Treatment of Intermediate-Risk Neuroblastoma
The Children's Oncology Group (COG) intermediate-risk group assignment criteria are described in Table 8.
|INSS Stage||Age||MYCN Status||INPC Classification||DNA Ploidyb|
|INPC = International Neuroblastoma Pathologic Classification; INSS = International Neuroblastoma Staging System.|
|aThe COG-P9641 (low risk) and COG-A3961 (intermediate risk) trials established the current standard of care for non–high-risk neuroblastoma patients in terms of risk group assignment and treatment strategies.|
|bDNA Ploidy: DNA Index (DI) > 1 is favorable, DI = 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 3 or stage 4 patients with clinical symptoms as listed above receive immediate chemotherapy.|
|dINSS stage 4S infants with favorable biology and clinical symptoms are treated with immediate chemotherapy until asymptomatic (2–4 cycles). Clinical symptoms include the following: 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.|
|≥365 d–21 y||Nonamplified||Favorable||-|
|4c||<548 d [1-3]||Nonamplified||Any||Any|
(Refer to the Treatment of Stage 4S Neuroblastoma section of this summary for more information about the treatment of stage 4S neuroblastoma.)
Treatment Options for Intermediate-Risk Neuroblastoma
Treatment options for intermediate-risk neuroblastoma include the following:
Chemotherapy with or without surgery
Patients categorized as intermediate risk have been successfully treated with surgery and four to eight cycles of chemotherapy (carboplatin, cyclophosphamide, doxorubicin, and etoposide; the cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen) (COG-A3961). As a rule, patients whose tumors had unfavorable biology received eight cycles of chemotherapy, compared with four cycles for patients whose tumors had favorable biology. The COG-A3961 phase III trial demonstrated that therapy could be significantly reduced for patients with intermediate-risk neuroblastoma while maintaining outstanding survival. A nonrandomized clinical trial in Japan also reported excellent outcomes for infants with stage 3 neuroblastoma without MYCN amplification.
Whether initial chemotherapy is indicated for all intermediate-risk infants with localized neuroblastoma requires further study.
Evidence (chemotherapy with or without surgery):
- In North America, the COG (COG-A3961) investigated a risk-based neuroblastoma treatment plan that assigned all patients to a low-, intermediate-, or high-risk group based on age, International Neuroblastoma Staging System (INSS) stage, and tumor biology (i.e., MYCN gene amplification, International Neuroblastoma Pathology Classification system, and DNA ploidy). This study investigated an overall reduction in treatment compared with prior treatment plans in patients with unresectable, localized, MYCN-nonamplified tumors and infants with stage 4 MYCN-nonamplified disease. The intermediate-risk group received four to eight cycles of moderate-dose neoadjuvant chemotherapy (carboplatin, cyclophosphamide, doxorubicin, and etoposide), additional surgery in some instances, and avoided radiation therapy. Of the 464 intermediate-risk tumors (stages 3, 4, and 4S), 69.6% of them had favorable features, defined as hyperdiploidy and favorable histology, and were assigned to receive four cycles of chemotherapy.
- The administration of neoadjuvant chemotherapy facilitated at least a partial resection of 99.6% of the previously unresectable tumors. No significant difference was noted in overall survival (OS) according to the degree of resection (complete vs. incomplete, P = .37).
- Only 2.5% of the 479 patients received local radiation therapy. The 3-year event-free survival (EFS) was 88% and OS was 95%.
- The 3-year EFS was 92% for patients with stage 3 disease (n = 269), 90% for patients with stage 4S disease (n = 31), and 81% for patients with stage 4 disease (n = 176) (P < .001 for stages 3 and 4S vs. stage 4); the 3-year OS estimates were 98% for stage 3 disease, 97% for stage 4S disease, and 93% for stage 4 disease (P = .002 for stages 3 and 4S vs. stage 4).
- There was no difference in OS in patients with favorable biologic features between those who received eight cycles of chemotherapy (100%) compared with those who received four cycles (96%).
- There was no unexpected toxicity.
- A German prospective clinical trial enrolled 340 infants aged 1 year or younger whose tumors were stage 1, 2, or 3, histologically verified, and lacked MYCN amplification. Chemotherapy was given at diagnosis to 57 infants with organs threatened by tumor. The tumor was completely resected or nearly so in 190 infants who underwent low-risk surgery. A total of 93 infants whose tumors were not resectable without high-risk surgery, due to age or organ involvement, were observed without chemotherapy.
- Three-year OS was excellent (95%) for infants receiving chemotherapy.
- Further surgery was avoided in 33 infants and chemotherapy was avoided in 72 infants.
- The 3-year OS rate for the infants who were observed without treatment was 99%. The metastases-free survival rate was 94% for infants with unresected tumors and was not different from infants treated with surgery or chemotherapy (median follow-up, 58 months).
- Forty-four of 93 infants with unresected tumors experienced spontaneous regression (17 were complete regressions) and 39 infants experienced progression.
- The investigators suggested that a wait-and-see strategy is appropriate for infants with localized neuroblastoma because regressions have been observed after the first year of life.
- Moderate-dose chemotherapy has been shown to be effective in the prospective Infant Neuroblastoma European Study (EURO-INF-NB-STUDY-1999-99.1); about one-half of the infants with unresectable, nonmetastatic neuroblastoma and no MYCN amplification underwent a safe surgical resection and avoided long-term adverse effects.[Level of evidence: 3iiA]
- The 5-year OS rate was 99% and the EFS rate was 90% (median follow-up, 6 years).
- In this study, infants undergoing surgical resection had a better EFS than those who did not have surgery.
- A prospective SIOPEN trial treated children with stage 2 or stage 3 unresectable neuroblastoma and those aged 12 to 18 months, with favorable International Neuroblastoma Pathology Classification.[Level of evidence: 3iiD]
- The EFS was 98% with conventional chemotherapy.
- These results are similar to the COG (COG-A3961) trial.
- In two European prospective trials of infants with disseminated neuroblastoma without MYCN gene amplification, infants with INSS stage 3 primary or positive skeletal scintigraphy were not started on chemotherapy unless life-threatening or organ-threatening symptoms developed. Chemotherapy when given consisted of short-dose and standard-dose chemotherapy.
- The OS was 100% in the 41 patients who did not have INSS stage 4S regardless of initial chemotherapy.
- In infants with overt metastases to the skeleton, lung, and central nervous system, the 2-year OS was 96% (n = 45).
- No patients died of surgery-related or chemotherapy-related complications on either protocol.
In cases of abdominal neuroblastoma thought to involve the kidney, nephrectomy is not undertaken before a trial of chemotherapy has been given.
Surgery and observation (in infants)
The need for chemotherapy in all asymptomatic infants with stage 3 or 4 disease is somewhat controversial, as some European studies have shown favorable outcomes with surgery and observation as described below.
Evidence (surgery and observation in infants):
- Infants classified as stage 4 (from 4S) due to a primary tumor infiltrating across the midline (INSS 3) or positive bone scintigraphy not associated with changes in the cortical bone documented on plain radiographs and/or computed tomography were reported to have a better outcome compared to other stage 4 infants (EFS, 90% vs. 27%).
- International Society of Paediatric Oncology European Neuroblastoma Group (SIOPEN) conducted a prospective trial of 125 infants (n = 41 with INSS 3 primary tumors or positive scintigraphy) with disseminated neuroblastoma without MYCN amplification to see if these patients could be observed in the absence of symptoms. However, treating physicians did not always follow the wait-and-see strategy.
- There was no significant difference in 2-year OS in patients with unresectable primary tumors and patients with resectable primary tumors (97% vs. 100%) and patients with negative or with positive skeletal scintigraphy without radiologic abnormalities (100% vs. 97%).
- A German prospective clinical trial enrolled 340 infants aged 1 year or younger whose tumors were stage 1, 2, or 3, verified histologically, and lacked MYCN amplification. Of the 190 infants undergoing resection, there were eight infants with stage 3 disease. A total of 93 infants whose tumors were not resectable without high-risk surgery, due to age or organ involvement, were observed without chemotherapy, which included 21 stage 3 patients. Fifty-seven infants, including 41 stage 3 patients, were treated with chemotherapy to control threatening symptoms.
- Three-year OS was excellent for the entire group of infants with unresected tumors (99%), infants receiving chemotherapy (95%), and infants with resected tumors (98%) (P = .45).
Radiation therapy (only for emergent therapy)
Radiation therapy is reserved for patients with the following:
- Symptomatic life-threatening or organ-threatening tumor that does not respond rapidly enough to chemotherapy and/or surgery and/or;
- Progressive disease.
Treatment Options Under Clinical Evaluation
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
- ANBL1232 (NCT02176967) (Response and Biology-Based Risk Factor–Guided Therapy in Treating Younger Patients With Non–High-Risk Neuroblastoma): This phase III trial is studying how well response and biology-based, risk factor–guided therapy works in treating younger patients with non–high-risk neuroblastoma.
|INRG Stage||Biology (Histology and Genomicsa)||Age||Other||Treatment|
|aGenomic features include MYCN gene amplification, segmental chromosome aberrations (somatic copy number loss at 1p, 3p, 4p, or 11q, or somatic copy number gain at 1p, 2p, or 17q), and DNA index.|
|bFavorable genomic features are defined by one or more whole-chromosome gains or hyperdiploid tumor (DNA index >1) in the absence of segmental chromosome aberrations as defined above.|
|cAsymptomatic is defined as no life-threatening symptoms and no impending neurologic or other sequelae (e.g., epidural or intraspinal tumors with existing or impending neurologic impairment, periorbital or calvarial-based lesions with existing or impending cranial nerve impairment, anatomic or mechanical compromise of critical organ function by tumor [abdominal compartment syndrome, urinary obstruction, etc.]).|
|dUnfavorable genomic features are defined by the presence of any segmental chromosome aberration (somatic copy number loss at 1p, 3p, 4p, or 11q, or somatic copy number gain at 1p, 2p, or 17q) or diploid tumor (DNA index = 1). This includes copy neutral loss of heterozygosity.|
|eOnly patients with MYCN-nonamplified tumors are eligible for the ANBL1232 study.|
|L2||Favorable histology and genomicsb||<18 months||Asymptomaticc||Observe on study|
|MS||Favorable histology and genomicsb||3–18 months||Asymptomaticc||Observe per clinical scoring system|
|Symptomatic||Response-based chemotherapy, as per protocol|
|Unfavorabled/unknown histology and genomicse||<18 months||Response-based chemotherapy, as per protocol|
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with neuroblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
- Schmidt ML, Lal A, Seeger RC, et al.: Favorable prognosis for patients 12 to 18 months of age with stage 4 nonamplified MYCN neuroblastoma: a Children's Cancer Group Study. J Clin Oncol 23 (27): 6474-80, 2005. [PUBMED Abstract]
- London WB, Castleberry RP, Matthay KK, et al.: Evidence for an age cutoff greater than 365 days for neuroblastoma risk group stratification in the Children's Oncology Group. J Clin Oncol 23 (27): 6459-65, 2005. [PUBMED Abstract]
- George RE, London WB, Cohn SL, et al.: Hyperdiploidy plus nonamplified MYCN confers a favorable prognosis in children 12 to 18 months old with disseminated neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 23 (27): 6466-73, 2005. [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]
- Iehara T, Hamazaki M, Tajiri T, et al.: Successful treatment of infants with localized neuroblastoma based on their MYCN status. Int J Clin Oncol 18 (3): 389-95, 2013. [PUBMED Abstract]
- 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]
- Rubie H, De Bernardi B, Gerrard M, et al.: Excellent outcome with reduced treatment in infants with nonmetastatic and unresectable neuroblastoma without MYCN amplification: results of the prospective INES 99.1. J Clin Oncol 29 (4): 449-55, 2011. [PUBMED Abstract]
- Kohler JA, Rubie H, Castel V, et al.: Treatment of children over the age of one year with unresectable localised neuroblastoma without MYCN amplification: results of the SIOPEN study. Eur J Cancer 49 (17): 3671-9, 2013. [PUBMED Abstract]
- De Bernardi B, Gerrard M, Boni L, et al.: Excellent outcome with reduced treatment for infants with disseminated neuroblastoma without MYCN gene amplification. J Clin Oncol 27 (7): 1034-40, 2009. [PUBMED Abstract]
- Shamberger RC, Smith EI, Joshi VV, et al.: The risk of nephrectomy during local control in abdominal neuroblastoma. J Pediatr Surg 33 (2): 161-4, 1998. [PUBMED Abstract]
- Minard V, Hartmann O, Peyroulet MC, et al.: Adverse outcome of infants with metastatic neuroblastoma, MYCN amplification and/or bone lesions: results of the French society of pediatric oncology. Br J Cancer 83 (8): 973-9, 2000. [PUBMED Abstract]