The treatment section of this document is organized to correspond with the Children’s Oncology Group (COG) risk-based schema for the treatment of neuroblastoma. This schema is based on three factors: patient age at diagnosis, certain biological characteristics of the patient’s neuroblastoma tumor, and the stage of the tumor as defined by the International Neuroblastoma Staging System (INSS). The INSS has replaced the previously used Children’s Cancer Group (CCG) and Pediatric Oncology Group (POG) staging systems. The INSS is described below, and the COG risk-based treatment schema is described in Table 1 in this section.
A thorough evaluation for metastatic disease should be performed prior to therapy initiation. The following investigations are recommended:
- Bone marrow should be assessed by bilateral posterior iliac crest marrow aspirates and trephine (core) bone marrow biopsies to exclude bone marrow involvement. To be considered adequate, core biopsy specimens must contain at least 1 cm of marrow, excluding cartilage. Bone marrow sampling may not be necessary for tumors that are otherwise stage 1.
- Before resection of the primary tumor, bone should be assessed by metaiodobenzylguanidine (MIBG) scan, which is applicable to all sites of disease, and by technetium 99 scan if the results of the MIBG scan are negative or unavailable. Imaging with 123I-MIBG is optimal for identifying soft tissue and bony metastases and is superior to 18F-FDG positron emission tomography/computerized tomography (PET/CT) in a prospective comparison. Additional imaging of isolated or equivocal positive lesions is recommended if the primary tumor does not take up MIBG.
- Palpable lymph nodes should be clinically examined and histologically confirmed if indicated for staging.
- The abdomen and liver should be assessed by CT scan and/or magnetic resonance imaging (MRI). Ultrasound is considered suboptimal for accurate 3D measurements. If extension of abdominal disease or pulmonary metastasis is suspected, the chest should be examined by CT scan.
- Lumbar puncture should be avoided as central nervous system (CNS) metastasis at diagnosis is rare, and lumbar puncture may be associated with an increased incidence of subsequent development of CNS metastasis.
- Paraspinal tumors may extend through neural foramina to compress the spinal cord. Therefore, MRI of the spine adjacent to any paraspinal tumor is recommended.
- Stage 1: Localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for tumor microscopically (i.e., nodes attached to and removed with the primary tumor may be positive).
- Stage 2A: Localized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph nodes negative for tumor microscopically.
- Stage 2B: Localized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumor. Enlarged contralateral lymph nodes must be negative microscopically.
- Stage 3: Unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph node involvement; or midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement. The midline is defined as the vertebral column. Tumors originating on one side and crossing the midline must infiltrate to or beyond the opposite side of the vertebral column.
- 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 stage 1, 2A, or 2B, with dissemination limited to skin, liver, and/or bone marrow (limited to infants younger than 18 months). Marrow involvement should be minimal (i.e., <10% of total nucleated cells identified as malignant by bone biopsy or by bone marrow aspirate). More extensive bone marrow involvement would be considered stage 4 disease. The results of the MIBG scan, if performed, should be negative for disease in the bone marrow.
In North America, the COG investigated a risk-based neuroblastoma treatment plan that assigned all patients to a low-, intermediate-, or high-risk group based on age, INSS stage, and tumor biology. The relevant biological attributes of the tumor included MYCN status, International Neuroblastoma Pathologic Classification (INPC) histopathology classification, and tumor DNA index. The low-risk group was observed without further treatment unless the patient had life- or organ-threatening tumors. The intermediate-risk group received limited chemotherapy, additional surgery in some instances, and avoided radiation therapy. This study involved an overall reduction in treatment compared to prior treatment plans. The high-risk group was treated with aggressive chemotherapy, second-look surgery, high-dose chemotherapy with stem cell rescue, radiation therapy, and cis-retinoic acid. The outcome for the low- and intermediate-risk groups combined was an event-free survival and overall 3-year survival of 88% and 96%, respectively. There was no unexpected toxicity. These studies (COG-P9641 and COG-A3961) have established a new standard of care for children in North America with neuroblastoma.
Some controversies exist regarding the treatment of several small subsets of patients and the INSS staging system;[12-14] risk group assignment and recommended treatment are expected to mature as additional outcome data are analyzed. For example, the risk group for INSS stage 4, including patients aged 12 to 18 months was changed for patients with MYCN-nonamplified status in 2005.[15-17] Table 1 describes the risk group assignment criteria used to assign treatment in these studies.Table 1. Children’s Oncology Group (COG) Neuroblastoma Low-, Intermediate-, and High-Risk Group Assignment Schema Used for COG-9641 and COG-A3961 Studiesa
|INSS Stage||Age||MYCN Status||INPC Classification||DNA Ploidyb||Risk Group|
|≥365 d–21 y||Nonamplified||Any||-||Low|
|≥365 d–21 y||Amplified||Favorable||-||Low|
|≥365 d–21 y||Amplified||Unfavorable||-||High|
|≥365 d–21 y||Nonamplified||Favorable||-||Intermediate|
|≥365 d–21 y||Nonamplified||Unfavorable||-||High|
|≥365 d–21 y||Amplified||Any||-||High|
|4d||<548 d [15-17]||Nonamplified||Any||Any||Intermediate|
|≥548 d–21 y||Any||Any||-||High|
|INPC = International Neuroblastoma Pathologic Classification; INSS = International Neuroblastoma Staging System.|
|aThe COG-9641 and COG-A3961 trials established the current standard of care for neuroblastoma patients in terms of risk group assignment and treatment strategies.|
|bDNA Ploidy: DNA Index (DI) > 1 is favorable, = 1 is unfavorable; hypodiploid tumors (with DI < 1) will be treated as a tumor with a DI > 1 (DI < 1 [hypodiploid] to be considered favorable ploidy).|
|cINSS stage 2A/2B symptomatic patients with spinal cord compression, neurologic deficits, or other symptoms should be treated with immediate chemotherapy for four cycles.|
|dINSS stage 3 or stage 4 patients with clinical symptoms as listed above should receive immediate chemotherapy.|
|eINSS stage 4S infants with favorable biology and clinical symptoms should be treated with immediate chemotherapy until asymptomatic (2–4 cycles). Clinical symptoms include: respiratory distress with or without hepatomegaly or cord compression and neurologic deficit or inferior vena cava compression and renal ischemia; or genitourinary obstruction; or gastrointestinal obstruction and vomiting; or coagulopathy with significant clinical hemorrhage unresponsive to replacement therapy.|
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