumor has decreased by 90% to 99%, and no evidence of
metastatic disease. Urine VMA/HVA are normal. Residual bone scan changes are allowed.
Partial Response (PR): 50% to 90% decrease in the size of all measurable lesions; the number of bone
scan positive sites is decreased by greater than 50% and no new lesions are present; no more than one
positive bone marrow site allowed if this represents a reduction in the number of sites originally positive for
tumor at diagnosis.
Mixed Response (MR): No new lesions, 50% to 90% reduction of any measurable lesion (primary or
metastatic) with less than 50% reduction in other lesions and less than 25% increase in any lesion.
No Response (NR) or Stable Disease (SD): No new lesions; less than 50% reduction and less than 25%
increase in any lesion.
Progressive Disease (PD): Any new lesion; increase in any measurable lesion by greater than 25%;
previous negative bone marrow now positive for tumor. Neither persistent elevation in urinary VMA/HVA
with stable disease nor an increase in VMA/HVA without clinical or radiographic evidence of progression
indicate progressive disease, but does warrant continued follow-up. Care should be taken in interpreting the
development of metastatic disease in an infant who was initially considered to have stage 1 or 2 disease. If
the pattern of metastases in such a patient is consistent with a 4S pattern of disease (skin, liver, bone
marrow less than 10% involved) these patients should not be classified as progressive/metastatic disease,
which would be a criteria for removal from protocol therapy. Instead, these patients should be managed as
stage 4S.
Surveillance for Recurrence of High-Risk Neuroblastoma

Surveillance studies during and following treatment are able to detect asymptomatic and unsuspected relapse in a
substantial portion of patients. As an element in an overall surveillance plan, the most reliable test to detect disease
progression or recurrence is the 123I-MIBG scan.[17,18]
References
1. Vik TA, Pfluger T, Kadota R, et al.: (123)I-mIBG scintigraphy in patients with known or suspected
neuroblastoma: Results from a prospective multicenter trial. Pediatr Blood Cancer 52 (7): 784-90, 2009.
[PUBMED Abstract]
3. Nishihira H, Toyoda Y, Tanaka Y, et al.: Natural course of neuroblastoma detected by mass screening: s 5-
year prospective study at a single institution. J Clin Oncol 18 (16): 3012-7, 2000. [PUBMED Abstract]
4. Holgersen LO, Subramanian S, Kirpekar M, et al.: Spontaneous resolution of antenatally diagnosed adrenal
masses. J Pediatr Surg 31 (1): 153-5, 1996. [PUBMED Abstract]
5. Fritsch P, Kerbl R, Lackner H, et al.: "Wait and see" strategy in localized neuroblastoma in infants: an
option not only for cases detected by mass screening. Pediatr Blood Cancer 43 (6): 679-82, 2004. [PUBMED
Abstract]
6. Rubie H, De Bernardi B, Gerrard M, et al.: Excellent outcome with reduced treatment in infants with
nonmetastatic and unresectable neuroblastoma without MYCN amplification: results of the prospective
INES 99.1. J Clin Oncol 29 (4): 449-55, 2011. [PUBMED Abstract]
8. Berthold F, Boos J, Burdach S, et al.: Myeloablative megatherapy with autologous stem-cell rescue versus
oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a
randomised controlled trial. Lancet Oncol 6 (9): 649-58, 2005. [PUBMED Abstract]
9. Matthay KK, Reynolds CP, Seeger RC, et al.: Long-term results for children with high-risk neuroblastoma
treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children's
oncology group study. J Clin Oncol 27 (7): 1007-13, 2009. [PUBMED Abstract]
10. Yu AL, Gilman AL, Ozkaynak MF, et al.: Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin
for neuroblastoma. N Engl J Med 363 (14): 1324-34, 2010. [PUBMED Abstract]
11. Katzenstein HM, Kent PM, London WB, et al.: Treatment and outcome of 83 children with intraspinal
neuroblastoma: the Pediatric Oncology Group experience. J Clin Oncol 19 (4): 1047-55, 2001. [PUBMED
Abstract]
12. De Bernardi B, Pianca C, Pistamiglio P, et al.: Neuroblastoma with symptomatic spinal cord compression at
diagnosis: treatment and results with 76 cases. J Clin Oncol 19 (1): 183-90, 2001. [PUBMED Abstract]
13. Plantaz D, Rubie H, Michon J, et al.: The treatment of neuroblastoma with intraspinal extension with
chemotherapy followed by surgical removal of residual disease. A prospective study of 42 patients--results
of the NBL 90 Study of the French Society of Pediatric Oncology. Cancer 78 (2): 311-9, 1996. [PUBMED
Abstract]
14. Sandberg DI, Bilsky MH, Kushner BH, et al.: Treatment of spinal involvement in neuroblastoma patients.
Pediatr Neurosurg 39 (6): 291-8, 2003. [PUBMED Abstract]
16. Brodeur GM, Seeger RC, Barrett A, et al.: International criteria for diagnosis, staging, and response to
treatment in patients with neuroblastoma. J Clin Oncol 6 (12): 1874-81, 1988. [PUBMED Abstract]
17. Kushner BH, Kramer K, Modak S, et al.: Sensitivity of surveillance studies for detecting asymptomatic and
unsuspected relapse of high-risk neuroblastoma. J Clin Oncol 27 (7): 1041-6, 2009. [PUBMED Abstract]
18. 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,
Treatment of Low-Risk Neuroblastoma

In North America, the Childrens Oncology Group (COG) 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 [INPC] system, and DNA index). The low-risk group was observed without further
treatment in most cases. Chemotherapy was given for four cycles (12 weeks) to treat patients with life- or organ-
threatening neuroblastoma. (Risk Groups are defined in Table 1 15 in the Stage Information section of this
summary.)
Patients with low-risk neuroblastoma have a cure rate higher than 90%.[1-5]
Studies suggest that selected presumed neuroblastomas detected in infants by screening may be safely observed
without surgical intervention and without pathologic diagnosis.[6,7] A COG trial investigating systematic
observation without diagnostic surgery for selected infants with presumed INSS stage 1 adrenal neuroblastoma
detected by prenatal or perinatal ultrasound (COG-ANBL00P2 16) has met its patient accrual goals. Analysis of
the trial is pending. There is some controversy whether additional surgical resection should be attempted in infants
with localized MYCN-nonamplified tumors after biopsy or partial resection. A German clinical trial observed a
group of these patients and some infants did not require further intervention, in part due to spontaneous regression.
[8]
The treatment of children with low-risk stage 4S disease is dependent on clinical presentation.[9,10] Children who
are clinically stable with this special pattern of neuroblastoma may not require therapy. The development of
complications, such as functional compromise from massive hepatomegaly, is an indication for intervention,
especially in infants younger than 2 to 3 months.[9,11,12] In a study of 80 infants with 4S disease, those who were
asymptomatic had 100% survival with supportive care only, and patients with symptoms had an 81% survival rate
when they received low-dose chemotherapy.[11] Resection of primary tumor is not associated with improved
outcome.[9-11] In 45 patients with 4S neuroblastoma diagnosed in the first month of life, 16 patients developed
dyspnea caused by massive liver enlargement; half of them did not survive.[13]

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with
neuroblastoma 17. 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 18.
References
Abstract]
2. Hayes FA, Green A, Hustu HO, et al.: Surgicopathologic staging of neuroblastoma: prognostic significance
of regional lymph node metastases. J Pediatr 102 (1): 59-62, 1983. [PUBMED Abstract]
3. Evans AR, Brand W, de Lorimier A, et al.: Results in children with local and regional neuroblastoma
managed with and without vincristine, cyclophosphamide, and imidazolecarboxamide. A report from the
Children's Cancer Study Group. Am J Clin Oncol 7 (1): 3-7, 1984. [PUBMED Abstract]
4. Alvarado CS, London WB, Look AT, et al.: Natural history and biology of stage A neuroblastoma: a
Pediatric Oncology Group Study. J Pediatr Hematol Oncol 22 (3): 197-205, 2000 May-Jun. [PUBMED Abstract]
5. Perez CA, Matthay KK, Atkinson JB, et al.: Biologic variables in the outcome of stages I and II
neuroblastoma treated with surgery as primary therapy: a children's cancer group study. J Clin Oncol 18
(1): 18-26, 2000. [PUBMED Abstract]
6. Nishihira H, Toyoda Y, Tanaka Y, et al.: Natural course of neuroblastoma detected by mass screening: s 5-
year prospective study at a single institution. J Clin Oncol 18 (16): 3012-7, 2000. [PUBMED Abstract]
7. Holgersen LO, Subramanian S, Kirpekar M, et al.: Spontaneous resolution of antenatally diagnosed adrenal
masses. J Pediatr Surg 31 (1): 153-5, 1996. [PUBMED Abstract]
9. Guglielmi M, De Bernardi B, Rizzo A, et al.: Resection of primary tumor at diagnosis in stage IV-S
neuroblastoma: does it affect the clinical course? J Clin Oncol 14 (5): 1537-44, 1996. [PUBMED Abstract]
10. Katzenstein HM, Bowman LC, Brodeur GM, et al.: Prognostic significance of age, MYCN oncogene
amplification, tumor cell ploidy, and histology in 110 infants with stage D(S) neuroblastoma: the pediatric
oncology group experience--a pediatric oncology group study. J Clin Oncol 16 (6): 2007-17, 1998. [PUBMED
Abstract]
11. Nickerson HJ, Matthay KK, Seeger RC, et al.: Favorable biology and outcome of stage IV-S
neuroblastoma with supportive care or minimal therapy: a Children's Cancer Group study. J Clin Oncol 18
(3): 477-86, 2000. [PUBMED Abstract]
12. Hsu LL, Evans AE, D'Angio GJ: Hepatomegaly in neuroblastoma stage 4s: criteria for treatment of the
vulnerable neonate. Med Pediatr Oncol 27 (6): 521-8, 1996. [PUBMED Abstract]
13. Gigliotti AR, Di Cataldo A, Sorrentino S, et al.: Neuroblastoma in the newborn. A study of the Italian
Neuroblastoma Registry. Eur J Cancer 45 (18): 3220-7, 2009. [PUBMED Abstract]
Treatment of Intermediate-Risk Neuroblastoma

Pathology Classification [INPC] system, and DNA ploidy). The intermediate-risk group received limited
chemotherapy, additional surgery in some instances, and avoided radiation therapy. This study involved an overall
reduction in treatment compared to prior treatment plans. Event-free survival (EFS) and overall survival (OS)
rates were 88% and 96%, respectively. There was no unexpected toxicity.[1] These studies (COG-P9641 11 and
COG-A3961 12) have established a new standard of care for children in North America with neuroblastoma.
(Risk groups are defined in Table 1 10 in the Stage Information section of this summary.)
Chemotherapy is given for four to eight cycles (12 to 24 weeks) and consists 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. Radiation therapy is reserved for patients with symptomatic
life-threatening or organ-threatening tumor that does not respond rapidly enough to chemotherapy and/or surgery.
There is considerable variation in outcome, and, therefore, in treatment for children with stage 3 disease (tumor
involving both sides of the midline by virtue of either invasion into normal tissues or lymph node metastasis).
Infants aged 1 year and younger have a greater than 80% cure rate while older children have a cure rate of 50%
to 70% with current, relatively intensive therapy.[2-5] In one study, those with favorable compared with
unfavorable biological features (i.e., INPC and MYCN gene amplification) had EFS rates of almost 100% and
about 50%, respectively.[6-8] In cases of abdominal neuroblastoma thought to involve the kidney, nephrectomy
should not be undertaken before a trial of chemotherapy has been given.[9]
Whether initial chemotherapy is indicated for all intermediate-risk infants with localized neuroblastoma is
controversial. 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 amplification of MYCN. 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. Further surgery was avoided in 33 infants and
chemotherapy was avoided in 72 infants. Some degree of spontaneous tumor regression occurred in nearly half
the infants. Overall survival of the 93 infants was 99%.[10]
Survival of patients with INSS stage 4 disease is strongly dependent on age. Children younger than 1 year at
diagnosis have a good chance of long-term survival (i.e., a 5-year disease-free survival rate of 50%80%),[11,12]
with outcome particularly dependent on MYCN amplification and tumor cell ploidy (e.g., hyperdiploidy confers a
favorable prognosis while diploidy predicts early treatment failure).[3,13] Infants aged18 months and younger at
diagnosis with INSS stage 4 neuroblastoma who do not have MYCN gene amplification are categorized as
intermediate risk.[14-17] The need for chemotherapy in all asymptomatic infants with stage 4 disease is somewhat
controversial.[18] Stage 4 and 4S infants (N = 170) aged 12 months or younger and Stage 4 asymptomatic infants
(N = 14) enrolled in an International Society of Pediatric Oncology (SIOP) trial had one of the following
characteristics: 1) metastases of the 4S pattern and including positive bone metastases by iodine I 131
metaiodobenzylguanidine (131I-MIBG) or technetium bone scan without cortical bone abnormality by computer
tomography (CT) scan or plain x-ray, or 2) primary tumor stage 3 with 4S metastatic pattern. These infants were
observed without initial chemotherapy, and in cases with surgical risk factors, the infants were observed without
resection of the primary tumor. Although three infants underwent tumor progression, all survived. Although many
were eventually treated with chemotherapy at the investigators choice, a substantial number of infants received
no chemotherapy.[18]
A small, single-institution study suggested that all MYCN-nonamplified INSS stage 3 tumors may be treated with
surgical resection followed by observation without chemotherapy.[19][Level of evidence: 3iiDi]

criteria.
References
2. Castleberry RP, Kun LE, Shuster JJ, et al.: Radiotherapy improves the outlook for patients older than 1
year with Pediatric Oncology Group stage C neuroblastoma. J Clin Oncol 9 (5): 789-95, 1991. [PUBMED
Abstract]
3. Bowman LC, Castleberry RP, Cantor A, et al.: Genetic staging of unresectable or metastatic
neuroblastoma in infants: a Pediatric Oncology Group study. J Natl Cancer Inst 89 (5): 373-80, 1997.
[PUBMED Abstract]
4. Castleberry RP, Shuster JJ, Altshuler G, et al.: Infants with neuroblastoma and regional lymph node
metastases have a favorable outlook after limited postoperative chemotherapy: a Pediatric Oncology Group
5. West DC, Shamberger RC, Macklis RM, et al.: Stage III neuroblastoma over 1 year of age at diagnosis:
improved survival with intensive multimodality therapy including multiple alkylating agents. J Clin Oncol 11
Abstract]
7. Perez CA, Matthay KK, Atkinson JB, et al.: Biologic variables in the outcome of stages I and II
neuroblastoma treated with surgery as primary therapy: a children's cancer group study. J Clin Oncol 18
8. Matthay KK, Sather HN, Seeger RC, et al.: Excellent outcome of stage II neuroblastoma is independent of
residual disease and radiation therapy. J Clin Oncol 7 (2): 236-44, 1989. [PUBMED Abstract]
9. Shamberger RC, Smith EI, Joshi VV, et al.: The risk of nephrectomy during local control in abdominal
neuroblastoma. J Pediatr Surg 33 (2): 161-4, 1998. [PUBMED Abstract]
11. Paul SR, Tarbell NJ, Korf B, et al.: Stage IV neuroblastoma in infants. Long-term survival. Cancer 67 (6):
12. Bowman LC, Hancock ML, Santana VM, et al.: Impact of intensified therapy on clinical outcome in infants
and children with neuroblastoma: the St Jude Children's Research Hospital experience, 1962 to 1988. J Clin
13. Look AT, Hayes FA, Shuster JJ, et al.: Clinical relevance of tumor cell ploidy and N-myc gene
amplification in childhood neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 9 (4): 581-91,
14. Schmidt ML, Lukens JN, Seeger RC, et al.: Biologic factors determine prognosis in infants with stage IV
neuroblastoma: A prospective Children's Cancer Group study. J Clin Oncol 18 (6): 1260-8, 2000. [PUBMED
Abstract]
15. 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,
16. 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,
17. 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
18. De Bernardi B, Gerrard M, Boni L, et al.: Excellent outcome with reduced treatment for infants with
disseminated neuroblastoma without MYCN gene amplification. J Clin Oncol 27 (7): 1034-40, 2009.
[PUBMED Abstract]
19. Modak S, Kushner BH, LaQuaglia MP, et al.: Management and outcome of stage 3 neuroblastoma. Eur J
Cancer 45 (1): 90-8, 2009. [PUBMED Abstract]
Treatment of High-Risk Neuroblastoma

Pathology Classification [INPC] system, and DNA ploidy) (COG-P9641 11 and COG-A3961 12). (Low-,
intermediate- and high-risk groups are defined in Table 1 10 in the Stage Information section of this summary.)
For children with high-risk neuroblastoma, long-term survival with current treatments is about 30%. Children with
aggressively treated, high-risk neuroblastoma may develop late recurrences, some more than 5 years after
completion of therapy.[1,2] A randomized study was performed comparing high-dose therapy with purged
autologous hematopoietic stem cell transplantation (HSCT) versus three cycles of intensive consolidation
chemotherapy. The 3-year event-free survival (EFS) was significantly better in the HSCT arm (34%) compared
with the consolidation chemotherapy arm (18%).[3] Superiority of myeloablative chemotherapy over maintenance
therapy was confirmed in another study.[4] In addition, patients on this study were subsequently randomized to
stop therapy or to receive 6 months of 13-cis-retinoic acid.[3] Patients who received 13-cis-retinoic acid had
significantly better 3-year EFS than patients who received no maintenance therapy. This was true for all patient
subgroups. The 5-year EFS and overall survival (OS) for patients treated with both HSCT and retinoic acid is 50%
and 59%, respectively. The 10-year OS remains greater than 50%.[5] However, these patients were selected for
having completed HSCT without developing progressive disease. Based on these results, clinical trials have built
upon autologous HSCT and 13-cis-retinoic acid for high-risk neuroblastoma.[3] Compared to retinoic acid alone,
the addition of chimeric anti-GD2 antibody ch14.18 combined with granulocyte macrophage-colony stimulating
factor and interleukin-2 improves EFS for high-risk neuroblastoma patients in remission after stem cell transplant
(SCT) (COG-ANBL0032 19 and COG-ANBL0931 20).[6]
The potential benefit of aggressive surgical approaches in high-risk patients with metastatic disease to achieve
complete tumor resection, either at the time of diagnosis or following chemotherapy, has not been unequivocally
demonstrated. Several studies have reported that complete resection of the primary tumor at diagnosis improved
survival; however, the outcome in these patients may be more dependent on the biology of the tumor, which itself
may determine resectability, than on the extent of surgical resection.[7-11] The use of radiation therapy to
consolidate local control after surgical resection is recommended.[12]; [13][Level of evidence: 3iiA]
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 EFS and OS were 53% and 72%, respectively. Survival was superior in patients
whose tumors were hyperdiploid rather than diploid (EFS 82% 20% vs. 37% 21%; OS 94% 11% vs. 54%
15%).[14] The overall EFS and OS for infants with stage 4 and 4S disease and MYCN-amplification was only
30% at 2 to 5 years post-treatment in a European study.[15]

Patients classified as high risk receive treatment with an aggressive regimen of combination chemotherapy
consisting of very high drug doses, generally termed induction. Drugs often used include cyclophosphamide,
ifosfamide, cisplatin, carboplatin, vincristine, doxorubicin, etoposide, and topotecan. COG has completed a pilot
study of induction demonstrating the feasibility of substituting two cycles of topotecan and cyclophosphamide for
two cycles of vincristine, cyclophosphamide, and doxorubicin.[16] After a response to chemotherapy, resection of
the primary tumor should be attempted, followed by myeloablative chemotherapy and stem cell rescue (i.e., bone
marrow and/or peripheral blood stem cell transplantation). Whether or not harvested stem cells should be purged
of neuroblastoma cells has been studied in a randomized fashion. There was no advantage to purging.[17] Two or
more sequential cycles of myeloablative chemotherapy and stem cell rescue given in a tandem fashion has been
studied and feasibility was established.[7,18] It is now under clinical evaluation in COG. Radiation to the primary
tumor site should be undertaken whether or not a complete excision was obtained. The optimal dose of radiation
therapy has not been determined. Radiation of sites of metastatic disease is determined on an individual case
basis. After recovery, patients are treated with oral 13-cis-retinoic acid for 6 months. Both myeloablative therapy
and postchemotherapy retinoic acid improve outcome in patients categorized as high risk.[3,5] For high risk-
patients in remission following HSCT, compared to retinoic acid alone, chimeric anti-GD2 antibody ch14.18
combined with granulocyte-macrophage colony stimulating factor and interleukin-2 and given in concert with
retinoic acid improves EFS.[6]
Treatment Options Under Clinical Evaluation

The following are examples of national and/or institutional clinical trials that are currently being conducted.
COG-ANBL09P1 21 (Induction Therapy Including 131I-MIBG and Chemotherapy in Treating Patients

With Newly Diagnosed High-Risk Neuroblastoma Undergoing SCT, Radiation Therapy, and Maintenance
Therapy With Isotretinoin ): This limited-participation pilot study for children with newly diagnosed high-risk
neuroblastoma assesses the tolerability and feasibility of an induction regimen containing five cycles of
multi-agent chemotherapy and a block of 131I-MIBG/irinotecan/vincristine followed by a consolidation
regimen of busulfan/melphalan with autologous stem cell rescue and external-beam radiation therapy.
COG-ANBL0032 19 (Isotretinoin With or Without Monoclonal Antibody, Interleukin-2, and Sargramostim

Following SCT in Treating Patients With Neuroblastoma): The COG is studying, in a nonrandomized
fashion, the use of monoclonal antibody therapy with granulocyte-macrophage colony-stimulating factor and
interleukin-2 combined with cis-retinoic acid following chemotherapy.[6,19,20]

criteria.
References
1. 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
2. Mertens AC, Yasui Y, Neglia JP, et al.: Late mortality experience in five-year survivors of childhood and
adolescent cancer: the Childhood Cancer Survivor Study. J Clin Oncol 19 (13): 3163-72, 2001. [PUBMED
Abstract]
4. Berthold F, Boos J, Burdach S, et al.: Myeloablative megatherapy with autologous stem-cell rescue versus
oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a
randomised controlled trial. Lancet Oncol 6 (9): 649-58, 2005. [PUBMED Abstract]
5. Matthay KK, Reynolds CP, Seeger RC, et al.: Long-term results for children with high-risk neuroblastoma
treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children's
oncology group study. J Clin Oncol 27 (7): 1007-13, 2009. [PUBMED Abstract]
6. Yu AL, Gilman AL, Ozkaynak MF, et al.: Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin
for neuroblastoma. N Engl J Med 363 (14): 1324-34, 2010. [PUBMED Abstract]
7. George RE, Li S, Medeiros-Nancarrow C, et al.: High-risk neuroblastoma treated with tandem autologous
peripheral-blood stem cell-supported transplantation: long-term survival update. J Clin Oncol 24 (18): 2891-
6, 2006. [PUBMED Abstract]
8. DeCou JM, Bowman LC, Rao BN, et al.: Infants with metastatic neuroblastoma have improved survival
with resection of the primary tumor. J Pediatr Surg 30 (7): 937-40; discussion 940-1, 1995. [PUBMED Abstract]
9. Adkins ES, Sawin R, Gerbing RB, et al.: Efficacy of complete resection for high-risk neuroblastoma: a
Children's Cancer Group study. J Pediatr Surg 39 (6): 931-6, 2004. [PUBMED Abstract]
10. Castel V, Tovar JA, Costa E, et al.: The role of surgery in stage IV neuroblastoma. J Pediatr Surg 37 (11):
11. La Quaglia MP, Kushner BH, Su W, et al.: The impact of gross total resection on local control and survival
in high-risk neuroblastoma. J Pediatr Surg 39 (3): 412-7; discussion 412-7, 2004. [PUBMED Abstract]
12. Haas-Kogan DA, Swift PS, Selch M, et al.: Impact of radiotherapy for high-risk neuroblastoma: a
Children's Cancer Group study. Int J Radiat Oncol Biol Phys 56 (1): 28-39, 2003. [PUBMED Abstract]
13. Gatcombe HG, Marcus RB Jr, Katzenstein HM, et al.: Excellent local control from radiation therapy for
high-risk neuroblastoma. Int J Radiat Oncol Biol Phys 74 (5): 1549-54, 2009. [PUBMED Abstract]
14. Bagatell R, Beck-Popovic M, London WB, et al.: Significance of MYCN amplification in international
neuroblastoma staging system stage 1 and 2 neuroblastoma: a report from the International Neuroblastoma
Risk Group database. J Clin Oncol 27 (3): 365-70, 2009. [PUBMED Abstract]
15. Canete A, Gerrard M, Rubie H, et al.: Poor survival for infants with MYCN-amplified metastatic
neuroblastoma despite intensified treatment: the International Society of Paediatric Oncology European
Neuroblastoma Experience. J Clin Oncol 27 (7): 1014-9, 2009. [PUBMED Abstract]
16. Park JR, Stewart CF, London WB, et al.: A topotecan-containing induction regimen for treatment of high
risk neuroblastoma. [Abstract] J Clin Oncol 24 (Suppl 18): A-9013, 505s, 2006.
17. Kreissman SG, Villablanca JG, Seeger RC, et al.: A randomized phase III trial of myeloablative autologous
peripheral blood stem cell (PBSC) transplant (ASCT) for high-risk neuroblastoma (HR-NB) employing
immunomagnetic purged (P) versus unpurged (UP) PBSC: A Children's Oncology Group study. [Abstract]
J Clin Oncol 26 (Suppl 15): A-10011, 2008.
18. Kletzel M, Katzenstein HM, Haut PR, et al.: Treatment of high-risk neuroblastoma with triple-tandem high-
dose therapy and stem-cell rescue: results of the Chicago Pilot II Study. J Clin Oncol 20 (9): 2284-92,
19. Cheung NK, Kushner BH, Cheung IY, et al.: Anti-G(D2) antibody treatment of minimal residual stage 4
neuroblastoma diagnosed at more than 1 year of age. J Clin Oncol 16 (9): 3053-60, 1998. [PUBMED Abstract]
20. Simon T, Hero B, Faldum A, et al.: Consolidation treatment with chimeric anti-GD2-antibody ch14.18 in
children older than 1 year with metastatic neuroblastoma. J Clin Oncol 22 (17): 3549-57, 2004. [PUBMED
Abstract]
Recurrent Neuroblastoma
Age, International Neuroblastoma Staging System (INSS) stage, MYCN status, and time from diagnosis to first
relapse are significant prognostic factors for postrelapse survival.[1] The Childrens Oncology Group (COG)
experience with recurrence in intermediate-risk neuroblastoma is that the majority of recurrences can be salvaged,
as demonstrated by a 3-year event free survival (EFS) of 88% and an overall survival (OS) of 96%.[2] When
neuroblastoma recurs in a child originally diagnosed with high-risk disease and is widespread, the prognosis is
usually poor despite additional intensive therapy.[1,3-5]
In selected patients originally diagnosed with low- or intermediate-risk disease, recurrence may be treated
successfully with limited intervention. The combination of cyclophosphamide plus topotecan has been active in
patients with recurrent or refractory disease who have not received topotecan previously.[6] Iodine I 131
metaiodobenzylguanidine (131I-MIBG) therapy is also active in patients with recurrent or refractory
neuroblastoma.[7] Clinical trials are appropriate and should be considered. Information about ongoing clinical trials
is available from the NCI Web site 2.
Central nervous system (CNS) involvement, though 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.[8,9] CNS relapses have
been almost always fatal with a median time to death of 6 months. Current treatment approaches generally include
eradicating bulky and microscopic residual disease in the CNS as well as minimal residual systemic disease that
may herald further relapses. Neurosurgical interventions serve to decrease edema, control hemorrhage, and
remove bulky tumor prior to starting radiation therapy. Compartmental radioimmunotherapy using intrathecal
radioiodinated monoclonal antibodies has been tested in patients with recurrent metastatic CNS neuroblastoma
following surgery, craniospinal radiation therapy, and chemotherapy.[10]
In North America, the COG investigated a risk-based neuroblastoma treatment plan that assigned all patients to a
low-, intermediate-, or high-risk group based on age, INSS stage, and tumor biology (i.e., MYCN gene
amplification, International Neuroblastoma Pathology Classification [INPC] system, and DNA ploidy).[11]
Treatment of recurrent disease was determined by risk group at the time of diagnosis (refer to Table 1 10), extent
of disease at recurrence, patient age at recurrence, and the tumor biology. If tumor was unavailable for biological
studies at recurrence, the biology of the tumor at time of diagnosis was used to help determine treatment.
Recurrent Neuroblastoma in Patients Initially Classified as Low Risk
(Risk categories are defined in Table 1 10 in the Stage Information section of this summary.)
Local regional recurrent cancer is resected if possible:
1. 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 12 weeks of chemotherapy.
2. Infants younger than 1 year at the time of local/regional 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 24 weeks of chemotherapy.
Chemotherapy consists 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 11 and COG-A3961 12). Older children with local recurrence with either
unfavorable INPC classification or MYCN gene amplification have a poor prognosis and should be treated with an
aggressive regimen of combination chemotherapy consisting of very high doses of the drugs listed above, and
often also including ifosfamide and high-dose cisplatin. Both myeloablative therapy and postchemotherapy retinoic
acid may improve outcome of newly diagnosed high-risk patients with a poor prognosis.[12] These modalities are
commonly employed in the treatment of patients with a recurrence that augurs a poor prognosis.
Metastatic recurrent or progressive neuroblastoma in an infant initially categorized as low risk (see Table 1 10 in
the Stage Information section of the summary) and younger than 1 year at recurrence, whether the patient has
INSS stage 1, 2, or 4S at the time of diagnosis, may be treated according to tumor biology as defined in the prior
COG trials (COG-P9641 11 and COG-A3961 12):
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 with completely favorable biology occurs more than 3 months
after diagnosis or not in a 4S pattern, then the primary tumor is resected if possible and 12 to 24 weeks of
chemotherapy are given, depending on response.
3. If the tumor in the infant with metastatic recurrence or progression has unfavorable INPC classification
and/or is diploid, the primary tumor is resected if possible and 24 weeks of chemotherapy is given.
Chemotherapy consists 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-P9641 11).
Any child initially categorized as low risk who is older than 1 year at the time of metastatic recurrent or
progressive disease who is not in the stage 4S pattern usually has a poor prognosis and should be treated with an
aggressive regimen of combination chemotherapy consisting of very high doses of the drugs listed above, and
often also including ifosfamide and high-dose cisplatin. Both myeloablative therapy and postchemotherapy retinoic
acid may improve outcome of newly diagnosed patients with a poor prognosis.[12] These modalities are commonly
employed in the treatment of patients with a recurrence that augurs a poor prognosis.
Recurrent Neuroblastoma in Patients Initially Classified as Intermediate Risk
(Risk categories are defined in Table 1 10 in the Stage Information section of the summary.)
The current standard of care is based on the experience from the COG Intermediate-Risk treatment plan (COG-
A3961 12). Local regional recurrence of neuroblastoma with favorable biology that occurs more than 3 months
after completion of 12 weeks of chemotherapy may be treated surgically. If resection is less than near total, then
12 additional weeks of chemotherapy may be given. Chemotherapy consists 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).
If the recurrence is metastatic and/or occurs while on chemotherapy or within 3 months of completing
chemotherapy and/or has unfavorable biologic properties, the prognosis is poor and the patient should be treated
with an aggressive regimen of combination chemotherapy consisting of very high doses of the drugs listed above,
and often also including ifosfamide and high-dose cisplatin. Both myeloablative therapy and postchemotherapy
retinoic acid may improve outcome of newly diagnosed patients with a poor prognosis.[12] These modalities are
commonly employed in the treatment of patients with a recurrence that augurs a poor prognosis.
Recurrent or Refractory Neuroblastoma in Patients Initially Classified as High Risk
(Risk categories are defined in Table 1 10 in the Stage Information section of this summary.)
Any recurrence in patients initially classified as high risk signifies a very poor prognosis.[1] Data from three
consecutive German high-risk neuroblastoma trials described 253 children relapsing after intensive chemotherapy
with autologous stem cell transplantation (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. Among these
patients, the 3-year OS rate was 43%, but the 5-year OS rate was less than 20%. This shows that intensive
second-line therapy is feasible, although even with intensive therapy and second autologous SCT, only a small
minority of relapsed high-risk neuroblastoma patients may benefit.[13][Level of evidence: 3iiiA] Whether this
intense therapeutic approach is better than other salvage therapy approaches is unknown. Topotecan alone and in
combination with cyclophosphamide or etoposide has been used in patients with recurrent disease who did not
receive topotecan initially.[14,15]; [16][Level of evidence: 1A] High-dose carboplatin-irinotecan-temozolomide has
been used in patients resistant or refractory to regimens containing topotecan.[15] The combination of irinotecan
and temozolomide had a 15% response rate in one study.[17][Level of evidence: 2A]
For adolescents and young adults with recurrent or refractory neuroblastoma, 131I-MIBG is a highly effective
salvage agent and should be considered.[18]
Additionally, phase I or II clinical trials are appropriate and should be considered.
Treatment options under clinical evaluation
The following is an example of a national and/or institutional clinical trial that is currently being conducted.
COG-ANBL1021 22 (Biological Therapy, Sargramostim [GM-CSF], and Isotretinoin in Treating Patients

With Relapsed or Refractory Neuroblastoma): Feasibility/phase II study of Hu14.18-IL2 immunocytokine,
GM-CSF, and isotretinoin in patients with relapsed or refractory neuroblastoma.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent
criteria.
References
1. 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):
3. Pole JG, Casper J, Elfenbein G, et al.: High-dose chemoradiotherapy supported by marrow infusions for
advanced neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 9 (1): 152-8, 1991. [PUBMED
Abstract]
4. Castel V, Caete A, Melero C, et al.: Results of the cooperative protocol (N-III-95) for metastatic relapses
and refractory neuroblastoma. Med Pediatr Oncol 35 (6): 724-6, 2000. [PUBMED Abstract]
5. Lau L, Tai D, Weitzman S, et al.: Factors influencing survival in children with recurrent neuroblastoma. J
Pediatr Hematol Oncol 26 (4): 227-32, 2004. [PUBMED Abstract]
6. Saylors RL 3rd, Stine KC, Sullivan J, et al.: Cyclophosphamide plus topotecan in children with recurrent or
refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 19 (15): 3463-9, 2001.
[PUBMED Abstract]
7. 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
8. 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,
9. Matthay KK, Brisse H, Couanet D, et al.: Central nervous system metastases in neuroblastoma: radiologic,
clinical, and biologic features in 23 patients. Cancer 98 (1): 155-65, 2003. [PUBMED Abstract]
10. Kramer K, Kushner BH, Modak S, et al.: Compartmental intrathecal radioimmunotherapy: results for
treatment for metastatic CNS neuroblastoma. J Neurooncol 97 (3): 409-18, 2010. [PUBMED Abstract]
11. Goto S, Umehara S, Gerbing RB, et al.: Histopathology (International Neuroblastoma Pathology
Classification) and MYCN status in patients with peripheral neuroblastic tumors: a report from the
Children's Cancer Group. Cancer 92 (10): 2699-708, 2001. [PUBMED Abstract]
13. Simon T, Berthold F, Borkhardt A, et al.: Treatment and outcomes of patients with relapsed, high-risk
neuroblastoma: results of German trials. Pediatr Blood Cancer 56 (4): 578-83, 2011. [PUBMED Abstract]
14. Simon T, Lngler 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,
15. 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,
16. London WB, Frantz CN, Campbell LA, et al.: Phase II randomized comparison of topotecan plus
cyclophosphamide versus topotecan alone in children with recurrent or refractory neuroblastoma: a
Children's Oncology Group study. J Clin Oncol 28 (24): 3808-15, 2010. [PUBMED Abstract]
17. 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,
18. Polishchuk AL, Dubois SG, Haas-Kogan D, et al.: Response, survival, and toxicity after iodine-131-
metaiodobenzylguanidine therapy for neuroblastoma in preadolescents, adolescents, and adults. Cancer 117
(18): 4286-93, 2011. [PUBMED Abstract]
Changes to this Summary (03/29/2012)

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 24
Revised text 25 to state that the 5-year overall survival 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.
Added Gustafson et al. as reference 29 26.
Stage Information 4
Added text 27 to state that imaging with iodine I 123 metaiodobenzylguanidine(123I-MIBG) is optimal for
identifying soft tissue and bony metastases and is superior to 18F-FDG positron emission
tomography/computerized tomography in a prospective comparison (cited Brisse et al. and Papathanasiou et al. as
references 3 and 4, respectively).
Treatment Option Overview 28
Added text 29 about a German prospective clinical trial that enrolled 340 infants aged 1 year or younger whose
tumors were stage 1, 2, or 3, histologically verified, and lacked MYCN amplification; the 3-year overall survival
(OS) rate was 99% and metastases-free survival rate was 94% for infants with unresected tumors and was not
different from infants treated with surgery or chemotherapy. The investigators suggested that a wait-and-see
strategy is appropriate for infants with localized neuroblastoma because regressions have been observed after the
first year of life.
Added text 30 about how moderate-dose chemotherapy has been shown to be effective in the prospective Infant
Neuroblastoma European Study, where about half of the infants with unresectable, nonmetastatic neuroblastoma
and no MYCN amplification underwent a safe surgical resection and avoided long-term adverse effects (cited
Rubie et al. as reference 6 and level of evidence 3iiA).
Added Papathanasiou et al. as reference 18 31.
Treatment of High-Risk Neuroblastoma 32
Added text 33 about the COG-ANBL09P1 clinical trial as a treatment option under clinical evaluation.
Recurrent Neuroblastoma 34
Added text 35 to state that age, International Neuroblastoma Staging System stage, MYCN status, and time from
diagnosis to first relapse are significant prognostic factors for postrelapse survival (cited London et al. as
reference 1).
Revised text 36 to state that data from three consecutive German high-risk neuroblastoma trials described 253
children relapsing after intensive chemotherapy with autologous stem cell transplantation (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. Among these patients, the 3-year OS rate was 43%, but the 5-year OS rate was less than
20%.This shows that intensive second-line therapy is feasible, although even with intensive therapy and second
autologous SCT, only a small minority of relapsed high-risk neuroblastoma patients may benefit (cited Kushner et
al. as reference 15).
Added text 37 to state that phase I or II clinical trials are appropriate and should be considered.
Added text 38 about the COG-ANBL1021 clinical trial as a treatment option under clinical evaluation.
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
39, which iseditorially 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:
be discussed at a meeting,
be cited with text, or
replace or update an existing article that is already cited.
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:
Christopher N. Frantz, MD (Alfred I. duPont Hospital for Children)

Michael P. LaQuaglia, MD (Memorial Sloan-Kettering Cancer Center)
Karen Jean Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
Nita Louise Seibel, MD (National Cancer Institute)
Stephen J. Shochat, MD (St. Jude Children's Research Hospital)
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's
Contact Form 40. 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 41 in developing its level-of-evidence designations.
Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be
identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly
updated. However, an author would be permitted to write a sentence such as NCIs PDQ cancer information
summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].
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>.
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ
summaries only. Permission to use images outside the context of PDQ information must be obtained from the
owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this
summary, along with many other cancer-related images, is available in Visuals Online 42, a collection of over 2,000
scientific images.
Disclaimer
Based on the strength of the available evidence, treatment options may be described as either standard or
under clinical evaluation. These classifications should not be used as a basis for insurance reimbursement
determinations. More information on insurance coverage is available on Cancer.gov on the Coping with Cancer:
Financial, Insurance, and Legal Information 43 page.
Contact Us
More information about contacting us or receiving help with the Cancer.gov Web site can be found on our Contact
Us for Help 44 page. Questions can also be submitted to Cancer.gov through the Web sites Contact Form 40.
Get More Information From NCI

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Glossary Terms
Level of evidence 1A
Randomized, controlled clinical trial with total mortality as an endpoint. See Levels of Evidence for Adult
and Pediatric Cancer Treatment Studies (PDQ) for more information.
Level of evidence 1iiA

Randomized, controlled, nonblinded clinical trial with total mortality as an endpoint. See Levels of
Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ) for more information.
Level of evidence 2A
Nonrandomized, controlled clinical trial with total mortality as an endpoint. See Levels of Evidence for
Adult and Pediatric Cancer Treatment Studies (PDQ) for more information.
Level of evidence 3iiA
Consecutive case series (not population-based) with total mortality as an endpoint. See Levels of
Level of evidence 3iiDi
Consecutive case series (not population-based) with event-free survival as an endpoint. See Levels of
Level of evidence 3iiiA
Nonconsecutive case series with total mortality as an endpoint. See Levels of Evidence for Adult and
Pediatric Cancer Treatment Studies (PDQ) for more information.
Table of Links
1 http://cancer.gov/cancerinfo/pdq/supportivecare
2 http://cancer.gov/clinicaltrials
3 http://www.cancer.gov/cancertopics/pdq/treatment/lateeffects/HealthProfessional
4 http://www.cancer.gov/cancertopics/pdq/treatment/neuroblastoma/HealthProfession
al/Page3#Section_14
5 http://www.cancer.gov/clinicaltrials/search/view?version=healthprofessional&
;cdrid=69271
al/Page2#Section_12
al/#Section_314
8 http://www.cancer.gov/cancertopics/pdq/screening/neuroblastoma/HealthProfession
al
9 http://seer.cancer.gov/csr/1975_2006
al/Page3#Section_17
;cdrid=65874
;cdrid=65804
al/Table1
;cdrid=68977
al/Page3#Section_140
;cdrid=78643
17 http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?Diagnosis=42067&tt=1&a
mp;format=2&cn=1
18 http://www.cancer.gov/clinicaltrials
;cdrid=69018
;cdrid=662673
;cdrid=682629
;cdrid=698589
23 http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?Diagnosis=43713&tt=1&a
mp;format=2&cn=1
al/#Section_1
al/#Section_320
al/#Section_312
al/Page4#Section_30
39 http://www.cancer.gov/cancertopics/pdq/pediatric-treatment-board
40 http://www.cancer.gov/contact
41 http://www.cancer.gov/cancertopics/pdq/levels-evidence-adult-treatment/HealthPr
ofessional
42 http://visualsonline.cancer.gov
43 http://www.cancer.gov/cancertopics/coping/financial-legal
44 http://www.cancer.gov/help
45 https://livehelp.cancer.gov
46 http://cancer.gov
47 https://cissecure.nci.nih.gov/ncipubs

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National Cancer Institute

at the National Institutes of Health

Neuroblastoma Treatment (PDQ)

Treatment Option Overview

Treatment of Low-Risk Neuroblastoma

Treatment of Intermediate-Risk Neuroblastoma

Treatment of High-Risk Neuroblastoma

Changes to this Summary (03/29/2012)

About This PDQ Summary

Get More Information From NCI

Unique Aspects of Neuroblastoma

Biologically discrete types of neuroblastoma

Spontaneous regression of neuroblastoma

12. Citak C, Karadeniz C, Dalgic B, et al.: Intestinal lymphangiectasia as a first manifestation of

15. Rudnick E, Khakoo Y, Antunes NL, et al.: Opsoclonus-myoclonus-ataxia syndrome in neuroblastoma:

19. Cooper R, Khakoo Y, Matthay KK, et al.: Opsoclonus-myoclonus-ataxia syndrome in neuroblastoma:

60. Schleiermacher G, Janoueix-Lerosey I, Ribeiro A, et al.: Accumulation of segmental alterations determines

2. Shimada H, Umehara S, Monobe Y, et al.: International neuroblastoma pathology classification for

3. Goto S, Umehara S, Gerbing RB, et al.: Histopathology (International Neuroblastoma Pathology

International Neuroblastoma Staging System

Childrens Oncology Group Neuroblastoma Risk Grouping

1 021 y Any Any Any Low

2A/2Bc <365 d Any Any Any Low

365 d21 y Nonamplified Any - Low

365 d21 y Amplified Favorable - Low

365 d21 y Amplified Unfavorable - High

3d <365 d Nonamplified Any Any Intermediate

<365 d Amplified Any Any High

365 d21 y Nonamplified Favorable - Intermediate

365 d21 y Nonamplified Unfavorable - High

365 d21 y Amplified Any - High

4d <548 d [14-16] Nonamplified Any Any Intermediate

<365 d Amplified Any Any High

548 d21 y Any Any - High

4Se <365 d Nonamplified Favorable >1 Low

<365 d Nonamplified Any =1 Intermediate

<365 d Nonamplified Unfavorable Any Intermediate

<365 d Amplified Any Any High

Observation without surgery for localized, suspected adrenal neuroblastoma in infants

Description of International Neuroblastoma Response Criteria

Surveillance for Recurrence of High-Risk Neuroblastoma

Treatment of Low-Risk Neuroblastoma

Standard Treatment Options

Current Clinical Trials

Treatment of Intermediate-Risk Neuroblastoma

Standard Treatment Options

Current Clinical Trials

Treatment of High-Risk Neuroblastoma

Standard Treatment Options

Treatment Options Under Clinical Evaluation

COG-ANBL09P1 21 (Induction Therapy Including 131I-MIBG and Chemotherapy in Treating Patients

COG-ANBL0032 19 (Isotretinoin With or Without Monoclonal Antibody, Interleukin-2, and Sargramostim

Current Clinical Trials

Recurrent Neuroblastoma in Patients Initially Classified as Low Risk

Local regional recurrent cancer is resected if possible:

Recurrent Neuroblastoma in Patients Initially Classified as Intermediate Risk

Recurrent or Refractory Neuroblastoma in Patients Initially Classified as High Risk

Additionally, phase I or II clinical trials are appropriate and should be considered.

Treatment options under clinical evaluation

COG-ANBL1021 22 (Biological Therapy, Sargramostim [GM-CSF], and Isotretinoin in Treating Patients

Current Clinical Trials

Changes to this Summary (03/29/2012)

Added Gustafson et al. as reference 29 26.