Standard Treatment
Under Clinical Evaluation
Current Clinical Trials

In North America, the Children’s Oncology Group (COG) 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, Shimada classification, and DNA ploidy) (COG-P9611). (Risk groups are defined in the table in the Stage Information section of this summary.)

The following patients are considered to have high-risk neuroblastoma (see table):

1. INSS stage 2A/2B tumors in children older than 1 year and in whom the tumor has both unfavorable Shimada classification and MYCN gene amplification.
2. INSS stage 3 tumors in infants younger than 1 year and in whom the tumor demonstrates MYCN gene amplification.
3. INSS stage 3 tumors in children older than 1 year and in whom the tumor demonstrates either MYCN gene amplification or unfavorable Shimada classification.
4. INSS stage 4 tumors in infants younger than 18 months at diagnosis and in whom the tumor demonstrates MYCN gene amplification.[1]
5. INSS stage 4 tumors in children older than 18 months with or without MYCN gene amplification.
6. INSS stage 4S tumors in infants younger than 1 year at diagnosis and in whom the tumor demonstrates MYCN gene amplification.

For children with high-risk neuroblastoma, long-term survival ranges from 10% to 40%. Children with aggressively treated, high-risk neuroblastoma may develop late recurrences, some more than 5 years after completion of therapy.[2,3] A randomized study was performed comparing high-dose therapy with purged autologous hematopoietic stem cell transplantation (HSCT) versus three cycles of intensive consolidation chemotherapy. The 3-year event-free survival (EFS) was significantly better in the HSCT arm (34%) compared with the consolidation chemotherapy arm (18%). Superiority of myeloablative chemotherapy over maintenance therapy was confirmed in another study.[4] In addition, patients on this study were subsequently randomized to stop therapy or to receive 6 months of 13-cis-retinoic acid.[5] Patients who received 13-cis-retinoic acid had significantly better 3-year EFS than patients who received no maintenance therapy. This was true for all patient subgroups. Based on these results, future clinical trials will build upon autologous HSCT and 13-cis-retinoic acid for high-risk neuroblastoma.[5]

The potential benefit of aggressive surgical approaches in high-risk patients with metastatic disease to achieve complete tumor resection, either at the time of diagnosis or following chemotherapy, has not been unequivocally demonstrated. Several studies have reported that complete resection of the primary tumor at diagnosis improved survival; however, the outcome in these patients may be more dependent on the biology of the tumor, which itself may determine resectability, than on the extent of surgical resection.[6-10] The use of radiation therapy to consolidate local control after surgical resection is recommended.[11]

Patients classified as high risk receive treatment with an aggressive regimen of combination chemotherapy consisting of very high drug doses. Drugs often used include cyclophosphamide, ifosfamide, cisplatin, carboplatin, vincristine, doxorubicin, and etoposide. After a response to chemotherapy, resection of the primary tumor should be attempted, followed by myeloablative chemotherapy and stem cell rescue (i.e., bone marrow and/or peripheral blood stem cell transplantation). The use of purged stem cells is under investigation. Radiation to the primary tumor site should be undertaken whether or not a complete excision was obtained. Radiation of sites of metastatic disease is determined on an individual case basis. After recovery, patients are treated with oral 13-cis-retinoic acid for 6 months. Both myeloablative therapy and postchemotherapy retinoic acid improve outcome in patients categorized as high risk.[5]

The following are examples of national and/or institutional clinical trials that are currently being conducted. For more information about clinical trials, please see the NCI Web site.

• Monoclonal antibody therapy with or without granulocyte-macrophage colony-stimulating factor (GM-CSF) following chemotherapy (COG-ANBL0032).[12,13]



• Tandem myeloablation and stem cell transplantation.[6,14]



• Inclusion of myeloablative doses of 131-I-MIBG prior to stem cell transplantation.[15]



• Use of topotecan and cyclophosphamide as initial induction chemotherapy (COG-ANBL02P1).

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, 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]
   
   
2. Cotterill SJ, Pearson AD, Pritchard J, et al.: Late relapse and prognosis for neuroblastoma patients surviving 5 years or more: a report from the European Neuroblastoma Study Group "Survey". Med Pediatr Oncol 36 (1): 235-8, 2001.  [PUBMED Abstract]
   
   
3. Mertens AC, Yasui Y, Neglia JP, et al.: Late mortality experience in five-year survivors of childhood and adolescent cancer: the Childhood Cancer Survivor Study. J Clin Oncol 19 (13): 3163-72, 2001.  [PUBMED Abstract]
   
   
4. Berthold F, Boos J, Burdach S, et al.: Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial. Lancet Oncol 6 (9): 649-58, 2005.  [PUBMED Abstract]
   
   
5. Matthay KK, Villablanca JG, Seeger RC, et al.: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group. N Engl J Med 341 (16): 1165-73, 1999.  [PUBMED Abstract]
   
   
6. George RE, Li S, Medeiros-Nancarrow C, et al.: High-risk neuroblastoma treated with tandem autologous peripheral-blood stem cell-supported transplantation: long-term survival update. J Clin Oncol 24 (18): 2891-6, 2006.  [PUBMED Abstract]
   
   
7. DeCou JM, Bowman LC, Rao BN, et al.: Infants with metastatic neuroblastoma have improved survival with resection of the primary tumor. J Pediatr Surg 30 (7): 937-40; discussion 940-1, 1995.  [PUBMED Abstract]
   
   
8. 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]
   
   
9. 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]
   
   
10. 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]
    
    
11. Haas-Kogan DA, Swift PS, Selch M, et al.: Impact of radiotherapy for high-risk neuroblastoma: a Children's Cancer Group study. Int J Radiat Oncol Biol Phys 56 (1): 28-39, 2003.  [PUBMED Abstract]
    
    
12. Cheung NK, Kushner BH, Cheung IY, et al.: Anti-G(D2) antibody treatment of minimal residual stage 4 neuroblastoma diagnosed at more than 1 year of age. J Clin Oncol 16 (9): 3053-60, 1998.  [PUBMED Abstract]
    
    
13. Simon T, Hero B, Faldum A, et al.: Consolidation treatment with chimeric anti-GD2-antibody ch14.18 in children older than 1 year with metastatic neuroblastoma. J Clin Oncol 22 (17): 3549-57, 2004.  [PUBMED Abstract]
    
    
14. Kletzel M, Katzenstein HM, Haut PR, et al.: Treatment of high-risk neuroblastoma with triple-tandem high-dose therapy and stem-cell rescue: results of the Chicago Pilot II Study. J Clin Oncol 20 (9): 2284-92, 2002.  [PUBMED Abstract]
    
    
15. Miano M, Garaventa A, Pizzitola MR, et al.: Megatherapy combining I(131) metaiodobenzylguanidine and high-dose chemotherapy with haematopoietic progenitor cell rescue for neuroblastoma. Bone Marrow Transplant 27 (6): 571-4, 2001.  [PUBMED Abstract]
    
    

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