Care of children with neuroblastoma 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 International Neuroblastoma Staging System (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 Children's Cancer Group (CCG) and Pediatric Oncology Group (POG), now known as the Children's Oncology Group (COG). Correlative biologic studies were pivotal in identifying biologic risk factors important for outcome. Currently, efforts are ongoing to develop an International Neuroblastoma Risk Group (INRG).
In addition, recently published results on correlative biologic studies and clinical outcome have 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. [17, 18] 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. 
Table 1. Current COG Neuroblastoma Risk Stratification (Open Table in a new window)
|Risk Group||Stage||Age||MYCN Amplification Status||Ploidy||Shimada|
Cooperative Group Treatment Strategies
Low-risk group treatment strategy
Patients with localized respectable neuroblastoma (stage 1) have excellent event-free survival (EFS) rates with surgical excision of tumor only. 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 assigned to a low-risk category if they have MYCN -non amplified tumors, regardless of age histology or ploidy. Patients with stage 2A/2B disease with amplified MYCN are considered high risk regardless of age and histology.
A study by the Pediatric Oncology Group of experience with conservative treatment of low-risk patients confirmed the excellent outcomes for these patients with surgery alone. However, overall survival seemed lower among patients with stage 2b, MYC-N nonamplified, unfavorable histology or diploid tumors; thus, in the future, this specific group of patients may require reconsideration of their risk categorization. 
Most patients with 4S disease (ie, non-MYCN –amplified tumors, favorable histology, hyperdiploid tumors in infants younger than 1 y) are also considered to be in the low-risk group and most experience spontaneous regression. Thus, observation or surgery alone is often all that is needed to manage these tumors. Chemotherapy may be used to control life-threatening situations such as respiratory distress or mechanical obstruction.
Intermediate-risk group treatment strategy
Surgery and multiagent chemotherapy comprise the backbone of therapy for intermediate risk group patients. Current efforts are ongoing to help understand which of this diverse group of patients can have therapy reduced without threatening the excellent EFS for these patients.
Intermediate-risk patients include children younger than 18 months with stage 3 and 4 disease and favorable biology (non-MYCN –amplified tumors, regardless of histology and DNA index). These patients are offered therapy with 4 of the most active drugs against neuroblastoma (ie, cyclophosphamide, doxorubicin, carboplatin, etoposide) for either 4 cycles, 6 cycles, or 8 cycles, depending on histology and DNA index and response to treatment. 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 suggested that it improves outcome when administered to areas of residual disease postchemotherapy.
Baker et al conducted a prospective, phase 3, nonrandomized trial of 479 patients (270 patients with stage 3 disease, 178 patients with stage 4 disease, and 31 patients with stage 4S disease) to determine whether a 3-year estimated overall survival of more than 90% could be maintained with reduced duration of chemotherapy and reduced drug doses.  The resulting 3-year estimate of overall for the entire group was 96%±1%. The study concluded that among patients with intermediate-risk neuroblastoma, substantially reduced duration of chemotherapy and reduced doses of chemotherapeutic agents still resulted in excellent outcomes.
High-risk group treatment strategy
This group of patients seem to require treatment with multiagent chemotherapy, surgery, and radiotherapy, followed by consolidation with high-dose chemotherapy and peripheral blood stem cell rescue.
Current therapeutic protocols involve 4 phases of therapy, including induction, local control, consolidation and treatment of minimal residual disease. 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.
Induction therapy currently involves multiagent chemotherapy with non–cross-resistant profiles, including alkylating agents, platinum, and anthracyclines and topoisomerase II inhibitors. Current studies are ongoing to look at addition of topoisomerase I inhibitors as part of an upfront therapy during induction. Topotecan does display activity against relapsed neuroblastoma.
Local control involves surgical resection of primary tumor site as well as radiation to primary tumor site. Primary tumors are often more amenable to surgical resection after receiving upfront induction chemotherapy. Neuroblastoma is a very radiosensitive tumor, and chemotherapy plays an important role in control of disease in the high-risk setting.
Myeloablative consolidation therapy has shown to improve EFS for patients with high-risk neuroblastoma. Current data from trials in the United States and Europe support improved outcomes for patients receiving myeloablative consolidation therapy with etoposide, carboplatin, and melphalan. Recently, a single-arm study of tandem stem cell transplantation reported an EFS of 58%. A randomized study of tandem stem cell transplant against a single transplant is currently ongoing in the Children’s Oncology Group.  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.
Control of minimal residual disease with biologic agents has also been shown to improve survival. The most experience is with 13-cis -retinoic acid in a maintenance phase of therapy. This agent has been shown to cause differentiation in neuroblastoma cell lines. CCG-3891 showed a significant survival advantage with 3-year EFS of 38% for those patients receiving maintenance therapy with 13-cis -RA compared with 18% for those who did not receive this therapy. Recent data have showed improved survival in patients receiving 13-cis -RA in combination with immunomodulatory therapy with interleukin (IL)-2, granulocyte macrophage colony-stimulating factor (GM-CSF), and the chimeric anti-GD2 (gangliosidase) antibody when compared with 13-cis -RA alone.
On March 10, 2015 the US Food and Drug Administration (FDA) approved dinutuximab, which is a monoclonal antibody against GD2, for use in the treatment of high-risk neuroblastoma. It was approved as part of a multimodality regimen, including surgery, chemotherapy, and radiation therapy, for patients who have achieved at least a partial response to prior first-line multiagent. It is indicated in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2) and 13-cis-retinoic acid (RA) for pediatric patients with high-risk neuroblastoma.
Future directions and experimental therapies
Other experimental therapies are currently under investigation for recurrent high-risk neuroblastoma, including aurora kinase inhibitors, antiangiogenic agents, histone deacetylase inhibitors, and therapeutic metaiodobenzylguanidine (MIBG). [22, 23]
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.
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.
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.
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.
What would you like to print?