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Neuroblastoma is a cancer that arises in immature nerve cells and affects mostly infants and children. Learn about neuroblastoma and find information on how we support and care for people with neuroblastoma before, during, and after treatment.
The Center for Neuro-Oncology offers state-of the-art treatments for patients with brain tumors, spinal cord tumors, and neurologic complications from cancer.
We specialize in services for patients with benign or malignant tumors, including:
Our clinicians are experts in precise neurosurgical techniques, radiation therapy that targets tumors while sparing surrounding tissues, and a variety of chemotherapy and molecular drugs targeting your type of cancer.
Our approach to compassionate care centers on the needs of our patients and their families. Our specialists work as a team to ensure that you receive carefully coordinated treatment and support. We focus on helping you cope with your illness and maintain the quality of your life.
Our research program is a leader in clinical trials for brain tumors. Our goal is to bring laboratory discoveries directly to patients, allowing us to offer new treatment options. We offer our patients access to a range of clinical trials for various types and stages of brain and spinal cord cancers.
We believe that you and your family are key members of the care team. While we understand your illness, you understand your own body. We welcome your questions and value your participation as we make decisions together.
Learn more about how we diagnose and treat brain tumors
If you have never been seen before at Dana-Farber/Brigham and Women's Cancer Center, please call 877-442-3324 or use this online form to request an appointment.
For all other inquiries, please call 617-632-2166
Referring physicians: 617-632-3703
Neuroblastoma often begins in the nervetissue of the adrenal glands. There are two adrenal glands, one on top of each kidney in the back of the upper abdomen. The adrenal glands make important hormones that help control heart rate, blood pressure, blood sugar, and the way the body reacts to stress. Neuroblastoma may also begin in the abdomen, in the chest, in nerve tissue near the spine in the neck, or in the spinal cord.
Neuroblastoma most often begins during early childhood, usually in children younger than 5 years of age. It is found when the tumor begins to grow and cause signs or symptoms. Sometimes it forms before birth and is found during a fetalultrasound.
By the time neuroblastoma is diagnosed, the cancer has usually metastasized (spread). Neuroblastoma spreads most often to the lymph nodes, bones, bone marrow, liver, and in infants, skin.
See the PDQ summary on Neuroblastoma Screening for more information.
Neuroblastoma is sometimes inherited (passed from the parent to the child). Neuroblastoma that is inherited usually occurs at a younger age than neuroblastoma that is not inherited. In inherited neuroblastoma, more than one tumor may form in the adrenal medulla.
The most common signs and symptoms of neuroblastoma are caused by the tumor pressing on nearby tissues as it grows or by cancer spreading to the bone. These and other signs and symptoms may be caused by neuroblastoma or by other conditions.
Check with your child’s doctor if your child has any of the following:
Less common signs and symptoms of neuroblastoma include the following:
The following tests and procedures may be used:
Cells and tissues are removed during a biopsy so they can be viewed under a microscope by a pathologist to check for signs of cancer. The way the biopsy is done depends on where the tumor is in the body. Sometimes the whole tumor is removed at the same time the biopsy is done.
The following tests may be done on the tissue that is removed:
Children who are 6 months old or younger may not need a biopsy or surgery to remove the tumor because the tumor may disappear without treatment.
The prognosis (chance of recovery) and treatment options depend on the following:
Prognosis and treatment options for neuroblastoma are also affected by tumor biology, which includes:
The tumor biology is said to be favorable or unfavorable, depending on these factors. A favorable tumor biology means there is a better chance of recovery.
In some children who are 6 months old and younger, neuroblastoma may disappear without treatment. The child is closely watched for signs or symptoms of neuroblastoma. If signs or symptoms occur, treatment may be needed.
The process used to find out the extent or spread of cancer is called staging. The information gathered from the staging process helps determine the stage of the disease. For neuroblastoma, stage is one of the factors used to plan treatment. The results of tests and procedures used to diagnose neuroblastoma may also be used for staging. See the General Information section for a description of these tests and procedures.
The following tests and procedures also may be used to determine the stage:
Cancer can spread through tissue, the lymph system, and the blood:
When cancer spreads to another part of the body, it is called metastasis. Cancer cells break away from where they began (the primary tumor) and travel through the lymph system or blood.
The metastatic tumor is the same type of cancer as the primary tumor. For example, if neuroblastoma spreads to the liver, the cancer cells in the liver are actually neuroblastoma cells. The disease is metastatic neuroblastoma, not liver cancer.
In stage 1, the tumor is in only one area and all of the tumor that can be seen is completely removed during surgery.
Stage 2 is divided into stages 2A and 2B.
In stage 3, one of the following is true:
Stage 4 is divided into stages 4 and 4S.
For many types of cancer, stages are used to plan treatment. For neuroblastoma, treatment depends on risk groups. The stage of neuroblastoma is one factor used to determine risk group. Other factors are the age of the child, tumor histology, and tumor biology.
There are three risk groups: low risk, intermediate risk, and high risk.
Recurrentneuroblastoma is cancer that has recurred (come back) after it has been treated. The cancer may come back in the same place or in other parts of the body.
Different types of treatment are available for patients with neuroblastoma. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment.
Because cancer in children is rare, taking part in a clinical trial should be considered. Some clinical trials are open only to patients who have not started treatment.
Treatment will be overseen by a pediatric oncologist, a doctor who specializes in treating children with cancer. The pediatric oncologist works with other pediatrichealth care providers who are experts in treating children with neuroblastoma and who specialize in certain areas of medicine. These may include the following specialists:
Some cancer treatments cause side effects that continue or appear years after cancer treatment has ended. These are called late effects. Late effects of cancer treatment may include:
Some late effects may be treated or controlled. It is important that parents of children who are treated for neuroblastoma talk with their doctors about the possible late effects caused by some treatments. See the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.
Observation is closely monitoring a patient's condition without giving any treatment until signs or symptoms appear or change.
Surgery is used to treat neuroblastoma unless it has spread to other parts of the body. Depending on where the tumor is, as much of the tumor as is safely possible will be removed. If the tumor cannot be removed, a biopsy may be done instead.
Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer.
The way the radiation therapy is given depends on the type and stage of the cancer being treated. External radiation therapy is used to treat neuroblastoma.
High-risk neuroblastoma that comes back after initial treatment is sometimes treated with mIBG (radioactive iodinetherapy). Radioactive iodine is given through an intravenous (IV) line and enters the bloodstream which carries radiation directly to tumor cells. Radioactive iodine collects in neuroblastoma cells and kills them with the radiation that is given off.
Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated.
The use of two or more anticancer drugs is called combination chemotherapy.
See Drugs Approved for Neuroblastoma for more information.
High-dose chemotherapy and radiation therapy with stem cell rescue is a way of giving high doses of chemotherapy and radiation therapy and replacing blood-forming cells destroyed by cancer treatment for high-risk neuroblastoma. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient and are frozen and stored. After chemotherapy and radiation therapy are completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body's blood cells.
Maintenance therapy is given after high-dose chemotherapy and radiation therapy with stem cell rescue to kill any cancer cells that may regrow and cause the disease to come back. Maintenance therapy is given for 6 months and includes the following treatments:
This summary section describes treatments that are being studied in clinical trials. It may not mention every new treatment being studied. Information about clinical trials is available from the NCI Web site.
Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells. Tyrosine kinase inhibitor (TKI) therapy is one type of targeted therapy being studied in the treatment of neuroblastoma.
TKI therapy blocks signals needed for tumors to grow. TKIs block the enzyme, tyrosine kinase, that causes stem cells to become more white blood cells (granulocytes or blasts) than the body needs. Crizotinib is one of the TKIs being studied to treat neuroblastoma that has come back after treatment. TKIs may be used in combination with other anticancer drugs as adjuvant therapy (treatment given after the initial treatment, to lower the risk that the cancer will come back).
Vaccine therapy is a type of biologic therapy. Biologic therapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer. This type of cancer treatment is also called biotherapy or immunotherapy.
Lenalidomide is a type of angiogenesis inhibitor. It prevents the growth of new blood vessels that are needed by a tumor to grow.
For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.
Many of today's standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.
Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.
Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.
Clinical trials are taking place in many parts of the country. See the Treatment Options section that follows for links to current treatment clinical trials. These have been retrieved from NCI's listing of clinical trials.
Some of the tests that were done to diagnose the cancer or to find out the stage of the cancer may be repeated. Some tests will be repeated in order to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests. This is sometimes called re-staging.
Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your child's condition has changed or if the cancer has recurred (come back). These tests are sometimes called follow-up tests or check-ups.
Treatment of low-risk neuroblastoma may include the following:
Treatment of intermediate-risk neuroblastoma may include the following:
Treatment of high-risk neuroblastoma may include the following:
There is no standard treatment for stage 4S neuroblastoma but treatment options include the following:
Patients First Treated for Low-Risk Neuroblastoma
Treatment for recurrentneuroblastoma that is found in one place in the body may include the following:
Treatment for recurrent neuroblastoma that has spread to other parts of the body may include the following:
Patients First Treated for Intermediate-Risk Neuroblastoma
Recurrent neuroblastoma that has spread to other parts of the body is treated the same way as newly diagnosed high-risk neuroblastoma.
Patients First Treated for High-Risk Neuroblastoma
Treatment for recurrentneuroblastoma may include the following:
Because there is no standard treatment for recurrent neuroblastoma in patients first treated for high-risk neuroblastoma, patients may want to consider a clinical trial. For information about clinical trials, please see the NCI Web site.
Patients with Recurrent CNS Neuroblastoma
Treatment for neuroblastoma that recurs (comes back) in the central nervous system (CNS; brain and spinal cord) may include the following:
Treatments in Clinical Trials for Progressive/Recurrent Neuroblastoma
Some of the treatments being studied in clinical trials for neuroblastoma that recurs (comes back) or progresses (grows, spreads, or does not respond to treatment) include the following:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with neuroblastoma. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your child's doctor about clinical trials that may be right for your child. General information about clinical trials is available from the NCI Web site.
For more information from the National Cancer Institute about neuroblastoma, see the following:
For more childhood cancer information and other general cancer resources, see the following:
This information is provided by the National Cancer Institute.
This information was last updated on August 28, 2014.
Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. Children and adolescents with
cancer are usually referred to medical centers that have a multidisciplinary team
of cancer specialists with experience treating the cancers that occur during
childhood and adolescence. This multidisciplinary team approach incorporates the skills
of the following health care professionals
and others to ensure that children receive treatment, supportive care, and rehabilitation
that will enable them to achieve optimal survival and quality of life:
(Refer to the PDQ summaries on Supportive and Palliative Care for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of
pediatric patients with cancer have been outlined by the American Academy of
Pediatrics. At these pediatric cancer centers, clinical trials are
available for most types of cancer that occur in children and
adolescents, and the opportunity to participate in these trials is offered to
most patients and families. Clinical trials for children and adolescents with
cancer are generally designed to compare potentially better therapy with
therapy that is currently accepted as standard. Most of the progress
made in identifying curative therapies for childhood cancers has been achieved
through clinical trials. Information about ongoing clinical trials is
available from the NCI Web site.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. Childhood and adolescent cancer survivors require close follow-up since cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Neuroblastoma is the most common extracranial solid tumor in childhood. More than 650 cases are diagnosed each year in North America. The prevalence is about 1 case per 7,000 live births; the incidence is about 10.54 cases per 1 million per year in children younger than 15 years. About 37% are diagnosed as infants, and 90% are younger than 5 years at diagnosis, with a median age at diagnosis of 19 months.
While there is no racial variation in incidence, there are racial differences in tumor
biology, with African Americans more likely to have high-risk disease and fatal outcome.
Population-based studies of screening for infants with neuroblastoma have demonstrated that spontaneous regression of neuroblastoma without clinical detection in the first year of life is at least as prevalent as clinically detected neuroblastoma.
Neuroblastoma originates in the adrenal medulla or the paraspinal sites where
sympathetic nervous system tissue is present.
Little is known about the events that predispose to the development of neuroblastoma. Parental exposures have not been definitively linked to neuroblastoma.
Germline deletion at the 1p36 or 11q14-23 locus is associated with neuroblastoma, and the same deletions are found somatically in sporadic neuroblastomas.
About 1% to 2% of patients with neuroblastoma have a family history of neuroblastoma. These children are on average younger (9 months at diagnosis), and about 20% have multifocal primary neuroblastomas. The primary cause of familial neuroblastoma is a germline mutation in the ALK gene. Familial neuroblastoma is rarely associated with congenital central hypoventilation syndrome (Ondine’s curse), which is caused by a germline mutation of the PHOX2B gene.
On the basis of biologic factors and an improved understanding of the molecular development of the neural crest cells that give rise to neuroblastoma, neuroblastic tumors have been categorized into the following three biological types:
These specific genetic changes may be combined with traditional clinical factors such as patient age and tumor stage to refine neuroblastoma risk classes.
Children whose tumors have lost a copy of 11q are older at diagnosis, and their tumors contain more segmental chromosome changes in gene copy number compared with children whose tumors show MYCN amplification. 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.
Approximately 6% to 10% of sporadic neuroblastomas carry somatic ALK-activating mutations, and an additional 3% to 4% have a high frequency of ALK gene amplification. The mutations result in constitutive phosphorylation of ALK, leading to dysregulation of cell signaling and uncontrolled proliferation of the ALK-mutant neuroblasts. Thus, inhibition of ALK kinase is a potential target for treatment of neuroblastoma, especially in children whose tumors harbor an ALK mutation or ALK gene amplification.
Genome-wide association studies in children with neuroblastoma have found common single-nucleotide polymorphisms (SNPs) associated with a modest susceptibility to develop high-risk neuroblastoma. Other SNPs are associated with susceptibility to develop low-risk neuroblastoma. SNPs associated with race predict a higher incidence of neuroblastoma and worse outcome.
Large genomic studies have found few recurrent gene mutations in patients with neuroblastoma, including ALK (9.2%), PTPN11 (2.9%), ATRX (2.5%; 7.1% focal deletions), MYCN (1.7%), and NRAS (0.8%).ATRX is involved in epigenetic gene silencing and telomere length. ATRX mutation without MYCN amplification is associated with older age at diagnosis in adolescents and young adults with metastatic neuroblastoma. It is unclear whether an ATRX mutation is an independent prognostic risk factor.
Current data do not support neuroblastoma screening. Screening at the ages of 3 weeks, 6 months, or 1 year caused no reduction in the incidence of advanced-stage neuroblastoma with
unfavorable biological characteristics in older children, nor did it reduce the number of deaths from neuroblastoma in infants screened at any age. No public health benefits have been shown from screening infants for neuroblastoma at these ages. (Refer to the PDQ summary on Neuroblastoma Screening for more information.)
Evidence (against neuroblastoma screening):
The most common presentation of neuroblastoma is an abdominal mass.
The most frequent signs and symptoms of neuroblastoma are due to tumor mass and metastases. They include the following:
The clinical characteristics of neuroblastoma in adolescents are similar to those observed in children. The only exception is that bone marrow involvement occurs less frequently in adolescents, and there is a greater frequency of metastases in unusual sites such as lung or brain.
findings, including cerebellar ataxia or opsoclonus/myoclonus, are rare in children with neuroblastoma.
Opsoclonus/myoclonus syndrome is frequently
associated with pervasive and permanent neurologic and cognitive deficits,
including psychomotor retardation. Neurologic dysfunction is most often a presenting symptom but may
arise long after removal of the tumor.
present with opsoclonus/myoclonus syndrome often have neuroblastomas with favorable biological
features and are likely to survive, though tumor-related deaths have been
opsoclonus/myoclonus syndrome appears to be caused by an immunologic mechanism
that is not yet fully defined. The primary
tumor is typically diffusely infiltrated with lymphocytes.
Some patients may clinically respond
to removal of the neuroblastoma, but improvement may be slow and partial;
symptomatic treatment is often necessary. Adrenocorticotropic hormone or corticosteroid treatment is thought to be effective, but some patients do not respond to
corticosteroids. Various drugs, plasmapheresis, intravenous gamma globulin, and rituximab have
been reported to be effective in selected cases. The long-term neurologic outcome may be superior in patients treated with
chemotherapy, possibly because of its immunosuppressive effects.
Diagnostic evaluation of neuroblastoma includes the following:
Serum catecholamines are not routinely used in the diagnosis of neuroblastoma except in unusual circumstances.
In rare cases,
neuroblastoma can be discovered prenatally by fetal ultrasonography. Management recommendations are evolving with regard to the need for immediate diagnostic biopsy in infants aged 6 months and younger with suspected neuroblastoma tumors that are likely to spontaneously regress. Biopsy was not required for infants entered into a COG study of expectant observation of small adrenal masses in neonates, and 81% avoided undergoing any surgery at all. In a German clinical trial, 25 infants aged 3 months and younger with presumed neuroblastoma were observed without biopsy for periods of 1 to 18 months before biopsy or resection. There were no apparent ill effects of the delay.
The diagnosis of neuroblastoma requires the involvement of pathologists who are
familiar with childhood tumors. Some neuroblastomas cannot be differentiated morphologically,
via conventional light microscopy with hematoxylin and eosin staining alone, from other small round blue cell tumors of childhood, such as lymphomas,
primitive neuroectodermal tumors, and rhabdomyosarcomas. In such cases, immunohistochemical and cytogenetic analysis may be needed to diagnose a specific small round blue cell tumor.
The minimum criterion for a diagnosis of neuroblastoma, as established by international agreement, is that diagnosis must be based on one of the following:
Between 1975 and 2002, the 5-year survival rate for neuroblastoma in the United States has remained stable at approximately 87% for children younger than 1 year and has increased from 37% to 65% in children aged 1 to 14 years. The 5-year overall survival (OS) for all infants and children with neuroblastoma has increased from 46% when diagnosed between 1974 and 1989, to 71% when diagnosed between 1999 and 2005; however, this single number can be misleading because of the extremely heterogeneous prognosis based on the neuroblastoma patient's age, stage, and biology. (Refer to the Cellular Classification of Neuroblastic Tumors section of this summary for more information.) Approximately 70% of patients with neuroblastoma have metastatic disease at diagnosis.
The prognosis for patients with neuroblastoma is related to the following:
Some of these prognostic factors have been combined to create risk groups to help define treatment. (Refer to the International Neuroblastoma Risk Group Staging System section and the Children’s Oncology Group Neuroblastoma Risk Grouping section of this summary for more information.)
The effect of age at diagnosis on 5-year survival is profound. According to the 1975 to 2006 U.S. Surveillance, Epidemiology, and End Results (SEER) statistics, the 5-year survival stratified by age is as follows:
Children of any age with localized neuroblastoma and infants aged 18 months and younger with advanced disease and favorable disease characteristics have a
high likelihood of long-term, disease-free survival. The prognosis of fetal and neonatal neuroblastoma are similar to that of older infants with neuroblastoma and similar biological features. Older children
with advanced-stage disease, however, have a significantly decreased chance for
cure, despite intensive therapy.
Survival of patients with International Neuroblastoma Staging System (INSS) stage 4 disease is strongly dependent on age. Children younger than 18 months at diagnosis have a good chance of long-term survival (i.e., a 5-year disease-free survival rate of 50%–80%), with outcome particularly dependent on MYCN amplification and tumor cell ploidy. Hyperdiploidy confers a favorable prognosis while diploidy predicts early treatment failure. Infants aged 18 months and younger at diagnosis with INSS stage 4 neuroblastoma who do not have MYCN gene amplification are categorized as intermediate risk and have a 3-year event-free survival (EFS) of 81% and OS of 93%.
Neuroblastoma has a worse long-term prognosis in an adolescent older than 12 years or in an adult compared with a child, regardless of stage or site
and, in many cases, a more prolonged course when treated with standard doses of chemotherapy. Aggressive chemotherapy and surgery have been shown to achieve a minimal disease state in more than 50% of these patients. Other modalities, such as local radiation therapy and the use of agents with confirmed activity, may improve the poor prognosis for adolescents and adults.
Site of primary tumor is not an independent prognostic factor. Multifocal (multiple primaries) neuroblastoma
occurs rarely, usually in infants, and generally has a good prognosis. Familial neuroblastoma and germline ALK gene mutation should be considered in patients with multiple primary neuroblastomas.
Neuroblastoma tumor histology has a significant impact on prognosis and risk group assignment (refer to the Cellular Classification of Neuroblastic Tumors section and Table 4 of this summary for more information).
Histologic characteristics considered prognostically favorable include the following:
Histologic characteristics considered prognostically unfavorable include the following:
A COG study of children with stage 1 and stage 2 neuroblastoma without MYCN amplification and with favorable histologic features reported a 5-year EFS of 90% to 94% and OS of 99% to 100%, while those with unfavorable histology had an EFS of 80% to 86% and an OS of 89% to 93%. Similar results were found in a European study.
According to the INSS, the presence of cancer in the regional lymph nodes on the same side of the body as the primary tumor has no effect on prognosis. However, when lymph nodes with metastatic neuroblastoma cross the midline and are on the opposite sides of the body from the primary tumor, the patient is upstaged (refer to the Stage Information for Neuroblastoma section of this summary for more information) and a poorer prognosis is conferred.
Response to treatment has been associated with outcome. In patients with high-risk disease, the persistence of neuroblastoma cells in bone marrow after induction chemotherapy, for example, is associated with a poor prognosis, which may be assessed by sensitive minimal residual disease techniques. The degree of tumor volume reduction predicts response in high-risk patients, as does a decrease in mitosis and an increase in histologic differentiation. Similarly, the persistence of mIBG-avid tumor after completion of induction therapy predicts a poor prognosis.
A number of biologic variables have been studied in children with this tumor:
The degree of expression of the MYCN gene in the tumor does not predict prognosis. 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.
Other biological prognostic factors that have been extensively investigated include tumor cell telomere length, telomerase activity, and telomerase ribonucleic acid; urinary VMA, HVA, and their ratio;MRP1; GABAergic receptor profile; dopamine; CD44 expression; TrkA gene expression; and serum neuron-specific enolase level, serum lactic dehydrogenase level, and serum ferritin level. These factors are currently not in use for stratification on clinical trials.
The phenomenon of spontaneous regression has been well described in infants with neuroblastoma, especially in infants with the 4S pattern of metastatic spread. (Refer to the Stage Information for Neuroblastoma section of this summary for more information.)
Spontaneous regression generally occurs only in tumors with the following features:
Additional features associated with spontaneous regression include the lack of telomerase expression, the expression of Ha-ras, and the expression of the neurotrophin receptor TrkA, a nerve growth factor receptor.
Studies have suggested that selected infants who appear to have asymptomatic, small, low-stage adrenal neuroblastoma detected by screening or during prenatal or incidental ultrasound examination, often have tumors that spontaneously regress and may be observed safely without surgical intervention or tissue diagnosis.
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Neuroblastomas are classified as one of the small, round, blue cell tumors of childhood. They are a heterogenous group of tumors composed of cellular aggregates with different degrees of differentiation, from mature ganglioneuromas to less mature ganglioneuroblastomas to immature neuroblastomas, reflecting the varying malignant potential of these tumors.
There are two cellular classification systems for neuroblastoma.
Favorable and unfavorable prognoses are defined on the basis of
these histologic parameters and patient age. The prognostic significance of
this classification system, and of related systems using similar criteria, has
been confirmed in several studies.
In the future, the INPC system is likely to be replaced by a system that does not include patient age as a part of cellular classification.
International Neuroblastoma Pathology classification
Original Shimada classification
Poorly differentiated or differentiating
& low or intermediate MKI tumor
Differentiating & low MKI tumor
a) undifferentiated tumorc
b) high MKI tumor
a) undifferentiated or poorly
b) intermediate or high MKI tumor
Well differentiated (favorable)
(composite Schwannian stroma-rich/stroma-dominate and stroma-poor)
Stroma-rich nodular (unfavorable)
MKI: mitosis-karyorrhexis index.
aReprinted with permission. Copyright © 1999 American Cancer Society. All rights reserved. Hiroyuki Shimada, Inge M. Ambros,
Louis P. Dehner,
Jun-ichi Hata, Vijay V. Joshi,
Borghild Roald, Daniel O. Stram, Robert B. Gerbing,
John N. Lukens,
Katherine K. Matthay,
Robert P. Castleberry, The International Neuroblastoma Pathology
Classification (the Shimada System), Cancer, volume 86, issue 2, pages 364–72.
bSubtypes of neuroblastoma were described in detail elsewhere.
cRare subtype, especially diagnosed in this age group. Further investigation and analysis required.
dPrognostic grouping for these tumor categories is not related to patient age.
Most neuroblastomas with MYCN amplification in the INPC system also have unfavorable histology, but about 7% have favorable histology. Of those with MYCN amplification and favorable histology, most do not express MYCN, despite the gene being amplified, and have a more favorable prognosis than those who do express MYCN.
Because patient age is used in all risk stratification systems, a cellular classification system that did not employ patient age was desirable, and underlying histologic criteria, rather than INPC or Shimada Classification, was used in the final decision tree. Histologic findings discriminated prognostic groups most clearly in two subsets of patients, as shown in Table 2.
INSS Stage/Histologic Subtype
Number of Cases
INSS stage 1, 2, 3, 4S
83 ± 1
91 ± 1
97 ± 2
98 ± 2
83 ± 1
90 ± 1
INSS stage 2, 3; age >547 d
69 ± 3
81 ± 2
11q normal and differentiating
80 ± 16
11q aberration or undifferentiated
61 ± 11
73 ± 11
EFS = event-free survival; GN = ganglioneuroma; GNB = ganglioneuroblastoma; INSS = International Neuroblastoma Staging System; NB = neuroblastoma; OS = overall survival.
aAdapted from Cohn et al.
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A thorough evaluation for metastatic disease is performed before
therapy initiation. The following studies are typically performed:
The extent of metastatic disease is assessed by mIBG scan, which is applicable to all sites of disease (including soft tissue, bone marrow, and cortical bone involvement). Cortical bone metastases are also evaluated by technetium-99 scan. If all sites of bone metastases are imaged by mIBG scan, then subsequent restaging for assessment of disease response may omit the technetium-99 bone scan. Approximately 90% of neuroblastomas will be mIBG avid. It has a sensitivity and specificity of 90% to 99% and is equally distributed between primary and metastatic sites. Although iodine 123 (123I) has a shorter half-life, it is preferred over131I because of its lower radiation dose, better quality images, less thyroid toxicity, and lower cost.
Imaging with 123I-mIBG is optimal for identifying soft tissue and bony metastases and was shown to be superior to 18F-fluorodeoxyglucose positron emission tomography–computerized tomography (PET-CT) in one prospective comparison. Baseline mIBG scans performed at diagnosis provide an excellent method for monitoring disease response and performing posttherapy surveillance.
A retrospective analysis of paired mIBG and PET scans in 60 newly diagnosed neuroblastoma patients demonstrated that for International Neuroblastoma Staging System (INSS) stages 1 and 2 patients, PET was superior at determining the extent of primary disease and more sensitive for detection of residual masses. In contrast, for stage 4 disease, 123I-mIBG imaging was superior for the detection of bone marrow and bony metastases.
Multiple groups have investigated a semi-quantitative scoring method to evaluate disease extent and prognostic value. The most common scoring methods in use for evaluation of disease extent and response are the Curie and the International Society of Paediatric Oncology European Neuroblastoma Group (SIOPEN) methods.
Other tests and procedures used to stage neuroblastoma include the following:
The INSS combines certain features from each of the previously used Evans and Pediatric Oncology Group (POG) staging systems  and is described in Table 3. This represented the first step in harmonizing disease staging and risk stratification worldwide. The INSS is a postoperative staging system that was developed in 1988 and used the extent of surgical resection to stage patients. This led to some variability in stage assignments in different countries because of regional differences in surgical strategy and, potentially, because of limitations in access to experienced pediatric surgeons. As a result of further advances in the understanding of neuroblastoma biology and genetics, a risk classification system was developed that incorporates clinical and biological factors in addition to INSS stage to facilitate risk group and treatment assignment for COG studies.
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).
Localized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph nodes negative for tumor microscopically.
Localized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumor. Enlarged contralateral lymph nodes must be negative microscopically
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.
Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs, except as defined for stage 4S.
Localized primary tumor, as defined for stage 1, 2A, or 2B, with dissemination limited to skin, liver, and/or bone marrow (by definition limited to infants younger than 12 months). Marrow involvement should be minimal (i.e., <10% of total nucleated cells identified as malignant by bone biopsy or by bone marrow aspirate). More extensive bone marrow involvement would be considered stage 4 disease. The results of the mIBG scan, if performed, should be negative for disease in the bone marrow.
mIBG = metaiodobenzylguanidine.
Controversy exists regarding the INSS staging system and the treatment of certain small subsets of patients. Risk group assignment and recommended treatment are expected to evolve as additional outcome data are analyzed. For example, the risk group assignment for INSS stage 4 neuroblastoma in patients aged 12 to 18 months changed in 2005 for those whose tumors had single copy MYCN and all favorable biological features; these patients had been previously classified as high risk, but data from both POG and Children's Cancer Group studies suggested that this subgroup of patients could be successfully treated as intermediate risk.
The INRGSS is a preoperative staging system that was developed specifically for the INRG classification system. The extent of disease is determined by the presence or absence of image-defined risk factors (IDRFs) and/or metastatic tumor at the time of diagnosis, before any treatment or surgery. IDRFs are surgical risk factors, detected by imaging, which could potentially make total tumor excision risky or difficult at the time of diagnosis.
The INRGSS simplifies stages into L1, L2, M or MS (refer to Table 4 for more information). Localized tumors are classified as stage L1 or L2 disease on the basis of whether one or more of the 20 IDRFs are present. For example, in the case of spinal cord compression, an IDRF is present when more than one-third of the spinal canal in the axial plane is invaded, when the leptomeningeal spaces are not visible, or when the spinal cord magnetic resonance signal intensity is abnormal. By combining the INRGSS, preoperative imaging and biological factors, each patient has a risk stage defined that predicts outcome and dictates the appropriate treatment approach to be followed. The INRGSS has predictive value for lower stage patients, with stage L1 having a 5-year EFS of 90%, compared with 78% for L2.
Most international protocols have begun to incorporate collection and use of IDRF in risk stratification and assignment of therapy. It is anticipated that the use of standardized nomenclature will contribute substantially to more uniform staging and thereby facilitate comparisons of clinical trials conducted in different parts of the world.
Localized tumor not involving vital structures as defined by the list of image-defined risk factorsa and confined to one body compartment.
Locoregional tumor with presence of one or more image-defined risk factors.a
Distant metastatic disease (except MS).
Metastatic disease in children younger than 18 months with metastases confined to skin, liver, and/or bone marrow.
aAdapted from Monclair et al.
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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.
Sharp SE, Shulkin BL, Gelfand MJ, et al.: 123I-MIBG scintigraphy and 18F-FDG PET in neuroblastoma. J Nucl Med 50 (8): 1237-43, 2009.
Decarolis B, Schneider C, Hero B, et al.: Iodine-123 metaiodobenzylguanidine scintigraphy scoring allows prediction of outcome in patients with stage 4 neuroblastoma: results of the Cologne interscore comparison study. J Clin Oncol 31 (7): 944-51, 2013.
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Cecchetto G, Mosseri V, De Bernardi B, et al.: Surgical risk factors in primary surgery for localized neuroblastoma: the LNESG1 study of the European International Society of Pediatric Oncology Neuroblastoma Group. J Clin Oncol 23 (33): 8483-9, 2005.
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Because most children with neuroblastoma in North America are treated according to the Children’s Oncology Group (COG) risk-group assignment, the treatments described in this summary are based on the most recently published COG risk stratification system. Each child is assigned to a low-risk, intermediate-risk, or high-risk group (refer to Tables 6, 7, and 8 for more information) based on the following:
Other biological factors that influence treatment selection include unbalanced 11q loss of heterozygosity and loss of heterozygosity for chromosome 1p.
The treatment of neuroblastoma has evolved over the past 60 years. Generally, treatment is based on whether the tumor is low, intermediate, or high risk:
Stage (COG Risk-Group Assignment)
Surgery followed by observation.
Chemotherapy with or without surgery (for symptomatic disease or unresectable progressive disease after surgery).
Observation without biopsy (for perinatal neuroblastoma with small adrenal tumors).
Chemotherapy with or without surgery.
Surgery and observation (in infants).
Radiation therapy (only for emergent therapy).
A regimen of chemotherapy, surgery, SCT, radiation therapy, and anti-GD2 antibody ch14.18, with interleukin-2/GM-CSF and isotretinoin.
Stage 4S Neuroblastoma
Observation with supportive care (for asymptomatic patients with favorable tumor biology).
Chemotherapy (for symptomatic patients, very young infants, or those with unfavorable biology).
Locoregional recurrence in patients initially classified as low risk
Surgery followed by observation or chemotherapy.
Chemotherapy that may be followed by surgery.
Metastatic recurrence in patients initially classified as low risk
Observation (if metastatic disease is in a 4S pattern in an infant).
Locoregional recurrence in patients initially classified as intermediate risk
Surgery (complete resection).
Surgery (incomplete resection) followed by chemotherapy.
Metastatic recurrence in patients initially classified as intermediate risk
Recurrence in patients initially classified as high risk
131 I-mIBG alone, in combination with other therapy, or followed by stem cell rescue.
Second autologous SCT after retrieval chemotherapy.
Recurrence in the central nervous system
Surgery and radiation therapy.
Novel therapeutic approaches.
COG = Children's Oncology Group; GM-CSF = granulocyte-macrophage colony-stimulating factor; 131I-mIBG = iodine 131-metaiodobenzylguanidine; SCT = stem cell transplant.
The treatment section of this document is organized to correspond with the COG risk-based treatment plan that assigns all patients to a low-, intermediate-, or high-risk group. This risk-based schema is based on the following factors:
Table 6 (in the Treatment of Low-Risk Neuroblastoma section), Table 7 (in the Treatment of Intermediate-Risk Neuroblastoma section), and Table 8 (in the Treatment of High-Risk Neuroblastoma section) describe the risk group assignment criteria used to assign treatment in the COG-P9641, COG-A3961, and COG-A3973 studies, respectively.
Assessment of risk for low-stage MYCN-amplified neuroblastoma is controversial because it is so rare. A study of 87 INSS stage 1 and 2 patients pooled from several clinical trial groups demonstrated no effect of age, stage, or initial treatment on outcome. The event-free survival (EFS) rate was 53% and the OS rate was 72%. Survival was superior in patients whose tumors were hyperdiploid, rather than diploid (EFS, 82% ± 20% vs. 37% ± 21%; OS, 94% ± 11% vs. 54% ± 15%). The overall EFS and OS for infants with stage 4 and 4S disease and MYCN-amplification was only 30% at 2 to 5 years after treatment in a European study. The COG considers infants with stage 4 and stage 4S disease with MYCN amplification to be at high risk.
Before therapy can be stopped after the initially planned number of cycles, certain response criteria, depending on risk group and treatment assignment, must be met. These criteria are defined as follows:
In patients without metastatic disease, the standard of care is to perform an initial surgery to accomplish the following:
The COG reported that expectant observation in infants younger than 6 months with small adrenal masses resulted in an excellent EFS and OS while avoiding surgical intervention in a large majority of patients.
Whether there is any advantage to gross-total resection of the primary tumor mass after chemotherapy in stage 4 patients older than 18 months remains controversial.
In the completed COG treatment plan, radiation therapy for patients with low-risk or intermediate-risk neuroblastoma was reserved for symptomatic life-threatening or
organ-threatening tumor bulk that did not respond rapidly enough to chemotherapy. Common situations in which radiation therapy is used in these patients include the following:
Spinal cord compression is considered a medical emergency. Immediate treatment is given because neurologic recovery is more likely when symptoms are present for a relatively short period of time before diagnosis and treatment. Recovery also depends on the severity of neurologic defects (weakness vs. paralysis). Neurologic outcome appears to be similar whether cord compression is treated with chemotherapy, radiation therapy, or surgery, although radiation therapy is used less frequently than in the past.
The completed COG low-risk and intermediate-risk neuroblastoma clinical trials recommended immediate chemotherapy for cord compression in patients grouped as low risk or intermediate risk.
Children with severe spinal cord compression that does not promptly improve or those with worsening symptoms may benefit from neurosurgical intervention. Laminectomy may result in later kyphoscoliosis and may not eliminate the need for chemotherapy. It was thought that osteoplastic laminotomy, a procedure that does not remove bone, would result in less spinal deformity. Osteoplastic laminotomy may be associated with a lower incidence of progressive spinal deformity requiring fusion but there is no evidence that functional deficit is improved with laminoplasty. In a series of 34 infants with symptomatic epidural spinal cord compression, both surgery and chemotherapy provided unsatisfactory results once paraplegia had been established. The frequency of grade 3 motor deficits and bowel dysfunction increased with a longer symptom duration interval. Most infants with symptomatic epidural spinal cord compression developed sequelae and it was severe in about one-half of them. This supports the need for greater awareness and timely intervention in these infants.
Surveillance studies during and after treatment are able to detect asymptomatic and unsuspected relapse in a substantial portion of patients. In an overall surveillance plan, one of the most reliable tests to detect disease progression or recurrence is the 123I-metaiodobenzylguanidine scan.
Moroz V, Machin D, Faldum A, et al.: Changes over three decades in outcome and the prognostic influence of age-at-diagnosis in young patients with neuroblastoma: a report from the International Neuroblastoma Risk Group Project. Eur J Cancer 47 (4): 561-71, 2011.
Berthold F, Trechow R, Utsch S, et al.: Prognostic factors in metastatic neuroblastoma. A multivariate analysis of 182 cases. Am J Pediatr Hematol Oncol 14 (3): 207-15, 1992.
Attiyeh EF, London WB, Mossé YP, et al.: Chromosome 1p and 11q deletions and outcome in neuroblastoma. N Engl J Med 353 (21): 2243-53, 2005.
Spitz R, Hero B, Simon T, et al.: Loss in chromosome 11q identifies tumors with increased risk for metastatic relapses in localized and 4S neuroblastoma. Clin Cancer Res 12 (11 Pt 1): 3368-73, 2006.
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.
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.
Castel V, Tovar JA, Costa E, et al.: The role of surgery in stage IV neuroblastoma. J Pediatr Surg 37 (11): 1574-8, 2002.
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.
Simon T, Häberle B, Hero B, et al.: Role of surgery in the treatment of patients with stage 4 neuroblastoma age 18 months or older at diagnosis. J Clin Oncol 31 (6): 752-8, 2013.
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.
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.
Simon T, Niemann CA, Hero B, et al.: Short- and long-term outcome of patients with symptoms of spinal cord compression by neuroblastoma. Dev Med Child Neurol 54 (4): 347-52, 2012.
McGirt MJ, Chaichana KL, Atiba A, et al.: Incidence of spinal deformity after resection of intramedullary spinal cord tumors in children who underwent laminectomy compared with laminoplasty. J Neurosurg Pediatr 1 (1): 57-62, 2008.
De Bernardi B, Quaglietta L, Haupt R, et al.: Neuroblastoma with symptomatic epidural compression in the infant: the AIEOP experience. Pediatr Blood Cancer 61 (8): 1369-75, 2014.
Low-risk neuroblastoma represents nearly one-half of all newly diagnosed patients. The success of prior Children's Oncology Group (COG) clinical trials has contributed to the continued reduction in therapy for select patients with neuroblastoma.
The COG low-risk group assignment criteria are described in Table 6.
≥365 d–21 y
≥365 d–21 y
INPC = International Neuroblastoma Pathologic Classification; INSS = International Neuroblastoma Staging System.
aThe COG-P9641 (low risk) and COG-A3961 (intermediate risk) trials established the current standard of care for neuroblastoma patients in terms of risk group assignment and treatment strategies.
bDNA Ploidy: DNA Index (DI) > 1 is favorable, = 1 is unfavorable; hypodiploid tumors
(with DI < 1) will be treated as a tumor with
a DI > 1 (DI < 1 [hypodiploid] to be
considered favorable ploidy).
cINSS stage 2A/2B symptomatic patients with spinal cord compression, neurologic
deficits, or other symptoms are treated with
immediate chemotherapy for four cycles.
dINSS stage 4S infants with favorable biology and clinical symptoms are treated with immediate chemotherapy until asymptomatic (2–4
cycles). Clinical symptoms include the following: respiratory distress with or without
hepatomegaly or cord compression and neurologic deficit or inferior vena cava compression and
renal ischemia; or genitourinary obstruction; or gastrointestinal obstruction
and vomiting; or coagulopathy with significant clinical hemorrhage unresponsive to replacement therapy.
(Refer to the Treatment of Stage 4S Neuroblastoma section of this summary for more information about the treatment of stage 4S neuroblastoma.)
For patients with localized disease that appears to be resectable (either based on the absence of image-defined risk factors [L1] or on the surgeon's expertise), the tumor should be resected by an experienced surgeon. If the biology is confirmed to be favorable, residual disease is not considered a risk factor for relapse. Several studies have shown that patients with favorable biology and residual disease have excellent outcomes with event-free survival (EFS) in excess of 90% and overall survival (OS) of 99% to 100%.
Treatment options for low-risk neuroblastoma include the following:
Treatment for patients categorized as low risk (refer to Table 6) may be surgery alone, which is curative for most patients with low-risk neuroblastoma. Patients need not undergo complete resection of disease to be cured by surgery alone.
There is controversy about the need to attempt resection, whether at the time of diagnosis or later, in asymptomatic infants aged 12 months or younger with apparent stage 2B and 3 MYCN-nonamplified and favorable biology disease. In a German clinical trial, some of these patients were observed after biopsy or partial resection without chemotherapy or radiation, and many did not progress locally and never received additional resection.
Results from the COG-P9641 study showed that surgery alone, even without complete resection, can cure nearly all patients with stage 1 neuroblastoma, and the vast majority of patients with asymptomatic, favorable biology, INSS stage 2A and 2B disease. The use of chemotherapy may be restricted to specific situations (e.g., children with MYCN-amplified stage 1 and 2 neuroblastoma and children with MYCN-nonamplified stage 2B neuroblastoma who are older than 18 months or who have unfavorable histology or diploid disease). These children have a less favorable outcome than other low-risk patients.
Chemotherapy is also reserved for low-risk patients who are symptomatic, such as from spinal cord compression or, in stage 4S, respiratory compromise secondary to hepatic infiltration. The chemotherapy consists of carboplatin, cyclophosphamide,
doxorubicin, and etoposide. The cumulative chemotherapy dose of each agent is kept low to minimize permanent injury (COG-P9641).
Studies suggest that selected small adrenal masses, presumed to be neuroblastoma, detected in infants younger than 6 months by screening or incidental ultrasound may safely be observed without obtaining a definitive histologic diagnosis and without surgical intervention, thus avoiding potential complications of surgery in the newborn. Additional studies are necessary to confirm this finding before it can be considered standard treatment.
Evidence (observation without biopsy):
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with neuroblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
The Children's Oncology Group (COG) intermediate-risk group assignment criteria are described in Table 7.
<548 d 
aThe COG-P9641 (low risk) and COG-A3961 (intermediate risk) trials established the current standard of care for non–high-risk neuroblastoma patients in terms of risk group assignment and treatment strategies.
bDNA Ploidy: DNA Index (DI) > 1 is favorable, DI = 1 is unfavorable; hypodiploid tumors
(with DI < 1) will be treated as a tumor with
a DI > 1 (DI < 1 [hypodiploid] to be
considered favorable ploidy).
cINSS stage 3 or stage 4 patients with clinical symptoms as listed above receive
Treatment options for intermediate-risk neuroblastoma include the following:
Patients categorized as intermediate risk have been successfully treated with surgery
and four to eight cycles of chemotherapy (carboplatin, cyclophosphamide, doxorubicin, and etoposide; the cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen)
As a rule, patients whose tumors had unfavorable biology received eight cycles of chemotherapy, compared with four cycles for patients whose tumors had favorable biology.
The COG-A3961 phase III trial demonstrated that therapy could be significantly reduced for patients with intermediate-risk neuroblastoma while maintaining outstanding survival.
Whether initial chemotherapy is indicated for all intermediate-risk infants with localized neuroblastoma requires further study.
Evidence (chemotherapy with or without surgery):
In cases of abdominal neuroblastoma thought to involve the kidney, nephrectomy is not undertaken before a trial of chemotherapy has been given.
The need for chemotherapy in all asymptomatic infants with stage 3 or 4 disease is somewhat controversial, as some European studies have shown favorable outcomes with surgery and observation as described below.
Evidence (surgery and observation in infants):
Radiation therapy is reserved for patients with the following:
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.
Kohler JA, Rubie H, Castel V, et al.: Treatment of children over the age of one year with unresectable localised neuroblastoma without MYCN amplification: results of the SIOPEN study. Eur J Cancer 49 (17): 3671-9, 2013.
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.
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.
Minard V, Hartmann O, Peyroulet MC, et al.: Adverse outcome of infants with metastatic neuroblastoma, MYCN amplification and/or bone lesions: results of the French society of pediatric oncology. Br J Cancer 83 (8): 973-9, 2000.
The Children's Oncology Group (COG) high-risk group assignment criteria are described in Table 8.
≥365 d–21 y
≥548 d–21 y
aDNA Ploidy: DNA Index (DI) > 1 is favorable, DI = 1 is unfavorable; hypodiploid tumors
(with DI < 1) will be treated as a tumor with
a DI > 1 (DI < 1 [hypodiploid] to be
considered favorable ploidy).
bINSS stage 2A/2B symptomatic patients with spinal cord compression, neurologic
deficits, or other symptoms are treated with
immediate chemotherapy for four cycles.
Approximately 8% to 10% of infants with stage 4S disease will have MYCN-amplified tumors and are usually treated on high-risk protocols. The overall event-free survival (EFS) and overall survival (OS) for infants with stage 4 and 4S disease and MYCN-amplification were only 30% at 2 to 5 years posttreatment in a European study.
For children with high-risk neuroblastoma, long-term survival with current treatments is about 54%. Children with aggressively treated, high-risk neuroblastoma may develop late recurrences, some more than 5 years after completion of therapy.
Outcomes for patients with high-risk neuroblastoma remain poor despite recent improvements in survival in randomized trials.
A treatment option for high-risk neuroblastoma is the following:
Treatment for patients with high-risk disease is generally divided into the following three phases:
The backbone of the most commonly used induction therapy includes dose-intensive cycles of cisplatin and etoposide alternating with vincristine, cyclophosphamide, and doxorubicin. Topotecan was added to this regimen based on the anti-neuroblastoma activity seen in relapsed patients. Response to therapy at the end of induction chemotherapy correlates with EFS at the completion of high-risk therapy. After a response to chemotherapy, resection of the primary tumor is usually attempted.
The consolidation phase of high-risk regimens involves myeloablative chemotherapy and HSCT, which attempts to eradicate minimal residual disease using lethal doses of chemotherapy and autologous stem cells collected during induction chemotherapy to repopulate the bone marrow. Several large randomized controlled studies have shown an improvement in 3-year EFS for HSCT (31% to 47%) versus conventional chemotherapy (22% to 31%). Previously, total-body irradiation had been used in HSCT conditioning regimens. Most current protocols use either carboplatin/etoposide/melphalan or busulfan/melphalan as conditioning for HSCT. Two or more sequential cycles of myeloablative chemotherapy and stem cell rescue given in a tandem fashion has been shown to be feasible for patients with high-risk neuroblastoma.
A randomized clinical study (COG-ANBL0532) testing the efficacy of two cycles versus one cycle of myeloablative chemotherapy with stem cell rescue has been completed. (Refer to the Autologous Hematopoietic Cell Transplantation section in the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation.)
Tandem consolidation using 131I-mIBG, vincristine, and irinotecan with autologous SCT followed by busulfan/melphalan with autologous SCT has been studied in refractory patients.
Radiation to the primary tumor site (whether or not a complete excision was obtained) and persistently metaiodobenzylguanidine-positive bony metastatic sites is often
performed before, during, or after myeloablative therapy. The optimal dose of radiation therapy has not been determined. Radiation of metastatic disease sites is determined on an individual case basis or according to protocol guidelines for patients enrolled in studies.
Preliminary outcomes for proton radiation therapy of high-risk neuroblastoma primary tumors have been published.
Differentiation therapy is used to treat potential minimal residual disease following HSCT. After recovery from myeloablative chemotherapy and stem cell rescue, patients are treated with the differentiating agent oral isotretinoin for 6 months. Immunotherapy is given along with differentiated therapy in the post-HSCT differentiation therapy regimen. Antibodies developed to target GD2, present on the surface of neuroblastoma cells, are used. For high risk-patients in remission following HSCT, chimeric anti-GD2 antibody ch14.18 combined with GM-CSF and interleukin-2 are given in concert with isotretinoin and have been shown to improve EFS.
Evidence (all treatments):
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.
The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
Maris JM: Recent advances in neuroblastoma. N Engl J Med 362 (23): 2202-11, 2010.
Cotterill SJ, Pearson AD, Pritchard J, et al.: Late relapse and prognosis for neuroblastoma patients surviving 5 years or more: a report from the European Neuroblastoma Study Group "Survey". Med Pediatr Oncol 36 (1): 235-8, 2001.
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.
Kushner BH, LaQuaglia MP, Bonilla MA, et al.: Highly effective induction therapy for stage 4 neuroblastoma in children over 1 year of age. J Clin Oncol 12 (12): 2607-13, 1994.
Park JR, Scott JR, Stewart CF, et al.: Pilot induction regimen incorporating pharmacokinetically guided topotecan for treatment of newly diagnosed high-risk neuroblastoma: a Children's Oncology Group study. J Clin Oncol 29 (33): 4351-7, 2011.
Cheung NK, Heller G, Kushner BH, et al.: Stage IV neuroblastoma more than 1 year of age at diagnosis: major response to chemotherapy and survival durations correlated strongly with dose intensity. Prog Clin Biol Res 366: 567-73, 1991.
Matthay KK, Villablanca JG, Seeger RC, et al.: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group. N Engl J Med 341 (16): 1165-73, 1999.
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.
Pritchard J, Cotterill SJ, Germond SM, et al.: High dose melphalan in the treatment of advanced neuroblastoma: results of a randomised trial (ENSG-1) by the European Neuroblastoma Study Group. Pediatr Blood Cancer 44 (4): 348-57, 2005.
Granger M, Grupp SA, Kletzel M, et al.: Feasibility of a tandem autologous peripheral blood stem cell transplant regimen for high risk neuroblastoma in a cooperative group setting: a Pediatric Oncology Group study: a report from the Children's Oncology Group. Pediatr Blood Cancer 59 (5): 902-7, 2012.
Seif AE, Naranjo A, Baker DL, et al.: A pilot study of tandem high-dose chemotherapy with stem cell rescue as consolidation for high-risk neuroblastoma: Children's Oncology Group study ANBL00P1. Bone Marrow Transplant 48 (7): 947-52, 2013.
French S, DuBois SG, Horn B, et al.: 131I-MIBG followed by consolidation with busulfan, melphalan and autologous stem cell transplantation for refractory neuroblastoma. Pediatr Blood Cancer 60 (5): 879-84, 2013.
Hattangadi JA, Rombi B, Yock TI, et al.: Proton radiotherapy for high-risk pediatric neuroblastoma: early outcomes and dose comparison. Int J Radiat Oncol Biol Phys 83 (3): 1015-22, 2012.
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.
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.
Cheung NK, Cheung IY, Kushner BH, et al.: Murine anti-GD2 monoclonal antibody 3F8 combined with granulocyte-macrophage colony-stimulating factor and 13-cis-retinoic acid in high-risk patients with stage 4 neuroblastoma in first remission. J Clin Oncol 30 (26): 3264-70, 2012.
Kreissman SG, Seeger RC, Matthay KK, et al.: Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial. Lancet Oncol 14 (10): 999-1008, 2013.
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.
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.
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.
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.
Many patients with stage 4S neuroblastoma do not require therapy. However, tumors with unfavorable biology or patients who are symptomatic due to evolving hepatomegaly and organ compromise are at increased risk of death and are treated with low-dose to moderate-dose chemotherapy. Eight percent to 10% of these patients will have MYCN amplification and are treated with high-risk protocols. (Refer to the Treatment of High-Risk Neuroblastoma section of this summary for more information about the treatment of stage 4S high-risk neuroblastoma.)
aThe COG-P9641, COG-A3961, and COG-A3973 trials established the current standard of care for neuroblastoma patients in terms of risk group assignment and treatment strategies.
bDNA Ploidy: DNA Index (DI) > 1 is favorable, = 1 is unfavorable; hypodiploid tumors (with DI < 1) will be treated as a tumor with a DI > 1 (DI < 1 [hypodiploid] to be considered favorable ploidy).
cINSS stage 4S infants with favorable biology and clinical symptoms are treated with immediate chemotherapy until asymptomatic or according to protocol guidelines. Clinical symptoms include the following: respiratory distress with or without hepatomegaly or cord compression and neurologic deficit or inferior vena cava compression and renal ischemia; or genitourinary obstruction; or gastrointestinal obstruction and vomiting; or coagulopathy with significant clinical hemorrhage unresponsive to replacement therapy.
There is no standard approach to the treatment of stage 4S neuroblastoma.
Treatment options for stage 4S neuroblastoma include the following:
Resection of primary tumor is not associated with improved outcome. Rarely, infants with massive hepatic 4S neuroblastoma develop cirrhosis from the chemotherapy and/or radiation therapy that is used to control the disease and may benefit from orthotopic liver transplantation.
The treatment of children with stage 4S disease is dependent on clinical presentation. Most patients do not require therapy unless bulk disease is causing organ compromise and risk of death.
Infants diagnosed with International Neuroblastoma Staging System (INSS) stage 4S neuroblastoma, particularly those with hepatomegaly or those younger than 2 months, have the potential for rapid clinical deterioration and may benefit from early initiation of therapy. It has been difficult to identify infants with stage 4S disease who will benefit from chemotherapy. Several clinical trials have evaluated the presence of symptoms in patients with 4S disease, including the following:
Various chemotherapy regimens (cyclophosphamide alone, carboplatin/etoposide, cyclophosphamide/doxorubicin/vincristine) have been used to treat symptomatic patients. The approach is to administer the chemotherapy only as long as symptoms persist in order to avoid toxicity, which contributes to lower survival. Additionally, lower doses of chemotherapy are often recommended for very young or low-weight infants along with granulocyte colony-stimulating factors after each cycle of chemotherapy.
Evidence (chemotherapy for symptomatic patients, very young infants, or those with unfavorable biology):
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.
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.
Steele M, Jones NL, Ng V, et al.: Successful liver transplantation in an infant with stage 4S(M) neuroblastoma. Pediatr Blood Cancer 60 (3): 515-7, 2013.
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.
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.
Park JR, Bagatell R, London WB, et al.: Children's Oncology Group's 2013 blueprint for research: neuroblastoma. Pediatr Blood Cancer 60 (6): 985-93, 2013.
Tumor growth due to maturation should be differentiated from tumor progression by performing a biopsy and reviewing histology. Patients may have persistent maturing disease with metaiodobenzylguanidine (mIBG) uptake that does not affect outcome, particularly in patients with low-risk and intermediate-risk disease. When neuroblastoma recurs in a child originally diagnosed with high-risk disease, the prognosis is usually poor despite additional intensive therapy. However, it is often possible to gain many additional months of life for these patients with alternative chemotherapy regimens. Clinical trials are appropriate for these patients and may be offered. Information about ongoing clinical trials is available from the NCI Web site.
The International Neuroblastoma Risk Group Project performed a decision-tree analysis of clinical and biological characteristics (defined at diagnosis) associated with survival after relapse in 2,266 patients with neuroblastoma entered on large clinical trials in well-established clinical trials groups around the world.
Significant prognostic factors determined at diagnosis for postrelapse survival include the following:
The Children’s Oncology Group (COG) experience with recurrence in low-risk and intermediate-risk neuroblastoma is that the majority of recurrences can be salvaged. The COG reported a 3-year event free survival (EFS) of 88% and an OS of 96% in intermediate-risk patients and a 5-year EFS of 89% and OS of 97% in low-risk patients. Moreover, in most patients originally diagnosed with low-risk or intermediate-risk disease, local recurrence or recurrence in the 4S pattern may be treated successfully with surgery and/or with moderate dose chemotherapy, without hematopoietic stem cell transplantation.
Treatment options for locoregional recurrent neuroblastoma initially classified as low risk include the following:
Local or regional recurrent cancer is resected if possible.
Those with favorable biology and regional recurrence more than 3 months after completion of planned treatment are observed if resection of the recurrence is total or near
total (≥90% resection). Those with favorable biology and a less than near-total
resection are treated with chemotherapy.
Infants younger than 1 year at the time of locoregional recurrence
whose tumors have any unfavorable biologic properties are observed if
resection is total or near total. If the resection is less than near total,
these same infants are treated with chemotherapy.
Chemotherapy may consist of moderate doses of carboplatin, cyclophosphamide,
doxorubicin, and etoposide, or cyclophosphamide and topotecan. The cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen as used in prior COG trials (COG-P9641 and COG-A3961).
children with local recurrence with either unfavorable International Neuroblastoma Pathology Classification at diagnosis or MYCN gene amplification have a poor prognosis and may be treated with surgery, aggressive combination chemotherapy, or offered entry into a clinical trial.
Evidence (surgery and chemotherapy):
Treatment options for metastatic recurrent neuroblastoma initially classified as low risk include the following:
Metastatic recurrent or progressive neuroblastoma in an infant initially
categorized as low risk and younger than 1 year at recurrence may be
treated according to tumor biology as defined in the prior COG trials (COG-P9641 and COG-A3961):
Chemotherapy may consist of moderate doses of carboplatin, cyclophosphamide,
doxorubicin, and etoposide. The cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen, as used in prior COG trials (COG-P9641 and COG-A3961).
Any child initially categorized as low risk who is older than 1 year at the
time of metastatic recurrent or progressive disease and whose recurrence is not in the stage 4S pattern usually has a poor
prognosis and should be considered for high-risk therapy.
The treatment options for locoregional and metastatic recurrence in patients with intermediate-risk neuroblastoma are derived from the results of the COG-A3961 trial. Among 479 patients with intermediate-risk neuroblastoma treated on the COG-A3961 clinical trial, 42 patients developed disease progression. The rate was 10% of those with favorable biology and 17% of those with unfavorable biology. Thirty patients had locoregional recurrence, 11 had metastatic recurrence, and one had both types of recurrent disease. Six of the 42 patients died of disease, while 36 patients were salvaged. Thus, most patients with intermediate-risk neuroblastoma and disease progression may be salvaged.
Treatment options for locoregional recurrent neuroblastoma initially classified as intermediate risk include the following:
The current standard of care is based on the experience from the COG Intermediate-Risk treatment plan (COG-A3961). Locoregional recurrence of neuroblastoma with favorable biology that occurs
more than 3 months after completion of chemotherapy may be treated
surgically. If resection is less than near total, then additional chemotherapy may be given. Chemotherapy may consist of moderate doses of carboplatin,
cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each
agent is kept low to minimize permanent injury from the chemotherapy
regimen, as used in a prior COG trial (COG-A3961).
Treatment options for metastatic recurrent neuroblastoma initially classified as intermediate risk include the following:
Patients with metastatic recurrent neuroblastoma are treated like patients with newly diagnosed high-risk neuroblastoma. (Refer to the Treatment Options for High-Risk Neuroblastoma section of this summary for more information.)
Any recurrence in patients initially classified as high risk signifies a very poor prognosis. Clinical trials may be considered. Palliative care should be considered as part of the patient's treatment plan.
Treatment options for recurrent or refractory neuroblastoma in patients initially classified as high risk include the following:
It is not known whether one therapeutic approach is superior to another.
Evidence (second autologous SCT following retrieval chemotherapy):
Central nervous system (CNS) involvement, although rare at initial presentation, may occur in 5% to 10% of patients with recurrent neuroblastoma.
Because upfront treatment for newly diagnosed patients does not adequately treat the CNS, the CNS has emerged as a sanctuary site leading to relapse. CNS relapses are almost always fatal, with a median time to death of 6 months.
Treatment options for recurrent neuroblastoma in the CNS include the following:
Current treatment approaches generally include eradicating bulky and microscopic residual disease in the CNS and minimal residual systemic disease that may herald further relapses. Neurosurgical interventions serve to decrease edema, control hemorrhage, and remove bulky tumor before starting therapy. Compartmental radioimmunotherapy using intrathecal radioiodinated monoclonal antibodies has been tested in patients with recurrent metastatic CNS neuroblastoma after surgery, craniospinal radiation therapy, and chemotherapy.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent neuroblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Marachelian A, Shimada H, Sano H, et al.: The significance of serial histopathology in a residual mass for outcome of intermediate risk stage 3 neuroblastoma. Pediatr Blood Cancer 58 (5): 675-81, 2012.
London WB, Castel V, Monclair T, et al.: Clinical and biologic features predictive of survival after relapse of neuroblastoma: a report from the International Neuroblastoma Risk Group project. J Clin Oncol 29 (24): 3286-92, 2011.
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.
Castel V, Cañete A, Melero C, et al.: Results of the cooperative protocol (N-III-95) for metastatic relapses and refractory neuroblastoma. Med Pediatr Oncol 35 (6): 724-6, 2000.
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.
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.
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.
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.
Simon T, Längler A, Harnischmacher U, et al.: Topotecan, cyclophosphamide, and etoposide (TCE) in the treatment of high-risk neuroblastoma. Results of a phase-II trial. J Cancer Res Clin Oncol 133 (9): 653-61, 2007.
Kushner BH, Kramer K, Modak S, et al.: Differential impact of high-dose cyclophosphamide, topotecan, and vincristine in clinical subsets of patients with chemoresistant neuroblastoma. Cancer 116 (12): 3054-60, 2010.
Bagatell R, London WB, Wagner LM, et al.: Phase II study of irinotecan and temozolomide in children with relapsed or refractory neuroblastoma: a Children's Oncology Group study. J Clin Oncol 29 (2): 208-13, 2011.
Kushner BH, Modak S, Kramer K, et al.: Ifosfamide, carboplatin, and etoposide for neuroblastoma: a high-dose salvage regimen and review of the literature. Cancer 119 (3): 665-71, 2013.
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.
Matthay KK, Yanik G, Messina J, et al.: Phase II study on the effect of disease sites, age, and prior therapy on response to iodine-131-metaiodobenzylguanidine therapy in refractory neuroblastoma. J Clin Oncol 25 (9): 1054-60, 2007.
Matthay KK, Tan JC, Villablanca JG, et al.: Phase I dose escalation of iodine-131-metaiodobenzylguanidine with myeloablative chemotherapy and autologous stem-cell transplantation in refractory neuroblastoma: a new approaches to Neuroblastoma Therapy Consortium Study. J Clin Oncol 24 (3): 500-6, 2006.
Matthay KK, Quach A, Huberty J, et al.: Iodine-131--metaiodobenzylguanidine double infusion with autologous stem-cell rescue for neuroblastoma: a new approaches to neuroblastoma therapy phase I study. J Clin Oncol 27 (7): 1020-5, 2009.
DuBois SG, Chesler L, Groshen S, et al.: Phase I study of vincristine, irinotecan, and ¹³¹I-metaiodobenzylguanidine for patients with relapsed or refractory neuroblastoma: a new approaches to neuroblastoma therapy trial. Clin Cancer Res 18 (9): 2679-86, 2012.
Johnson K, McGlynn B, Saggio J, et al.: Safety and efficacy of tandem 131I-metaiodobenzylguanidine infusions in relapsed/refractory neuroblastoma. Pediatr Blood Cancer 57 (7): 1124-9, 2011.
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.
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.
The PDQ cancer information summaries are reviewed regularly and updated as
new information becomes available. This section describes the latest
changes made to this summary as of the date above.
General Information About Neuroblastoma
Added Figure 1 to illustrate that neuroblastoma may be found in the adrenal glands and paraspinal nerve tissue from the neck to the pelvis.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is
editorially independent of NCI. The summary reflects an independent review of
the literature and does not represent a policy statement of NCI or NIH. More
information about summary policies and the role of the PDQ Editorial Boards in
maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
This information was last updated on August 29, 2014.
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