Treatment of Intermediate-Risk Neuroblastoma

Standard Treatment Options
Treatment Options 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, International Neuroblastoma Pathology Classification [INPC] system, and DNA ploidy). 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. Event-free survival (EFS) and overall survival (OS) rates were 88% and 96%, respectively. There was no unexpected toxicity.[1] These studies (COG-P9641 ¹ and COG-A3961 ²) have established a new standard of care for children in North America with neuroblastoma. (Risk groups are defined in Table 1 ³ in the Stage Information section of this summary.)

Chemotherapy is given for four to eight cycles (12 to 24 weeks) and consists of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen. Radiation therapy is reserved for patients with symptomatic life-threatening or organ-threatening tumor that does not respond rapidly enough to chemotherapy and/or surgery.

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 aged 1 year and younger have a greater than 80% cure rate while older children have a cure rate of 50% to 70% with current, relatively intensive therapy.[2-5] In one study, those with favorable compared with unfavorable biological features (i.e., INPC and MYCN gene amplification) had EFS rates of almost 100% and about 50%, respectively.[6-8] In cases of abdominal neuroblastoma thought to involve the kidney, nephrectomy should not be undertaken before a trial of chemotherapy has been given.[9]

Whether initial chemotherapy is indicated for all intermediate-risk infants with localized neuroblastoma is controversial. A German prospective clinical trial enrolled 340 infants aged one year or younger whose tumors were stage 1, 2, or 3; histologically verified; and lacked amplification of MYCN. 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. Further surgery was avoided in 33 infants and chemotherapy was avoided in 72 infants. Some degree of spontaneous tumor regression occurred in nearly half the infants. Overall survival of the 93 infants was 99%.[10]

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%),[11,12] with outcome particularly dependent on MYCN amplification and tumor cell ploidy (e.g., hyperdiploidy confers a favorable prognosis while diploidy predicts early treatment failure).[3,13] Infants aged18 months and younger at diagnosis with INSS stage 4 neuroblastoma who do not have MYCN gene amplification are categorized as intermediate risk.[14-17] The need for chemotherapy in all asymptomatic infants with stage 4 disease is somewhat controversial.[18] Stage 4 and 4S infants (N = 170) aged 12 months or younger and Stage 4 asymptomatic infants (N = 14) enrolled in an International Society of Pediatric Oncology (SIOP) trial had one of the following characteristics: 1) metastases of the 4S pattern and including positive bone metastases by iodine-131-meta-iodobenzylguanidine (MIBG) or technetium bone scan without cortical bone abnormality by computer tomography (CT) scan or plain x-ray, or 2) primary tumor stage 3 with 4S metastatic pattern. These infants were observed without initial chemotherapy, and in cases with surgical risk factors, without resection of the primary tumor. Although three infants underwent tumor progression, all survived. Although many were eventually treated with chemotherapy at the investigator’s choice, a substantial number of infants received no chemotherapy.[18]

A small single institution study suggested that all MYCN-nonamplified INSS stage 3 tumors may be treated with surgical resection followed by observation without chemotherapy.[19][Level of evidence: 3iiDi]

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site ⁴.

• COG-ANBL0531 ⁵: This COG trial is a response- and biology-based trial for intermediate-risk neuroblastoma. The COG is studying a reduction of chemotherapy duration for most intermediate risk group patients, based in part on a reduction of the degree of tumor response required to stop chemotherapy.

  A new risk/treatment group classification system has been developed for this study and is described in Table 2 ⁶ in the Treatment of Low-Risk Neuroblastoma section of this summary. Patients previously classified as intermediate risk are now in risk Groups 2, 3, or 4. Some children aged 8 to 12 months previously classified as high risk are now in intermediate-risk Group 4.

  • The risk/treatment Groups 2 and 3 are upstaged by one risk/treatment group if the tumor cannot be studied for loss of heterozygosity (LOH) or if LOH of 1p or unbalanced LOH of 11q is found.
  • The treatment for intermediate-risk patients involves surgery and the chemotherapy treatment regimen described below. Radiation therapy is reserved for patients with symptomatic life-threatening or organ-threatening tumor that does not respond rapidly to chemotherapy and/or surgery.

    Chemotherapy

    • Treatment Group 2: Two cycles of chemotherapy—stop chemotherapy when a partial response is achieved.

    • Treatment Group 3: Four cycles of chemotherapy—stop chemotherapy when a partial response is achieved.

    • Treatment Group 4: Eight cycles of chemotherapy—stop chemotherapy when a good partial response is achieved.

    For all Groups noted above, the chemotherapy consists of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen. If needed, additional cycles of this chemotherapy regimen, up to eight total, are given until partial response is obtained. If the required response has not been obtained with eight cycles of the afore-mentioned chemotherapy regimen, an additional one to six cycles of topotecan and cyclophosphamide chemotherapy is given.

    (Refer to the International Neuroblastoma Response Criteria ⁷ in the Treatment Option Overview section of this summary for more information.)

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with neuroblastoma ⁸. 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 ⁴.

References

1. 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]
   
   
2. 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]
   
   
3. 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]
   
   
4. 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]
   
   
5. 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]
   
   
6. 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]
   
   
7. 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]
   
   
8. 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]
   
   
9. 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]
   
   
10. 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]
    
    
11. Paul SR, Tarbell NJ, Korf B, et al.: Stage IV neuroblastoma in infants. Long-term survival. Cancer 67 (6): 1493-7, 1991.  [PUBMED Abstract]
    
    
12. 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]
    
    
13. 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]
    
    
14. 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]
    
    
15. 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]
    
    
16. 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]
    
    
17. 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]
    
    
18. 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]
    
    
19. Modak S, Kushner BH, LaQuaglia MP, et al.: Management and outcome of stage 3 neuroblastoma. Eur J Cancer 45 (1): 90-8, 2009.  [PUBMED Abstract]