Recurrent Neuroblastoma in Patients Initially Classified as Low Risk
        Local/regional recurrence
        Metastatic recurrence
Recurrent Neuroblastoma in Patients Initially Classified as Intermediate Risk
        Local/regional recurrence
        Metastatic recurrence
Recurrent or Refractory Neuroblastoma in Patients Initially Classified as High Risk
        Treatment options under clinical evaluation
Current Clinical Trials

The prognosis and treatment of recurrent or progressive neuroblastoma depends on many factors including initial stage, tumor biological characteristics at recurrence, the site and extent of the recurrence or progression, previous treatment, and individual patient considerations. In selected patients originally diagnosed with low- or intermediate-risk disease, recurrence may be treated successfully with limited intervention. The Children’s Oncology Group (COG) experience with recurrence in intermediate-risk neuroblastoma is that the majority of recurrences can be salvaged, as demonstrated by a 3-year event free survival (EFS) of 88% and an overall survival (OS) of 96%.[1] When neuroblastoma recurs in a child originally diagnosed with high-risk disease and is widespread, the prognosis is usually poor despite additional intensive therapy.[2-4] The combination of cyclophosphamide plus topotecan has been active in patients with recurrent or refractory disease who have not received topotecan previously.[5] 131-I-metaiodobenzylguanidine (131-I-MIBG) therapy is also active in patients with recurrent or refractory neuroblastoma.[6] Clinical trials are appropriate and should be considered. Information about ongoing clinical trials is available from the NCI Web site.

Central nervous system (CNS) involvement, though rare at initial presentation, may occur in 5% to 10% of patients with recurrent neuroblastoma. Inward compression of the brain from cranial metastases can occur, and rarely meningeal and isolated intracranial metastases occur. Early recognition and treatment of CNS involvement may result in reduced neurologic impairment.[7,8]

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, International Neuroblastoma Staging System (INSS) stage, and tumor biology (i.e., MYCN gene amplification, International Neuroblastoma Pathology Classification [INPC] system, and DNA ploidy).[9] Treatment of recurrent disease was determined by risk group at the time of diagnosis (refer to Table 1), extent of disease at recurrence, patient age at recurrence, and the tumor biology. If tumor was unavailable for biological studies at recurrence, the biology of the tumor at time of diagnosis was used to help determine treatment.

(Risk categories are defined in the Table 1 in the Stage Information section of this summary.)

Local regional recurrent cancer is resected if possible:

1. Those with favorable biology and regional recurrence more than 3 months after completion of planned treatment are observed if resection of the recurrence is total or near total (≥90% resection). Those with favorable biology and a less than near-total resection are treated with 12 weeks of chemotherapy.
2. Infants younger than 1 year at the time of local/regional recurrence whose tumors have any unfavorable biologic properties are observed if resection is total or near total. If the resection is less than near total, these same infants are treated with 24 weeks of chemotherapy.

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 (COG-P9641 and COG-A3961). Older children with local recurrence with either unfavorable INPC classification or MYCN gene amplification have a poor prognosis and should be treated with an aggressive regimen of combination chemotherapy consisting of very high doses of the drugs listed above, and often also including ifosfamide and high-dose cisplatin. Both myeloablative therapy and postchemotherapy retinoic acid may improve outcome of newly diagnosed high-risk patients with a poor prognosis.[10] These modalities are commonly employed in the treatment of patients with a recurrence that augurs a poor prognosis.

The following is an example of a national and/or institutional clinical trial that is currently being conducted. For more information about clinical trials, please see the NCI Web site.

• The COG Intermediate-Risk study (COG-ANBL0531) treats risk/treatment Group 2 and Group 3 patients (previously classified as low risk) with progressive nonmetastatic disease with surgery if possible. If surgery achieves a very good partial response (VGPR), no further therapy is given. If a VGPR is not achieved, additional cycles of chemotherapy are given to total eight cycles and additional surgery is performed if possible. Those who still do not reach a VGPR receive up to six cycles of topotecan and cyclophosphamide chemotherapy until a VGPR is achieved.

Metastatic recurrent or progressive neuroblastoma in an infant initially categorized as low risk (see Table 1 in the Stage Information section of the summary.) and younger than 1 year at recurrence, whether the patient has INSS stage 1, 2, or 4S at the time of diagnosis, may be treated according to tumor biology as defined in the prior COG trials (COG-P9641 and COG-A3961):

1. If the biology is completely favorable, metastasis is in a 4S pattern, and the recurrence or progression is within 3 months of diagnosis, the patient is observed systematically.
2. If the metastatic progression or recurrence with completely favorable biology occurs more than 3 months after diagnosis or not in a 4S pattern, then the primary tumor is resected if possible and 12 to 24 weeks of chemotherapy are given, depending on response.
3. If the tumor in the infant with metastatic recurrence or progression has unfavorable INPC classification and/or is diploid, the primary tumor is resected if possible and 24 weeks of chemotherapy is given.

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 (COG-P9641).

Any child initially categorized as low risk who is older than 1 year at the time of metastatic recurrent or progressive disease who is not in the stage 4S pattern usually has a poor prognosis and should be treated with an aggressive regimen of combination chemotherapy consisting of very high doses of the drugs listed above, and often also including ifosfamide and high-dose cisplatin. Both myeloablative therapy and postchemotherapy retinoic acid may improve outcome of newly diagnosed patients with a poor prognosis.[10] These modalities are commonly employed in the treatment of patients with a recurrence that augurs a poor prognosis.

(Risk categories are defined in Table 1 in the Stage Information section of the summary.)

The current standard of care is based on the experience from the COG Intermediate-Risk treatment plan (COG-A3961). Local regional recurrence of neuroblastoma with favorable biology that occurs more than 3 months after completion of 12 weeks of chemotherapy may be treated surgically. If resection is less than near total, then 12 additional weeks of chemotherapy may be given. 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 (COG-A3961).

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

• COG-ANBL0531: The current COG Intermediate-Risk study treats risk/treatment Group 2 or 3 patients (previously classified as intermediate risk) who develop progressive nonmetastatic disease with surgery if possible. If surgery achieves a very good partial response (VGPR), no further therapy is given. If a VGPR is not achieved, additional cycles of chemotherapy are given to total eight cycles and additional surgery is performed if possible. For those patients that still do not reach a VGPR, six cycles of topotecan and cyclophosphamide chemotherapy are given until a VGPR is achieved. Treatment Group 4 patients have already received eight cycles of chemotherapy or have progressed on the standard chemotherapy regimen, and surgery and up to six cycles of topotecan and cyclophosphamide chemotherapy are administered until a VGPR is achieved.

If the recurrence is metastatic and/or occurs while on chemotherapy or within 3 months of completing chemotherapy and/or has unfavorable biologic properties, the prognosis is poor and the patient should be treated with an aggressive regimen of combination chemotherapy consisting of very high doses of the drugs listed above, and often also including ifosfamide and high-dose cisplatin. Both myeloablative therapy and postchemotherapy retinoid acid may improve outcome of newly diagnosed patients with a poor prognosis.[10] These modalities are commonly employed in the treatment of patients with a recurrence that augurs a poor prognosis.

(Risk categories are defined in Table in the Stage Information section of this summary.)

Any recurrence in patients initially classified as high risk signifies a very poor prognosis. If the tumor has recurred in spite of the administration of aggressive high-dose combination chemotherapy, often with myeloablative therapy plus stem cell rescue, phase I or phase II clinical trials are appropriate and should be considered.[3] The combination of cyclophosphamide and topotecan with or without etoposide has been used in recurrent disease.[5,11]

For more information about clinical trials, please see the NCI Web site.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent 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. 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. 
   
   
2. Pole JG, Casper J, Elfenbein G, et al.: High-dose chemoradiotherapy supported by marrow infusions for advanced neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 9 (1): 152-8, 1991.  [PUBMED Abstract]
   
   
3. Castel V, Cañete A, Melero C, et al.: Results of the cooperative protocol (N-III-95) for metastatic relapses and refractory neuroblastoma. Med Pediatr Oncol 35 (6): 724-6, 2000.  [PUBMED Abstract]
   
   
4. Lau L, Tai D, Weitzman S, et al.: Factors influencing survival in children with recurrent neuroblastoma. J Pediatr Hematol Oncol 26 (4): 227-32, 2004.  [PUBMED Abstract]
   
   
5. Saylors RL 3rd, Stine KC, Sullivan J, et al.: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 19 (15): 3463-9, 2001.  [PUBMED Abstract]
   
   
6. Matthay KK, Yanik G, Messina J, et al.: Phase II study on the effect of disease sites, age, and prior therapy on response to iodine-131-metaiodobenzylguanidine therapy in refractory neuroblastoma. J Clin Oncol 25 (9): 1054-60, 2007.  [PUBMED Abstract]
   
   
7. 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]
   
   
8. Blatt J, Fitz C, Mirro J Jr: Recognition of central nervous system metastases in children with metastatic primary extracranial neuroblastoma. Pediatr Hematol Oncol 14 (3): 233-41, 1997 May-Jun.  [PUBMED Abstract]
   
   
9. Goto S, Umehara S, Gerbing RB, et al.: Histopathology (International Neuroblastoma Pathology Classification) and MYCN status in patients with peripheral neuroblastic tumors: a report from the Children's Cancer Group. Cancer 92 (10): 2699-708, 2001.  [PUBMED Abstract]
   
   
10. 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]
    
    
11. Simon T, Längler A, Harnischmacher U, et al.: Topotecan, cyclophosphamide, and etoposide (TCE) in the treatment of high-risk neuroblastoma. Results of a phase-II trial. J Cancer Res Clin Oncol 133 (9): 653-61, 2007.  [PUBMED Abstract]
    
    

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