Current Clinical Trials

In North America, the Children’s Oncology Group (COG) is investigating a risk-based neuroblastoma treatment plan that assigns 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, Shimada classification, and DNA ploidy). (Risk groups are defined in the table in the Stage Information section of this summary.)

Patients with intermediate-risk neuroblastoma generally have a cure rate of 70% to 90%. The following patients are categorized as intermediate risk (see table):

1. INSS stage 3 tumors in infants younger than 1 year and in whom the tumor lacks MYCN gene amplification.
2. INSS stage 3 tumors in children aged 1 year or older and in whom the tumor lacks MYCN gene amplification and has favorable Shimada classification.
3. INSS stage 4 tumors in infants younger than 18 months and in whom the tumor lacks MYCN gene amplification.[1-3]
4. INSS stage 4S tumors in infants younger than 1 year and in whom the tumor lacks MYCN gene amplification and has either unfavorable Shimada classification or is near diploid in chromosome number, or both.

There is considerable variation in outcome, and, therefore, in treatment for children with stage 3 disease (tumor involving both sides of the midline by virtue of either invasion into normal tissues or lymph node metastasis). Infants younger than 1 year have a greater than 80% cure rate while older children have a cure rate of 50% to 70% with current relatively intensive therapy.[4-7] In one study, those with favorable compared with unfavorable biological features (i.e., Shimada classification and MYCN gene amplification) had event-free survival rates of almost 100% and about 50%, respectively.[8-10] In cases of abdominal neuroblastoma thought to involve the kidney, nephrectomy should not be undertaken before a trial of chemotherapy has been given.[11]

Patients classified as intermediate risk with stage 3 tumors with favorable or unfavorable Shimada classification are treated with 12 weeks and 24 weeks of chemotherapy, respectively. In patients classified as intermediate risk with favorable biology, radiation therapy is reserved for patients with symptomatic life-threatening or organ-threatening tumor that does not respond rapidly enough to chemotherapy. In patients classified as intermediate risk with unfavorable biologic features, radiation therapy is given if residual viable tumor remains after 24 weeks of chemotherapy and second-look surgery.

Survival of patients with INSS stage 4 disease is strongly dependent on age. Children younger than 1 year at diagnosis have a good chance of long-term survival (i.e., a 5-year disease-free survival rate of 50%–80%),[12,13] with outcome particularly dependent on tumor cell ploidy (e.g., hyperploidy confers a favorable prognosis while diploidy predicts early treatment failure).[5,14]

Infants younger than 18 months at diagnosis with INSS stage 4 neuroblastoma who do not have MYCN gene amplification are categorized as intermediate risk.[15,1-3] These infants are treated with 12 weeks of chemotherapy if the tumor has both favorable Shimada classification and hyperdiploidy, and if not, these infants are treated with 24 weeks of chemotherapy.

Infants younger than 1 year at diagnosis with INSS stage 4S neuroblastoma without amplification of the MYCN gene, but with unfavorable Shimada classification, diploid DNA, or both, are classified as intermediate risk. These infants are treated with 24 weeks of chemotherapy.

Chemotherapy for intermediate-risk patients consists of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide given for 12 to 24 weeks. The cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen (COG-A3961).

The COG Neuroblastoma Treatment Plan also defines the treatment for progression or recurrence of intermediate-risk neuroblastoma. This treatment depends on the characteristics of the progression or recurrence. (Refer to the Recurrent Neuroblastoma section of this summary for more information.)

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.

References

1. 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]
   
   
2. 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]
   
   
3. 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]
   
   
4. Castleberry RP, Kun LE, Shuster JJ, et al.: Radiotherapy improves the outlook for patients older than 1 year with Pediatric Oncology Group stage C neuroblastoma. J Clin Oncol 9 (5): 789-95, 1991.  [PUBMED Abstract]
   
   
5. Bowman LC, Castleberry RP, Cantor A, et al.: Genetic staging of unresectable or metastatic neuroblastoma in infants: a Pediatric Oncology Group study. J Natl Cancer Inst 89 (5): 373-80, 1997.  [PUBMED Abstract]
   
   
6. Castleberry RP, Shuster JJ, Altshuler G, et al.: Infants with neuroblastoma and regional lymph node metastases have a favorable outlook after limited postoperative chemotherapy: a Pediatric Oncology Group study. J Clin Oncol 10 (8): 1299-304, 1992.  [PUBMED Abstract]
   
   
7. West DC, Shamberger RC, Macklis RM, et al.: Stage III neuroblastoma over 1 year of age at diagnosis: improved survival with intensive multimodality therapy including multiple alkylating agents. J Clin Oncol 11 (1): 84-90, 1993.  [PUBMED Abstract]
   
   
8. 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]
   
   
9. Perez CA, Matthay KK, Atkinson JB, et al.: Biologic variables in the outcome of stages I and II neuroblastoma treated with surgery as primary therapy: a children's cancer group study. J Clin Oncol 18 (1): 18-26, 2000.  [PUBMED Abstract]
   
   
10. Matthay KK, Sather HN, Seeger RC, et al.: Excellent outcome of stage II neuroblastoma is independent of residual disease and radiation therapy. J Clin Oncol 7 (2): 236-44, 1989.  [PUBMED Abstract]
    
    
11. 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]
    
    
12. Paul SR, Tarbell NJ, Korf B, et al.: Stage IV neuroblastoma in infants. Long-term survival. Cancer 67 (6): 1493-7, 1991.  [PUBMED Abstract]
    
    
13. Bowman LC, Hancock ML, Santana VM, et al.: Impact of intensified therapy on clinical outcome in infants and children with neuroblastoma: the St Jude Children's Research Hospital experience, 1962 to 1988. J Clin Oncol 9 (9): 1599-608, 1991.  [PUBMED Abstract]
    
    
14. 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]
    
    
15. 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]
    
    

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