AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Neuroblastoma is the most common extracranial solid tumor in infancy. It is an embryonal malignancy of the sympathetic nervous system arising from neuroblasts (pluripotent sympathetic cells). In the developing embryo, these cells invaginate, migrate along the neuraxis, and populate the sympathetic ganglia, adrenal medulla, and other sites. The pattern of distribution of these cells correlates with the sites of primary disease presentation.

Age, stage, and some molecular defects encountered in tumor cells are important prognostic factors and are used for risk stratification and treatment assignment. The differences in outcome for patients with neuroblastoma are striking. Infants younger than 1 year have a good prognosis, even in the presence of metastatic disease, whereas older patients with metastatic disease fare poorly, even when treated with aggressive therapy. Unfortunately, approximately 70-80% of patients older than 1 year present with metastatic disease, usually in the lymph nodes, liver, bone, and bone marrow. Less than half of these patients are cured, even with the use of high-dose therapy followed by autologous bone marrow or stem cell rescue.

Pathophysiology

Anatomic

Origin and migration pattern of neuroblasts during fetal development explains the multiple anatomic sites where these tumors occur; location of tumors appears to vary with age. Tumors can occur in the abdominal cavity (40% adrenal, 25% paraspinal ganglia) or can involve other sites (15% thoracic, 5% pelvic, 3% cervical tumors, 12% miscellaneous). Infants more commonly present with thoracic and cervical tumors, whereas older children more frequently have abdominal tumors.

Most patients present with signs and symptoms related to tumor growth, although small tumors have been detected in infants using prenatal ultrasonography. Large abdominal tumors often result in increased abdominal girth and other local symptoms (eg, pain). Paraspinal dumbbell tumors can extend into the spinal canal, impinge on the spinal cord, and cause neurologic dysfunction.

Stage of the tumor at the time of diagnosis and age of the patient are the most important prognostic factors. Although patients with localized tumors (regardless of age) have an excellent outcome (80-90% 3-year event-free survival [EFS] rate), patients older than 1 year with metastatic disease fare poorly. Generally, more than 50% of patients present with metastatic disease at the time of diagnosis, 20-25% have localized disease, 15% have regional extension, and approximately 7% present during infancy with disseminated disease limited to the skin, liver, and bone marrow (stage 4S).

Physiologic and biochemical

More than 90% of patients have elevated homovanillic acid (HVA) and/or vanillylmandelic acid (VMA) detectable in urine. Mass screening studies using urinary catecholamines in neonates and infants in Japan, Quebec, and Europe have demonstrated the ability to detect neuroblastoma before it is clinically apparent. However, most of the tumors identified using this method occur in infants who have a good prognosis. No data suggest that mass screening has decreased deaths due to high-risk neuroblastoma. Markers associated with a poor prognosis include (1) elevated ferritin levels, (2) elevated serum lactate dehydrogenase (LDH) levels, and (3) elevated serum neuron-specific enolase (NSE) levels. However, these markers are less important because of the discovery of more relevant biomarkers (ie, chromosomal and molecular markers).

Histologic

Pluripotent sympathetic stem cells migrate and differentiate to form the different organs of the sympathetic nervous system. The normal adrenal gland consists of chromaffin cells, which produce and secrete catecholamines and neuropeptides. Other cells include sustentacular cells, which are similar to Schwann cells, and scattered ganglion cells. Histologically, neural crest tumors can be classified as neuroblastoma, ganglioneuroblastoma, and ganglioneuroma, depending on the degree of maturation and differentiation of the tumor.

The undifferentiated neuroblastomas histologically present as small, round, blue cell tumors with dense nests of cells in a fibrovascular matrix and Homer-Wright pseudorosettes. These pseudorosettes, which are observed in 15-50% of tumor samples, can be described as neuroblasts surrounding eosinophilic neuritic processes. The typical tumor shows small uniform cells with scant cytoplasm and hyperchromatic nuclei. A neuritic process, also called neuropil, is a pathognomonic feature of neuroblastoma cells. NSE, chromogranin, synaptophysin, and S-100 immunohistochemical stains are usually positive. Electron microscopy can be useful because ultrastructural features (eg, neurofilaments, neurotubules, synaptic vessels, dense core granules) are diagnostic for neuroblastoma.

In contrast, the completely benign ganglioneuroma is typically composed of mature ganglion cells, Schwann cells, and neuritic processes, whereas ganglioneuroblastomas include the whole spectrum of differentiation between pure ganglioneuromas and neuroblastomas. Because of the presence of different histologic components, the pathologist must thoroughly evaluate the tumor; the regions with different gross appearance may demonstrate a different histology.

Neuroblastic nodules are present in the fetal adrenal gland and peak at 17-18 weeks' gestation. Most of these nodules spontaneously regress and likely represent remnants of fetal development. Some of these may persist and lead to the development of neuroblastoma.

Shimada histopathologic classification system

Shimada et al have developed a histopathologic classification in patients with neuroblastoma.¹ This classification system was retrospectively evaluated and correlated with outcome in 295 patients with neuroblastoma who were treated by the Children's Cancer Group (CCG). Important features of the classification include (1) the degree of neuroblast differentiation, (2) the presence or absence of Schwannian stromal development (stroma-rich, stroma-poor), (3) the index of cellular proliferation (known as mitosis-karyorrhexis index [MKI]), (4) nodular pattern, and (5) age. Using these components, patients can be classified into the following histology groups:

• Favorable histology group
• • Patients of any age with stroma-rich tumors without a nodular pattern
  • Patients younger than 18 months with stroma-poor tumors, an MKI of less than 200/5000 (200 karyorrhectic cells per 5000 cells scanned), and differentiated or undifferentiated neuroblasts
  • Patients younger than 60 months with stroma-poor tumors, an MKI of less than 100/5000, and well-differentiated tumor cells
• Unfavorable histology group
• • Patients of any age with stroma-rich tumors and a nodular pattern
  • Patients of any age with stroma-poor tumors, undifferentiated or differentiated neuroblasts, and an MKI more than 200/5000
  • Patients older than 18 months with stroma-poor tumors, undifferentiated neuroblasts, and an MKI more than 100/5000
  • Patients older than 18 months with stroma-poor tumors, differentiated neuroblasts, and an MKI of 100-200/5000
  • Patients older than 60 months stroma-poor, differentiated neuroblasts, and an MKI less than 100/5000

Joshi histopathologic classification system

Another classification developed by Joshi et al (using patients treated by the Pediatric Oncology Group [POG]) attempted to simplify the Shimada classification while maintaining its predictive value.² This system classifies tumors based on the presence of calcification and mitotic rate, as follows: (1) good prognosis (ie, low mitotic rate and calcification), (2) intermediate prognosis (ie, low mitotic rate or calcification), and (3) poor prognosis (ie, high mitotic rate and no calcification). Joshi et al modified the Shimada classification, as follows:

• Favorable histology group
• • A low mitotic rate (£10 mitoses per 10 high-power fields) and calcification present in any age group
  • Either a low mitotic rate or calcification present in any patient younger than 1 year
  • • Unfavorable histology group
    • Either a low mitotic rate or calcification present in any patient older than 1 year
    • A high mitotic rate and no calcification in any age group

Joshi, Shimada, and other pathologists have developed an international pathologic classification incorporating features of both these systems.

Chromosomal and molecular markers

During the last 2 decades, many chromosomal and molecular abnormalities have been identified in neuroblastoma. These biologic markers have been evaluated to determine their value in assigning prognosis, and some of these have been incorporated into the strategies used for risk-assignment.

The most important of these biologic markers is MYCN. MYCN is an overexpressed oncogene in neuroblastoma with the amplification of the distal arm of chromosome 2. This gene is amplified in approximately 25% of de novo cases and is more common in patients with advanced-stage disease. Patients whose tumors have MYCN amplification tend to have rapid tumor progression and a poor prognosis, even in the setting of other coexisting favorable factors such as low stage disease or 4S disease. In contrast to MYCN, expression of the H-ras oncogene correlates with lower stages of the disease. Cytogenetically, the presence of double minute chromatin bodies and homogeneously staining regions correlates with MYCN gene amplification.

Deletion of the short arm of chromosome 1 is the most common chromosomal abnormality present in neuroblastomas, and it confers a poor prognosis. The 1p chromosome region likely harbors tumor suppressor genes or genes that control neuroblast differentiation. Deletion of 1p is more common in near-diploid tumors and is associated with a more advanced stage of the disease. Most of the deletions of 1p are located in the 1p36 area of the chromosome. A relationship between 1p loss of heterozygosity (LOH) and MYCN amplification has been described.

Other allelic losses of chromosomes 11q, 14q, and 17q have been reported, suggesting that other tumor suppressor genes may be located in these chromosomes. Another characteristic of neuroblastoma is the frequent gain of chromosome 1.

DNA index is another useful test that correlates with response to therapy in infants. Look et al demonstrated that infants whose neuroblastomas have hyperdiploidy (ie, DNA index >1) have a good therapeutic response to cyclophosphamide and doxorubicin.³ In contrast, infants whose tumors have a DNA index of 1 are less responsive to the latter combination and require more aggressive therapy. DNA index does not have any prognostic significance in older children. In fact, hyperdiploidy in children more frequently occurs in the context of other chromosomal and molecular abnormalities that confer a poor prognosis.

Three neurotrophin receptor gene products, TrkA, TrkB, and TrkC, are tyrosine kinases that code for a receptor of members of the nerve growth factor (NGF) family. Their ligands include p75 neurotrophin receptor (p75NTR) NGF, and brain-derived neurotrophic factors (BDNFs). Interestingly, TrkA expression is correlated inversely with the amplification of the MYCN gene, and the expression of the TrkC gene is correlated with TrkA expression. In most patients younger than 1 year, a high expression of TrkA correlates with a good prognosis, especially in patients with stages 1, 2, and 4S. In contrast, TrkB is more commonly expressed in tumors with MYCN amplification. This association may represent an autocrine survival pathway.

Other biologic markers associated with poor prognosis include increased levels of telomerase RNA and lack of expression of glycoprotein CD44 on the tumor cell surface.

P-glycoprotein (P-gp) and multidrug resistance protein (MRP) are 2 proteins expressed in neuroblastoma. These proteins confer a multidrug-resistant (MDR) phenotype in some cancers. Their role in neuroblastoma is controversial. MDR is one target for novel drug development.

Frequency

United States

Neuroblastoma accounts for approximately 7.8% of childhood cancers in the United States. Approximately 650 new cases are diagnosed in the United States each year. According to the Surveillance, Epidemiology, and End Report (SEER), incidence is approximately 9.5 cases per million children.⁴

International

Incidence in other industrialized nations appears to be similar to that observed in the United States.

Mortality/Morbidity

According to the SEER data, the overall 5-year survival rate for children with neuroblastoma has improved from 24% in 1960-1963 to 55% in 1985-1994.⁴ In part, this increase in survival rate may be due to better detection of low-risk tumors in infants. The survival rate 5 years from diagnosis is approximately 83% for infants, 55% for children aged 1-5 years, and 40% for children older than 5 years. Improvements in diagnostic imaging modalities, medical and surgical management, and supportive care have contributed to the improved survival rates.

Most patients with neuroblastoma present with disseminated disease, which confers a poor prognosis and is associated with a high mortality rate. Tumors in patients in this category usually have unfavorable pathologic and/or molecular features. The 3-year EFS for high-risk patients treated with conventional chemotherapy, radiation therapy, and surgery is less than 20%. Differentiating agents and dose intensification of active drugs, followed by autologous bone marrow transplant, have been reported to improve the outcome for these patients, contributing to an EFS of 38%. A recent single-arm study of tandem stem cell transplantation reported a 3-year EFS of 58%, but this has not been tested in a randomized fashion.⁵

Morbidity of high-dose chemotherapy approaches can be substantial, although the treatment-related mortality rates have decreased with improvements in supportive care and hematopoietic support with growth factors and stem cells instead of bone marrow.

Race

Incidence of neuroblastoma is higher in white children than in black children. However, race does not appear to have any effect on outcome.

Sex

Males have a slightly higher incidence of neuroblastoma than females, with a male-to-female ratio of 1.2:1.

Age

Age distribution is as follows: 40% of patients are younger than 1 year when diagnosed, 35% are aged 1-2 years, and 25% are older than 2 years when diagnosed. According to SEER, incidence decreases every consecutive year up to age 10 years, after which the disease is rare.⁴

CLINICAL

Section 3 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Signs and symptoms of disease vary with site of presentation. Generally, symptoms include abdominal pain, emesis, weight loss, anorexia, fatigue, bone pain, and chronic diarrhea. Hypertension is an uncommon sign of the disease and generally is caused by renal artery compression, not catecholamine excess.

• Because more than 50% of patients present with advanced-stage disease, usually to the bone and bone marrow, the most common presentation includes bone pain and a limp. However, patients may also present with unexplained fever, weight loss, irritability, and periorbital ecchymosis secondary to metastatic disease to the orbits. The presence of bone metastases can lead to pathologic fractures.
• Approximately two thirds of patients with neuroblastoma have abdominal primaries. In these circumstances, patients can present with an asymptomatic abdominal mass that usually is discovered by the parents or a caregiver.
• Symptoms produced by the presence of the mass depend on its proximity to vital structures and usually progress over time.
• • Tumors that arise from the paraspinal sympathetic ganglia can grow through the spinal foramina into the spinal canal and impinge on the spinal cord. This may result in the presence of neurologic symptoms, including weakness, limping, paralysis, and even bladder and bowel dysfunction.
  • Thoracic neuroblastomas (posterior mediastinum) may be asymptomatic and are usually diagnosed by imaging studies obtained for other reasons. Presenting signs or symptoms may be insignificant and involve mild airway obstruction or chronic cough, leading to chest radiography.
  • Thoracic tumors extending to the neck can produce Horner syndrome. Primary cervical neuroblastoma is rare but should be considered in the differential diagnosis of masses of the neck, especially in infants younger than 1 year with feeding or respiratory difficulties.
• In a small proportion of infants younger than 6 months, neuroblastoma presents with a small primary tumor and metastatic disease confined to the liver, skin, and bone marrow (stage 4S). If this type of tumor develops in neonates, skin lesions may be confused with congenital rubella, and, if the patient has severe skin involvement, the term "blueberry muffin baby" may be used.
• Approximately 2% of patients present with opsoclonus and myoclonus a paraneoplastic syndrome characterized by the presence of myoclonic jerking and random eye movements. These patients often have localized disease and a good long-term prognosis. Unfortunately, the neurologic abnormalities can persist or progress and can be devastating.
• Finally, intractable diarrhea is a rare paraneoplastic symptom and is associated with more differentiated tumors and a good prognosis.

Physical

• Children are usually referred to a pediatric oncologist by primary care providers who have identified a persistent unexplained symptom or sign, either upon physical examination or based on screening test findings.
• In patients with suspected neuroblastoma, performing a thorough examination with careful attention to vital signs (eg, blood pressure), neck, chest, abdomen, skin, and nervous system is essential.
• Metastatic lesions of the skin are common in infants younger than 6 months and may represent stage 4S disease.
• Examination of the abdomen may reveal an abdominal mass, leading to the appropriate workup.
• Neurologic examination may reveal Horner syndrome. In the case of dumbbell tumors, compression of the spinal cord may produce lower extremity weakness or paraplegia. Patients with neurologic involvement by tumor should be treated emergently, secondary to the risk of permanent neurologic sequelae.

Causes

• The cause of neuroblastoma is unknown, and no specific environmental exposure or risk factors have been identified.
• Because of young age of onset with this disease, investigators have focused on events before conception and during gestation.
• According to SEER, factors investigated for which evidence is limited or inconsistent include medications, hormones, birth characteristics, congenital anomalies, previous spontaneous abortion or fetal death, alcohol or tobacco use, and paternal occupational exposures.

DIFFERENTIALS

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Other Problems to be Considered

Neoplastic or nonneoplastic disease of childhood, including osteomyelitis and rheumatoid arthritis
Disseminated bone disease
Primary neurologic disease
Inflammatory bowel disease

WORKUP

Section 5 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Any child with a presumed diagnosis of neuroblastoma or any other childhood cancer should be referred to a pediatric cancer center for proper care and evaluation. Laboratory studies should include the following:
• • Serum LDH (useful as biologic marker)
  • Ferritin (useful as biologic marker)
  • CBC count and differential (Anemia or other cytopenias suggest bone marrow involvement.)
  • Urine collection for catecholamines (VMA/HVA)
  • • The spot test for VMA/HVA is highly inaccurate. Centers usually send samples to a specialty laboratory and/or perform a timed collection of urine.
    • A urinary catecholamine level is considered to be elevated if it is 3 standard deviations higher than the age-related reference range levels.
  • Serum creatinine
  • Liver function tests
  • • Alanine aminotransferase (ALT)
    • Aspartate aminotransferase (AST)
    • Total bilirubin
    • Alkaline phosphatase
    • Total protein
    • Albumin
    • Prothrombin time (PT)/activated prothrombin time (aPTT)
  • Electrolytes
  • Calcium
  • Magnesium
  • Uric acid

Imaging Studies

• Obtain chest and abdominal radiographs to evaluate for the presence of a posterior mediastinal mass or calcifications.
• A CT scan of the primary site is essential to determine tumor extent. The main body of the tumor is usually indistinguishable from nodal masses.
• In cases of paraspinal masses, MRI aids in determining the presence of intraspinal tumor and cord compression.
• I123/131-methyliodobenzylguanadine (MIBG) accumulates in catecholaminergic cells and provides a specific way of identifying primary and metastatic disease if present. Increasing numbers of institutions have access to MIBG scanning.
• A technetium-99 bone scan can also be used to evaluate bone metastases. Especially in patients with negative MIBG study findings.
• Skeletal surveys may also be useful, especially in patients with multiple metastatic lesions.
• Positron emission tomography (PET) scan are under evaluation.

Other Tests

• Obtain the following as baseline studies before therapy with anthracyclines:
• • ECG
  • Echocardiogram or resting radionuclide ejection fraction scan
• Baseline hearing tests are recommended before cisplatin therapy.
• Baseline creatinine clearance should be measured, especially if serum creatinine is abnormal.

Procedures

• Perform bilateral bone marrow aspirate and biopsies to exclude metastatic disease
• Tumor biopsy or surgical resection. Biopsy or resection of the primary tumor (stage I or II disease) is performed to collect tissue sample(s) for biologic studies used to assign the patient into the appropriate risk category. This is particularly important in patients with nonmetastatic disease.
• • Tissue samples from a primary or metastatic tumor may be undifferentiated and confused with other small, round, blue cell tumors of childhood; however, techniques such as immunohistochemistries can aid with tissue diagnosis.
  • Molecular techniques, such as fluorescent in situ hybridization (FISH), can detect MYCN amplification, an important prognostic marker. Polymerase chain reaction (PCR) can identify specific translocations, such as t(11;22), in Ewing sarcoma and t(2;13) in alveolar rhabdomyosarcoma, thus ruling out neuroblastoma.
  • Neuroblastoma in bone marrow can be difficult to distinguish from other small, round, blue cell tumors of childhood.

Histologic Findings

Biopsy findings are usually required to diagnose neuroblastoma. Depending on the extent of disease at presentation, consider complete surgical resection, especially in patients with low-stage disease. Even without a biopsy, the presence of elevated urinary catecholamines and a bone marrow aspirate or biopsy with unequivocal neuroblastoma cells is diagnostic.

Histologically, neural crest tumors can be classified as neuroblastoma, ganglioneuroblastoma, and ganglioneuroma, depending on the degree of maturation and differentiation of the tumor. Undifferentiated neuroblastomas histologically present as small, round, blue cell tumors with dense nests of cells in a fibrovascular matrix and Homer-Wright pseudorosettes. These pseudorosettes, observed in 15-50% of tumor samples can be described as neuroblasts surrounding eosinophilic neuritic processes. The typical tumor shows small uniform cells with scant cytoplasm and hyperchromatic nuclei. A neuritic process, also called neuropil, is a pathognomonic feature of neuroblastoma.

NSE, chromogranin, synaptophysin, and S-100 immunohistochemical stain findings are usually positive. Electron microscopy can be useful because ultrastructural features (eg, neurofilaments, neurotubules, synaptic vessels, dense core granules) are diagnostic for neuroblastoma. In contrast, the completely benign ganglioneuroma is typically composed of mature ganglion cells, Schwann cells, and neuritic processes, whereas ganglioneuroblastomas include the whole spectrum of differentiation between pure ganglioneuromas and neuroblastomas.

The pathologist must thoroughly evaluate the tumor because regions with different gross appearance may exhibit a different histology.

Staging

The patient should undergo a staging workup along with surgical resection or biopsy, as appropriate. Using various molecular features in conjunction with pathology and staging is essential to appropriately stratify patients and determine the best therapy (see Table).

The International Neuroblastoma Staging System (INSS) is currently used in all cooperative group studies. A comparison of INSS, POG, and CCG staging criteria is detailed below. In general, the CCG staging system is based on clinical findings, whereas the POG system is clinicopathologic. INSS uses features of the other 2 systems.

As of July 2007, efforts are ongoing to develop an international neuroblastoma risk group classification system (INRG).⁶

• International neuroblastoma staging system
• • Stage 1
  • • Localized tumor with complete gross excision, microscopic residual disease, or both
    • Ipsilateral lymph nodes negative for tumor (Nodes attached to the primary tumor may be positive for tumor.)
  • Stage 2A
  • • Localized tumor with incomplete gross resection
    • Representative ipsilateral nonadherent lymph nodes microscopically negative for tumor
  • Stage 2B
  • • Localized tumor, complete gross excision, or both with ipsilateral nonadherent lymph nodes positive for tumor
    • Enlarged contralateral lymph nodes, which are negative for tumor microscopically
  • Stage 3
  • • Unresectable unilateral tumor infiltrating across the midline, regional lymph node involvement, or both
    • Alternately, localized unilateral tumor with contralateral regional lymph node involvement
  • Stage 4 - Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs (except as defined for stage 4S)
  • Stage 4S
  • • Localized primary tumor (as defined for stages 1, 2A, or 2B) with dissemination limited to skin, liver, and/or bone marrow (<10% involvement)
    • Limited to infants

TREATMENT

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Medical Care

Care of children with cancer is provided by a multidisciplinary team involving pediatric oncology, radiation oncologists, surgeons, and anesthesiologists, as well as nurse practitioners, nurses, pharmacists, psychologists, and physical and occupational therapists dedicated to the special needs of these children.

The table below outlines criteria for risk assignment based on the INSS, age, and biologic risk factors. This, in turn, determines the intensity of the therapy. These treatment strategies have been developed from more than 2 decades of experience with clinical trials in CCG and POG. Correlative biologic studies were pivotal in identifying biologic risk factors important for outcome. Currently, efforts are ongoing to develop an INRG. In addition, recently published results on correlative biologic studies and clinical outcome may lead to changes in an age cut-off of more than 365 days (365-547 d) for some patients with tumors in stages 3 and 4.⁷ These criteria are based on the analysis of several thousands of patients treated in cooperative group protocols in Australia, Canada, Europe, Japan, and the United States.⁶


Criteria for Risk Assignment

Cooperative group treatment strategies

• Low-risk group treatment strategy
• • Patients with localized resectable neuroblastoma (stage 1) have excellent EFS with surgical excision of tumor alone. Adjuvant chemotherapy is generally not needed for this group of patients. Even the presence of residual microscopic disease does not significantly affect the EFS. If patients develop recurrent disease, chemotherapy can be used, and the overall survival rate remains higher than 95%.
  • Similar therapy is offered to patients with stage 2A/2B disease who are presently being assigned to a low-risk category if they are younger than 1 year, regardless of MYCN status or histology. Additionally, patients with stage 2B/2C disease who are older than 1 year are considered low-risk if they have non-MYCN–amplified or amplified tumors with favorable histology. CCG studies have consistently shown that these patients have a 3-year EFS and survival rate higher than 90% with surgical excision. In previous POG studies, patients with subtotal tumor resection who were treated with chemotherapy had a similar outcome.
  • Patients with 4S disease (ie, non-MYCN–amplified tumors, favorable histology, hyperdiploid tumors) are also considered to be in the low-risk group and are offered resection of the primary tumor, followed by observation. Chemotherapy may be used to control life-threatening situations.
• Intermediate-risk group treatment strategy
• • These patients receive multimodality therapy, including surgery, chemotherapy, and, in selected situations, radiation therapy.
  • Intermediate-risk patients include children younger than 1 year with stage 3/4/4S disease and favorable biology (non-MYCN–amplified tumors, regardless of histology and DNA index). In the future, some patients older than 1 year may be included in this group.
  • Patients are considered to be in the intermediate-risk group if they are older than 1 year with stage 3 non-MYCN and favorable histology tumors. These patients are offered therapy with 4 of the most active drugs against neuroblastoma (ie, cyclophosphamide, doxorubicin, carboplatin, etoposide) for either 4 or 8 cycles, depending on histology and DNA index. In these patients, surgery can be performed either at time of diagnosis or following multiagent chemotherapy. If residual disease is present after chemotherapy and surgery, radiation therapy could be considered. However, the use of radiation is controversial, although a POG study suggests that it improves outcome when administered to areas of residual disease postchemotherapy.
• High-risk group treatment strategy
• • Patients with high-risk disease include those with stage 2A/2B disease who are older than 1 year and have MYCN-amplified unfavorable histology tumors.
  • Infants with stage 3/4/4S and with MYCN-amplified tumors or children older than 1 year with stage 3, MYCN-amplified or non-MYCN–amplified tumors, and unfavorable histology tumors are also considered high-risk.
  • All patients older than 1 year with stage 4 tumors are considered to be in the high-risk group, regardless of MYCN status or histology. These patients seem to require treatment with multiagent chemotherapy, surgery, and radiotherapy, followed by consolidation with high-dose chemotherapy and peripheral blood stem cell rescue. In the future, some patients older than 1 year with favorable biologic characteristics may be downgraded to the intermediate-risk group.
  • The 3-year EFS for patients in the high-risk group who are treated without such high-intensity therapy is less than 20%, compared with an EFS of 38% in patients treated with a single bone marrow transplant and cis-retinoic acid after transplant. Recently, a single-arm study of tandem stem cell transplantation reported an EFS of 58%, but this has not been tested in a randomized study against a single transplant.⁵ Because of significant improvements in time to recovery and a lower risk of tumor cell contamination, most centers now recommend the use of peripheral blood stem cell support over bone marrow for consolidation therapy.
  • Risk of relapse from minimal residual disease after consolidation may be decreased with cis-retinoic acid treatment.

Surgical Care

Surgical resection plays an important role in the treatment of patients with neuroblastoma.

• For patients with localized disease, surgical resection is curative.
• For patients with regional or metastatic disease, surgery to establish a diagnosis and obtain adequate samples for biologic studies is essential. Typically, second-look surgery postchemotherapy is used to attempt a complete resection. The emphasis in the second-look procedure is as complete a debulking as possible without sacrificing major organ function.
• Patients with residual disease postchemotherapy and surgery may benefit from the use of radiotherapy.

Consultations

• Neuroblastoma can be confused with other neoplastic or nonneoplastic diseases of childhood. The diagnosis can be challenging in the 10% of patients who present with normal urinary catecholamines.
• Radiation oncologists may participate in the care of patients with neuroblastoma. Typically, they are consulted to evaluate patients whenever radiation therapy is a consideration. Usually, radiotherapy is localized to areas of residual microscopic disease, persistent disease, or both after chemotherapy and surgery.
• In high risk patients, the need for stem cell harvest and transplantation should be anticipated. These services should be included early in the planning phase of treatment.

Diet

• Nutrition plays an important role in therapy.
• Children need adequate caloric intake to attain normal growth and development, and to recover from the adverse effects of therapy.
• Nutritionists typically help to provide adequate supportive care during therapy.
• Supplemental nutrition is often required during therapy. This should occur via the enteral route (nasogastric or gastric tube). The parenteral route should be used only after failure to supplement adequately using enteral feedings.

Activity

No specific restrictions are placed on activity.

• Patients who are thrombocytopenic should avoid strenuous activity and contact sports.
• Patients should avoid ill contacts, especially if neutropenic.

MEDICATION

Section 7 of 11  

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• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

All chemotherapy orders are written by pediatric oncologists and countersigned, usually by another physician. With recurrent disease, various salvage protocols may be used; with refractory disease, a limited number of phase I/II studies are available through the COG and New Approaches to Neuroblastoma Therapy (NANT) consortia. 

Resources presented in this section should serve as a guide to indication, usual dosages, and adverse effects of specific agents. Antineoplastic drugs have a narrow therapeutic index and effective doses usually cause severe toxicities, some of which can be life threatening.

Individual chemotherapy drugs are discussed below. These agents are almost invariably given in combination. Commonly used combinations include the following:

• Vincristine, cyclophosphamide, and doxorubicin
• Carboplatin and etoposide
• Cisplatin and etoposide
• Ifosfamide and etoposide

Consolidation regimens used in neuroblastoma include the following:

• Carboplatin and etoposide with melphalan or cyclophosphamide
• Thiotepa and cyclophosphamide
• Melphalan and total body irradiation

In Europe, several studies have used busulfan with melphalan or cyclophosphamide. One commonly used salvage or relapse therapy regimen is the combination of topotecan and cyclophosphamide. The use or retinoids have been incorporated in maintenance regimens in the postransplant setting. Irinotecan is also under investigation.

Drug Category: Antineoplastics agents

Cancer chemotherapy is based on an understanding of tumor cell growth and how drugs affect this growth. After cells divide, they enter a period of growth (ie, phase G1), followed by DNA synthesis (ie, phase S). The next phase is a premitotic phase (ie, G2), which is followed by a mitotic cell division (ie, phase M).

Cell division rate varies for different tumors. Most common cancers increase very slowly in size compared with normal tissues, and the rate may decrease further in large tumors. This difference allows normal cells to recover more quickly from chemotherapy than malignant cells; it is the rationale behind current cyclic dosage schedules.

Antineoplastic agents interfere with cell reproduction. Some agents are cell cycle specific, whereas others (eg, alkylating agents, anthracyclines, cisplatin) are not phase specific. Cellular apoptosis (ie, programmed cell death) is also a potential mechanism of many antineoplastic agents.

Drug Category: Colony-stimulating factors

These agents act as a hematopoietic growth factor that stimulates the development of granulocytes. They are used to treat or prevent neutropenia when receiving myelosuppressive cancer chemotherapy and to reduce the period of neutropenia associated with bone marrow transplantation. They are also used to mobilize autologous peripheral blood progenitor cells for bone marrow transplantation and in the management of chronic neutropenia.

Drug Category: Chemoprotective agents

Mesna is a prophylactic detoxifying agent used to inhibit hemorrhagic cystitis caused by ifosfamide and cyclophosphamide. In the kidney, mesna disulfide is reduced to free mesna. Free mesna has thiol groups that react with acrolein, which is the ifosfamide and cyclophosphamide metabolite considered to be responsible for urotoxicity.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Children are admitted to the hospital to expedite the diagnostic workup when unstable or significantly symptomatic.
• In an asymptomatic child, workup can be performed in the outpatient setting.
• A central line is commonly placed when biopsy or resection is scheduled in intermediate- or high-risk patients.
• A pediatric oncologist and surgeons with expertise in managing childhood malignancies perform the initial evaluation.
• Other subspecialists, such as neurosurgeons or radiation oncologists, may participate in patient care, especially in cases of cord compression.
• Once the diagnosis is established and the staging workup is completed, the patient and family are instructed on the diagnosis and therapeutic options.
• Once the treatment plan is developed, chemotherapy is administered, usually in the inpatient setting.
• Following completion of the treatment cycle, patients are discharged home with detailed instructions for home care and with outpatient follow-up.

Further Outpatient Care

• Patients are periodically monitored in the clinic after each course of therapy to monitor for complications and to assess response to therapy with diagnostic imaging.
• • Myelosuppression and pancytopenia are common complications, and a CBC count with platelet count is obtained as often as twice per week.
  • Some drugs (eg, cisplatin, carboplatin, ifosfamide) affect renal function; thus, close monitoring of electrolytes is required, with oral electrolyte supplementation when necessary.
  • Blood product support is provided when the hemoglobin drops to less than 8 g/dL, the platelet count drops to less than 10,000, or any signs of bleeding are present.
• Long-term follow-up care and surveillance
• • After completion of therapy, successfully treated patients require follow-up care and close surveillance for any signs or symptoms of recurrent disease.
  • Follow-up care includes monitoring of urinary catecholamines, physical examination, and diagnostic imaging.
  • Because most recurrences occur during the first 2 years following treatment, most protocols recommend close follow-up care during this interval.
• Long-term issues 
• • Patients who remain free of recurrent disease for 5 years are considered cured, although rare later relapses have been reported.
  • Long-term follow-up care to assess impact of therapy on growth, development, and organ toxicity is essential.

In/Out Patient Meds

• Infection prophylaxis
• • Chemotherapy agents cause myelosuppression and immunosuppression.
  • All patients should receive prophylaxis against Pneumocystis carinii with trimethoprim/sulfamethoxazole (trimethoprim 2.5 mg/kg/dose twice daily), administered on 3 consecutive days per week.
  • Prophylaxis is started before chemotherapy and continued for at least 3 months after completing therapy.
• Colony-stimulating factors
• • Granulocyte colony stimulating factor (GCSF) support has become common in pediatric oncology as intensity of chemotherapy has increased.
  • Treat with 5-10 mcg/kg/d subcutaneously to start 24-36 hours after the last dose of chemotherapy. GCSF is continued until the absolute neutrophil count is 2,000-10,000.

Transfer

• Management by primary care provider
• • With oncology team supervision, routine care can be carried out by the primary care provider for patient convenience.
  • Monitoring of blood counts or chemistries and administration of blood products are common.
  • Some primary care providers with experience in the treatment of febrile neutropenia may be able to manage this complication of chemotherapy. Patients may quickly destabilize upon initiation of antibiotic therapy; thus, access to critical care services is required.
  • Maintain close contact with subspecialists and transfer the patient to the pediatric oncology center for any complications that may require specialized care.

Deterrence/Prevention

• The cause of neuroblastoma is unknown.
• No specific environmental exposure or risk factors have been identified.
• Currently, no specific recommendations on how to prevent this disease are known.
• Screening for neuroblastoma in an attempt to diagnose high-risk patients earlier in the course of their disease has uncovered many patients with low-risk disease but has not had an impact on high-risk disease.

Complications

• At disease presentation
• • The most worrisome complication at disease presentation is cord compression from a paraspinal tumor. Evaluation of the patient by a neurosurgeon and consultation with a radiation oncologist are important.
  • In some individuals with neuroblastomas, early institution of chemotherapy is accepted if the tumor can be biopsied within 72 hours to make a diagnosis and to obtain necessary biologic studies. In the acute setting, chemotherapy may be as efficient as radiotherapy or laminectomy, and it may cause less morbidity. Because treatment of cord compression with chemotherapy remains controversial, radiation therapy or surgery often is used as front line to prevent further neurologic damage.
  • Tumor lysis syndrome is unusual in neuroblastoma
  • Patients may present with severe hypertension or renal insufficiency, making initiation of chemotherapy, especially with platinum drugs, more difficult.
• During therapy
• • Myelosuppression and immunosuppression place the patient at risk of bleeding and infection. Febrile neutropenia is a medical emergency and requires immediate admission to the hospital and initiation of broad-spectrum antibiotic treatment.
  • After several cycles of therapy, depending on drugs administered, patients may develop impaired renal function, hearing loss, or delayed count recovery.

Prognosis

• Determinants of response and outcome
• • Stage, age, and several biologic characteristics of the tumor determine outcome.
  • Similarly, the patient may also have genetic polymorphism characteristics that influence drug absorption, distribution, metabolism, and excretion.
• Several treatment strategies are available to treat patients with recurrent neuroblastoma.
• • A local recurrence in a patient with low-stage disease generally has a good prognosis, and patients usually receive standard chemotherapy, surgery, and/or radiation as necessary.
  • Patients with disseminated disease at presentation have a high recurrence rate and a poor outcome.
  • For patients with recurrent disease in this setting, various phase I/II agents are generally available.
• Response criteria are used to evaluate the efficacy of therapy.
• • Complete clinical response - More than 90% decrease (sum of the products of the greatest perpendicular diameters) of the primary tumor and metastatic disease (if any), no new lesions, healing of bone lesions
  • Partial clinical response -  A decrease of 50% or less (sum of the products of the greatest perpendicular diameters) of the primary tumor and metastatic disease (if any), no new lesions, healing of bone lesions
  • Minor response - More than 25% and less than 50% decrease (sum of the products of the greatest perpendicular diameters) of primary tumor and metastatic disease (if any), no new lesions, healing of bone lesions
  • No response - Less than 25% decrease (sum of the products of the greatest perpendicular diameters) of primary tumor or metastatic disease (if any), no new lesions
  • Progressive disease - More than 25% increase (sum of the products of the greatest perpendicular diameters) of the primary tumor or all metastatic lesions (if any), appearance of new lesions

Patient Education

For compliance and good medical care, patients and families must understand the importance of treatment and adverse effects of medications used. In addition, they should learn to recognize and identify signs and symptoms of complications that require urgent medical care.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Diagnostic workup: Cancer is rare in children; therefore, if neuroblastoma is suspected, prompt referral to a pediatric oncology center for multidisciplinary evaluation and appropriate care is essential. Most patients initially present for evaluation to either the primary care providers or a general surgeon. A surgeon without expertise in the management of pediatric tumors may attempt to biopsy or resect a mass without the availability of the necessary resources to obtain and process tumor samples for biologic studies. This intervention can lead to difficulty in risk-assignment and in administration of appropriate therapy.
• Informed consent: Pediatric oncology has benefited from the high level of participation of children in clinical trials. The pediatric oncologist must be an effective communicator in providing informed consent to patients and families; a thorough discussion of the potential benefits and risks is warranted. Without compromising the enthusiasm and desire by the subspecialist to achieve a cure for the patient, families must be made aware that complications during cancer treatment can result in death or long-term morbidities.

Special Concerns

• Drug toxicity
• • The cornerstone of pediatrics is prevention and treatment of disease to foster the normal growth and development of children. The use of chemotherapy in infants, children, and adolescents with cancer presents many challenges.
• • The pediatric oncologist must strive to maintain a balance between administering curative therapy and minimizing long-term morbidity.
  • Chemotherapy may have effects on the growth and development of children (eg, when administered to infants, ototoxicity of cisplatin and carboplatin may affect language development; neurotoxicity of vincristine may interfere with motor development; refractory nausea and emesis may lead to food aversion). Recognizing these sequelae is important, so that patients can receive appropriate therapy.
• Physiologic processes
• • Equally important is the understanding that several physiologic processes during infancy and childhood can affect the pharmacokinetics and pharmacodynamics of drugs. Body composition varies during infancy, childhood, and adolescence. Total body water and extracellular fluid volumes are larger in the first year of life, and blood volume and fat composition do not approach adult levels until adolescence. Protein binding is also lower during the first year of life, therefore increasing the amount of unbound drug. These variables affect the volume of distribution of drugs; therefore, drug dosages are calculated differently in infants.
• • Drug doses in pediatric oncology most commonly are calculated using body surface area (BSA). However, because the BSA is larger in relation to an infant's weight, the use of BSA for dose calculation results in a larger dose per weight in infants than in older children and adults. As a result, many physicians dose chemotherapy in infants on a per kilogram basis rather than by BSA.
  • Data are lacking concerning the disposition of most antineoplastic agents in young children and infants. However, guidelines are available for doxorubicin, etoposide, teniposide, and vincristine. The caveat for most of these recommendations is that only a small number of infants were included in the studies used to formulate these recommendations. In addition, not all studies included analysis of plasma-binding proteins, unbound drug systemic clearance, and other relevant factors.
  • The widespread practice of altering dosing in infants may be unwise because any rational approach should be based on the pharmacokinetic behavior of each agent. As we learn more about the pharmacokinetics of drugs and their relationship to efficacy and toxicity, the use of pharmacokinetically guided dosing may become more common.
  • Because evidence of increased toxicity with vincristine and doxorubicin is lacking, adjustment of dosing based on weight rather than on BSA is recommended in infants or children younger than 2 years and those with a BSA of less than 0.5 m². Drugs that are excreted via the kidney can have limited clearance in young infants because the percentage of the cardiac output that reaches the kidneys is only 5%, whereas it is 25% in an older child or adult.
• Nephrotoxicity
• • Drugs excreted via the kidney can have limited clearance in young infants because the amount of cardiac output that reaches the kidneys is only 5%, compared with 25% in an older child or adult.
• • Ifosfamide can cause renal tubular injury manifested as Fanconi syndrome, metabolic acidosis, hypokalemia, hypophosphatemia proteinuria, and rickets. The chronic nature of these injuries may interfere with normal growth, and close follow-up monitoring is required. Age younger than 3 years, presence of a single kidney, and the use of a cumulative dose of ifosfamide more than 45-72 g/m² are important risk factors for nephrotoxicity.
  • The use of ifosfamide in patients with preexisting renal abnormalities is indicated only if potential benefit outweighs risk of further nephrotoxicity. Although this type of injury appears reversible, its long-term outcome remains unknown.
  • Cisplatin and, less frequently, carboplatin can cause glomerular injury manifested as acute or chronic decreased glomerular filtration rate.
• Cardiotoxicity
• • The heart is another organ at risk for early and late toxicity
  • Anthracyclines have been useful in the treatment of a large number of pediatric cancers. However, the use of anthracyclines, especially in high cumulative doses, can lead to the development of a cardiomyopathy.
  • Several studies have suggested that age is an important risk factor for this complication because these drugs appear to damage cardiac myocytes and limit the heart's ability to grow.
• Chemoprotectants and growth factor