Neuroblastoma
Encyclopedia
Neuroblastoma is the most common extracranial solid cancer
in childhood and the most common cancer in infancy, with an annual incidence of about 650 cases per year in the US , and 100 cases per year in the UK . Close to 50 percent of neuroblastoma cases occur in children younger than two years old. It is a neuroendocrine tumor, arising from any neural crest
element of the sympathetic nervous system
or SNS. It most frequently originates in one of the adrenal gland
s, but can also develop in nerve tissues in the neck
, chest
, abdomen
, or pelvis
.
Neuroblastoma is one of the few human malignancies known to demonstrate spontaneous regression from an undifferentiated state to a completely benign
cellular appearance. It is a disease exhibiting extreme heterogeneity, and is stratified into three risk categories: low, intermediate, and high risk. Low-risk disease is most common in infants and good outcomes are common with observation only or surgery, whereas high-risk disease is difficult to treat successfully even with the most intensive multi-modal therapies available.
Esthesioneuroblastoma
, also known as olfactory neuroblastoma, is believed to arise from the olfactory epithelium
and its classification remains controversial. However, since it is not a sympathetic nervous system malignancy it is a distinct clinical entity and is not to be confused with neuroblastoma.
s of neuroblastoma are often vague making diagnosis difficult. Fatigue, loss of appetite, fever
, and joint pain are common. Symptoms depend on primary tumor locations and metastases if present:
Neuroblastoma often spreads to other parts of the body before any symptoms are apparent and 50 to 60% of all neuroblastoma cases present with metastases
.
The most common location for neuroblastoma to originate (i.e. the primary tumor) is on the adrenal glands. This occurs in 40% of localized tumors and in 60% of cases of widespread disease. Neuroblastoma can also develop anywhere along the sympathetic nervous system chain from the neck to the pelvis. Frequencies in different locations include: neck (1%), chest (19%), abdomen (30% non-adrenal), or pelvis (1%). In rare cases, no primary tumor can be discerned.
Rare but characteristic presentations include transverse myelopathy
(tumor spinal cord compression, 5% of cases), treatment-resistant diarrhea (tumor vasoactive intestinal peptide
secretion, 4% of cases), Horner's syndrome
(cervical tumor, 2.4% of cases), opsoclonus myoclonus syndrome
and ataxia
(suspected paraneoplastic cause, 1.3% of cases), and hypertension
(catecholamine
secretion or renal artery compression, 1.3% of cases).
of neuroblastoma is not well understood. Certain cases however do run in families and have been linked to genetics. Familial neuroblastoma is caused by a very rare germline mutation in the anaplastic lymphoma kinase
(ALK) gene.
LMO1 gene has been found to be a contributor to neuroblastoma, increasing the risk of developing an aggressive form of the cancer.
Neuroblastoma has been linked to problems with the gene NBPF10
in relation to copy-number variants which cause the 1q21.1 deletion syndrome
and 1q21.1 duplication syndrome
.
Several risk factors have been proposed and are the subject of ongoing research.
Due to characteristic early onset many studies have focused on parental factors around conception
and during gestation
. Factors investigated have included occupation (i.e. exposure to chemicals in specific industries), smoking, alcohol consumption, use of medicinal drugs during pregnancy and birth factors; however, results have been inconclusive.
Other studies have examined possible links with atopy
and exposure to infection
early in life, use of hormones and fertility drugs, and maternal use of hair dye.
The diagnosis is usually confirmed by a surgical pathologist
, taking into account the clinical presentation, microscopic findings, and other laboratory tests.
, homovanillic acid
(HVA), and/or vanillylmandelic acid (VMA).
. When it is radio-ionated with I-131 or I-123 (radioactive iodine isotopes), it is a very good radiopharmaceutical for diagnosis and monitoring of response to treatment for this disease. With a half-life
of 13 hours, I-123 is the preferred isotope for imaging sensitivity and quality. I-131 has a half-life of 8 days and at higher doses is an effective therapy as targeted radiation against relapsed and refractory neuroblastoma.
On microscopy, the tumor cells are typically described as small, round and blue, and rosette
patterns (Homer-Wright
pseudo-rosettes) may be seen. Homer-Wright pseudorosettes, are tumor cells around neuropil, not to be confused with true rosettes (Flexner-Wintersteiner) rosettes which are tumor cells around a blood vessel often seen in retinoblastomas. They are also distinct from the pseudorosettes of an ependymoma which consist of tumor cells with glial fibrillary acidic protein (GFAP)–positive processes tapering off toward a blood vessel (thus a combination of the two). A variety of immunohistochemical stains are used by pathologists to distinguish neuroblastomas from histological mimics, such as rhabdomyosarcoma
, Ewing's sarcoma, lymphoma
and Wilms' tumor
.
Neuroblastoma is one of the peripheral neuroblastic tumors (pNTs) that have similar origins and show a wide pattern of differentiation ranging from benign
ganglioneuroma
to stroma
-rich ganglioneuroblastoma
with neuroblastic cells intermixed or in nodules, to highly malignant neuroblastoma. This distinction in the pre-treatment tumor pathology is an important prognostic factor, along with age and mitosis
-karyorrhexis
index (MKI). This pathology classification system describes "favorable" and "unfavorable" tumors by the International Neuroblastoma Pathology Committee (INPC, also called Shimada system) which was established in 1999 and revised in 2003.
Although international agreement on staging (INSS) has been used, the need for an international consensus on risk assignment has also been recognized in order to compare similar cohorts in results of studies. Beginning in 2005, representatives of the major pediatric oncology cooperative groups have met to review data for 8,800 neuroblastoma patients treated in Europe, Japan, USA, Canada, and Australia between 1990 and 2002. This task force has proposed the International Neuroblastoma Risk Group (INRG) classification system. Retrospective studies revealed the high survival rate of 12-18 month old age group, previously categorized as high-risk, and prompted the decision to reclassify 12-18 month old children without N-myc (also commonly referred to as MYCN) amplification to intermediate risk category.
The new INRG risk assignment will classify neuroblastoma at diagnosis based on a new International Neuroblastoma Risk Group Staging System (INRGSS):
The new risk stratification will be based on the new INRGSS staging system, age (dichotomized at 18 months), tumor grade, N-myc
amplification, unbalanced 11q aberration, and ploidy
into four pre-treatment risk groups: very low, low, intermediate, and high risk.
level can be elevated in pre-clinical neuroblastoma. Screening asymptomatic infants at three weeks, six months, and one year has been performed in Japan, Canada, Austria and Germany since the 1980s. Japan began screening six-month olds for neuroblastoma via analysis of the levels of homovanillic acid
and vanilmandelic acid in 1984. Screening was halted in 2004 after studies in Canada and Germany showed no reduction in deaths due to neuroblastoma, but rather caused an increase in diagnoses that would have disappeared without treatment, subjecting those infants to unnecessary surgery and chemotherapy.
is localized, it is generally curable. However, long-term survival for children with advanced disease older than 18 months of age is poor despite aggressive multimodal therapy
(intensive chemotherapy
, surgery
, radiation therapy
, stem cell transplant, differentiation agent isotretinoin
also called 13-cis-retinoic acid, and frequently immunotherapy
with anti-GD2
monoclonal antibody therapy
).
Biologic and genetic characteristics have been identified, which, when added to classic clinical staging, has allowed patient assignment to risk groups for planning treatment intensity. These criteria include the age of the patient, extent of disease spread, microscopic appearance, and genetic features including DNA ploidy and N-myc
oncogene
amplification (N-myc regulates microRNAs), into low, intermediate, and high risk disease. A recent biology study (COG ANBL00B1) analyzed 2687 neuroblastoma patients and the spectrum of risk assignment was determined: 37% of neuroblastoma cases are low risk, 18% are intermediate risk, and 45% are high risk. (There is some evidence that the high- and low-risk types are caused by different mechanisms, and are not merely two different degrees of expression of the same mechanism.)
The therapies for these different risk categories are very different.
With current treatments, patients with low and intermediate risk disease have an excellent prognosis with cure rates above 90% for low risk and 70%-90% for intermediate risk. In contrast, therapy for high-risk neuroblastoma the past two decades resulted in cures only about 30% of the time. The addition of antibody therapy has raised survival rates for high-risk disease significantly. In March 2009 an early analysis of a Children's Oncology Group (COG) study with 226 high-risk patients showed that two years after stem cell transplant 66% of the group randomized to received ch14.18 antibody with GM-CSF and IL-2 were alive and disease-free compared to only 46% in the group that did not receive the antibody. The randomization was stopped so all patients enrolling on the trial will receive the antibody therapy.
Chemotherapy agents used in combination have been found to be effective against neuroblastoma. Agents commonly used in induction and for stem cell transplant conditioning are platinum compounds (cisplatin
, carboplatin
), alkylating agents (cyclophosphamide
, ifosfamide
, melphalan
), topoisomerase
II inhibitor (etoposide
), anthracycline
antibiotics (doxorubicin
) and vinca alkaloids (vincristine
). Some newer regimens include topoisomerase I inhibitors (topotecan
and irinotecan
) in induction which have been found to be effective against recurrent disease.
Most long-term survivors alive today had low or intermediate risk disease and milder courses of treatment compared to high-risk disease. The majority of survivors have long-term effects from the treatment. Survivors of intermediate and high-risk treatment often experience hearing loss. Growth reduction, thyroid function disorders, learning difficulties, and greater risk of secondary cancers affect survivors of high-risk disease. An estimated two of three survivors of childhood cancer will ultimately develop at least one chronic and sometimes life-threatening health problem within 20 to 30 years after the cancer diagnosis.
, is a predictor of outcome in neuroblastoma:
Earlier publications categorized neuroblastomas into three major subtypes based on cytogenetic profiles:
Virtual karyotyping
can be performed on fresh or paraffin-embedded tumors to assess copy number at these loci. SNP array virtual karyotyping is preferred for tumor samples, including neuroblastomas, because they can detect copy neutral loss of heterozygosity (acquired uniparental disomy). Copy neutral LOH can be biologically equivalent to a deletion and has been detected at key loci in neuroblastoma. ArrayCGH, FISH, or conventional cytogenetics cannot detect copy neutral LOH.
The highest incidence is in the first year of life, and some cases are congenital. The age range is broad, including older children and adults, but only 10% of cases occur in people older than 5 years of age. A large European study reported less than 2% of over 4000 neuroblastoma cases were over 18 years old.
In 1864 German physician Rudolf Virchow
was the first to describe an abdominal tumor in a child as a "glioma". The characteristics of tumors from the sympathetic nervous system and the adrenal medulla were then noted in 1891 by German pathologist Felix Marchand
.
In 1901 the distinctive presentation of stage 4S in infants (liver but no bone metastases) was described by William Pepper. In 1910 James Homer Wright
understood the tumor to originate from primitive neural cells, and named it neuroblastoma. He also noted the circular clumps of cells in bone marrow samples which are now termed "Homer-Wright pseudorosettes."
By contrast, focus the past 20 years or more has been to intensify treatment for high-risk neuroblastoma. Chemotherapy induction variations, timing of surgery, stem cell transplant regimens, various delivery schemes for radiation, and use of monoclonal antibodies and retinoids to treat minimal residual disease continue to be examined. Recent phase III clinical trials with randomization have been carried out to answer these questions to improve survival of high-risk disease:
In addition to these phase III studies, some research institutions offer pilot treatment protocols. For example, St Jude's recently finished (2007) testing a new up-front chemotherapy regimen in 23 children which included irinotecan
and gefitinib
with 16 months of maintenance chemotherapy after stem cell transplant with alternating oral 13-cis-retinoic acid and topotecan
. Memorial Sloan-Kettering Cancer Center in New York offers treatment that includes a mouse-derived monoclonal antibody, 3F8
, used in protocols since the mid 1980s. This antibody is used for treating minimal residual disease or consolidation instead of stem cell transplant. A new pilot protocol COG-ANBL09P1 available for newly diagnosed (high-risk) children at several Children's Oncology Group (COG) centers will offer MIBG radiotherapy and chemotherapy for the transplant regimen.
Some children (particularly in high-risk cases) do not respond completely to frontline treatment (with a complete response or very good partial response) and are labeled refractory. These children are removed from the frontline therapy (clinical trial) and are eligible for clinical trials using new therapies. Many high-risk children have a good response to frontline therapy and achieve a remission, but later the disease recurs (relapse). These children are also eligible for new therapies being tested in clinical trials.
Chemotherapy with topotecan and cyclophosphamide is frequently used in refractory setting and after relapse. A randomized study (2004) with 119 patients (comparing topotecan alone to topotecan and cyclophosphamide) revealed a 31% complete or partial response rate with two-year progression-free survival at 36% in the topotecan and cyclophosphamide group. Irinotecan (intravenous or oral) and oral temozolomide are also used in refractory and recurrent neuroblastoma.
Many phase I and phase II trials are currently testing new agents against neuroblastoma in children who have relapsed or are resistant to initial therapy. Investigators are currently studying new agents, alone and in new combinations, using small molecule targeted therapy
, 131-I MIBG radiation therapy, angiogenesis
agents, new monoclonal antibodies
, vaccines, oncolytic viruses, as well as new myeloablative regimens.
A group of 16 children’s hospitals in the United States known as the New Advances in Neuroblastoma Therapy (NANT) consortium coordinates the I-131 MIBG radiation therapy trials. The NANT consortium also offers trials using an oral powder formulation of fenretinide
, intravenous fenretinide, bisphosphonate
(Zometa) with other agents, and combining I-131 MIBG with the inhibitor vorinostat
.
Other research study groups such as The Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC) also conduct clinical trials to treat relapse neuroblastoma. Institutions in Europe are studying novel therapies to treat relapse, including haploidentical stem cell transplant. Many hospitals conduct their own institutional studies as well.
The protein p53 is believed to play a role in the development of resistance to chemotherapy. A November 2009 study in mice shows that activating the tumor suppressor p53 with a new drug, nutlin-3, may slow tumor growth. In this study, physician Tom Van Maerken of Ghent University Hospital in Belgium and his colleagues used nutlin-3 to neutralize MDM2, a protein that binds to the p53 protein and obstructs p53’s ability to trigger programmed cell death. Earlier studies have shown that nutlin-3 can specifically prevent MDM2 from disabling p53.
of Waco
, Texas
, successfully introduced legislation to earmark $150 million toward a cure for neuroblastoma and other cancers. The measure was signed into law in July 2008 by U.S. President George W. Bush
. Edwards was inspired in the endeavor by the illness and subsequent death of Erin Channing Buenger (1997–2009) of Bryan
, daughter of one of his constituents, Walter L. Buenger
, head of the history department at Texas A&M University
.
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
in childhood and the most common cancer in infancy, with an annual incidence of about 650 cases per year in the US , and 100 cases per year in the UK . Close to 50 percent of neuroblastoma cases occur in children younger than two years old. It is a neuroendocrine tumor, arising from any neural crest
Neural crest
Neural crest cells are a transient, multipotent, migratory cell population unique to vertebrates that gives rise to a diverse cell lineage including melanocytes, craniofacial cartilage and bone, smooth muscle, peripheral and enteric neurons and glia....
element of the sympathetic nervous system
Sympathetic nervous system
The sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
or SNS. It most frequently originates in one of the adrenal gland
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...
s, but can also develop in nerve tissues in the neck
Neck
The neck is the part of the body, on many terrestrial or secondarily aquatic vertebrates, that distinguishes the head from the torso or trunk. The adjective signifying "of the neck" is cervical .-Boner anatomy: The cervical spine:The cervical portion of the human spine comprises seven boney...
, chest
Chest
The chest is a part of the anatomy of humans and various other animals. It is sometimes referred to as the thorax or the bosom.-Chest anatomy - Humans and other hominids:...
, abdomen
Abdomen
In vertebrates such as mammals the abdomen constitutes the part of the body between the thorax and pelvis. The region enclosed by the abdomen is termed the abdominal cavity...
, or pelvis
Pelvis
In human anatomy, the pelvis is the lower part of the trunk, between the abdomen and the lower limbs .The pelvis includes several structures:...
.
Neuroblastoma is one of the few human malignancies known to demonstrate spontaneous regression from an undifferentiated state to a completely benign
Benign
A benign tumor is a tumor that lacks the ability to metastasize. Common examples of benign tumors include moles and uterine fibroids.The term "benign" implies a mild and nonprogressive disease. Indeed, many kinds of benign tumors are harmless to human health...
cellular appearance. It is a disease exhibiting extreme heterogeneity, and is stratified into three risk categories: low, intermediate, and high risk. Low-risk disease is most common in infants and good outcomes are common with observation only or surgery, whereas high-risk disease is difficult to treat successfully even with the most intensive multi-modal therapies available.
Esthesioneuroblastoma
Esthesioneuroblastoma
Esthesioneuroblastoma is a rare form of cancer involving nasal cavity and believed to arise from the olfactory epithelium. It can cause loss of vision, sight and taste....
, also known as olfactory neuroblastoma, is believed to arise from the olfactory epithelium
Olfactory epithelium
The olfactory epithelium is a specialized epithelial tissue inside the nasal cavity that is involved in smell. In humans, it measures about 1 square centimetre and lies on the roof of the nasal cavity about 7 cm above and behind the nostrils...
and its classification remains controversial. However, since it is not a sympathetic nervous system malignancy it is a distinct clinical entity and is not to be confused with neuroblastoma.
Signs and symptoms
The first symptomSymptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...
s of neuroblastoma are often vague making diagnosis difficult. Fatigue, loss of appetite, fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
, and joint pain are common. Symptoms depend on primary tumor locations and metastases if present:
- In the abdomenAbdomenIn vertebrates such as mammals the abdomen constitutes the part of the body between the thorax and pelvis. The region enclosed by the abdomen is termed the abdominal cavity...
, a tumor may cause a swollen belly and constipationConstipationConstipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
. - A tumor in the chestChestThe chest is a part of the anatomy of humans and various other animals. It is sometimes referred to as the thorax or the bosom.-Chest anatomy - Humans and other hominids:...
may cause breathing problems. - A tumor pressing on the spinal cordSpinal cordThe spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
may cause weaknessWeaknessWeakness is a symptom represented, medically, by a number of different conditions, including: lack of muscle strength, malaise, dizziness, or fatigue. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a...
and thus an inability to stand, crawl, or walk. - Bone lesions in the legs and hips may cause pain and limping.
- A tumor in the bones around the eyes or orbitsOrbit (anatomy)In anatomy, the orbit is the cavity or socket of the skull in which the eye and its appendages are situated. "Orbit" can refer to the bony socket, or it can also be used to imply the contents...
may cause distinct bruising and swelling. - Infiltration of the bone marrow may cause pallorPallorPallor is a reduced amount of oxyhaemoglobin in skin or mucous membrane, a pale color which can be caused by illness, emotional shock or stress, stimulant use, lack of exposure to sunlight, anaemia or genetics....
from anemiaAnemiaAnemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
.
Neuroblastoma often spreads to other parts of the body before any symptoms are apparent and 50 to 60% of all neuroblastoma cases present with metastases
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
.
The most common location for neuroblastoma to originate (i.e. the primary tumor) is on the adrenal glands. This occurs in 40% of localized tumors and in 60% of cases of widespread disease. Neuroblastoma can also develop anywhere along the sympathetic nervous system chain from the neck to the pelvis. Frequencies in different locations include: neck (1%), chest (19%), abdomen (30% non-adrenal), or pelvis (1%). In rare cases, no primary tumor can be discerned.
Rare but characteristic presentations include transverse myelopathy
Myelopathy
Myelopathy refers to pathology of the spinal cord. When due to trauma, it is known as spinal cord injury. When inflammatory, it is known as myelitis. Disease that is vascular in nature is known as vascular myelopathy....
(tumor spinal cord compression, 5% of cases), treatment-resistant diarrhea (tumor vasoactive intestinal peptide
Vasoactive intestinal peptide
Vasoactive intestinal peptide also known as the vasoactive intestinal polypeptide or VIP is a peptide hormone containing 29 amino acid residues that is produced in many tissues of vertebrates including the gut, pancreas and suprachiasmatic nuclei of the hypothalamus in the brain...
secretion, 4% of cases), Horner's syndrome
Horner's syndrome
Horner's syndrome is the combination of drooping of the eyelid and constriction of the pupil , sometimes accompanied by decreased sweating of the face on the same side; redness of the conjunctiva of the eye is often also present...
(cervical tumor, 2.4% of cases), opsoclonus myoclonus syndrome
Opsoclonus myoclonus syndrome
Opsoclonus Myoclonus Syndrome is a rare neurological disorder of unknown causes which appears to be the result of an autoimmune process involving the nervous system. It is an extremely rare condition, affecting as few as 1 in 10,000,000 people per year. It affects 2 to 3% of children with...
and ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
(suspected paraneoplastic cause, 1.3% of cases), and hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
(catecholamine
Catecholamine
Catecholamines are molecules that have a catechol nucleus consisting of benzene with two hydroxyl side groups and a side-chain amine. They include dopamine, as well as the "fight-or-flight" hormones adrenaline and noradrenaline released by the adrenal medulla of the adrenal glands in response to...
secretion or renal artery compression, 1.3% of cases).
Cause
The etiologyEtiology
Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....
of neuroblastoma is not well understood. Certain cases however do run in families and have been linked to genetics. Familial neuroblastoma is caused by a very rare germline mutation in the anaplastic lymphoma kinase
Anaplastic lymphoma kinase
Anaplastic lymphoma kinase also known as ALK tyrosine kinase receptor or CD246 is an enzyme that in humans is encoded by the ALK gene.-Function:...
(ALK) gene.
LMO1 gene has been found to be a contributor to neuroblastoma, increasing the risk of developing an aggressive form of the cancer.
Neuroblastoma has been linked to problems with the gene NBPF10
NBPF10
Neuroblastoma breakpoint family member 10 is a protein that in Homo sapiens is encoded by the NBPF10 gene.The full gene is 75,313 bp, with the major isoform of mRNA being 10,697 bp long. The gene is located at 1q21.1. NBPF contains what is known as the DUF1220 repeats. The highly conserved,...
in relation to copy-number variants which cause the 1q21.1 deletion syndrome
1q21.1 deletion syndrome
1q21.1 deletion syndrome or 1q21.1 microdeletion is a rare aberration of chromosome 1. , the international rare chromosome disorder group, has 48 genetically confirmed registered cases of this deletion worldwide ....
and 1q21.1 duplication syndrome
1q21.1 duplication syndrome
1q21.1 duplication syndrome or 1q21.1 microduplication is a rare aberration of chromosome 1. , the international rare chromosome disorder group, has 38 genetically confirmed registered cases of this duplication worldwide ....
.
Several risk factors have been proposed and are the subject of ongoing research.
Due to characteristic early onset many studies have focused on parental factors around conception
Fertilisation
Fertilisation is the fusion of gametes to produce a new organism. In animals, the process involves the fusion of an ovum with a sperm, which eventually leads to the development of an embryo...
and during gestation
Gestation
Gestation is the carrying of an embryo or fetus inside a female viviparous animal. Mammals during pregnancy can have one or more gestations at the same time ....
. Factors investigated have included occupation (i.e. exposure to chemicals in specific industries), smoking, alcohol consumption, use of medicinal drugs during pregnancy and birth factors; however, results have been inconclusive.
Other studies have examined possible links with atopy
Atopy
Atopy or atopic syndrome is a predisposition toward developing certain allergic hypersensitivity reactions.Atopy may have a hereditary component, although contact with the allergen must occur before the hypersensitivity reaction can develop ....
and exposure to infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
early in life, use of hormones and fertility drugs, and maternal use of hair dye.
Diagnosis
Anatomical pathology
Anatomical pathology or Anatomic pathology is a medical specialty that is concerned with the diagnosis of disease based on the gross, microscopic, chemical, immunologic and molecular examination of organs, tissues, and whole bodies...
, taking into account the clinical presentation, microscopic findings, and other laboratory tests.
Biochemistry
In about 90% of cases of neuroblastoma, elevated levels of catecholamines or their metabolites are found in the urine or blood. Catecholamines and their metabolites include dopamineDopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
, homovanillic acid
Homovanillic acid
Homovanillic acid is a major catecholamine metabolite...
(HVA), and/or vanillylmandelic acid (VMA).
Imaging
Another way to detect neuroblastoma is the mIBG scan (meta-iodobenzylguanidine), which is taken up by 90 to 95% of all neuroblastomas, often termed "mIBG-avid." The mechanism is that mIBG is taken up by sympathetic neurons, and is a functioning analog of the neurotransmitter norepinephrineNorepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
. When it is radio-ionated with I-131 or I-123 (radioactive iodine isotopes), it is a very good radiopharmaceutical for diagnosis and monitoring of response to treatment for this disease. With a half-life
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
of 13 hours, I-123 is the preferred isotope for imaging sensitivity and quality. I-131 has a half-life of 8 days and at higher doses is an effective therapy as targeted radiation against relapsed and refractory neuroblastoma.
Histology
Rosette (design)
A rosette is a round, stylized flower design, used extensively in sculptural objects from antiquity. Appearing in Mesopotamia and used to decorate the funeral stele in Ancient Greece...
patterns (Homer-Wright
James Homer Wright
Dr. James Homer Wright was an early and influential American pathologist, who from 1896 to 1926 was chief of pathology at Massachusetts General Hospital. Wright was born in Pittsburgh, Pennsylvania....
pseudo-rosettes) may be seen. Homer-Wright pseudorosettes, are tumor cells around neuropil, not to be confused with true rosettes (Flexner-Wintersteiner) rosettes which are tumor cells around a blood vessel often seen in retinoblastomas. They are also distinct from the pseudorosettes of an ependymoma which consist of tumor cells with glial fibrillary acidic protein (GFAP)–positive processes tapering off toward a blood vessel (thus a combination of the two). A variety of immunohistochemical stains are used by pathologists to distinguish neuroblastomas from histological mimics, such as rhabdomyosarcoma
Rhabdomyosarcoma
A rhabdomyosarcoma is a type of cancer, specifically a sarcoma , in which the cancer cells are thought to arise from skeletal muscle progenitors. It can also be found attached to muscle tissue, wrapped around intestines, or in any anatomic location...
, Ewing's sarcoma, lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
and Wilms' tumor
Wilms' tumor
Wilms' tumor or nephroblastoma is cancer of the kidneys that typically occurs in children, rarely in adults.Its common name is an eponym, referring to Dr. Max Wilms, the German surgeon who first described this kind of tumor....
.
Neuroblastoma is one of the peripheral neuroblastic tumors (pNTs) that have similar origins and show a wide pattern of differentiation ranging from benign
Benign
A benign tumor is a tumor that lacks the ability to metastasize. Common examples of benign tumors include moles and uterine fibroids.The term "benign" implies a mild and nonprogressive disease. Indeed, many kinds of benign tumors are harmless to human health...
ganglioneuroma
Ganglioneuroma
Ganglioneuroma is a tumor of the sympathetic nerve fibers arising from neural crest cells.For example, it can be found also in the eye , or in the medulla of adrenal glands. Some may be a progressive form of a neuroblastoma....
to stroma
Stroma (animal tissue)
In animal tissue, stroma refers to the connective, supportive framework of a biological cell, tissue, or organ.The stroma in animal tissue is contrasted with the parenchyma.Examples include:* Stroma of iris...
-rich ganglioneuroblastoma
Ganglioneuroblastoma
Ganglioneuroblastoma is a variant of neuroblastoma that is surrounded by ganglion cells.It can be difficult to diagnose.Nodular ganglioneuroblastoma can be divided by prognosis....
with neuroblastic cells intermixed or in nodules, to highly malignant neuroblastoma. This distinction in the pre-treatment tumor pathology is an important prognostic factor, along with age and mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
-karyorrhexis
Karyorrhexis
Karyorrhexis is the destructive fragmentation of the nucleus of a dying cell whereby its chromatin is distributed irregularly throughout the cytoplasm. It is usually preceded by pyknosis and is followed by karyolysis and can occur as a result of either programmed cell death or necrosis....
index (MKI). This pathology classification system describes "favorable" and "unfavorable" tumors by the International Neuroblastoma Pathology Committee (INPC, also called Shimada system) which was established in 1999 and revised in 2003.
Staging
The "International Neuroblastoma Staging System" (INSS) established in 1986 and revised in 1988 stratifies neuroblastoma according to its anatomical presence at diagnosis:- Stage 1: Localized tumor confined to the area of origin.
- Stage 2A: Unilateral tumor with incomplete gross resection; identifiable ipsilateral and contralateral lymph node negative for tumor.
- Stage 2B: Unilateral tumor with complete or incomplete gross resection; with ipsilateral lymph node positive for tumor; identifiable contralateral lymph node negative for tumor.
- Stage 3: Tumor infiltrating across midline with or without regional lymph node involvement; or unilateral tumor with contralateral lymph node involvement; or midline tumor with bilateral lymph node involvement.
- Stage 4: Dissemination of tumor to distant lymph nodes, bone marrow, bone, liver, or other organs except as defined by Stage 4S.
- Stage 4S: Age <1 year old with localized primary tumor as defined in Stage 1 or 2, with dissemination limited to liver, skin, or bone marrow (less than 10 percent of nucleated bone marrow cells are tumors).
Although international agreement on staging (INSS) has been used, the need for an international consensus on risk assignment has also been recognized in order to compare similar cohorts in results of studies. Beginning in 2005, representatives of the major pediatric oncology cooperative groups have met to review data for 8,800 neuroblastoma patients treated in Europe, Japan, USA, Canada, and Australia between 1990 and 2002. This task force has proposed the International Neuroblastoma Risk Group (INRG) classification system. Retrospective studies revealed the high survival rate of 12-18 month old age group, previously categorized as high-risk, and prompted the decision to reclassify 12-18 month old children without N-myc (also commonly referred to as MYCN) amplification to intermediate risk category.
The new INRG risk assignment will classify neuroblastoma at diagnosis based on a new International Neuroblastoma Risk Group Staging System (INRGSS):
- Stage L1: Localized disease without image-defined risk factors.
- Stage L2: Localized disease with image-defined risk factors.
- Stage M: Metastatic disease.
- Stage MS: Metastatic disease "special" where MS is equivalent to stage 4S.
The new risk stratification will be based on the new INRGSS staging system, age (dichotomized at 18 months), tumor grade, N-myc
N-Myc
V-myc myelocytomatosis viral related oncogene, neuroblastoma derived , also known as MYCN, is a protein which in humans is encoded by the MYCN gene.- Function :...
amplification, unbalanced 11q aberration, and ploidy
Ploidy
Ploidy is the number of sets of chromosomes in a biological cell.Human sex cells have one complete set of chromosomes from the male or female parent. Sex cells, also called gametes, combine to produce somatic cells. Somatic cells, therefore, have twice as many chromosomes. The haploid number is...
into four pre-treatment risk groups: very low, low, intermediate, and high risk.
Screening
Urine catecholamineCatecholamine
Catecholamines are molecules that have a catechol nucleus consisting of benzene with two hydroxyl side groups and a side-chain amine. They include dopamine, as well as the "fight-or-flight" hormones adrenaline and noradrenaline released by the adrenal medulla of the adrenal glands in response to...
level can be elevated in pre-clinical neuroblastoma. Screening asymptomatic infants at three weeks, six months, and one year has been performed in Japan, Canada, Austria and Germany since the 1980s. Japan began screening six-month olds for neuroblastoma via analysis of the levels of homovanillic acid
Homovanillic acid
Homovanillic acid is a major catecholamine metabolite...
and vanilmandelic acid in 1984. Screening was halted in 2004 after studies in Canada and Germany showed no reduction in deaths due to neuroblastoma, but rather caused an increase in diagnoses that would have disappeared without treatment, subjecting those infants to unnecessary surgery and chemotherapy.
Treatment
When the lesionLesion
A lesion is any abnormality in the tissue of an organism , usually caused by disease or trauma. Lesion is derived from the Latin word laesio which means injury.- Types :...
is localized, it is generally curable. However, long-term survival for children with advanced disease older than 18 months of age is poor despite aggressive multimodal therapy
Multimodal Therapy
Multimodal therapy is approach to psychotherapy founded by Arnold Lazarus. It is based on the idea that humans are biological beings that think, feel, act, sense, imagine, and interact; and that each of these "modalities" should be addressed in psychological treatment...
(intensive chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
, surgery
Surgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...
, radiation therapy
Radiation therapy
Radiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...
, stem cell transplant, differentiation agent isotretinoin
Isotretinoin
Isotretinoin, INN, is a medication used mostly for cystic acne. It was first developed for brain, pancreatic and other cancers. It is used to treat harlequin-type ichthyosis, a usually lethal skin disease, and lamellar ichthyosis. Its effects are systemic and nonselective...
also called 13-cis-retinoic acid, and frequently immunotherapy
Immunotherapy
Immunotherapy is a medical term defined as the "treatment of disease by inducing, enhancing, or suppressing an immune response". Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies. While immunotherapies that reduce or suppress are...
with anti-GD2
GD2
GD2 is a disialoganglioside expressed on tumors of neuroectodermal origin, including human neuroblastoma and melanoma, with highly restricted expression on normal tissues, principally to the cerebellum and peripheral nerves in humans....
monoclonal antibody therapy
Monoclonal antibody therapy
Monoclonal antibody therapy is the use of monoclonal antibodies to specifically bind to target cells or proteins. This may then stimulate the patient's immune system to attack those cells...
).
Biologic and genetic characteristics have been identified, which, when added to classic clinical staging, has allowed patient assignment to risk groups for planning treatment intensity. These criteria include the age of the patient, extent of disease spread, microscopic appearance, and genetic features including DNA ploidy and N-myc
N-Myc
V-myc myelocytomatosis viral related oncogene, neuroblastoma derived , also known as MYCN, is a protein which in humans is encoded by the MYCN gene.- Function :...
oncogene
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
amplification (N-myc regulates microRNAs), into low, intermediate, and high risk disease. A recent biology study (COG ANBL00B1) analyzed 2687 neuroblastoma patients and the spectrum of risk assignment was determined: 37% of neuroblastoma cases are low risk, 18% are intermediate risk, and 45% are high risk. (There is some evidence that the high- and low-risk types are caused by different mechanisms, and are not merely two different degrees of expression of the same mechanism.)
The therapies for these different risk categories are very different.
- Low-risk disease can frequently be observed without any treatment at allWatchful waitingWatchful waiting is an approach to a medical problem in which time is allowed to pass before medical intervention or therapy is used. During this time, repeated testing may be performed....
or cured with surgery alone.
- Intermediate-risk disease is treated with surgery and chemotherapyChemotherapyChemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
.
- High-risk neuroblastoma is treated with intensive chemotherapy, surgerySurgerySurgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...
, radiation therapyRadiation therapyRadiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...
, bone marrowBone marrowBone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
/ hematopoietic stem cell transplantation, biological-based therapy with 13-cis-retinoic acid (isotretinoinIsotretinoinIsotretinoin, INN, is a medication used mostly for cystic acne. It was first developed for brain, pancreatic and other cancers. It is used to treat harlequin-type ichthyosis, a usually lethal skin disease, and lamellar ichthyosis. Its effects are systemic and nonselective...
or Accutane) and antibody therapy usually administered with the cytokines GM-CSF and IL-2Interleukin 2Interleukin-2 is an interleukin, a type of cytokine immune system signaling molecule, which is a leukocytotrophic hormone that is instrumental in the body's natural response to microbial infection and in discriminating between foreign and self...
.
With current treatments, patients with low and intermediate risk disease have an excellent prognosis with cure rates above 90% for low risk and 70%-90% for intermediate risk. In contrast, therapy for high-risk neuroblastoma the past two decades resulted in cures only about 30% of the time. The addition of antibody therapy has raised survival rates for high-risk disease significantly. In March 2009 an early analysis of a Children's Oncology Group (COG) study with 226 high-risk patients showed that two years after stem cell transplant 66% of the group randomized to received ch14.18 antibody with GM-CSF and IL-2 were alive and disease-free compared to only 46% in the group that did not receive the antibody. The randomization was stopped so all patients enrolling on the trial will receive the antibody therapy.
Chemotherapy agents used in combination have been found to be effective against neuroblastoma. Agents commonly used in induction and for stem cell transplant conditioning are platinum compounds (cisplatin
Cisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
, carboplatin
Carboplatin
Carboplatin, or cis-Diammineplatinum is a chemotherapy drug used against some forms of cancer...
), alkylating agents (cyclophosphamide
Cyclophosphamide
Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
, ifosfamide
Ifosfamide
Ifosfamide is a nitrogen mustard alkylating agent used in the treatment of cancer.It is sometimes abbreviated "IFO".-Uses:It is given as a treatment for a variety of cancers, including:...
, melphalan
Melphalan
Melphalan hydrochloride is a chemotherapy drug belonging to the class of nitrogen mustard alkylating agents.An alkylating agent adds an alkyl group to DNA...
), topoisomerase
Topoisomerase
Topoisomerases are enzymes that regulate the overwinding or underwinding of DNA. The winding problem of DNA arises due to the intertwined nature of its double helical structure. For example, during DNA replication, DNA becomes overwound ahead of a replication fork...
II inhibitor (etoposide
Etoposide
Etoposide phosphate is an anti-cancer agent. It is known in the laboratory as a topoisomerase poison. Etoposide is often incorrectly referred to as a topoisomerase inhibitor in order to avoid using the term "poison" in a clinical setting...
), anthracycline
Anthracycline
Anthracyclines are a class of drugs used in cancer chemotherapy derived from Streptomyces bacterium Streptomyces peucetius var...
antibiotics (doxorubicin
Doxorubicin
Doxorubicin INN is a drug used in cancer chemotherapy. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines, it works by intercalating DNA....
) and vinca alkaloids (vincristine
Vincristine
Vincristine , formally known as leurocristine, sometimes abbreviated "VCR", is a vinca alkaloid from the Catharanthus roseus , formerly Vinca rosea and hence its name. It is a mitotic inhibitor, and is used in cancer chemotherapy.-Mechanism:Tubulin is a structural protein that polymerizes to...
). Some newer regimens include topoisomerase I inhibitors (topotecan
Topotecan
Topotecan hydrochloride is a chemotherapy agent that is a topoisomerase I inhibitor. It is the water-soluble derivative of camptothecin...
and irinotecan
Irinotecan
Irinotecan is a drug used for the treatment of cancer.Irinotecan prevents DNA from unwinding by inhibition of topoisomerase 1. In chemical terms, it is a semisynthetic analogue of the natural alkaloid camptothecin....
) in induction which have been found to be effective against recurrent disease.
Prognosis
Between 20% and 50% of high-risk cases do not respond adequately to induction high-dose chemotherapy and are progressive or refractory. Relapse after completion of frontline therapy is also common. Further treatment is available in phase I and phase II clinical trials that test new agents and combinations of agents against neuroblastoma, but the outcome remains very poor for relapsed high-risk disease.Most long-term survivors alive today had low or intermediate risk disease and milder courses of treatment compared to high-risk disease. The majority of survivors have long-term effects from the treatment. Survivors of intermediate and high-risk treatment often experience hearing loss. Growth reduction, thyroid function disorders, learning difficulties, and greater risk of secondary cancers affect survivors of high-risk disease. An estimated two of three survivors of childhood cancer will ultimately develop at least one chronic and sometimes life-threatening health problem within 20 to 30 years after the cancer diagnosis.
Cytogenetic profiles
Based on a series of 493 neuroblastoma samples, it has been reported that overall genomic pattern, as tested by array-based karyotypingVirtual Karyotype
Virtual karyotype detects genomic copy number variations at a higher resolution level than conventional karyotyping or chromosome-based comparative genomic hybridization .-Background:...
, is a predictor of outcome in neuroblastoma:
- Tumors presenting exclusively with whole chromosome copy number changes were associated with excellent survival.
- Tumors presenting with any kind of segmental chromosome copy number changes were associated with a high risk of relapse.
- Within tumors showing segmental alterations, additional independent predictors of decreased overall survival were N-mycN-MycV-myc myelocytomatosis viral related oncogene, neuroblastoma derived , also known as MYCN, is a protein which in humans is encoded by the MYCN gene.- Function :...
amplification, 1p and 11q deletions, and 1q gain.
Earlier publications categorized neuroblastomas into three major subtypes based on cytogenetic profiles:
- Subtype 1: favorable neuroblastoma with near triploidy and a predominance of numerical gains and losses, mostly representing non-metastatic NB stages 1, 2 and 4S.
- Subtypes 2A and 2B: found in unfavorable widespread neuroblastoma, stages 3 and 4, with 11q loss and 17q gain without N-myc amplification (subtype 2A) or with N-myc amplification often together with 1p deletions and 17q gain (subtype 2B).
Virtual karyotyping
Virtual Karyotype
Virtual karyotype detects genomic copy number variations at a higher resolution level than conventional karyotyping or chromosome-based comparative genomic hybridization .-Background:...
can be performed on fresh or paraffin-embedded tumors to assess copy number at these loci. SNP array virtual karyotyping is preferred for tumor samples, including neuroblastomas, because they can detect copy neutral loss of heterozygosity (acquired uniparental disomy). Copy neutral LOH can be biologically equivalent to a deletion and has been detected at key loci in neuroblastoma. ArrayCGH, FISH, or conventional cytogenetics cannot detect copy neutral LOH.
Epidemiology
Neuroblastoma comprises 6-10% of all childhood cancers, and 15% of cancer deaths in children. The annual mortality rate is 10 per million children in the 0- to 4-year-old age group, and 4 per million in the 4- to 9-year old age group.The highest incidence is in the first year of life, and some cases are congenital. The age range is broad, including older children and adults, but only 10% of cases occur in people older than 5 years of age. A large European study reported less than 2% of over 4000 neuroblastoma cases were over 18 years old.
History
Rudolf Virchow
Rudolph Carl Virchow was a German doctor, anthropologist, pathologist, prehistorian, biologist and politician, known for his advancement of public health...
was the first to describe an abdominal tumor in a child as a "glioma". The characteristics of tumors from the sympathetic nervous system and the adrenal medulla were then noted in 1891 by German pathologist Felix Marchand
Felix Jacob Marchand
Felix Jacob Marchand was a German pathologist who was born in Halle an der Saale. He studied medicine in Berlin, and later became an assistant at the pathological institute in Halle. In 1881 he became a professor of pathological anatomy in Giessen, and two years later garnered the same position at...
.
In 1901 the distinctive presentation of stage 4S in infants (liver but no bone metastases) was described by William Pepper. In 1910 James Homer Wright
James Homer Wright
Dr. James Homer Wright was an early and influential American pathologist, who from 1896 to 1926 was chief of pathology at Massachusetts General Hospital. Wright was born in Pittsburgh, Pennsylvania....
understood the tumor to originate from primitive neural cells, and named it neuroblastoma. He also noted the circular clumps of cells in bone marrow samples which are now termed "Homer-Wright pseudorosettes."
Treatments
Recent focus has been to reduce therapy for low and intermediate risk neuroblastoma while maintaining survival rates at 90%. A study of 467 intermediate risk patients enrolled in A3961 from 1997 to 2005 confirmed the hypothesis that therapy could be successfully reduced for this risk group. Those with favorable characteristics (tumor grade and response) received four cycles of chemotherapy, and those with unfavorable characteristics received eight cycles, with three-year event free survival and overall survival stable at 90% for the entire cohort. Future plans are to intensify treatment for those patients with aberration of 1p36 or 11q23 chromosomes as well as for those who lack early response to treatment.By contrast, focus the past 20 years or more has been to intensify treatment for high-risk neuroblastoma. Chemotherapy induction variations, timing of surgery, stem cell transplant regimens, various delivery schemes for radiation, and use of monoclonal antibodies and retinoids to treat minimal residual disease continue to be examined. Recent phase III clinical trials with randomization have been carried out to answer these questions to improve survival of high-risk disease:
- 1982-1985: European Neuroblastoma Study Group (ENSG1) enrolled 167 children and randomized to melphalan autologous bone marrow transplant or no further therapy (no radiation therapy given to any). Transplant and no-transplant arms each had 65 patients, and recent long-term follow-up report revealed significantly better 5 year event-free survival for stage 4 over 1 year old in melphalan-transplant group versus no further treatment: 33% versus 17% respectively.
- 1990-1999: European study (EU-20592 or CCLGNB-1990-11) randomized 262 high-risk children over 1 year old and revealed higher survival rate for rapid sequence induction (10-day cycle) versus standard induction (21-day cycle) with same total dose. Ten-year event free survival was 27% and 18% respectively with non-aggressive surgical approach, no radiotherapy, and melphalan-only autologous bone marrow or stem cell transplant for both groups.
- 1991-1996: Phase III trial with two sequential randomizations for 379 high-risk NB patients was carried out by the Children's Cancer Group (CCG-3891) which demonstrated improved survival with myeloablative therapy (with total body irradiation) and 13-cis-retinoic acid (Accutane) with 50 patients in each of the four arms of the study.,
- 1996-2003: The German (GPOH) study NB97 compared outcomes of 295 high-risk NB patients randomized for stem cell transplant or consolidation chemotherapy. Results showed increased survival with transplant.
- 2000-2006: The recent study (COG-A3973) questioned the need for purged stem cells for CEM-LI (carboplatin, etoposide, melphalan, with local irradiation) transplant, and accrued 486 patients. Purging stem cells was not found to improve survival
- 2000-2012: A concurrent study (COG-ANBL0032) determined in early review that the antibody ch14.18 with interleukin 2Interleukin 2Interleukin-2 is an interleukin, a type of cytokine immune system signaling molecule, which is a leukocytotrophic hormone that is instrumental in the body's natural response to microbial infection and in discriminating between foreign and self...
and GMCSF (studied retrospectively in German GPOH NB90 and NB 97 at a lower dose and without cytokines) improved survival, and will accrue a total of 423 patients. A follow on Phase III study COG-ANBL0931 opened Jan 2010 to accrue 105 patients to gather further safety and efficacy data for FDA approval. - 2002-2008: SIOP (International Society of Paediatric Oncology) formed the European SIOP Neuroblastoma Group (ESIOP NB) in 1994 and activated a phase III high-risk NB protocol in 2002 (SIOP-EUROPE-HR-NBL-1) using “rapid” COJEC (8 cycles of chemotherapy given at 10-day intervals) followed by transplant randomization to CEM (carboplatin, etoposide, melphalan) or BuMel (busulfan, melphalan) and the study has been recently amended to randomize children to ch14.18 antibody treatment with or without subcutaneous IL2 (without GM-CSF as given in the COG). This study recently reported the benefit of growth factors (GCSF), and all patients receive retinoic acid. This trial will accrue 1000 patients (175 per year).
- 2005-2010: The current German NB2004 randomization will include MIBG therapy and randomize topotecan use in up-front therapy and will accrue a total of 642 for all risk groups (roughly half will be high-risk). After transplant, the high-risk protocol includes six months of cis-retinoic acid, a three month break, and another three months of retinoic acid.
- 2007: The COG phase III ANBL0532 trial opened December 2007 for accrual of 495 and will compare single versus tandem transplants, and induction begins with two cycles of topotecan.
In addition to these phase III studies, some research institutions offer pilot treatment protocols. For example, St Jude's recently finished (2007) testing a new up-front chemotherapy regimen in 23 children which included irinotecan
Irinotecan
Irinotecan is a drug used for the treatment of cancer.Irinotecan prevents DNA from unwinding by inhibition of topoisomerase 1. In chemical terms, it is a semisynthetic analogue of the natural alkaloid camptothecin....
and gefitinib
Gefitinib
Gefitinib INN , trade name Iressa, is a drug used in the treatment of certain types of cancer, particularly those with mutated and overactive EGFR. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor in target cells...
with 16 months of maintenance chemotherapy after stem cell transplant with alternating oral 13-cis-retinoic acid and topotecan
Topotecan
Topotecan hydrochloride is a chemotherapy agent that is a topoisomerase I inhibitor. It is the water-soluble derivative of camptothecin...
. Memorial Sloan-Kettering Cancer Center in New York offers treatment that includes a mouse-derived monoclonal antibody, 3F8
3F8
3F8 is a murine IgG3 monoclonal antibody which binds to GD2.It has been used in the detection and treatment of neuroblastoma. For imaging neuroblastoma, it is labelled with one of the radioisotopes iodine-124 and iodine-131....
, used in protocols since the mid 1980s. This antibody is used for treating minimal residual disease or consolidation instead of stem cell transplant. A new pilot protocol COG-ANBL09P1 available for newly diagnosed (high-risk) children at several Children's Oncology Group (COG) centers will offer MIBG radiotherapy and chemotherapy for the transplant regimen.
Refractory and relapsed neuroblastoma
Chemotherapy with topotecan and cyclophosphamide is frequently used in refractory setting and after relapse. A randomized study (2004) with 119 patients (comparing topotecan alone to topotecan and cyclophosphamide) revealed a 31% complete or partial response rate with two-year progression-free survival at 36% in the topotecan and cyclophosphamide group. Irinotecan (intravenous or oral) and oral temozolomide are also used in refractory and recurrent neuroblastoma.
Many phase I and phase II trials are currently testing new agents against neuroblastoma in children who have relapsed or are resistant to initial therapy. Investigators are currently studying new agents, alone and in new combinations, using small molecule targeted therapy
Targeted therapy
Targeted therapy is a type of medication that blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with rapidly dividing cells...
, 131-I MIBG radiation therapy, angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
agents, new monoclonal antibodies
Monoclonal antibodies
Monoclonal antibodies are monospecific antibodies that are the same because they are made by identical immune cells that are all clones of a unique parent cell....
, vaccines, oncolytic viruses, as well as new myeloablative regimens.
A group of 16 children’s hospitals in the United States known as the New Advances in Neuroblastoma Therapy (NANT) consortium coordinates the I-131 MIBG radiation therapy trials. The NANT consortium also offers trials using an oral powder formulation of fenretinide
Fenretinide
Fenretinide is a synthetic retinoid deriverative. Retinoids are substances related to vitamin A. It has been investigated for potential use in the treatment of cancer, as well as in the treatment of cystic fibrosis, rheumatoid arthritis, acne, psoriasis, and has been found to also slow the...
, intravenous fenretinide, bisphosphonate
Bisphosphonate
Bisphosphonates are a class of drugs that prevent the loss of bone mass, used to treat osteoporosis and similar diseases...
(Zometa) with other agents, and combining I-131 MIBG with the inhibitor vorinostat
Vorinostat
Vorinostat or suberoylanilide hydroxamic acid is a member of a larger class of compounds that inhibit histone deacetylases...
.
Other research study groups such as The Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC) also conduct clinical trials to treat relapse neuroblastoma. Institutions in Europe are studying novel therapies to treat relapse, including haploidentical stem cell transplant. Many hospitals conduct their own institutional studies as well.
The protein p53 is believed to play a role in the development of resistance to chemotherapy. A November 2009 study in mice shows that activating the tumor suppressor p53 with a new drug, nutlin-3, may slow tumor growth. In this study, physician Tom Van Maerken of Ghent University Hospital in Belgium and his colleagues used nutlin-3 to neutralize MDM2, a protein that binds to the p53 protein and obstructs p53’s ability to trigger programmed cell death. Earlier studies have shown that nutlin-3 can specifically prevent MDM2 from disabling p53.
Legislative efforts
U.S. Representative Chet EdwardsChet Edwards
Thomas Chester "Chet" Edwards is a former member of the United States House of Representatives from Texas. He represented a district based in Waco, Texas from 1991 to 2011, and served in the Texas Senate from 1983 until 1990. He is a member of the Democratic Party...
of Waco
Waco, Texas
Waco is a city in and the county seat of McLennan County, Texas. Situated along the Brazos River and on the I-35 corridor, halfway between Dallas and Austin, it is the economic, cultural, and academic center of the 'Heart of Texas' region....
, Texas
Texas
Texas is the second largest U.S. state by both area and population, and the largest state by area in the contiguous United States.The name, based on the Caddo word "Tejas" meaning "friends" or "allies", was applied by the Spanish to the Caddo themselves and to the region of their settlement in...
, successfully introduced legislation to earmark $150 million toward a cure for neuroblastoma and other cancers. The measure was signed into law in July 2008 by U.S. President George W. Bush
George W. Bush
George Walker Bush is an American politician who served as the 43rd President of the United States, from 2001 to 2009. Before that, he was the 46th Governor of Texas, having served from 1995 to 2000....
. Edwards was inspired in the endeavor by the illness and subsequent death of Erin Channing Buenger (1997–2009) of Bryan
Bryan, Texas
Bryan is a city in Brazos County, Texas, United States. As of the 2010 census, the city had a total population of 76,201. It is the county seat of Brazos County and is located in the heart of the Brazos Valley . It shares its border with the city of College Station, which lies to its south...
, daughter of one of his constituents, Walter L. Buenger
Walter L. Buenger
Walter Louis Buenger is an historian of Texas and the American South and, since 2003, the head of the department of history at Texas A&M University in College Station.-Background:...
, head of the history department at Texas A&M University
Texas A&M University
Texas A&M University is a coeducational public research university located in College Station, Texas . It is the flagship institution of the Texas A&M University System. The sixth-largest university in the United States, A&M's enrollment for Fall 2011 was over 50,000 for the first time in school...
.
External links
- VIDEO - Neuroblastoma: New Advances in the Treatment of a Deadly Disease Dr. Kenneth DeSantes speaks at the University of Wisconsin-Madison School of Medicine and Public Health. 2011.