Treatment Option Overview for Neuroblastoma
Previously, most children with neuroblastoma in North America were treated according to the Children’s Oncology Group (COG) risk-group assignment, even if they were not enrolled in a COG study. In the most recent COG study, the International Neuroblastoma Risk Group (INRG) system was used to assign treatment. Because the older system is still being used by some physicians to assign treatments, the treatments described in this summary are based on both the INRG system and the most recently published COG risk stratification system. In the INRG system, each child is assigned to a group on the basis of image-defined potential surgical risk, age, and the presence or absence of metastasis. (Refer to the list of image-defined risk factors for more information.) In the previous COG risk system, each child was assigned to a low-risk, intermediate-risk, or high-risk group (refer to Tables 6, 8, and 10 for more information) based on the following:[1-6]
Other biological factors that influenced treatment selection in previous COG studies include unbalanced 11q loss of heterozygosity and loss of heterozygosity for chromosome 1p.[7,8] However, in 2012, the COG Neuroblastoma Committee defined favorable genomics, for purposes of risk assignment, as hyperdiploid neuroblastoma cells without segmental copy number aberrations, including no loss of copy number at 1p, 3p, 4p, or 11q and no gain of copy number at 1q, 2p, or 17q.
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 INRG L1 or COG low-risk tumors, the approach is either observation or resection. Five-year overall survival (OS) was 97% in a large COG study.
- For INRG L2 or COG intermediate-risk tumors, chemotherapy is often given before definitive resection, with the amount and duration based on clinical and tumor biological risk factors and response to therapy. In recent studies, select patients have been observed without undergoing chemotherapy or attempted resection. 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 8 (in the Treatment of Intermediate-Risk Neuroblastoma section), and Table 10 (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.
In patients with L1 tumors (defined as having no image-defined surgical risk factors), resection is less likely to result in surgical complications and, generally, the tumors have been resected. L2 tumors, which have at least one image-defined surgical risk factor, have been treated with chemotherapy when deemed too risky to attempt resection, followed by surgery when the tumors have responded. Recent German studies of selected groups of patients have biopsied tissue and observed infants with both L1 and L2 tumors without MYCN amplification, avoiding additional surgery and chemotherapy in most patients.
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. According to the surgical guidelines described in the recent intermediate-risk neuroblastoma clinical trial (ANBL0531 [NCT00499616]), the primary tumor is not routinely resected in patients with 4S neuroblastoma.
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.
Treatment of Spinal Cord Compression
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.[21-23] 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.[26,27]
- Cotterill SJ, Pearson AD, Pritchard J, et al.: Clinical prognostic factors in 1277 patients with neuroblastoma: results of The European Neuroblastoma Study Group 'Survey' 1982-1992. Eur J Cancer 36 (7): 901-8, 2000. [PUBMED Abstract]
- Moroz V, Machin D, Faldum A, et al.: Changes over three decades in outcome and the prognostic influence of age-at-diagnosis in young patients with neuroblastoma: a report from the International Neuroblastoma Risk Group Project. Eur J Cancer 47 (4): 561-71, 2011. [PUBMED Abstract]
- Look AT, Hayes FA, Shuster JJ, et al.: Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 9 (4): 581-91, 1991. [PUBMED Abstract]
- Schmidt ML, Lukens JN, Seeger RC, et al.: Biologic factors determine prognosis in infants with stage IV neuroblastoma: A prospective Children's Cancer Group study. J Clin Oncol 18 (6): 1260-8, 2000. [PUBMED Abstract]
- Berthold F, Trechow R, Utsch S, et al.: Prognostic factors in metastatic neuroblastoma. A multivariate analysis of 182 cases. Am J Pediatr Hematol Oncol 14 (3): 207-15, 1992. [PUBMED Abstract]
- Matthay KK, Perez C, Seeger RC, et al.: Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children's Cancer Group study. J Clin Oncol 16 (4): 1256-64, 1998. [PUBMED Abstract]
- Attiyeh EF, London WB, Mossé YP, et al.: Chromosome 1p and 11q deletions and outcome in neuroblastoma. N Engl J Med 353 (21): 2243-53, 2005. [PUBMED Abstract]
- Spitz R, Hero B, Simon T, et al.: Loss in chromosome 11q identifies tumors with increased risk for metastatic relapses in localized and 4S neuroblastoma. Clin Cancer Res 12 (11 Pt 1): 3368-73, 2006. [PUBMED Abstract]
- Strother DR, London WB, Schmidt ML, et al.: Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children's Oncology Group study P9641. J Clin Oncol 30 (15): 1842-8, 2012. [PUBMED Abstract]
- Baker DL, Schmidt ML, Cohn SL, et al.: Outcome after reduced chemotherapy for intermediate-risk neuroblastoma. N Engl J Med 363 (14): 1313-23, 2010. [PUBMED Abstract]
- Bagatell R, Beck-Popovic M, London WB, et al.: Significance of MYCN amplification in international neuroblastoma staging system stage 1 and 2 neuroblastoma: a report from the International Neuroblastoma Risk Group database. J Clin Oncol 27 (3): 365-70, 2009. [PUBMED Abstract]
- Canete A, Gerrard M, Rubie H, et al.: Poor survival for infants with MYCN-amplified metastatic neuroblastoma despite intensified treatment: the International Society of Paediatric Oncology European Neuroblastoma Experience. J Clin Oncol 27 (7): 1014-9, 2009. [PUBMED Abstract]
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- Hero B, Simon T, Spitz R, et al.: Localized infant neuroblastomas often show spontaneous regression: results of the prospective trials NB95-S and NB97. J Clin Oncol 26 (9): 1504-10, 2008. [PUBMED Abstract]
- Nuchtern JG, London WB, Barnewolt CE, et al.: A prospective study of expectant observation as primary therapy for neuroblastoma in young infants: a Children's Oncology Group study. Ann Surg 256 (4): 573-80, 2012. [PUBMED Abstract]
- Adkins ES, Sawin R, Gerbing RB, et al.: Efficacy of complete resection for high-risk neuroblastoma: a Children's Cancer Group study. J Pediatr Surg 39 (6): 931-6, 2004. [PUBMED Abstract]
- Castel V, Tovar JA, Costa E, et al.: The role of surgery in stage IV neuroblastoma. J Pediatr Surg 37 (11): 1574-8, 2002. [PUBMED Abstract]
- La Quaglia MP, Kushner BH, Su W, et al.: The impact of gross total resection on local control and survival in high-risk neuroblastoma. J Pediatr Surg 39 (3): 412-7; discussion 412-7, 2004. [PUBMED Abstract]
- Simon T, Häberle B, Hero B, et al.: Role of surgery in the treatment of patients with stage 4 neuroblastoma age 18 months or older at diagnosis. J Clin Oncol 31 (6): 752-8, 2013. [PUBMED Abstract]
- Katzenstein HM, Kent PM, London WB, et al.: Treatment and outcome of 83 children with intraspinal neuroblastoma: the Pediatric Oncology Group experience. J Clin Oncol 19 (4): 1047-55, 2001. [PUBMED Abstract]
- De Bernardi B, Pianca C, Pistamiglio P, et al.: Neuroblastoma with symptomatic spinal cord compression at diagnosis: treatment and results with 76 cases. J Clin Oncol 19 (1): 183-90, 2001. [PUBMED Abstract]
- Simon T, Niemann CA, Hero B, et al.: Short- and long-term outcome of patients with symptoms of spinal cord compression by neuroblastoma. Dev Med Child Neurol 54 (4): 347-52, 2012. [PUBMED Abstract]
- McGirt MJ, Chaichana KL, Atiba A, et al.: Incidence of spinal deformity after resection of intramedullary spinal cord tumors in children who underwent laminectomy compared with laminoplasty. J Neurosurg Pediatr 1 (1): 57-62, 2008. [PUBMED Abstract]
- De Bernardi B, Quaglietta L, Haupt R, et al.: Neuroblastoma with symptomatic epidural compression in the infant: the AIEOP experience. Pediatr Blood Cancer 61 (8): 1369-75, 2014. [PUBMED Abstract]
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- Kushner BH, Kramer K, Modak S, et al.: Sensitivity of surveillance studies for detecting asymptomatic and unsuspected relapse of high-risk neuroblastoma. J Clin Oncol 27 (7): 1041-6, 2009. [PUBMED Abstract]