Treatment Option Overview

Low-Risk Neuroblastoma
        Observation without surgery for localized, suspected adrenal neuroblastoma in infants
Intermediate-Risk Neuroblastoma
High-Risk Neuroblastoma
Radiation Therapy
Chemotherapy
Description of International Neuroblastoma Response Criteria
Surveillance for Recurrence of High-Risk Neuroblastoma

The treatments described in this summary are based on the Children’s Oncology Group (COG) group assignment, which is described in the Stage Information section of this summary. Treatment information is presented in this format because most children with neuroblastoma in North America are treated according to the COG schema. The prior COG risk-based neuroblastoma studies established the standard of care. They assigned each patient to a low-, intermediate-, or high-risk group and the basis of the assignment is described in Table 1.

In patients without metastatic disease, the standard of care is to perform an initial surgery 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. Accurate determination of biological characteristics, such as INPC system, usually requires an open biopsy. The accuracy of diagnosis and staging is increased by performing a metaiodobenzylguanidine (MIBG) scan.[1] 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.

There is controversy about the need for immediate diagnostic biopsy in infants aged 3 months and younger with suspected neuroblastoma tumors that are likely to spontaneously regress. Biopsy is not required for infants entered into a COG study of expectant observation of adrenal masses in neonates. In a German clinical trial, 25 infants aged 3 months and younger with presumed neuroblastoma were observed without biopsy for periods of 1 to 18 months prior to biopsy or resection. There were no apparent ill effects of the delay.[2]

There is also controversy about the need for attempted resection, whether at the time of diagnosis or later, in asymptomatic infants aged 12 months or younger with apparent stage 2B and 3 MYCN-nonamplified disease. In a German clinical trial, some of these patients were observed after biopsy or partial resection without chemotherapy or radiation, and many did not progress locally and never received additional resection.[2]

Treatment for patients categorized as low risk (refer to Table 1 in the Stage Information section of this summary) may be surgery alone, but surgery may be combined with 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).

The COG study COG-P9641 demonstrated excellent survival in patients with asymptomatic, low-risk, stage 2A or 2B disease with favorable histology.[3]

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.[4-6] 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.[4] The COG is investigating systematic observation without surgery for infants with presumed small Evans stage I adrenal neuroblastoma detected by prenatal or perinatal ultrasound.

Patients categorized as intermediate risk (refer to Table 1 in the Stage Information section of this summary) have been successfully treated with surgery and 12 to 24 weeks of the same chemotherapy regimen described above (COG-A3961). As a rule, patients whose tumors have unfavorable biology receive twice as many cycles of chemotherapy as those with favorable biology.

Whether initial chemotherapy is indicated for all intermediate-risk infants with localized neuroblastoma is controversial. A German prospective clinical trial enrolled 340 infants aged 1 year or younger whose tumors were stage 1, 2, or 3, histologically verified, and lacked MYCN amplification. Forty-four of 93 infants with unresected tumors experienced spontaneous regression (17 were complete regressions) and 39 infants experienced progression. The 3-year overall survival (OS) rate was 99%, and the metastases-free survival rate was 94% for infants with unresected tumors and was not different from infants treated with surgery or chemotherapy (median follow-up, 58 months). The investigators suggested that a wait-and-see strategy is appropriate for infants with localized neuroblastoma because regressions have been observed after the first year of life.[2]

Moderate-dose chemotherapy has been shown to be effective in the prospective Infant Neuroblastoma European Study (INES 99.1 [EURO-INF-NB-STUDY-1999-99.1]), where about half of the infants with unresectable, nonmetastatic neuroblastoma and no MYCN amplification underwent a safe surgical resection and avoided long-term adverse effects. The 5-year OS rate was 99% and the event-free survival (EFS) rate was 90% (median follow-up, 6 years). In this study, infants undergoing surgical resection had a better EFS than those who did not have surgery.[7][Level of evidence: 3iiA]

In contrast, patients categorized as high risk (refer to Table 1 of the Stage Information section of the summary) are generally treated with dose-intensive 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 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.[8,9]; [10][Level of evidence: 1iiA] Compared to retinoic acid alone, chimeric anti-GD2 antibody ch14.18 combined with granulocyte macrophage-colony stimulating factor and interleukin-2 and given in concert with retinoic acid improves event-free survival for high-risk neuroblastoma patients in remission after stem cell transplant.[11]

Radiation therapy for patients with low- or intermediate-risk neuroblastoma in the completed COG treatment plan was reserved for symptomatic life-threatening or organ-threatening tumor bulk that did not respond rapidly enough to chemotherapy. The common situations where radiation is used in these patients include: 1) infants aged 60 days and younger with stage 4S and marked respiratory compromise from liver metastases that has not responded to chemotherapy, or 2) for symptomatic spinal cord compression that has not responded to initial chemotherapy and/or surgical decompression. In contrast, radiation therapy to the primary site is often recommended for high-risk patients even in cases of complete resection.

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.[12-14] The completed COG neuroblastoma treatment plans recommended immediate chemotherapy for cord compression in patients classified as low or intermediate risk. Children with neuroblastoma whose spinal cord compression worsens on medical therapy may benefit from surgical intervention.[15]

In order to stop therapy after the initially planned number of cycles, certain response criteria, depending on treatment group, must be met. These criteria are defined below:[16,17]

• Complete Response: Total disappearance of tumor, with no evidence of disease. VMA/HVA are normal.

• Very Good Partial Response: Primary tumor has decreased by 90% to 99%, and no evidence of metastatic disease. Urine VMA/HVA are normal. Residual bone scan changes are allowed.

• Partial Response: 50% to 90% decrease in the size of all measurable lesions; the number of bone scan positive sites is decreased by greater than 50% and no new lesions are present; no more than one positive bone marrow site allowed if this represents a reduction in the number of sites originally positive for tumor at diagnosis.

• Mixed Response: No new lesions, 50% to 90% reduction of any measurable lesion (primary or metastatic) with less than 50% reduction in other lesions and less than 25% increase in any lesion.

• No Response or Stable Disease: No new lesions; less than 50% reduction and less than 25% increase in any lesion.

• Progressive Disease: Any new lesion; increase in any measurable lesion by greater than 25%; previous negative bone marrow now positive for tumor. Neither persistent elevation in urinary VMA/HVA with stable disease nor an increase in VMA/HVA without clinical or radiographic evidence of progression indicate progressive disease, but does warrant continued follow-up. Care should be taken in interpreting the development of metastatic disease in an infant who was initially considered to have stage 1 or 2 disease. If the pattern of metastases in such a patient is consistent with a 4S pattern of disease (skin, liver, bone marrow less than 10% involved) these patients should not be classified as progressive/metastatic disease, which would be a criteria for removal from protocol therapy. Instead, these patients should be managed as stage 4S.

Surveillance studies during and following treatment are able to detect asymptomatic and unsuspected relapse in a substantial portion of patients. As an element in an overall surveillance plan, the most reliable test to detect disease progression or recurrence is the ¹²³I-MIBG scan.[18,19]

1. Vik TA, Pfluger T, Kadota R, et al.: (123)I-mIBG scintigraphy in patients with known or suspected neuroblastoma: Results from a prospective multicenter trial. Pediatr Blood Cancer 52 (7): 784-90, 2009.  [PUBMED Abstract]
   
   
2. 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]
   
   
3. Strother DR, London WB, Schmidt ML, et al.: Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children's Oncology Group study P9641. J Clin Oncol 30 (15): 1842-8, 2012.  [PUBMED Abstract]
   
   
4. 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]
   
   
5. 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]
   
   
6. 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]
   
   
7. Rubie H, De Bernardi B, Gerrard M, et al.: Excellent outcome with reduced treatment in infants with nonmetastatic and unresectable neuroblastoma without MYCN amplification: results of the prospective INES 99.1. J Clin Oncol 29 (4): 449-55, 2011.  [PUBMED Abstract]
   
   
8. 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]
   
   
9. 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]
   
   
10. Matthay KK, Reynolds CP, Seeger RC, et al.: Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children's oncology group study. J Clin Oncol 27 (7): 1007-13, 2009.  [PUBMED Abstract]
    
    
11. Yu AL, Gilman AL, Ozkaynak MF, et al.: Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med 363 (14): 1324-34, 2010.  [PUBMED Abstract]
    
    
12. 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]
    
    
13. 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]
    
    
14. 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]
    
    
15. Sandberg DI, Bilsky MH, Kushner BH, et al.: Treatment of spinal involvement in neuroblastoma patients. Pediatr Neurosurg 39 (6): 291-8, 2003.  [PUBMED Abstract]
    
    
16. Brodeur GM, Pritchard J, Berthold F, et al.: Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 11 (8): 1466-77, 1993.  [PUBMED Abstract]
    
    
17. Brodeur GM, Seeger RC, Barrett A, et al.: International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma. J Clin Oncol 6 (12): 1874-81, 1988.  [PUBMED Abstract]
    
    
18. Kushner BH, Kramer K, Modak S, et al.: Sensitivity of surveillance studies for detecting asymptomatic and unsuspected relapse of high-risk neuroblastoma. J Clin Oncol 27 (7): 1041-6, 2009.  [PUBMED Abstract]
    
    
19. Papathanasiou ND, Gaze MN, Sullivan K, et al.: 18F-FDG PET/CT and 123I-metaiodobenzylguanidine imaging in high-risk neuroblastoma: diagnostic comparison and survival analysis. J Nucl Med 52 (4): 519-25, 2011.  [PUBMED Abstract]