International Neuroblastoma Staging System
Children’s Oncology Group Neuroblastoma Risk Grouping

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:[1]

1. 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.[2]
2. 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.[3] Plain radiographs of positive lesions are recommended.
3. Palpable lymph nodes should be clinically examined and histologically confirmed if indicated for staging.[1]
4. The abdomen and liver should be assessed by computerized tomography (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.
5. Lumbar puncture should be avoided as central nervous system (CNS) metastasis at diagnosis is rare,[4] and lumbar puncture may be associated with an increased incidence of subsequent development of CNS metastasis.[5]
6. Paraspinal tumors may extend through neural foramina to compress the spinal cord. Therefore, MRI of the spine adjacent to any paraspinal tumor is recommended.

INSS combines certain features of the previously used POG and CCG systems [1,6] and has identified distinct prognostic groups.[1,6-8]

• 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 1 year). 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.[9] 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.[9] 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;[10-12] 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.[13-15] Table 1 describes the risk group assignment criteria used to assign treatment in these studies.

Table 1. Children’s Oncology Group Neuroblastoma Low-, Intermediate-, and High-Risk Group Assignment Schema Used for COG-9641 and COG-A3961 Studies

Enlarge

INSS Stage	Age	MYCN Status	INPC Classification	DNA Ploidyb	Risk Group
1	0–21 y	Any	Any	Any	Low
2A/2Bb	<365 d	Any	Any	Any	Low
	≥365 d–21 y	Nonamplified	Any	-	Low
	≥365 d–21 y	Amplified	Favorable	-	Low
	≥365 d–21 y	Amplified	Unfavorable	-	High
3d	<365 d	Nonamplified	Any	Any	Intermediate
	<365 d	Amplified	Any	Any	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 [13-15]	Nonamplified	Any	Any	Intermediate
	< 365 d	Amplified	Any	Any	High
	≥548 d–21 y	Any	Any	-	High
4Se	<365 d	Nonamplified	Favorable	>1	Low
	<365 d	Nonamplified	Any	=1	Intermediate
	<365 d	Nonamplified	Unfavorable	Any	Intermediate
	<365 d	Amplified	Any	Any	High

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 unresponsiveeplacement therapy.

References

1. Brodeur GM, Pritchard J, Berthold F, et al.: Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 11 (8): 1466-77, 1993.  [PUBMED Abstract]
   
   
2. Russell HV, Golding LA, Suell MN, et al.: The role of bone marrow evaluation in the staging of patients with otherwise localized, low-risk neuroblastoma. Pediatr Blood Cancer 45 (7): 916-9, 2005.  [PUBMED Abstract]
   
   
3. Vik TA, Pfluger T, Kadota R, et al.: (123)I-mIBG scintigraphy in patients with known or suspected neuroblastoma: Results from a prospective multicenter trial. Pediatr Blood Cancer 52 (7): 784-90, 2009.  [PUBMED Abstract]
   
   
4. DuBois SG, Kalika Y, Lukens JN, et al.: Metastatic sites in stage IV and IVS neuroblastoma correlate with age, tumor biology, and survival. J Pediatr Hematol Oncol 21 (3): 181-9, 1999 May-Jun.  [PUBMED Abstract]
   
   
5. Kramer K, Kushner B, Heller G, et al.: Neuroblastoma metastatic to the central nervous system. The Memorial Sloan-kettering Cancer Center Experience and A Literature Review. Cancer 91 (8): 1510-9, 2001.  [PUBMED Abstract]
   
   
6. Brodeur GM, Seeger RC, Barrett A, et al.: International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma. J Clin Oncol 6 (12): 1874-81, 1988.  [PUBMED Abstract]
   
   
7. Castleberry RP, Shuster JJ, Smith EI: The Pediatric Oncology Group experience with the international staging system criteria for neuroblastoma. Member Institutions of the Pediatric Oncology Group. J Clin Oncol 12 (11): 2378-81, 1994.  [PUBMED Abstract]
   
   
8. Ikeda H, Iehara T, Tsuchida Y, et al.: Experience with International Neuroblastoma Staging System and Pathology Classification. Br J Cancer 86 (7): 1110-6, 2002.  [PUBMED Abstract]
   
   
9. Baker DL, Schmidt M, Cohn S, et al.: A phase III trial of biologically-based therapy reduction for intermediate risk neuroblastoma. [Abstract] J Clin Oncol 25 (Suppl 18): A-9504, 2007. 
   
   
10. Kushner BH, Cheung NK: Treatment reduction for neuroblastoma. Pediatr Blood Cancer 43 (6): 619-21, 2004.  [PUBMED Abstract]
    
    
11. Kushner BH, Kramer K, LaQuaglia MP, et al.: Liver involvement in neuroblastoma: the Memorial Sloan-Kettering Experience supports treatment reduction in young patients. Pediatr Blood Cancer 46 (3): 278-84, 2006.  [PUBMED Abstract]
    
    
12. Navarro S, Amann G, Beiske K, et al.: Prognostic value of International Neuroblastoma Pathology Classification in localized resectable peripheral neuroblastic tumors: a histopathologic study of localized neuroblastoma European Study Group 94.01 Trial and Protocol. J Clin Oncol 24 (4): 695-9, 2006.  [PUBMED Abstract]
    
    
13. 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]
    
    
14. 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]
    
    
15. 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]
    
    

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