Treatment Option Overview for Neuroblastoma
Children’s Oncology Group (COG) Neuroblastoma Risk Grouping
Description of International Neuroblastoma Response Criteria
Treatment of Spinal Cord Compression
Surveillance During and After Treatment
Because most children with neuroblastoma in North America are treated according to the Children’s Oncology Group (COG) risk-group assignment, the treatments described in this summary are based on the most recently published COG risk stratification system. Each child is assigned to a low-risk, intermediate-risk, or high-risk group (refer to Tables 6, 7, and 8 for more information) based on the following:[1-6]
- International Neuroblastoma Staging System (INSS) stage.
- International Neuroblastoma Pathologic Classification (INPC).
- Amplification of the MYCN oncogene within tumor tissue.[1-6]
The treatment of neuroblastoma has evolved over the past 60 years. Generally, treatment is based on whether the tumor is low, intermediate, or high risk:
- For low-risk tumors, the approach is either observation or resection. Five-year overall survival (OS) was 97% in a large COG study.
- For intermediate-risk tumors, chemotherapy is usually given before definitive resection, with the amount and duration based on clinical and tumor biological risk factors and response to therapy. The 3-year OS rate for intermediate-risk patients was about 96% in a large COG study, and thus, the current trend is to decrease chemotherapy to diminish side effects.
- For high-risk patients, treatment has intensified to include chemotherapy, surgery, radiation therapy, hematopoietic stem cell transplantation, differentiation therapy, and immunotherapy, resulting in survival rates of 40% to 50%.
|Stage (COG Risk-Group Assignment)||Treatment Options|
|COG = Children's Oncology Group; GM-CSF = granulocyte-macrophage colony-stimulating factor; 131I-mIBG = iodine 131-metaiodobenzylguanidine; SCT = stem cell transplant.|
|Low-Risk Neuroblastoma||Surgery followed by observation.|
|Chemotherapy with or without surgery (for symptomatic disease or unresectable progressive disease after surgery).|
|Observation without biopsy (for perinatal neuroblastoma with small adrenal tumors).|
|Intermediate-Risk Neuroblastoma||Chemotherapy with or without surgery.|
|Surgery and observation (in infants).|
|Radiation therapy (only for emergent therapy).|
|High-Risk Neuroblastoma||A regimen of chemotherapy, surgery, SCT, radiation therapy, and anti-GD2 antibody ch14.18, with interleukin-2/GM-CSF and isotretinoin.|
|Stage 4S Neuroblastoma||Observation with supportive care (for asymptomatic patients with favorable tumor biology).|
|Chemotherapy (for symptomatic patients, very young infants, or those with unfavorable biology).|
|Recurrent Neuroblastoma||Locoregional recurrence in patients initially classified as low risk||Surgery followed by observation or chemotherapy.|
|Chemotherapy that may be followed by surgery.|
|Metastatic recurrence in patients initially classified as low risk||Observation (if metastatic disease is in a 4S pattern in an infant).|
|Locoregional recurrence in patients initially classified as intermediate risk||Surgery (complete resection).|
|Surgery (incomplete resection) followed by chemotherapy.|
|Metastatic recurrence in patients initially classified as intermediate risk||High-risk therapy.|
|Recurrence in patients initially classified as high risk||Chemotherapy.|
|131 I-mIBG alone, in combination with other therapy, or followed by stem cell rescue.|
|Second autologous SCT after retrieval chemotherapy.|
|Recurrence in the central nervous system||Surgery and radiation therapy.|
|Novel therapeutic approaches.|
Children’s Oncology Group (COG) Neuroblastoma Risk Grouping
The treatment section of this document is organized to correspond with the COG risk-based treatment plan that assigns all patients to a low-, intermediate-, or high-risk group. This risk-based schema is based on the following factors:
- Patient age at diagnosis.
- Certain biological characteristics of the tumor, which include MYCN status, INPC histopathology classification, and tumor DNA index.
- Stage of the tumor as defined by the INSS.
Table 6 (in the Treatment of Low-Risk Neuroblastoma section), Table 7 (in the Treatment of Intermediate-Risk Neuroblastoma section), and Table 8 (in the Treatment of High-Risk Neuroblastoma section) describe the risk group assignment criteria used to assign treatment in the COG-P9641, COG-A3961, and COG-A3973 studies, respectively.
Assessment of risk for low-stage MYCN-amplified neuroblastoma is controversial because it is so rare. A study of 87 INSS stage 1 and 2 patients pooled from several clinical trial groups demonstrated no effect of age, stage, or initial treatment on outcome. The event-free survival (EFS) rate was 53% and the OS rate was 72%. Survival was superior in patients whose tumors were hyperdiploid, rather than diploid (EFS, 82% ± 20% vs. 37% ± 21%; OS, 94% ± 11% vs. 54% ± 15%). The overall EFS and OS for infants with stage 4 and 4S disease and MYCN-amplification was only 30% at 2 to 5 years after treatment in a European study. The COG considers infants with stage 4 and stage 4S disease with MYCN amplification to be at high risk.Description of International Neuroblastoma Response Criteria
Before therapy can be stopped after the initially planned number of cycles, certain response criteria, depending on risk group and treatment assignment, must be met. These criteria are defined as follows:[13,14]
- Complete Response: Total disappearance of tumor, with no evidence of disease. Vanillylmandelic acid (VMA) and homovanillic acid (HVA) are normal.
- Very Good Partial Response: Primary tumor has decreased by 90% to 99%, and no evidence of metastatic disease. Urine VMA/HVA are normal. Residual bone scan changes are allowed.
- Partial Response: 50% to 90% decrease in the size of all measurable lesions; the number of bone scan–positive sites is decreased by greater than 50% and no new lesions are present; no more than one positive bone marrow site allowed if this represents a reduction in the number of sites originally positive for tumor at diagnosis.
- Mixed Response: No new lesions, 50% to 90% reduction of any measurable lesion (primary or metastatic) with less than 50% reduction in other lesions and less than 25% increase in any lesion.
- No Response or Stable Disease: No new lesions; less than 50% reduction and less than 25% increase in any lesion.
- Progressive Disease: Any new lesion; increase in any measurable lesion by greater than 25%; previous negative bone marrow now positive for tumor. Persistent elevation in urinary VMA/HVA with stable disease or an increase in VMA/HVA without clinical or radiographic evidence of progression does not indicate progressive disease, but warrants continued follow-up. Care should be taken in interpreting the development of metastatic disease in an infant who was initially considered to have stage 1 or 2 disease. If the pattern of metastases in such a patient is consistent with a 4S pattern of disease (skin, liver, bone marrow less than 10% involved), these patients are not classified as progressive/metastatic disease, which would typically be a criteria for removal from protocol therapy. Instead, these patients are managed as stage 4S.
In patients without metastatic disease, the standard of care is to perform an initial surgery to accomplish the following:
- Establish the diagnosis.
- Resect as much of the primary tumor as is safely possible.
- Accurately stage disease through sampling of regional lymph nodes that are not adherent to the tumor.
- Obtain adequate tissue for biological studies.
The COG reported that expectant observation in infants younger than 6 months with small adrenal masses resulted in an excellent EFS and OS while avoiding surgical intervention in a large majority of patients.Radiation Therapy
In the completed COG treatment plan, radiation therapy for patients with low-risk or intermediate-risk neuroblastoma was reserved for symptomatic life-threatening or organ-threatening tumor bulk that did not respond rapidly enough to chemotherapy. Common situations in which radiation therapy is used in these patients include the following:
- Infants aged 60 days and younger with stage 4S and marked respiratory compromise from liver metastases that has not responded to chemotherapy.
- Symptomatic spinal cord compression that has not responded to initial chemotherapy and/or surgical decompression.
Spinal cord compression is considered a medical emergency. Immediate treatment is given because neurologic recovery is more likely when symptoms are present for a relatively short period of time before diagnosis and treatment. Recovery also depends on the severity of neurologic defects (weakness vs. paralysis). Neurologic outcome appears to be similar whether cord compression is treated with chemotherapy, radiation therapy, or surgery, although radiation therapy is used less frequently than in the past.
Children with severe spinal cord compression that does not promptly improve or those with worsening symptoms may benefit from neurosurgical intervention. Laminectomy may result in later kyphoscoliosis and may not eliminate the need for chemotherapy.[20-22] It was thought that osteoplastic laminotomy, a procedure that does not remove bone, would result in less spinal deformity. Osteoplastic laminotomy may be associated with a lower incidence of progressive spinal deformity requiring fusion but there is no evidence that functional deficit is improved with laminoplasty. In a series of 34 infants with symptomatic epidural spinal cord compression, both surgery and chemotherapy provided unsatisfactory results once paraplegia had been established. The frequency of grade 3 motor deficits and bowel dysfunction increased with a longer symptom duration interval. Most infants with symptomatic epidural spinal cord compression developed sequelae and it was severe in about one-half of them. This supports the need for greater awareness and timely intervention in these infants.Surveillance During and After Treatment
Surveillance studies during and after treatment are able to detect asymptomatic and unsuspected relapse in a substantial portion of patients. In an overall surveillance plan, one of the most reliable tests to detect disease progression or recurrence is the 123I-metaiodobenzylguanidine scan.[25,26]References
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