Low Risk
Intermediate Risk
High Risk
Radiation
Relapse Therapy for Low- and Intermediate-Risk Patients
Urgent Chemotherapy
Observation without Surgery of Localized, Presumed Adrenal Neuroblastoma in Infants

The treatments described in this summary are based on the Children’s Oncology Group (COG) Risk Stratification Schema, which is described in the Stage Information section of this summary. The risk of progression of the tumor causing morbidity and mortality is gauged based on the stage of the tumor, the age of the child at diagnosis, and tumor biology. The biological features considered are the Shimada classification, amplification of the MYCN gene, and the number of chromosomes in tumor cells. Treatment information is presented in this format because most children with neuroblastoma in North America are treated according to the COG schema. Accurate determination of biological characteristics, such as Shimada classification, usually requires an open biopsy. The accuracy of staging is increased by performing a metaiodobenzylguanidine (MIBG) scan. Urinary excretion of the catecholamine metabolites vanillylmandelic acid (VMA) and homovanillic acid (HVA) per mg of excreted creatinine should be measured prior to therapy. If elevated, these markers can be used to determine the persistence of disease.

This risk-based neuroblastoma treatment plan assigns each patient to a low-, intermediate-, or high-risk group. (Risk groups are defined in the table in the Stage Information section of this summary.) In patients without metastatic disease, initial surgery is performed to establish the diagnosis, to resect as much of the primary tumor as is safely possible, to accurately stage disease through sampling of regional lymph nodes that are not adherent to the tumor, and to obtain adequate tissue for biological studies.

Treatment for patients categorized as low risk (refer to table) is with surgery alone, but surgery may be combined with 6 to 12 weeks of chemotherapy in some cases. Chemotherapy is reserved for patients who are symptomatic, such as from spinal cord compression or, in stage 4S, respiratory compromise secondary to hepatic infiltration. The chemotherapy consists 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).

Patients categorized as intermediate risk (refer to table) are treated with surgery and 12 to 24 weeks of the same chemotherapy regimen described above (COG-3961).

In contrast, patients categorized as high risk (refer to table) are generally treated with aggressive multiagent chemotherapy consisting of very high doses of the drugs listed above but often also including ifosfamide and high-dose cisplatin. After a response to chemotherapy, resection of the primary tumor should be attempted, followed by myeloablative chemotherapy, sometimes total-body irradiation, and autologous stem cell transplantation. Radiation of residual tumor and original sites of metastases is often performed before, during, or after myeloablative therapy. After recovery, patients are treated with oral 13-cis-retinoic acid for 6 months. Both myeloablative therapy and retinoic acid improve outcome in patients categorized as high risk.[1,2]

Radiation therapy is reserved for patients with symptomatic life-threatening or organ-threatening tumor that does not respond rapidly enough to chemotherapy, or for intermediate-risk patients whose tumor has responded incompletely to both chemotherapy and attempted resection and also has unfavorable biological characteristics. Radiation therapy to the primary site is often recommended for high-risk patients even in cases of complete resection.

As part of the COG treatment plan, specific relapse therapy is defined for low- and intermediate-risk patients determined by patient age at recurrence, stage, and biology of the recurrence.

Immediate treatment should be given for symptomatic spinal cord compression. Neurologic recovery is more likely the less the severity of compromise and the shorter the duration of symptoms. Neurologic outcome appears to be similar whether cord compression is treated with chemotherapy, radiation therapy, or laminectomy. Laminectomy, however, may result in later scoliosis, and chemotherapy is often needed whether or not surgery or radiation is used.[3-5] The COG neuroblastoma treatment plan recommends immediate chemotherapy for cord compression in patients classified as low or intermediate risk (COG-P9641, COG-A3961). Children with high-risk neuroblastoma whose spinal cord compression worsens on medical therapy may benefit from surgical intervention.[6]

Studies suggest that selected presumed neuroblastomas detected in infants by screening or incidental ultrasound may safely be observed without obtaining a definitive histologic diagnosis and without surgical intervention, thus avoiding potential complications of surgery in the newborn.[7-9] The experience with tumors detected by mass urinary catecholamine metabolite screening in Japan appears to be applicable to tumors detected by prenatal or perinatal ultrasound in the United States. Twenty-six infants who had presumed Evans stage I, II, or IVS by imaging, urinary VMA and HVA levels of less than 50 μg/mg creatinine, no tumor involvement of great vessels or invasion into the spinal canal, and tumor size smaller than 5 cm, were observed with frequent imaging. Biopsy and tissue diagnosis were not obtained initially. The tumor increased in size in about one-third of the infants and was resected without any apparent increase in stage. All had favorable biological features. In two-thirds of the infants, after observation for 6 to 73 months, no surgery had been performed, the VMA and HVA had normalized, and in several cases the tumors had become undetectable by imaging.[7] The COG is currently investigating systematic observation without surgery for infants with presumed small Evans stage I adrenal neuroblastoma detected by prenatal or perinatal ultrasound.

References

1. 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]
   
   
2. 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]
   
   
3. Katzenstein HM, Kent PM, London WB, et al.: Treatment and outcome of 83 children with intraspinal neuroblastoma: the Pediatric Oncology Group experience. J Clin Oncol 19 (4): 1047-55, 2001.  [PUBMED Abstract]
   
   
4. De Bernardi B, Pianca C, Pistamiglio P, et al.: Neuroblastoma with symptomatic spinal cord compression at diagnosis: treatment and results with 76 cases. J Clin Oncol 19 (1): 183-90, 2001.  [PUBMED Abstract]
   
   
5. Plantaz D, Rubie H, Michon J, et al.: The treatment of neuroblastoma with intraspinal extension with chemotherapy followed by surgical removal of residual disease. A prospective study of 42 patients--results of the NBL 90 Study of the French Society of Pediatric Oncology. Cancer 78 (2): 311-9, 1996.  [PUBMED Abstract]
   
   
6. Sandberg DI, Bilsky MH, Kushner BH, et al.: Treatment of spinal involvement in neuroblastoma patients. Pediatr Neurosurg 39 (6): 291-8, 2003.  [PUBMED Abstract]
   
   
7. Nishihira H, Toyoda Y, Tanaka Y, et al.: Natural course of neuroblastoma detected by mass screening: s 5-year prospective study at a single institution. J Clin Oncol 18 (16): 3012-7, 2000.  [PUBMED Abstract]
   
   
8. Holgersen LO, Subramanian S, Kirpekar M, et al.: Spontaneous resolution of antenatally diagnosed adrenal masses. J Pediatr Surg 31 (1): 153-5, 1996.  [PUBMED Abstract]
   
   
9. Fritsch P, Kerbl R, Lackner H, et al.: "Wait and see" strategy in localized neuroblastoma in infants: an option not only for cases detected by mass screening. Pediatr Blood Cancer 43 (6): 679-82, 2004.  [PUBMED Abstract]
   
   

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