Neuroblastoma

Practice Essentials

Neuroblastoma (NB) is a poorly differentiated neoplasm derived from neural crest cells. It is the most common cancer in infants and the most common extracranial solid tumor in childhood. Median age at diagnosis is 17 months; 90% of patients are younger than 5 years at diagnosis, and less than 5% are adolescents or adults.^{[1, 2]} Neuroblastoma accounts for 7% of pediatric malignancies but for more than 10% of childhood cancer-related mortality.^[3]

Neuroblastomas originate in the adrenal medulla and paraspinal or periaortic regions.^[2] Its presentation varies, depending on the primary site of origin, metastatic burden, and metabolically active by-products, but 65% of primary neuroblastomas occur in the abdomen—40% in the adrenal gland—so most children present with abdominal symptoms, such as fullness or distension.

Neuroblastoma is remarkable in that it has a documented spontaneous rate of resolution and is also one of the few tumors in which the surgical capsule can be violated yet a good outcome might be achieved, even if residual tumor is left behind.

Signs and symptoms

Abdominal symptoms such as fullness or distention are the most common symptoms. However, children with localized disease are typically asymptomatic. Children with disseminated neuroblastoma are generally sick and may have systemic manifestations, including the following:

• Unexplained fevers
• Weight loss
• Anorexia
• Failure to thrive
• General malaise
• Irritability
• Bone pain

Infants often present with consequences of compression of the sympathetic ganglia in the thoracic region, such as Horner syndrome (myosis, anhydrosis, and ptosis) or superior vena cava syndrome. Older children typically present with abdominal symptoms; the most common physical examination finding is a nontender, firm, irregular abdominal mass that crosses the midline.

See Presentation for more detail.

Diagnosis

Recommended laboratory studies include the following:

• Complete blood cell (CBC) count and differential
• Urine collection for catecholamines and urinalysis
• Erythrocyte sedimentation rate
• Vanillylmandelic acid–to–homovanillic acid (VMA-to-HVA) ratio

Neuron-specific enolase (NSE), lactate dehydrogenase (LDH), and ferritin are markers useful in the identification of active disease.

Standard diagnostic imaging modalities include the following:

• Plain abdominal radiography (kidneys, ureters, bladder [KUB])
• Renal/bladder ultrasonography
• Bone scintigraphy
• Computed tomography (CT) or magnetic resonance imaging (MRI)

Biopsy is the sine qua non in the diagnostic evaluation of neuroblastoma.

See Workup for more detail.

Treatment

Treatment of neuroblastoma is risk based.^[2]

Low-risk neuroblastoma:

• Observation, with or without biopsy
• Surgical resection, then observation
• Chemotherapy, with or without surgery, for symptomatic disease or unresectable progressive disease after surgery
• Radiation therapy (for emergency treatment only)

Intermediate-risk neuroblastoma:

• Multiple-agent chemotherapy (eg, doxorubicin, cyclophosphamide, cisplatin or carboplatin, and etoposide)
• Chemotherapy is often given before definitive resection
• Surgery and observation (in infants).
• Radiation therapy (if needed)

High-risk neuroblastoma:

• Chemotherapy, surgery, tandem cycles of myeloablative therapy and hematopoietic stem cell transplantation, radiation therapy, and dinutuximab, with granulocyte-macrophage colony-stimulating factor (GM-CSF) and isotretinoin.
• Eflornithine, to reduce the risk of relapse after at least partial response to prior multiagent therapy

See Treatment for more detail.

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Background

Virchow first described neuroblastoma in 1864; at that time, it was referred to as a glioma.^[4]  In 1891, Marchand histologically linked neuroblastoma to sympathetic ganglia.^[5]  More substantial evidence of the neural origins of neuroblastoma became apparent in 1914, when Herxheimer showed that fibrils of the tumor stained positively with special neural silver stains.^[6]

In 1927, Cushing and Wolbach further characterized neuroblastoma by describing the transformation of malignant neuroblastoma into its benign counterpart, ganglioneuroma.^[7]  Everson and Cole reported that this type of transformation is rare in children older than 6 months.^[8]  In 1957, Mason published a report of a child with neuroblastoma whose urine contained pressor amines.^[9]  This discovery further contributed to the understanding of neuroblastoma and its possible sympathetic neural origin.

Spontaneous regression of microscopic clusters of neuroblastoma cells, called neuroblastoma in situ, was noted to occur quite commonly. According to Beckwith and Perrin in 1963, regression occurs nearly 40 times more often than clinically apparent neuroblastoma.^[10]

Neuroblastoma is one of the small, blue, round cell tumors of childhood. Other such tumors include the following:

• Ewing sarcoma
• Non-Hodgkin lymphoma
• Primitive neuroectodermal tumors
• Undifferentiated soft tissue sarcoma (rhabdomyosarcoma)

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Relevant Anatomy

During the fifth week of embryogenesis, primitive sympathetic neuroblasts migrate from the neural crest to the site where the adrenal anlage eventuates into the developing embryo. These neuroblasts migrate along the entire sympathetic chain; therefore, neuroblastoma can arise  anywhere along the sympathetic nervous system, in the adrenal glands and in the paraspinal nerves from the neck to the pelvis.^[2] The name neuroblastoma is derived from the fact that the cells resemble primitive neuroblasts.

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Pathophysiology

Embryologically, tumors of the sympathetic nervous system differentiate along one of two distinct pathways: the pheochromocytoma line or the sympathoblastoma line.^[11] The sympathoblastomas, also called neurocristopathies, include the well-differentiated ganglioneuroma, the moderately differentiated ganglioneuroblastoma, and the malignant neuroblastoma. All of these tumors arise from primordial neural crest cells, which ultimately populate the sympathetic chain and the adrenal medulla.^[12]  

Amplification of the MYCN oncogene occurs in 20% of primary neuroblastoma tumors and 50% of high-risk tumors; it is associated with high rates of metastasis and a poor prognosis in children older than 1 year but not in children younger than 1 year.^[13] The precise role of MYCN in nonamplified tumors is unknown.

Hyperdiploid tumor DNA is associated with a favorable prognosis. N-myc amplification is associated with a poor prognosis In 2000, Maris et al reported from the Children's Cancer Group (CCG) that 1p deletion independently predicted a lower event-free survival but not overall survival. The clinical relevance of 14q LOH is unclear at this time.

Allelic loss of 11q is present in 35-45% of primary tumors. Notably, this aberration is rarely seen in tumors with MYCN amplification yet remains highly associated with other high-risk features.

Bosse and colleagues identified Glypican-2 (GPC2) as a molecule specifically expressed by neuroblastoma cells and not by normal tissues. GPC2 expression has been detected on the cell surface in the majority of high-risk neuroblastoma, and such expression correlated with worse prognosis of neuroblastoma patients. GPC2 expression is driven by somatic gain of chromosome 7q (where the GPC2 gene is located) and by MYCN amplification. Additionally, Bosse et al developed a GPC2-directed antibody-drug conjugate with a potent cytotoxic activity against GPC2-expressing neuroblastoma cells, which may represent a promising immunotherapeutic target for high-risk neuroblastoma.^[14]

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Etiology

About 1-2% of patients with neuroblastoma have a family history of the disease. Germline mutations associated with a genetic predisposition to neuroblastoma in these cases include the following^[2] :

• ALK mutation - Point mutations in the tyrosine kinase domain of the ALK gene are found in about 75% of familial neuroblastoma cases; somatic activating point mutations in ALK are also seen in about 9% of sporadic neuroblastoma cases. In addition, co-amplification of ALK and MYCN (the two genes are near each other on chromosome 2) occurs in a small proportion of neuroblastoma cases
• PHOX2B mutation - Germline loss-of-function PHOX2B mutations have been identified in rare patients with sporadic neuroblastoma and Ondine curse (congenital central hypoventilation) and/or Hirschsprung disease. Somatic PHOX2B mutations are found in about 2% of patients with sporadic neuroblastoma.
• Deletion at the 1p36 or 11q14-23 locus

Increased risk of malignancies including neuroblastoma have been noted in children with various cancer predisposition syndromes, including Costello syndrome, Noonan syndrome, and neurofibromatosis type 1.^[15]

Malignant transformation and maintenance of the dedifferentiated state of neural crest cells may result from failure of those cells to respond to normal signals that are responsible for normal morphologic differentiation. The factors involved in the cascade of events are poorly understood but most likely involve one or more ligand-receptor pathways. One of the most studied pathways is the nerve growth factor (NGF) and its receptor (NGFR). The dedifferentiated state of neuroblastoma leads to the variable presentations commonly observed in patients with neuroblastoma.

Environmental and paternal exposures linked to neuroblastoma have not been identified.^[16]

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Epidemiology

Frequency

Neuroblastoma is the most common cancer in infants. Approximately 700-800 cases are diagnosed each year in the United States, accounting for about 6% of cancers in children.^[1] Clinical frequency is approximately one case per 8000-10,000 children.

Neuroblastoma is more common in whites and is slightly more prevalent in boys than in girls (male-to-female ratio of 1.3:1). In rare cases, neuroblastoma is detected by prenatal ultrasound. About 37% of cases are diagnosed in infancy, and nearly 90% of cases are diagnosed before the age of 5 years. Median age at diagnosis is 19 months.^[2] Neuroblastoma is rare in people over the age of 10 years.^[1] Neuroblastoma is thought to occur sporadically, with 1-2% of cases considered familial.

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Prognosis

For more than 40 years, the age at diagnosis and the stage have been the dominant independent variables used as prognostic factors in children with neuroblastoma. In 1984, Shimada et al classified neuroblastoma by relating its histopathologic features to its clinical behavior.^[17]  To this end, Shimada et al divided neuroblastoma into favorable and unfavorable categories, depending on the degree of neuroblast differentiation, Schwannian stromal content, mitosis-karyorrhexis index, and age at diagnosis. In 1999, the Shimada classification was modified to the International Neuroblastoma Pathology Classification system.

Because of the various approaches to risk stratification, efforts have been made to develop a consensus approach that will allow comparison of patients around the world. In 2009, the International Neuroblastoma Risk Group (INRG) Task Force published a classification based on the review of a large number of patients from Europe, Japan, the United States, Canada, and Australia diagnosed with neuroblastoma between 1974 and 2002.^[18] The Task Force identified the following as the most highly statistically significant and clinically relevant factors:

• Tumor stage
• Patient age
• Tumor histologic category
• Grade of tumor differentiation
• DNA ploidy
• Copy-number status of the MYCN oncogene
• Chromosome 11q status

On the basis of those factors the Task Force identified four broad prognostic clinical categories (see Workup/Risk Groups), which correlated with 5-year event-free survival (EFS) rates as follows^[18] :

• Very low risk: EFS  > 85%
• Low risk: EFS > 75% to 85%
• Intermediate risk: EFS 50% to 75%
• High risk: EFS < 50%

The Children's Oncology Group (COG) subsequently developed a process called the Neuroblastoma Risk Stratification System (NRSS), which is used for treatment stratification. The NRSS, which was most recently revised in 2021 (see Workup/Risk Groups) classifies patients into low-, intermediate-, or high-risk categories.^[19] Five-year EFS and overall survival (OS) rates are as follows:

• Low risk: EFS 90.7% ± 1.1%, OS 97.9% ± 0.5%
• Intermediate risk: EFS 85.1% ± 1.4%, OS 95.8% ± 0.8%
• High risk: EFS 51.2% ± 1.4%, OS 62.5% ± 1.3%

Other variables carry varying degrees of prognostic significance. These include the site of the primary tumor, serum ferritin levels, neuron-specific enolase (NSE) level, and nutritional status.

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History

Neuroblastoma has been called the great mimicker because of its myriad clinical presentations related to the site of the primary tumor, metastatic disease, and its metabolic tumor by-products. Sixty-five percent of primary neuroblastomas occur in the abdomen, with most of these occurring in the adrenal gland. As a result, most children present with abdominal symptoms, such as fullness or distension.

Obtaining a complete history and physical examination are paramount to an accurate diagnosis and subsequent management of neuroblastoma. Eliciting a history of the child's general appearance, recent trauma, changes in appetite and weight, and recurrent abdominal pain is important. Symptoms are usually related to either an abdominal mass or bone pain secondary to metastatic neuroblastoma. Reports of fatigue, bone pain, and changes in bowel or bladder habits may contribute to an accurate diagnosis. Physical findings might include hepatomegaly; blanching subcutaneous nodules; or a large, irregular, firm abdominal mass.

Typically, children with localized disease are asymptomatic, whereas children with disseminated neuroblastoma are generally sick and may have systemic manifestations, including unexplained fevers, weight loss, anorexia, failure to thrive, general malaise, irritability, and bone pain. 

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Physical Examination

The most common finding upon physical examination is a nontender, firm, irregular abdominal mass that crosses the midline. In contrast, children who present with Wilms tumor have a smooth mobile flank mass that typically does not cross the midline.

At diagnosis, the site of neuroblastoma is predictably age-dependent. Infants often present with compression of the sympathetic ganglia in the thoracic region, which might result, for example, in Horner syndrome (myosis, anhydrosis, and ptosis) or superior vena cava syndrome. Older children typically present with abdominal symptoms because, as stated above, more than 40% of neuroblastomas are adrenal in origin. Children who are preschool aged should have working differential diagnoses for an abdominal mass, including lymphoma, hepatoblastoma, rhabdomyosarcoma, renal cell carcinoma, and neuroblastoma.

More than 50% of patients who present with neuroblastoma have metastatic disease. The fact that many other syndromes related to metastatic neuroblastoma are also common in these patients is not surprising.

For example, Pepper syndrome occurs in infants with overwhelming metastatic neuroblastoma of the liver that results in respiratory compromise. Described by William Pepper in 1901, Pepper syndrome was identified as a localized primary tumor and metastatic disease limited to the skin, liver, and bone marrow in infants. Pepper syndrome has since been associated with stage 4S neuroblastoma, a unique entity that occurs only in infants younger than 1 year. Pepper syndrome generally confers a better prognosis, as it is associated with spontaneous regression. Some infants with stage 4S neuroblastoma, however, die of massive hepatomegaly, respiratory failure, and overwhelming sepsis.

"Blueberry muffin" babies are infants in whom neuroblastoma has metastasized to random subcutaneous sites. When provoked, the nodules become intensely red and subsequently blanch for several minutes thereafter. The response is probably secondary to the release of vasoconstrictive metabolic tumor by-products. These nodules can be diagnostic of neuroblastoma, but leukemic infiltrates that metastasize to the skin should be considered in the differential diagnoses when these children are evaluated.

Widespread metastasis of neuroblastoma to the bone may result in Hutchinson syndrome, which results in bone pain with consequent limping and pathologic fractures. Neuroblastomas that arise in the paraspinal ganglia may invade through the neural foramina, compress the spinal cord, and subsequently cause paralysis.

Infrequently, neuroblastoma can become metastatic to the retrobulbar region, leading to rapidly progressive, unilateral, painless proptosis; periorbital edema; and ecchymosis of the upper lid. This lesion often can be confused with trauma or child abuse. See the image below.

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Upper periorbital edema, proptosis, and ocular ecchymosis in a 9-month-old girl.

Most neuroblastomas produce catecholamines as metabolic by-products, which result in some of the most interesting presentations observed in children with neuroblastoma. For example, Kerner-Morrison syndrome causes intractable secretory diarrhea, resulting in hypovolemia, hypokalemia, and prostration. This syndrome is caused by vasoactive intestinal peptide (VIP) tumor secretion and is more commonly associated with ganglioneuroblastoma or ganglioneuroma. Kerner-Morrison syndrome typically resolves following the complete removal of the tumor.

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Laboratory Studies

General laboratory studies should be routinely obtained in children suspected of having neuroblastoma. Results are as follows:

• A complete blood cell count (CBC) should be obtained to determine if the child has anemia, which typically does not occur until the tumor has become widely disseminated; in patients with overwhelming bone marrow involvement, thrombocytopenia may also be present
• Once dissemination occurs, abnormalities in findings of coagulation studies (prothrombin time [PT], activated partial thromboplastin time [aPTT]) may occur secondary to liver involvement
• The erythrocyte sedimentation rate, a nonspecific acute-phase reactant, is elevated in classic neuroblastoma

Elevated metabolic catecholamine by-products can be detected in the urine of patients with neuroblastoma. The presence of these by-products serves as useful inclusion criteria when the diagnosis of neuroblastoma is being considered.

Phenylalanine and tyrosine are catecholamine precursors, which are converted through a sequence of enzymatic events to dihydroxyphenylalanine (DOPA), dopamine, norepinephrine, and epinephrine. DOPA and dopamine are metabolized into their final product, homovanillic acid (HVA), while norepinephrine and epinephrine are metabolized into vanillylmandelic acid (VMA).

Ninety percent of neuroblastoma tumors secrete these by-products. This fact becomes clinically relevant because children with dedifferentiated tumors excrete higher levels of HVA than VMA. This occurs because dedifferentiated tumors have lost the final enzymatic pathway that converts HVA to VMA. A low VMA-to-HVA ratio is consistent with a poorly differentiated tumor and indicative of a poor prognosis.

Neuroblastoma cells lack the enzyme that converts norepinephrine to epinephrine. Despite this fact, elevated levels of norepinephrine are not identified in the serum of patients with neuroblastoma. This might be explained by at least two processes: (1) norepinephrine may be catabolized within the tumor; and/or (2) tyrosine hydrolase, the initial enzyme in catecholamine synthesis, is subject to a negative feedback loop by norepinephrine.

A LaBrosse VMA spot test may be used to screen patients in certain institutions. It is economical but has low sensitivity and specificity.

High-performance liquid chromatography has a much lower false-positive rate and is more sensitive than the LaBrosse VMA spot test, but it is more expensive and is therefore often used only to confirm a positive result on a spot test.

Nonspecific tumor markers can be identified in patients with neuroblastoma.^[20] Neuron-specific enolase (NSE), lactate dehydrogenase (LDH), and ferritin are markers useful in the identification of active disease, as well as in prognostication. Approximately 96% of patients with metastatic neuroblastomas demonstrate an elevated NSE level, which has been associated with a poor prognosis.

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Imaging Studies

Radiographic assessment is recommended in all infants and children with an abdominal mass. The standard diagnostic imaging modalities include the following:

• Plain abdominal radiography (kidneys, ureters, bladder [KUB])
• Renal/bladder ultrasonography
• Bone scintigraphy
• Computed tomography (CT) or magnetic resonance imaging (MRI)

KUB most commonly reveals finely stippled calcifications of the abdomen or posterior mediastinum.

Renal/bladder ultrasonography improves the diagnostic evaluation and is probably the single best imaging modality to obtain. Ultrasonography is noninvasive and provides relevant information regarding the laterality, consistency, and size of the mass.

Abdominal CT scanning or MRI usually follows ultrasonography. Both of these studies are more invasive, in that they require general sedation for young children. The benefit is that they enhance the ultrasonographic findings by providing information about regional lymph nodes, vessel invasion, and distant metastatic disease. See the images below.

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CT scan in a 2-week-old boy noted to have an abdominal mass on a prenatal sonogram. This postnatal abdominal CT scan revealed a left suprarenal mass w....

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Abdominal CT scan in a 2-week-old boy noted to have an abdominal mass on a prenatal sonogram. A postnatal abdominal CT scan revealed a left suprarenal....

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A 2-week-old boy is noted to have an abdominal mass on prenatal ultrasound. A postnatal abdominal CT scan revealed a left suprarenal mass with mass ef....

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Bulky lymph nodes just medial to the left kidney.

Bone scintigraphy and a skeletal survey to detect cortical bone disease are helpful in the diagnosis of neuroblastoma. Metaiodobenzylguanidine (MIBG) is a compound taken up by catecholaminergic cells that competes for uptake even in neuroblastoma cells. In this way, MIBG is quite sensitive and specific in the detection of metastasis to bones and soft tissue, with highest sensitivity (91-97%) in the detection of bone deposits.^[21]

Bone scintigraphy using 99Tc diphosphonate and a skeletal bone survey to detect cortical bone disease are essential if MIBG scintigraphy results are negative in the bone. MIBG is recommended for re-assessment both during and after therapy in high-risk patients with MIBG-avid disease at diagnosis.

Expression of somatostatin (SS) receptors has been described in neuroblastoma cell lines and tumors. Studies have shown that these tumors can be successfully targeted with radioactive SS analogs as a method of detection. Currently, the indication for scanning with radio-labeled SS analog in children with neuroblastoma is not well-defined because this method is less sensitive than MIBG scanning (64% vs 94%). However, because the presence of neuroblastoma SS receptors is associated with favorable clinical and biological prognostic factors, radio-labeled SS analog could provide valuable information. In fact, improved survival has been found in patients with SS receptor–positive neuroblastoma. However, more studies need to be performed to confirm the benefits of SS receptor scanning.

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Diagnostic Procedures

Biopsy is the sine qua non in the diagnostic evaluation of neuroblastoma. To confirm the diagnosis of neuroblastoma, histologic evidence of neural origin or differentiation is required. Samples of tumor tissue can be viewed via light or electron microscopy or via immunohistochemistry. Although open surgical biopsy has traditionally been advocated, Mullassery and colleagues reported that image-guided needle biopsy can also yield adequate tissue samples.^[22]

Another option is to sample bone marrow, a frequent metastatic site for neuroblastoma. The literature is confusing in terms of the number of bone marrow aspirates or biopsies needed to diagnose neuroblastoma. An international committee on neuroblastoma staging has recommended obtaining two bone marrow aspirates and two biopsies, one from each posterior iliac crest.

The issue of biopsies might become obsolete because immunocytology of marrow aspirates may offer the single best source of diagnostic information. A large body of published work has addressed the use of immunocytochemical and polymerase chain reaction (PCR)–based technologies to detect neuroblastoma cells and neuroblastoma-specific transcripts such as tyrosine hydroxylase and disialoganglioside (GD2) synthase in marrow or blood samples.^[23] This method is used to assess minimal disease during the course of treatment. Although these techniques can greatly increase sensitivity, whether this increased sensitivity provides prognostic information about the likelihood of relapse is still unclear.

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Histologic Findings

The three distinct histologic patterns of the neurocristopathies include neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. They represent a spectrum of maturation and dedifferentiation. The typical neuroblastoma is characterized by small uniform cells that contain dense hyperchromatic nuclei and scant cytoplasm. A neuritic process called neuropil is pathognomonic of all except the most primitive neuroblastoma. Homer-Wright pseudorosettes are clusters of neuroblasts surrounding areas of eosinophilic neuropil and are observed in 15-50% of patients. If identified, they are diagnostic of neuroblastoma.

The minimal diagnostic criteria for diagnosing neuroblastoma have been established by an international group of conferees and corresponding participants. These criteria include (1) unequivocal pathologic diagnosis or (2) unequivocal bone marrow (syncytia) and elevated levels of urinary catecholamine metabolic by-products. Both of these diagnostic criteria require a histopathologic diagnosis.

Molecular pathogenesis

The cancer genes most commonly altered in adult carcinogenesis (eg, TP53, CDKN2A, ras) are rarely aberrant in neuroblastoma. TP53-inactivating mutations are uncommon in primary tumors due to neuroblastoma, although they have been documented in cell lines among patients with relapsing neuroblastoma.^[24] Thus, with the exception of MYCN, major pathways of human neoplasia do not seem to be deregulated. Indeed, the only reliable genetically engineered murine model of neuroblastoma results from targeted overexpression of human MYCN copy DNA to the murine neural crest.

Activating mutations in the tyrosine kinase domain of the anaplastic lymphoma kinase (ALK) gene occur in the majority of hereditary neuroblastoma cases, and also in some sporadic cases of advanced neuroblastoma. Subclonal ALK mutations can be present at diagnosis, with subsequent clonal expansion at relapse.^[25]

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Staging

At least six different staging systems for neuroblastoma exist. Historically, each staging system represents a temporal improvement in the understanding of the tumor. However, the presence of so many systems has not only confounded the literature but also complicated the comparison of studies between institutions. In 1988, the International Neuroblastoma Staging System (INSS) was established to provide a uniform staging system.^[26]

The INSS is a clinical, radiographic, and surgical appraisal of children with neuroblastoma. The system combines many of the most important diagnostic criteria from each of the staging systems and includes initial distribution and surgical resectability of the tumor.

Specific requirements to stage neuroblastoma include the following:

• Bone marrow aspirates and biopsy samples
• Body CT scan (excluding head, if not clinically indicated)
• Bone scan
• MIBG scintigraphy

Arabic numerals are used to distinguish INSS staging from other systems. INSS stages are as follows:

• Stage 1 is characterized by a localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes that test negative for tumor are present microscopically (nodes attached to and removed with the primary tumor may test positive)
• Stage 2A is characterized by a localized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph nodes that test negative for tumor are present microscopically
• Stage 2B is characterized by a localized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes that test positive for tumor; enlarged contralateral lymph nodes must test negative microscopically
• Stage 3 is an unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node involvement; a localized unilateral tumor with contralateral regional lymph node involvement; or a midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement (the midline is defined as the vertebral column; tumors that originate on one side and cross the midline must infiltrate to or beyond the opposite side of the vertebral column)
• Stage 4 is any primary tumor disseminated to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs (except as defined for stage 4S)
• Stage 4S (S = special) occurs in infants younger than 12 months and is characterized by a localized primary tumor (as defined for stage 1, 2A, or 2B), with dissemination limited to skin, liver, and/or bone marrow

Other features of stage 4S include the following:

• Marrow involvement should be minimal (ie, < 10% of total nucleated cells identified as malignant via bone biopsy or bone marrow aspirate); more extensive bone marrow involvement is considered stage 4 disease
• The results of the MIBG scan (if performed) should be negative for disease in the bone marrow.

Stage 4S is the most unusual group, comprising approximately 5% of patients with neuroblastoma. All else being equal, these children would normally be classified as having stage 1 or 2 disease; however, disease in this special group of infants almost always spontaneously regresses. Nonetheless, infants younger than 2 months frequently develop extensive and rapidly progressive intrahepatic expansion of neuroblastoma that can result in respiratory compromise. The 5-year survival rate in patients with stage 4S disease is 75%.

Stage for stage, infants with neuroblastoma have a better prognosis than older children. In fact, statistically, age is the most significant clinical prognosticator for neuroblastoma. Forty percent of infants (< 1 y) have localized neuroblastoma, compared with 20% of children older than 1 year. Additionally, nearly 70% of children older than 1 year have disseminated neuroblastoma, compared with less than 25% of infants.

The INSS is a postsurgical staging system. In 2009, the International Neuroblastoma Risk Group published a pretreatment risk classification system, the International Neuroblastoma Risk Group Staging System (INRGSS).^[27] This system classifies neuroblastomas as locoregional (L), based on the absence or presence of one or more of 20 image-defined risk factors (IDRFs), or metastatic (M). Stages are as follows:

• L1 – Localized tumor not involving vital structures and confined to one body compartment
• L2 – Locoregional tumor with presence of one or more IDRFs
• M – Distant metastatic disease (except stage MS)
• MS – Metastatic disease in children younger than 18 months with metastases confined to skin, liver, and/or bone marrow

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Risk Groups

The Children’s Oncology Group (COG) uses the major prognostic factors, including those based on imaging studies, to place children into three risk groups: low, intermediate, and high.^[28] COG risk groups are used to guide treatment selection.

In the 2006 version, COG defines low-risk group criteria as follows:

• Stage 1 disease
• Stage 2A or 2B disease, patient age younger than 12 months
• Stage 2A or 2B disease, no extra copies of the MYCN gene, resection ≥50%
• Stage 4S disease, patient age < 12 months, no extra copies of MYCN, hyperdiploid  (DNA index > 1), favorable histology, asymptomatic

Intermediate-risk group criteria are as follows:

• Stage 2A or 2B disease, age ≤12 years, no extra copies of MYCN, biopsy or resection < 50%
• Stage 3 disease, age < 18 months, no extra copies of MYCN, any DNA ploidy or histology
• Stage 3 disease, age 18 months–12 years, no extra copies of MYCN, favorable histology
• Stage 4 disease, age < 12 months, no extra copies of MYCN
• Stage 4 disease, age 12 to < 18 months, no extra copies of MYCN, DNA index > 1,favorable histology
• Stage 4S disease, age < 12 months, no extra copies of MYCN, symptomatic
• Stage 4S disease, age < 12 months, no extra copies of MYCN, DNA index = 1, asymptomatic or symptomatic
• Stage 4S disease, age < 12 months, no extra copies of MYCN, unfavorable histology, asymptomatic or symptomatic
• Stage 4S disease, age < 12 months; MYCN status, DNA ploidy, and histology missing; too sick for biopsy

High-risk group criteria are as follows:

• Stage 2A or 2B disease, any age, extra copies of MYCN, any DNA ploidy or histology, any degree of resection
• Stage 3 disease, any age, extra copies of MYCN
• Stage 3 disease, age ≥ 18 months, no extra copies of MYCN, unfavorable histology
• Stage 4 disease, age < 12 months, extra copies of MYCN
• Stage 4 disease, age 12 to < 18 months, extra copies of MYCN
• Stage 4 disease, age 12 to < 18 months, any MYCN status, DNA index = 1, any histology
• Stage 4 disease, age 12 to < 18 months, any MYCN status or DNA ploidy, unfavorable histology
• Stage 4 disease; age ≥ 18 months; any MYCN status, DNA ploidy, or histology
• Stage 4S disease, age < 12 months; extra copies of MYCN; any DNA ploidy or histology; asymptomatic or symptomatic

The most recent revision of the COG risk group classification, published in 2021, uses the International Neuroblastoma Risk Group Staging System (INRGSS; see Staging) and International Neuroblastoma Pathology Classification (INPC) histology and incorporates loss or gain of a portion of a chromosome arm at 1p or 11q, termed segmental chromosome aberrations (SCA), as an additional genomic biomarker.^[19]

Low-risk neuroblastoma criteria comprise the following:

• INRGSS L1; no MYCN amplification; any SCA, DNA ploidy, or INPC
• INRGSS L1; MYCN amplification; any SCA, DNA ploidy, or INPC; gross total surgical resection (otherwise this qualifies as high risk)

Intermediate-risk neuroblastoma criteria comprise the following:

• INRGSS L2, age < 18 months, no MYCN amplification, SCA absent, DNA pIoidy index > 1, favorable INPC histology
• INRGSS L2; age < 18 months; no MYCN amplification; any SCA, DNA ploidy, or INPC
• INRGSS L2, age 18 months to 5 years, no MYCN amplification, any SCA or DNA ploidy, favorable INPC histology
• INRGSS L2, age ≥5 years, no MYCN amplification, any SCA or DNA ploidy, unfavorable INPC histology but histologic differentiation

High-risk neuroblastoma criteria comprise the following:

• INRGSS L2; MYCN amplification; any SCA, DNA ploidy, or INPC
• INRGSS L2, age 18 months to 5 years, no MYCN amplification, any SCA or DNA ploidy, unfavorable INPC histology
• INRGSS L2, age ≥5 years, no MYCN amplification, any SCA or DNA ploidy, unfavorable INPC histology (undifferentiated or poorly differentiated)

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Approach Considerations

Spontaneous regression of neuroblastoma occurs commonly in infants with asymptomatic, small, low-stage adrenal neuroblastoma detected by screening or during prenatal or incidental ultrasonography. Observation, without surgical intervention or tissue diagnosis, may be a safe option in these patients.^[2]

In 1988, the Pediatric Oncology Group (POG) released a prospective study showing that patients with localized neuroblastoma who were treated with surgical extirpation had a 2-year disease-free survival rate of 89%.^[29]  Additionally, chemotherapy appeared to offer no advantage when residual disease was present in these patients. Thus, in patients with low-stage favorable disease, surgery is the mainstay of therapy. The primary goals of surgery are as follows: 

1. Determine an accurate diagnosis
2. Completely remove all of the primary tumor
3. Provide accurate surgical staging
4. Offer adjuvant therapy for delayed primary surgery
5. Remove residual disease with second-look surgery

As stated above, surgery plays a major role in children with low-stage disease. It has a controversial role in children with advanced disease, especially as it applies to the extent of surgical resection. A multimodal approach is suggested for the management of children with advanced neuroblastoma. Multiple-agent chemotherapy has increased the 5-year survival rate to 75% in patients younger than 1 year. Radiation therapy has been shown to produce superior initial and long-term disease control when administered synergistically with chemotherapy. In any event, follow-up of these patients follows a clear POG protocol.

Adult-onset neuroblastoma is rare, and there is no established therapy for it. Anti-disialoganglioside (anti-GD2) immunotherapy may be beneficial in these patients.^[30]

For relapsed high-risk neuroblastoma, studies have reported response to a variety of chemotherapy regimens. However, the most effective therapeutic strategy for these patients has not been determined.^[31]

• References

Medical Therapy

Because surgery is used to manage only low-stage (stages I and II) neuroblastoma, multiple-agent chemotherapy is the conventional therapy for patients with more advanced stages of neuroblastoma. Interestingly, infants with disseminated neuroblastoma have favorable outcomes with combined chemotherapy and surgery. In contrast, children older than 1 year with high-stage neuroblastoma have very poor survival rates despite intensive multimodal therapy.^[32]

Because of these findings, pioneering work in Japan during the 1980s claimed that aggressive screening of infants younger than 6 months with urinary catecholamines could detect neuroblastoma earlier and lead to better outcomes. However, follow-up population-based, controlled trials in Europe and North America did not confirm the benefit of early screening reported in the Japanese studies.

Despite these contradictory findings, symptomatic treatments are available for patients with neuroblastoma. Adrenocortical hormone (ACTH) is thought to be fairly efficacious, although some cases are resistant. Plasmapheresis and gamma globulin have been used in the treatment of selected patients with neuroblastoma, but chemotherapeutic agents are thought to result in better neurological outcomes.

Commonly used chemotherapeutic agents include cisplatin, doxorubicin, cyclophosphamide, and the epipodophyllotoxins (teniposide and etoposide). Drug combination protocols have used strategies that take advantage of drug synergism, mechanisms of toxicity, and differences of adverse effects.

A randomized, multi-arm, open-label, phase 3 trial in children with high-risk neuroblastoma who had an adequate response to induction treatment found that busulfan plus melphalan improved event-free survival and caused fewer severe adverse events than did carboplatin, etoposide, and melphalan. The 3-year event-free survival was 50% (95% confidence index [CI] 45-56%) with busulfan plus melphalan versus 38% (95% CI, 32-43%; P=0.0005) with carboplatin, etoposide, and melphalan. The researchers concluded that busulfan and melphalan should be considered standard high-dose chemotherapy.^[33]

Despite these various drug combinations, the cure rate has not been significantly affected. The long-term survival in patients with metastatic neuroblastoma is poor, perhaps because of the abundance of nonproliferating tumor cells. However, chemotherapeutic agents used to manage neuroblastoma have reduced the size of the primary tumor, occasionally sterilized the bone marrow, and, rarely, transformed the neuroblastoma into benign ganglioneuroma.

Current trends in chemotherapy for the management of neuroblastoma include (1) more dose-intensive chemotherapy with secondary surgical extirpation, (2) myeloablative therapy using escalating chemotherapeutic combinations followed by autologous bone marrow infusion, and (3) biologic response modifiers that cause tumor differentiation and a reduction in tumor involvement of the bone marrow. Some of these seminal chemotherapeutic trials have demonstrated promising results. Multimodal therapeutic protocols established by the POG are the standard of care in children with neuroblastoma.

Topotecan, a topoisomerase I inhibitor, alone or in combination with cyclophosphamide, has been shown to have activity against recurrent neuroblastoma. A Thai study reported a favorable treatment response with minimal toxicity in 107 patients with high-risk neuroblastoma who received six cycles of the following induction regimen^[34] :

• Two cycles of topotecan (1.2 mg/m²/day) and cyclophosphamide (400 mg/m²/day) for 5 days followed by cisplatin (50 mg/m²/day) for 4 days plus
• Etoposide (200 mg/m²/day) for 3 days on the third and fifth cycles plus
• Cyclophosphamide (2100 mg/m²/day) for 2 days combined with doxorubicin (25 mg/m²/day) and vincristine (0.67 mg/m²/day) for 3 days on the fourth and sixth cycles

However, a European open-label, multicenter, prospective randomized controlled trial in 422 patients with high-risk neuroblastoma reported disappointing results with the addition of two courses of topotecan, cyclophosphamide, and etoposide to six courses of standard induction chemotherapy. Patients receiving the additional courses did not have significantly improved event-free or overall survival, and they experienced a higher number of toxic adverse effects.^[35]

Retinoids (natural and synthetic derivatives of vitamin A) have been shown in vitro to down-regulate MYCN mRNA expression, which arrests tumor cell proliferation. These observations have led to clinical trials designed to test the efficacy of 13-cis-retinoic acid in children with relapsed neuroblastoma. In phase I and II trials, results were disappointing in patients with a high tumor burden; however, in patients with minimal disease, randomized phase III trials involving 13-cis RA resulted in improved survival rates.^[36]  

Anti-disialoganglioside monoclonal antibodies

In 2015, the US Food and Drug Administration (FDA) approved dinutuximab (Unituxin), which is a monoclonal antibody against disialoganglioside (anti-GD2), for use in the treatment of pediatric patients with high-risk neuroblastoma. It was approved for use as part of a multimodality regimen in patients who have achieved at least a partial response to prior first-line multiagent treatment. Dinutuximab is indicated in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid. Improvement in both event-free survival and overall survival has been shown to be significant.^[37]

Naxitamab (Danyelza), a humanized anti-GD2 monoclonal antibody, was granted accelerated approval by the FDA for use in combination with GM-CSF for relapsed or refractory high-risk neuroblastoma in bone or bone marrow demonstrating a partial response, minor response, or stable disease with prior therapy, in adults and in pediatric patients age 1 year or older.

Approval of naxitamab was based on two single-arm open-label studies, Study 201 and Study 12-230. In Study 201, the overall response rate (ORR) 45% (95% CI: 24%, 68%) and duration of response (DOR) ≥6 months was 30%. In Study 12-230, the ORR was 34% (95% CI: 20%, 51%) with 23% of patients having a DOR ≥6 months. For both trials, responses were observed in bone, bone marrow, or both.^[38]  

Eflornithine 

Oral eflornithine (Iwilfin) was approved by the FDA in December 2023 to reduce the risk of relapse in adult and pediatric patients with high-risk neuroblastoma who have demonstrated at least a partial response to prior multiagent, multimodality therapy including anti-GD2 immunotherapy.^[39]

Eflornithine is an irreversible inhibitor of the enzyme ornithine decarboxylase (ODC), the first and rate-limiting enzyme in biosynthesis of polyamines and a transcriptional target of MYCN. 

Inhibiting polyamine synthesis restores balance of the LIN28/Let-7 metabolic pathway, which is involved in regulation of cancer stem cells and glycolytic metabolism, by decreasing expression of the oncogenic drivers MYCN and LIN28B in MYCN-amplified neuroblastoma. 

Approval was supported for postimmunotherapy maintenance of high-risk neuroblastoma from patients who received eflornithine following standard up-front or refractory/relapse treatment. Eflornithine after completion of immunotherapy was associated with improved event-free survival (P = 0.008) and overall survival (P = 0.007) compared with historical controls who received other therapies.^[40]

Other therapies

Because neuroblastoma is often a radiation-sensitive systemic disease, interest has arisen in use of radioactive molecules that are selectively concentrated in neuroblastoma cells. Clinical trials have been conducted in Europe and North America to delineate the efficacy of iodine-131–radiolabeled meta-iodobenzylguanidine (¹³¹I-MIBG), with and without combined myeloablative chemotherapy followed by autologous stem cell rescue. Determining the optimal doses, schedules, and timing of MIBG therapy are the goals of these clinical trials. Initially studied in relapsed or refractory neuroblastoma, ¹³¹I-MIBG has subsequently drawn interest for use as first-line therapy, alone or in combination with chemotherapeutic drugs.^{[41, 42]}

Antiangiogenesis therapy has more than a theoretical role in the treatment of neuroblastoma. In fact, preclinical studies have demonstrated that these agents inhibit neuroblastoma growth in vivo, especially in minimal residual disease states. Phase I protocols testing angiogenesis inhibitors are in progress to determine whether highly vascular neuroblastoma tumors respond to these agents.

In vitro cultures demonstrate that neuroblastoma is radiosensitive, but results from clinical trials have been inconsistent and inconclusive. As a primary treatment modality, radiation therapy has a limited yet well-defined role.^[43] Indications include the following:

• Patients with regional lymph node metastases (used with sequential cyclophosphamide therapy)
• Infants with stage 4 disease who have Pepper syndrome (to control respiratory compromise)
• Total-body irradiation (TBI) combined with autologous bone marrow transplantation (ABMT)

Other immunotherapies that have shown promising results against neuroblastoma include the following:

• Cytotoxic T lymphocytes
• Modified dendritic cells
• Recombinant IC-2

Opsoclonus-myoclonus syndrome in neuroblastoma

Opsoclonus-myoclonus syndrome (OMS) is thought to be immune-mediated, because 60% of patients who develop this in association with neuroblastoma respond to ACTH or corticosteroids. However, the need for more comprehensive treatment of OMS was demonstrated by long-term outcomes in those patients, which included recurrent neurologic symptoms, developmental delay, and intellectual disability.^[44]

Improved long-term results have been demonstrated in patients with neuroblastoma who develop OMS when they are treated with multimodal chemotherapy. A prospective randomized trial in 53 children with opsoclonus-myoclonus ataxia syndrome associated with neuroblastoma found that the addition of intravenous immune globulin (IVIG) to prednisone and risk-adapted chemotherapy significantly improves the response rate.^[45]

• References

Surgical Therapy

In 1988, the Pediatric Oncology Group (POG) released a prospective study showing that patients with localized neuroblastoma who were treated by surgical extirpation had a 2-year disease-free survival rate of 89%.^[29] Additionally, chemotherapy appeared to offer no advantage in patients with residual disease. Thus, in patients with low-stage favorable disease, surgery is the mainstay of therapy. The primary goals of surgery are as follows:

1. Determine an accurate diagnosis
2. Completely remove all of the primary tumor
3. Provide accurate surgical staging
4. Offer adjuvant therapy for delayed primary surgery
5. Remove residual disease with second-look surgery

Neuroblastoma metastatic to the paraspinal region may extend through the vertebral foramina and may manifest as cord compression. This occurs in 7-15% of patients with neuroblastoma. Cord compression is a medical emergency and should be treated aggressively to reduce the risk of neurological deficit. Unfortunately, the optimal treatment for cord compression secondary to metastatic neuroblastoma has yet to be determined.

Options to relieve cord compression in these situations include surgical resection with or without laminectomy, multimodal chemotherapy, and external beam radiation therapy. In a retrospective review of the POG experience, chemotherapy and laminectomy were associated with similar rates of neurologic recovery, although laminectomy was associated with more orthopedic morbidity. Given these results, a conservative, primary medical approach might be the best initial therapy, with laminectomy reserved for patients who do not respond to chemotherapy.

Neuroblastoma continues to be one of the most frustrating childhood tumors to manage. Although the tumor has been studied extensively and great efforts have been made to secure appropriate therapy and achieve a cure, little has altered the prognosis in affected children over the past 20 years. Additionally, some pediatric retroperitoneal tumors cannot be determined accurately before surgery. Therefore, surgeons who treat these children must be conversant with current staging systems and treatment modalities.

• References

Preoperative Details

An adequate history and physical examination are essential to the preoperative screening in a child being evaluated for neuroblastoma. All radiographic studies (chest radiography, bone scanning, CT scanning, MRI) should be reviewed. Serum chemistries and a CBC count are essential. Additional blood studies include measurement of vanillylmandelic acid–to–homovanillic acid (VMA-to-HVA) ratio, serum ferritin, and neuron-specific enolase (NSE). Other studies specific to the child being evaluated include obtaining bone marrow aspirate and biopsy specimens, MCYN oncogene copy number of tumor, and chromosome studies or transketolase (TRK) analysis.

A general bowel preparation and a antimicrobial prophylaxis with a third-generation cephalosporin are used, depending on the clinical stage of the tumor.

All children with suspected neuroblastoma should undergo anesthetic evaluation. However, unlike in pheochromocytoma (in which the anesthetic choice is crucial), neuroblastoma does not require a specific anesthetic protocol. In patients with large or complicated tumors, an ICU bed should be obtained for postoperative management.

• References

Intraoperative Details

Adequate exposure in the child with neuroblastoma is paramount. In order to achieve this goal, the surgeon must adhere to a number of principles. The patient should be in the supine position, with all pressure points padded. Excellent light sources should be available, including main operating room (OR) lights, overhanging OR lights, and individual head lights, as needed. Various surgical incisions are available, and any surgeon operating on an adrenal mass should be familiar with them prior to surgery. Finally, the surgeon should be intimately familiar with the anatomy of the adrenal gland, surrounding organs, and their respective blood supplies.

The type of incision is partially dictated by the mass and certainly is at the discretion of the operating surgeon. For most abdominal neuroblastomas, a midline transperitoneal incision provides excellent exposure to the peritoneal cavity, retroperitoneum, and, specifically, the ipsilateral suprarenal area. Other incisions for this particular surgery include an upper transverse abdominal incision or a chevron incision for tumors that involve the upper abdomen and retroperitoneum.

Knowledge of the metastatic properties unique to neuroblastoma helps to understand the protocol for safe abdominal exploration and extirpation. The viscera are reflected to the midline and secured in an intestinal bag. The abdomen and retroperitoneum are explored. Careful attention must be given to the anatomical relationships of the tumor to the surrounding structures because this dictates the possible extirpative field. To complete the protocol, regional lymph nodes are evaluated, and a biopsy specimen is obtained from the liver.

Surgical management is dictated by the staging laparotomy. If the tumor cannot be removed primarily, a wedge biopsy of the tumor may be performed for histopathology, immunohistochemistry, and genetic studies. Proper surgical techniques are used to prevent excessive bleeding and tumor spillage.

If the staging laparotomy reveals that primary resection of the tumor is tenable, attention is turned to removal of the tumor. Neuroblastoma is known to invade the tunica adventitia of large blood vessels; therefore, the surgeon should have a vascular set and take precautions to obtain distal and proximal control of the major blood vessels. A preoperative consultation with a vascular specialist should be considered for large tumors.

Access to the tumor is gained by starting in a distal subadventitial plane and dissecting proximally. In this plane, the anterior abdominal aorta, inferior and superior mesenteric arteries, and celiac arteries are identified, isolated, and preserved (as much as possible). In cases in which the renal hilum is involved with tumor, an ipsilateral nephrectomy is performed. Other attachments to the tumor are released and the tumor can be delivered to the surface.

Proper surgical principles and techniques are critical; otherwise, the risk of morbidity and mortality is high.

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Postoperative Details

Postoperative treatment in a child who has undergone a major abdominal exploration and extirpation is dictated, in part, by the extent of resection, duration of surgery, and possible intraoperative complications. The most common complication associated with the removal of a neuroblastoma is related to vascular injury. Hypotension may lead to acute kidney injury and an ischemic bowel, which must be addressed appropriately in an intensive care setting.

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Complications

Surgical complication rates in patients with neuroblastoma range from 5-25%, depending on the stage of the tumor. More aggressive primary abdominal extirpations carry the highest complication rate. Incidental nephrectomy or splenectomy, operative hemorrhage, postoperative intussusception, and injury to major vessels or nerves are some of the more common complications associated with high-stage tumors. Infants with neuroblastoma enjoy a significant survival advantage over all other age groups. Aggressive treatment in these children is therefore warranted only when they have complications related to tumor burden (as in Pepper syndrome), coagulopathy, and renal compromise.

Intensive multimodal treatment in patients with neuroblastoma has resulted in improved survival rates. However, the late effects, which can have diverse and devastating manifestations, should be considered. Cancer survivors should be monitored closely in multidisciplinary clinics, with emphasis on long-term sequelae. Surgery and radiation therapy can result in many late orthopedic effects, such as scoliosis, osteoporosis, and hypoplasia of bony and soft tissue structures. Chemotherapeutic regimens used to treat neuroblastoma may result in long-term toxicities, including cardiopulmonary toxicities (anthracyclines), ototoxicity (cisplatin), chronic kidney disease (ifosfamide and cisplatin), infertility and erectile dysfunction (alkylating agents and radiation therapy), secondary cancers, and psychological effects.

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Medication Summary

The goals of pharmacotherapy are to induce remission, reduce morbidity, and prevent complications. 

• References

Eflornithine (Iwilfin)

• Dosing, Interactions, etc.

Clinical Context:  Blocks the action of the enzyme ornithine decarboxylase (ODC), which is involved in mechanisms by which genes may promote uncontrolled tumor growth. This effect may inhibit the rate of cancer growth. 

• References

Cisplatin (Kemoplat)

• Dosing, Interactions, etc.

Clinical Context:  Platinum coordination compound that inhibits DNA synthesis, cross-links and denatures strands of DNA and disrupts DNA function by covalently binding to DNA bases

• References

Doxorubicin (Adriamycin)

• Dosing, Interactions, etc.

Clinical Context:  Multiple mechanisms of action are recognized for doxorubicin (eg, DNA intercalation, topoisomerase-mediated DNA strand breaks, oxidative damage by free radical production).

• References

Cyclophosphamide

• Dosing, Interactions, etc.

Clinical Context:  This agent exerts its cytotoxic effect through alkylation of DNA, which leads to interstrand and intrastrand DNA crosslinks, DNA-protein crosslinks, and inhibition of DNA replication.

• References

Teniposide

• Dosing, Interactions, etc.

Clinical Context:  Semisynthetic podophyllotixin derivative which inhibits topoisomerase II to cause DNA strand breaks by inhibiting DNA strand-passing and DNA ligase activity., Prevents cells from entering mytosis by delaying the transit of cells through the S phase and causing arrest in late S or early G2 phase of the cell cycle.

• References

Etoposide

• Dosing, Interactions, etc.

Clinical Context:  A glycosidic derivative of podophyllotoxin that exerts a cytotoxic effect by stabilizing the normally transient covalent intermediates formed between the DNA substrate and topoisomerase II. The drug leads to single-stranded and double-stranded DNA breaks that arrest cellular proliferation in the late S or early G2 phase of cell cycle.

• References

Busulfan (Busulfex, Myleran)

• Dosing, Interactions, etc.

Clinical Context:  As an alkylating agent, the mechanism of action of active metabolites may involve cross-linking of deoxyribonucleic acid (DNA), which may interfere with the growth of normal and neoplastic cells.

• References

Melphalan (Evomela)

• Dosing, Interactions, etc.

Clinical Context:  Melphalan is an alkylating agent and derivative of mechlorethamine which inhibits mitosis by cross-linking DNA strands. It is indicated in low doses for the palliative treatment of multiple myeloma and is given in high doses for stem cell transplantation.

• References

Topotecan (Hycamtin)

• Dosing, Interactions, etc.

Clinical Context:  Topotecan binds to topoisomerase I aggregate, preventing the religation of the cleaved DNA strand by stabilizing cleavable complex. This results in the accumulation of single-strand breaks and subsequently in apoptosis and cell death. Acts in the S phase of the cell cycle. 

• References

Naxitamab (Danyelza)

• Dosing, Interactions, etc.

Clinical Context:  Induces antibody-dependent cell-mediated cytotoxicity and complement-mediated cytotoxicity by binding to cell-surface glycolipids disialoganglioside (GD2), which is highly expressed in neuroblastoma and other cells of neuroectodermal origin, subsequently inducing cell lysis.

• References

Aldesleukin (Interleukin 2, Proleukin)

• Dosing, Interactions, etc.

Clinical Context:  Activates T cells and amplifies their responses. IL-2 enhances antitumor activity of NK cells and cytotoxic T cells. 

• References

Class Summary

Antineoplastic agents are used to reduce tumor burden and induce remission. This may be accomplished, among other things, by reducing angiogenesis and metastasis. Choice of antineoplastic may depend on tumor type and stage.

• References