Purpose of This PDQ Summary
General Information

Presentation of Neuroblastoma Opsoclonus/Myoclonus Syndrome Diagnosis Prognosis         Age         Etiology         Biologic factors Unique Aspects of Neuroblastoma         Biologically discrete types of neuroblastoma         Neuroblastoma screening         Spontaneous regression of neuroblastoma         Low-stage neuroblastoma in the fetus and newborn

Cellular Classification
Stage Information

International Neuroblastoma Staging System Children’s Oncology Group Neuroblastoma Risk Grouping

Treatment Option Overview

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

Treatment of Low-Risk Neuroblastoma

Current Clinical Trials

Treatment of Intermediate-Risk Neuroblastoma

Current Clinical Trials

Treatment of High-Risk Neuroblastoma

Standard Treatment Under Clinical Evaluation Current Clinical Trials

Recurrent Neuroblastoma

Children’s Oncology Group Treatment Plan 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 Neuroblastoma in Patients Initially Classified as High Risk Under Clinical Evaluation Current Clinical Trials

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Changes to this Summary (11/06/2008)
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of neuroblastoma. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board ¹.

Information about the following is included in this summary:

• Unique aspects of neuroblastoma.
• Cellular classification.
• Stage information.
• Treatment options.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal evidence ranking system ² in developing their level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version ³, which is written in less-technical language, and in Spanish ⁴.

General Information

The National Cancer Institute (NCI) provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.

Cancer in children and adolescents is rare. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will enable them to achieve optimal survival and quality of life. (Refer to the PDQ summaries on Supportive Care ⁵ for specific information about supportive care for children and adolescents with cancer).

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[1] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site ⁶.

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. Childhood and adolescent cancer survivors require close follow-up since cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer ⁷ for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors).

Neuroblastoma is predominantly a tumor of early childhood, with two-thirds of the cases presenting in children younger than 5 years. Neuroblastoma originates in the adrenal medulla or the paraspinal sites where sympathetic nervous system tissue is present. These tumors can be divided into low-, intermediate-, and high-risk groups as illustrated in the Stage Information ⁸ section of this summary. Low- and intermediate-risk patients usually have localized disease or are infants younger than 18 months. In rare cases, neuroblastoma can be discovered prenatally by fetal ultrasonography.[2] The most common presentation of neuroblastoma is an abdominal mass. The most common symptoms in high-risk patients are due to a tumor mass or to bone pain from metastases. Proptosis and periorbital ecchymosis are common in these high-risk patients and arise from retrobulbar metastasis. Extensive bone marrow metastasis may result in pancytopenia. Abdominal distention with respiratory compromise due to massive liver metastases may occur in infants. Because they originate in paraspinal ganglia, neuroblastomas may invade through neural foramina and compress the spinal cord extradurally, causing paralysis. Horner syndrome may be caused by neuroblastoma in the stellate ganglion, and children with Horner syndrome without apparent cause should be examined for neuroblastoma and other tumors.[3] Fever, anemia, and hypertension are occasionally found. Multifocal (multiple primaries) neuroblastoma occurs rarely, usually in infants, and generally has a good prognosis.[4] On rare occasions, children may have severe, watery diarrhea due to the secretion of vasoactive intestinal peptide by the tumor, or may have protein-losing enteropathy with intestinal lymphangiectasia.[5]

Children with neuroblastoma rarely present with paraneoplastic neurologic findings, including cerebellar ataxia or opsoclonus/myoclonus.[6] The opsoclonus/myoclonus syndrome appears to be caused by an immunologic mechanism that is not yet fully defined.[7,8] Unlike most other neuroblastomas, the primary tumor is typically diffusely infiltrated with lymphocytes.[9] Patients who present with this syndrome often have neuroblastomas with favorable biological features and are likely to survive, though tumor-related deaths have been reported. Neurologic dysfunction is most often a presenting symptom but may arise long after removal of the tumor. Opsoclonus/myoclonus syndrome is frequently associated with pervasive and permanent neurologic and cognitive deficits, including psychomotor retardation.[8,10,11] Some patients may clinically respond to removal of the neuroblastoma, but improvement may be slow and partial; symptomatic treatment is often necessary. Adrenocorticotropic hormone (ACTH) treatment is thought to be effective, but some patients do not respond to ACTH.[7,10] Various drugs, plasmapheresis, intravenous gamma-globulin, and rituximab have been reported to be effective in selected cases.[10,12,13] The long-term neurologic outcome may be superior in patients treated with chemotherapy, possibly because of its immunosuppressive effects.[6,12] The use of immunosuppressive therapy with and without intravenous gamma-globulin in the treatment of patients with neuroblastoma and opsoclonus/myoclonus syndrome is currently under study by the Children's Oncology Group (COG) (COG-ANBL00P3 ⁹).

The diagnosis of neuroblastoma requires the involvement of pathologists who are familiar with childhood tumors. Some neuroblastomas cannot be differentiated, via conventional light microscopy, from other small round blue cell tumors of childhood, such as lymphomas, primitive neuroectodermal tumors, and rhabdomyosarcomas. Evidence for sympathetic neuronal differentiation may be demonstrated by immunohistochemistry, electron microscopy, or by finding elevated levels of serum catecholamines (e.g., dopamine and norepinephrine) or urine catecholamine metabolites, such as vanillylmandelic acid (VMA) or homovanillic acid (HVA). The minimum criterion for a diagnosis of neuroblastoma, as has been established by international agreement, is that it must be based on one of the following: (1) an unequivocal pathologic diagnosis made from tumor tissue by light microscopy (with or without immunohistology, electron microscopy, or increased levels of serum catecholamines or urinary catecholamine metabolites); or (2) the combination of bone marrow aspirate or trephine biopsy containing unequivocal tumor cells (e.g., syncytia or immunocytologically-positive clumps of cells) and increased levels of serum catecholamines or urinary catecholamine metabolites, as described above.[14]

Approximately 70% of patients with neuroblastoma have metastatic disease at diagnosis. The prognosis for patients with neuroblastoma is related to their age at diagnosis, clinical stage of disease, and, in patients older than 1 year, regional lymph node involvement. Other conventional prognostic variables include the site of the primary tumor and tumor histology.[15-18] (Refer to the Cellular Classification ¹⁰ section of this summary for more information.) Biological prognostic variables are also used to help determine treatment.

Children of any age with localized neuroblastoma and infants younger than 1 year with advanced disease and favorable disease characteristics have a high likelihood of long-term, disease-free survival.[15,19] Older children with advanced-stage disease, however, have a significantly decreased chance for cure, despite intensive therapy. Long-term disease-free survival with aggressive chemotherapy, including stem cell rescue and cis-retinoic acid, is approximately 30%.[20]

The clinical characteristics of neuroblastoma in adolescents are similar to those observed in children. The only exception is that bone marrow involvement occurs less frequently, and there is a greater frequency of metastases in unusual sites such as lung or brain.[21] Neuroblastoma in an adolescent or an adult has a worse long-term prognosis regardless of stage or site and, in many cases, a more prolonged course when treated with standard doses of chemotherapy. High-dose chemotherapy and surgery have been shown to achieve a minimal disease state in more than 50% of these patients. Other modalities, such as local radiation therapy and the use of agents with confirmed activity, may improve the poor prognosis.[22,23]

Neuroblastoma is an embryonal cancer; it is thought to arise from partially committed primordial cells during fetal or early childhood development. Little is known about the events that predispose to the developments of neuroblastoma. Epidemiologic studies and genetic studies of hereditary diseases have not provided insight into the etiology. No commonly mutated gene has been identified. In a genome-wide association study of 1032 patients with neuroblastoma, a significant association was observed between common genetic variation at chromosome 6p22 and susceptibility to neuroblastoma.[24]

A number of biologic variables have been studied in children with this tumor.[25] Treatment decisions may be based on important factors such as Shimada classification, tumor cell chromosome number, amplification of the MYCN oncogene within tumor tissue, unbalanced 11q loss of heterozygosity (LOH), and LOH for chromosome 1p.[18,19,26-31] An open biopsy is usually needed to obtain adequate tissue for determination of these biological characteristics.

Many biological characteristics of tumors are not currently used in determining therapy; however, as clinical research matures, these characteristics may be found useful as therapeutic targets or as clinically important prognostic factors. Amplification of the MYCN gene is associated with deletion of chromosome 1p and gain of the long arm of chromosome 17(17q), the latter of which independently predicts a poor prognosis.[32] In contrast to MYCN gene amplification, the degree of expression of the MYCN gene in the tumor does not predict prognosis.[33] Other biological prognostic factors that have been extensively investigated include tumor cell telomere length, telomerase activity, and RNA;[34,35] urinary VMA, HVA, and their ratio;[36] dopamine; CD44 expression; TrkA gene expression; neuron-specific enolase level, serum lactic dehydrogenase level, and serum ferritin level.[25] High-level expression of the MRP1 drug resistance gene is an independent indicator of decreased survival.[37] The profile of GABAergic receptors expressed in neuroblastoma is predictive of prognosis regardless of age, stage, and MYCN gene amplification.[38] Gene expression profiling may prove useful for prognosis prediction.[39] In addition, reponse to treatment has been associated with outcome. The persistence of neuroblastoma cells in bone marrow during or after chemotherapy, for example, is associated with a poor prognosis.[40,41]

Based on these biologic factors and an improved understanding of the molecular development of the neural crest cells that give rise to neuroblastoma, the tumors have been categorized into three biological groups. These groups are not used to determine treatment at this time. One type expresses the TrkA neurotrophin receptor, is hyperdiploid, and tends to spontaneously regress. Another type expresses the TrkB neurotrophin receptor, has gained an additional chromosome, 17q, has loss of heterozygosity of 14q or 11q, and is genomically unstable. In a third type, in addition to a gain of 17q, chromosome 1p is lost and the MYCN gene becomes amplified.[42,43]

Current data do not support neuroblastoma screening. Screening infants for neuroblastoma by assay of urinary catecholamine metabolites was initiated in Japan.[44] A large population-based North American study, in which most infants in Quebec were screened at the ages of 3 weeks and 6 months, has shown that screening detects many neuroblastomas with favorable characteristics [45,46] that would never have been detected clinically, apparently due to spontaneous regression of the tumors. Another study of infants screened at the age of 1 year shows similar results.[47] Screening at the ages of 3 weeks, 6 months, or 1 year caused no reduction in the incidence of advanced-stage neuroblastoma with unfavorable biological characteristics in older children, nor did it reduce the number of deaths from neuroblastoma in infants screened at any age.[46,47] No public health benefits have been shown from screening infants for neuroblastoma at these ages.

This phenomenon has been well described in infants, especially in those with the 4S pattern of metastatic spread.[48] (Refer to the Stage Information ⁸ section of this summary for more information.) Regression generally occurs only in tumors with a near triploid number of chromosomes, no MYCN amplification, and no loss of chromosome 1p. Additional features associated with spontaneous regression [49,50] include the lack of telomerase expression,[51,52] the expression of Ha-ras,[53] and the expression of the neurotrophin receptor TrkA, a nerve growth factor receptor.

Recent studies have suggested that selected infants who appear to have asymptomatic, small, low-stage adrenal neuroblastoma detected by screening or as an incidental finding by ultrasound, often have tumors that spontaneously regress and may be observed safely without surgical intervention or tissue diagnosis.[54-56] The COG is currently studying whether it is feasible to simply observe neonates with small adrenal masses that are presumed to be neuroblastomas (COG ANBL00P2). These masses are usually found during prenatal or incidental ultrasound examination.

(Refer to the PDQ summary on Screening for Neuroblastoma ¹¹ for more information.)

References

1. Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.  [PUBMED Abstract]
   
   
2. Jennings RW, LaQuaglia MP, Leong K, et al.: Fetal neuroblastoma: prenatal diagnosis and natural history. J Pediatr Surg 28 (9): 1168-74, 1993.  [PUBMED Abstract]
   
   
3. Mahoney NR, Liu GT, Menacker SJ, et al.: Pediatric horner syndrome: etiologies and roles of imaging and urine studies to detect neuroblastoma and other responsible mass lesions. Am J Ophthalmol 142 (4): 651-9, 2006.  [PUBMED Abstract]
   
   
4. Hiyama E, Yokoyama T, Hiyama K, et al.: Multifocal neuroblastoma: biologic behavior and surgical aspects. Cancer 88 (8): 1955-63, 2000.  [PUBMED Abstract]
   
   
5. Citak C, Karadeniz C, Dalgic B, et al.: Intestinal lymphangiectasia as a first manifestation of neuroblastoma. Pediatr Blood Cancer 46 (1): 105-7, 2006.  [PUBMED Abstract]
   
   
6. Matthay KK, Blaes F, Hero B, et al.: Opsoclonus myoclonus syndrome in neuroblastoma a report from a workshop on the dancing eyes syndrome at the advances in neuroblastoma meeting in Genoa, Italy, 2004. Cancer Lett 228 (1-2): 275-82, 2005.  [PUBMED Abstract]
   
   
7. Connolly AM, Pestronk A, Mehta S, et al.: Serum autoantibodies in childhood opsoclonus-myoclonus syndrome: an analysis of antigenic targets in neural tissues. J Pediatr 130 (6): 878-84, 1997.  [PUBMED Abstract]
   
   
8. Rudnick E, Khakoo Y, Antunes NL, et al.: Opsoclonus-myoclonus-ataxia syndrome in neuroblastoma: clinical outcome and antineuronal antibodies-a report from the Children's Cancer Group Study. Med Pediatr Oncol 36 (6): 612-22, 2001.  [PUBMED Abstract]
   
   
9. Cooper R, Khakoo Y, Matthay KK, et al.: Opsoclonus-myoclonus-ataxia syndrome in neuroblastoma: histopathologic features-a report from the Children's Cancer Group. Med Pediatr Oncol 36 (6): 623-9, 2001.  [PUBMED Abstract]
   
   
10. Pranzatelli MR: The neurobiology of the opsoclonus-myoclonus syndrome. Clin Neuropharmacol 15 (3): 186-228, 1992.  [PUBMED Abstract]
    
    
11. Mitchell WG, Davalos-Gonzalez Y, Brumm VL, et al.: Opsoclonus-ataxia caused by childhood neuroblastoma: developmental and neurologic sequelae. Pediatrics 109 (1): 86-98, 2002.  [PUBMED Abstract]
    
    
12. Russo C, Cohn SL, Petruzzi MJ, et al.: Long-term neurologic outcome in children with opsoclonus-myoclonus associated with neuroblastoma: a report from the Pediatric Oncology Group. Med Pediatr Oncol 28 (4): 284-8, 1997.  [PUBMED Abstract]
    
    
13. Bell J, Moran C, Blatt J: Response to rituximab in a child with neuroblastoma and opsoclonus-myoclonus. Pediatr Blood Cancer 50 (2): 370-1, 2008.  [PUBMED Abstract]
    
    
14. 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]
    
    
15. Adams GA, Shochat SJ, Smith EI, et al.: Thoracic neuroblastoma: a Pediatric Oncology Group study. J Pediatr Surg 28 (3): 372-7; discussion 377-8, 1993.  [PUBMED Abstract]
    
    
16. Evans AE, Albo V, D'Angio GJ, et al.: Factors influencing survival of children with nonmetastatic neuroblastoma. Cancer 38 (2): 661-6, 1976.  [PUBMED Abstract]
    
    
17. Hayes FA, Green A, Hustu HO, et al.: Surgicopathologic staging of neuroblastoma: prognostic significance of regional lymph node metastases. J Pediatr 102 (1): 59-62, 1983.  [PUBMED Abstract]
    
    
18. Cotterill SJ, Pearson AD, Pritchard J, et al.: Clinical prognostic factors in 1277 patients with neuroblastoma: results of The European Neuroblastoma Study Group 'Survey' 1982-1992. Eur J Cancer 36 (7): 901-8, 2000.  [PUBMED Abstract]
    
    
19. Brodeur GM, Azar C, Brother M, et al.: Neuroblastoma. Effect of genetic factors on prognosis and treatment. Cancer 70 (6 Suppl): 1685-94, 1992.  [PUBMED Abstract]
    
    
20. 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]
    
    
21. Conte M, Parodi S, De Bernardi B, et al.: Neuroblastoma in adolescents: the Italian experience. Cancer 106 (6): 1409-17, 2006.  [PUBMED Abstract]
    
    
22. Kushner BH, Kramer K, LaQuaglia MP, et al.: Neuroblastoma in adolescents and adults: the Memorial Sloan-Kettering experience. Med Pediatr Oncol 41 (6): 508-15, 2003.  [PUBMED Abstract]
    
    
23. Franks LM, Bollen A, Seeger RC, et al.: Neuroblastoma in adults and adolescents: an indolent course with poor survival. Cancer 79 (10): 2028-35, 1997.  [PUBMED Abstract]
    
    
24. Maris JM, Mosse YP, Bradfield JP, et al.: Chromosome 6p22 locus associated with clinically aggressive neuroblastoma. N Engl J Med 358 (24): 2585-93, 2008.  [PUBMED Abstract]
    
    
25. Riley RD, Heney D, Jones DR, et al.: A systematic review of molecular and biological tumor markers in neuroblastoma. Clin Cancer Res 10 (1 Pt 1): 4-12, 2004.  [PUBMED Abstract]
    
    
26. 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]
    
    
27. 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]
    
    
28. Berthold F, Trechow R, Utsch S, et al.: Prognostic factors in metastatic neuroblastoma. A multivariate analysis of 182 cases. Am J Pediatr Hematol Oncol 14 (3): 207-15, 1992.  [PUBMED Abstract]
    
    
29. 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]
    
    
30. Attiyeh EF, London WB, Mossé YP, et al.: Chromosome 1p and 11q deletions and outcome in neuroblastoma. N Engl J Med 353 (21): 2243-53, 2005.  [PUBMED Abstract]
    
    
31. Spitz R, Hero B, Simon T, et al.: Loss in chromosome 11q identifies tumors with increased risk for metastatic relapses in localized and 4S neuroblastoma. Clin Cancer Res 12 (11 Pt 1): 3368-73, 2006.  [PUBMED Abstract]
    
    
32. Bown N, Cotterill S, Lastowska M, et al.: Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma. N Engl J Med 340 (25): 1954-61, 1999.  [PUBMED Abstract]
    
    
33. Cohn SL, London WB, Huang D, et al.: MYCN expression is not prognostic of adverse outcome in advanced-stage neuroblastoma with nonamplified MYCN. J Clin Oncol 18 (21): 3604-13, 2000.  [PUBMED Abstract]
    
    
34. Poremba C, Hero B, Goertz HG, et al.: Traditional and emerging molecular markers in neuroblastoma prognosis: the good, the bad and the ugly. Klin Padiatr 213 (4): 186-90, 2001 Jul-Aug.  [PUBMED Abstract]
    
    
35. Ohali A, Avigad S, Ash S, et al.: Telomere length is a prognostic factor in neuroblastoma. Cancer 107 (6): 1391-9, 2006.  [PUBMED Abstract]
    
    
36. Strenger V, Kerbl R, Dornbusch HJ, et al.: Diagnostic and prognostic impact of urinary catecholamines in neuroblastoma patients. Pediatr Blood Cancer 48 (5): 504-9, 2007.  [PUBMED Abstract]
    
    
37. Haber M, Smith J, Bordow SB, et al.: Association of high-level MRP1 expression with poor clinical outcome in a large prospective study of primary neuroblastoma. J Clin Oncol 24 (10): 1546-53, 2006.  [PUBMED Abstract]
    
    
38. Roberts SS, Mori M, Pattee P, et al.: GABAergic system gene expression predicts clinical outcome in patients with neuroblastoma. J Clin Oncol 22 (20): 4127-34, 2004.  [PUBMED Abstract]
    
    
39. Wei JS, Greer BT, Westermann F, et al.: Prediction of clinical outcome using gene expression profiling and artificial neural networks for patients with neuroblastoma. Cancer Res 64 (19): 6883-91, 2004.  [PUBMED Abstract]
    
    
40. Burchill SA, Lewis IJ, Abrams KR, et al.: Circulating neuroblastoma cells detected by reverse transcriptase polymerase chain reaction for tyrosine hydroxylase mRNA are an independent poor prognostic indicator in stage 4 neuroblastoma in children over 1 year. J Clin Oncol 19 (6): 1795-801, 2001.  [PUBMED Abstract]
    
    
41. Seeger RC, Reynolds CP, Gallego R, et al.: Quantitative tumor cell content of bone marrow and blood as a predictor of outcome in stage IV neuroblastoma: a Children's Cancer Group Study. J Clin Oncol 18 (24): 4067-76, 2000.  [PUBMED Abstract]
    
    
42. Maris JM, Matthay KK: Molecular biology of neuroblastoma. J Clin Oncol 17 (7): 2264-79, 1999.  [PUBMED Abstract]
    
    
43. Lastowska M, Cullinane C, Variend S, et al.: Comprehensive genetic and histopathologic study reveals three types of neuroblastoma tumors. J Clin Oncol 19 (12): 3080-90, 2001.  [PUBMED Abstract]
    
    
44. Sawada T: Past and future of neuroblastoma screening in Japan. Am J Pediatr Hematol Oncol 14 (4): 320-6, 1992.  [PUBMED Abstract]
    
    
45. Takeuchi LA, Hachitanda Y, Woods WG, et al.: Screening for neuroblastoma in North America. Preliminary results of a pathology review from the Quebec Project. Cancer 76 (11): 2363-71, 1995.  [PUBMED Abstract]
    
    
46. Woods WG, Gao RN, Shuster JJ, et al.: Screening of infants and mortality due to neuroblastoma. N Engl J Med 346 (14): 1041-6, 2002.  [PUBMED Abstract]
    
    
47. Schilling FH, Spix C, Berthold F, et al.: Neuroblastoma screening at one year of age. N Engl J Med 346 (14): 1047-53, 2002.  [PUBMED Abstract]
    
    
48. Nickerson HJ, Matthay KK, Seeger RC, et al.: Favorable biology and outcome of stage IV-S neuroblastoma with supportive care or minimal therapy: a Children's Cancer Group study. J Clin Oncol 18 (3): 477-86, 2000.  [PUBMED Abstract]
    
    
49. Reynolds CP: Ras and Seppuku in neuroblastoma. J Natl Cancer Inst 94 (5): 319-21, 2002.  [PUBMED Abstract]
    
    
50. Ambros PF, Brodeur GM: Concept of tumorigenesis and regression. In: Brodeur GM, Sawada T, Tsuchida Y: Neuroblastoma. New York, NY: Elsevier Science, 2000, pp 21-32. 
    
    
51. Hiyama E, Hiyama K, Yokoyama T, et al.: Correlating telomerase activity levels with human neuroblastoma outcomes. Nat Med 1 (3): 249-55, 1995.  [PUBMED Abstract]
    
    
52. Hiyama E, Reynolds CP: Telomerase as a biological and prognostic marker in neuroblastoma. In: Brodeur GM, Sawada T, Tsuchida Y: Neuroblastoma. New York, NY: Elsevier Science, 2000, pp 159-174. 
    
    
53. Kitanaka C, Kato K, Ijiri R, et al.: Increased Ras expression and caspase-independent neuroblastoma cell death: possible mechanism of spontaneous neuroblastoma regression. J Natl Cancer Inst 94 (5): 358-68, 2002.  [PUBMED Abstract]
    
    
54. Yamamoto K, Ohta S, Ito E, et al.: Marginal decrease in mortality and marked increase in incidence as a result of neuroblastoma screening at 6 months of age: cohort study in seven prefectures in Japan. J Clin Oncol 20 (5): 1209-14, 2002.  [PUBMED Abstract]
    
    
55. Okazaki T, Kohno S, Mimaya J, et al.: Neuroblastoma detected by mass screening: the Tumor Board's role in its treatment. Pediatr Surg Int 20 (1): 27-32, 2004.  [PUBMED Abstract]
    
    
56. 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]
    
    

Cellular Classification

One clinicopathologic staging system involves evaluation of tumor specimens obtained prior to therapy for the amount of stromal development, the degree of neuroblastic maturation, and the mitosis-karyorrhexis index of the neuroblastic cells.[1,2] Favorable and unfavorable prognoses are defined on the bases of these histologic parameters and on patient age. The prognostic significance of this classification system, and of related systems using similar criteria, has been confirmed in several studies.[1-3] Neuroblastoma containing many differentiating cells, termed ganglioneuroblastoma, can have nodules of undifferentiated cells whose histology, along with MYCN amplification, determines prognosis.[4,5]

References

1. Shimada H, Ambros IM, Dehner LP, et al.: The International Neuroblastoma Pathology Classification (the Shimada system). Cancer 86 (2): 364-72, 1999.  [PUBMED Abstract]
   
   
2. Shimada H, Umehara S, Monobe Y, et al.: International neuroblastoma pathology classification for prognostic evaluation of patients with peripheral neuroblastic tumors: a report from the Children's Cancer Group. Cancer 92 (9): 2451-61, 2001.  [PUBMED Abstract]
   
   
3. 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]
   
   
4. Kubota M, Suita S, Tajiri T, et al.: Analysis of the prognostic factors relating to better clinical outcome in ganglioneuroblastoma. J Pediatr Surg 35 (1): 92-5, 2000.  [PUBMED Abstract]
   
   
5. Peuchmaur M, d'Amore ES, Joshi VV, et al.: Revision of the International Neuroblastoma Pathology Classification: confirmation of favorable and unfavorable prognostic subsets in ganglioneuroblastoma, nodular. Cancer 98 (10): 2274-81, 2003.  [PUBMED Abstract]
   
   

Stage Information

The treatment section of this document is organized to correspond with the Children’s Oncology Group (COG) risk-based schema for the treatment of neuroblastoma. This schema is based on three factors: patient age at diagnosis, certain biological characteristics of the patient’s neuroblastoma tumor, and the stage of the tumor as defined by the International Neuroblastoma Staging System (INSS). The INSS has replaced the previously used Children’s Cancer Group (CCG) and Pediatric Oncology Group (POG) staging systems. The INSS is described below, and the COG risk-based treatment schema is described in Table 1 ¹² in this section.

A thorough evaluation for metastatic disease should be performed prior to therapy initiation. The following investigations are recommended:[1]

1. Bone marrow should be assessed by bilateral posterior iliac crest marrow aspirates and trephine (core) bone marrow biopsies to exclude bone marrow involvement. To be considered adequate, core biopsy specimens must contain at least 1 cm of marrow, excluding cartilage. Bone marrow sampling may not be necessary for tumors that are otherwise stage 1.[2]



2. Bone should be assessed by metaiodobenzylguanidine (MIBG) scan, which is applicable to all sites of disease, and by technetium 99 scan if the results of the MIBG scan are negative or unavailable. Plain radiographs of positive lesions are recommended.



3. Palpable lymph nodes should be clinically examined and histologically confirmed. Nonpalpable lymph nodes should be assessed by computerized tomography (CT) scan with three-dimensional (3D) measurements.



4. The abdomen and liver should be assessed by CT scan and/or magnetic resonance imaging (MRI). Ultrasound is considered suboptimal for accurate 3D measurements. The chest should be examined by CT scan to detect extension of abdominal disease and the rare occurrence of pulmonary metastasis.



5. Lumbar puncture should be avoided as central nervous system (CNS) metastasis at diagnosis is rare,[3] and lumbar puncture may be associated with an increased incidence of subsequent development of CNS metastasis.[4]



6. Paraspinal tumors may extend through neural foramina to compress the spinal cord. MRI of the spine adjacent to any paraspinal tumor is recommended.

INSS combines certain features of the previously used POG and CCG systems [1,5] and has identified distinct prognostic groups.[1,5-7]

• Stage 1: Localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for tumor microscopically (i.e., nodes attached to and removed with the primary tumor may be positive).



• Stage 2A: Localized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph nodes negative for tumor microscopically.



• Stage 2B: Localized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumor. Enlarged contralateral lymph nodes must be negative microscopically.



• Stage 3: Unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph node involvement; or midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement. The midline is defined as the vertebral column. Tumors originating on one side and crossing the midline must infiltrate to or beyond the opposite side of the vertebral column.



• Stage 4: Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, and/or other organs, except as defined for stage 4S.



• Stage 4S: Localized primary tumor, as defined for stage 1, 2A, or 2B, with dissemination limited to skin, liver, and/or bone marrow (limited to infants younger than 1 year). Marrow involvement should be minimal (i.e., <10% of total nucleated cells identified as malignant by bone biopsy or by bone marrow aspirate). More extensive bone marrow involvement would be considered stage 4 disease. The results of the MIBG scan, if performed, should be negative for disease in the bone marrow.

In North America, the COG is investigating a risk-based neuroblastoma treatment plan that assigns all patients to a low-, intermediate-, or high-risk group based on age, INSS stage, and tumor biology.

The following table outlines the COG neuroblastoma risk group assignment schema. The risk group assignment determines the treatment plan for each patient. Patients assigned to the low-, intermediate-, and high-risk groups have an overall survival of more than 90%, 70% to 90%, and about 30%, respectively, 3 years after diagnosis. European studies suggest that the inclusion of chromosome 1p status of neuroblastoma cells may improve risk grouping [8] and the clinical significance of additional tumor genetic characteristics including 17q gain, 1p deletion, and 11q deletion are under study. The COG has found unbalanced 11q loss of heterozygosity to be a negative prognostic factor in a subset of children with otherwise biologically favorable neuroblastoma and will study whether these children will benefit from more aggressive therapy.[9] Some controversies exist regarding the treatment of several small subsets of patients and the INSS staging system;[10-12] risk group assignment and recommended treatment are expected to mature as additional outcome data are analyzed. The risk group for INSS Stage 4, including patients aged 12 to 18 months, for example, was changed for patients with non-MYCN-amplified status in 2005.[13-15]

References

1. 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]
   
   
2. Russell HV, Golding LA, Suell MN, et al.: The role of bone marrow evaluation in the staging of patients with otherwise localized, low-risk neuroblastoma. Pediatr Blood Cancer 45 (7): 916-9, 2005.  [PUBMED Abstract]
   
   
3. DuBois SG, Kalika Y, Lukens JN, et al.: Metastatic sites in stage IV and IVS neuroblastoma correlate with age, tumor biology, and survival. J Pediatr Hematol Oncol 21 (3): 181-9, 1999 May-Jun.  [PUBMED Abstract]
   
   
4. 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]
   
   
5. 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]
   
   
6. Castleberry RP, Shuster JJ, Smith EI: The Pediatric Oncology Group experience with the international staging system criteria for neuroblastoma. Member Institutions of the Pediatric Oncology Group. J Clin Oncol 12 (11): 2378-81, 1994.  [PUBMED Abstract]
   
   
7. Ikeda H, Iehara T, Tsuchida Y, et al.: Experience with International Neuroblastoma Staging System and Pathology Classification. Br J Cancer 86 (7): 1110-6, 2002.  [PUBMED Abstract]
   
   
8. Simon T, Spitz R, Faldum A, et al.: New definition of low-risk neuroblastoma using stage, age, and 1p and MYCN status. J Pediatr Hematol Oncol 26 (12): 791-6, 2004.  [PUBMED Abstract]
   
   
9. Attiyeh EF, London WB, Mossé YP, et al.: Chromosome 1p and 11q deletions and outcome in neuroblastoma. N Engl J Med 353 (21): 2243-53, 2005.  [PUBMED Abstract]
   
   
10. Kushner BH, Cheung NK: Treatment reduction for neuroblastoma. Pediatr Blood Cancer 43 (6): 619-21, 2004.  [PUBMED Abstract]
    
    
11. Kushner BH, Kramer K, LaQuaglia MP, et al.: Liver involvement in neuroblastoma: the Memorial Sloan-Kettering Experience supports treatment reduction in young patients. Pediatr Blood Cancer 46 (3): 278-84, 2006.  [PUBMED Abstract]
    
    
12. Navarro S, Amann G, Beiske K, et al.: Prognostic value of International Neuroblastoma Pathology Classification in localized resectable peripheral neuroblastic tumors: a histopathologic study of localized neuroblastoma European Study Group 94.01 Trial and Protocol. J Clin Oncol 24 (4): 695-9, 2006.  [PUBMED Abstract]
    
    
13. 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]
    
    
14. 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]
    
    
15. 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]
    
    

Treatment Option Overview

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 ⁸ 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 ¹⁴ 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 ¹⁴) 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 ¹⁵).

Patients categorized as intermediate risk (refer to table ¹⁴) are treated with surgery and 12 to 24 weeks of the same chemotherapy regimen described above (COG-3961 ¹⁶).

In contrast, patients categorized as high risk (refer to table ¹⁴) 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]
   
   

Treatment of Low-Risk Neuroblastoma

In North America, the Children’s Oncology Group (COG) is investigating a risk-based neuroblastoma treatment plan that assigns 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-P9641 ¹⁵). (Risk groups are defined in the table ¹² in the Stage Information section of this summary.)

Patients with low-risk neuroblastoma have a cure rate higher than 90%.[1-5] The following tumors are categorized as low risk (see table ¹²):

1. INSS stage 1 tumors in patients of any age. Stage 1 is defined as gross complete resection.
2. INSS stage 2A and 2B tumors in infants.
3. INSS stage 2A and 2B tumors in children older than 1 year and in whom the tumor demonstrates either favorable Shimada classification or nonamplification of MYCN.
4. INSS stage 4S tumors in infants younger than 1 year with all favorable biological features (i.e., MYCN not amplified, favorable Shimada classification, and hyperdiploid DNA).

Low-risk neuroblastomas are generally treated with surgical resection and observation or observation alone (COG-9641).

Stage 2 low-risk tumors are treated with chemotherapy only if less than 50% of the tumor has been resected. In the other low-risk patients, chemotherapy is recommended only for life-threatening or organ-threatening symptoms that cannot be relieved by safe surgical resection of the mass. Such symptoms include respiratory distress, renal or bowel ischemia, spinal cord compression, gastrointestinal or genitourinary obstruction, or coagulopathy (COG-9641). Chemotherapy is given for 6 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 (COG-9641). Radiation therapy is reserved for patients with symptomatic life-threatening or organ-threatening tumor that does not respond rapidly enough to chemotherapy.

Studies suggest that selected presumed neuroblastomas detected in infants by screening may be safely observed without surgical intervention and without pathologic diagnosis.[6,7] The COG is investigating systematic observation without diagnostic surgery for selected infants with presumed INSS stage 1 adrenal neuroblastoma detected by prenatal or perinatal ultrasound (COG-ANBL00P2).

The treatment of children with low-risk stage 4S disease is dependent on clinical presentation.[8,9] Children who are clinically stable with this special pattern of neuroblastoma may not require therapy. The development of complications, such as functional compromise from massive hepatomegaly, is an indication for intervention, especially in infants younger than 2 to 3 months.[8,10,11] In a study of 80 infants with 4S disease, those who were asymptomatic had 100% survival with supportive care only, and patients with symptoms had an 81% survival rate when they received low-dose chemotherapy.[10] Resection of primary tumor is not associated with improved outcome.[8-10]

The COG neuroblastoma treatment plan also defines the treatment for progression or recurrence of low-risk neuroblastoma. The treatment is dependent on the characteristics of the progression or recurrence. (Refer to the Recurrent Neuroblastoma ¹⁷ section of this summary for more information.)

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with neuroblastoma ¹⁸. 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 ¹⁹.

References

1. 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]
   
   
2. Hayes FA, Green A, Hustu HO, et al.: Surgicopathologic staging of neuroblastoma: prognostic significance of regional lymph node metastases. J Pediatr 102 (1): 59-62, 1983.  [PUBMED Abstract]
   
   
3. Evans AR, Brand W, de Lorimier A, et al.: Results in children with local and regional neuroblastoma managed with and without vincristine, cyclophosphamide, and imidazolecarboxamide. A report from the Children's Cancer Study Group. Am J Clin Oncol 7 (1): 3-7, 1984.  [PUBMED Abstract]
   
   
4. Alvarado CS, London WB, Look AT, et al.: Natural history and biology of stage A neuroblastoma: a Pediatric Oncology Group Study. J Pediatr Hematol Oncol 22 (3): 197-205, 2000 May-Jun.  [PUBMED Abstract]
   
   
5. 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]
   
   
6. 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]
   
   
7. 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]
   
   
8. Guglielmi M, De Bernardi B, Rizzo A, et al.: Resection of primary tumor at diagnosis in stage IV-S neuroblastoma: does it affect the clinical course? J Clin Oncol 14 (5): 1537-44, 1996.  [PUBMED Abstract]
   
   
9. Katzenstein HM, Bowman LC, Brodeur GM, et al.: Prognostic significance of age, MYCN oncogene amplification, tumor cell ploidy, and histology in 110 infants with stage D(S) neuroblastoma: the pediatric oncology group experience--a pediatric oncology group study. J Clin Oncol 16 (6): 2007-17, 1998.  [PUBMED Abstract]
   
   
10. Nickerson HJ, Matthay KK, Seeger RC, et al.: Favorable biology and outcome of stage IV-S neuroblastoma with supportive care or minimal therapy: a Children's Cancer Group study. J Clin Oncol 18 (3): 477-86, 2000.  [PUBMED Abstract]
    
    
11. Hsu LL, Evans AE, D'Angio GJ: Hepatomegaly in neuroblastoma stage 4s: criteria for treatment of the vulnerable neonate. Med Pediatr Oncol 27 (6): 521-8, 1996.  [PUBMED Abstract]
    
    

Treatment of Intermediate-Risk Neuroblastoma

In North America, the Children’s Oncology Group (COG) is investigating a risk-based neuroblastoma treatment plan that assigns 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). (Risk groups are defined in the table ¹⁴ in the Stage Information section of this summary.)

Patients with intermediate-risk neuroblastoma generally have a cure rate of 70% to 90%. The following patients are categorized as intermediate risk (see table ¹⁴):

1. INSS stage 3 tumors in infants younger than 1 year and in whom the tumor lacks MYCN gene amplification.
2. INSS stage 3 tumors in children aged 1 year or older and in whom the tumor lacks MYCN gene amplification and has favorable Shimada classification.
3. INSS stage 4 tumors in infants younger than 18 months and in whom the tumor lacks MYCN gene amplification.[1-3]
4. INSS stage 4S tumors in infants younger than 1 year and in whom the tumor lacks MYCN gene amplification and has either unfavorable Shimada classification or is near diploid in chromosome number, or both.

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 younger than 1 year have a greater than 80% cure rate while older children have a cure rate of 50% to 70% with current relatively intensive therapy.[4-7] In one study, those with favorable compared with unfavorable biological features (i.e., Shimada classification and MYCN gene amplification) had event-free survival rates of almost 100% and about 50%, respectively.[8-10] In cases of abdominal neuroblastoma thought to involve the kidney, nephrectomy should not be undertaken before a trial of chemotherapy has been given.[11]

Patients classified as intermediate risk with stage 3 tumors with favorable or unfavorable Shimada classification are treated with 12 weeks and 24 weeks of chemotherapy, respectively. In patients classified as intermediate risk with favorable biology, radiation therapy is reserved for patients with symptomatic life-threatening or organ-threatening tumor that does not respond rapidly enough to chemotherapy. In patients classified as intermediate risk with unfavorable biologic features, radiation therapy is given if residual viable tumor remains after 24 weeks of chemotherapy and second-look surgery.

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%),[12,13] with outcome particularly dependent on tumor cell ploidy (e.g., hyperploidy confers a favorable prognosis while diploidy predicts early treatment failure).[5,14]

Infants younger than 18 months at diagnosis with INSS stage 4 neuroblastoma who do not have MYCN gene amplification are categorized as intermediate risk.[15,1-3] These infants are treated with 12 weeks of chemotherapy if the tumor has both favorable Shimada classification and hyperdiploidy, and if not, these infants are treated with 24 weeks of chemotherapy.

Infants younger than 1 year at diagnosis with INSS stage 4S neuroblastoma without amplification of the MYCN gene, but with unfavorable Shimada classification, diploid DNA, or both, are classified as intermediate risk. These infants are treated with 24 weeks of chemotherapy.

Chemotherapy for intermediate-risk patients consists of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide given for 12 to 24 weeks. The cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen (COG-A3961 ¹⁶).

The COG Neuroblastoma Treatment Plan also defines the treatment for progression or recurrence of intermediate-risk neuroblastoma. This treatment depends on the characteristics of the progression or recurrence. (Refer to the Recurrent Neuroblastoma ¹⁷ section of this summary for more information.)

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with neuroblastoma ¹⁸. 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 ¹⁹.

References

1. 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]
   
   
2. 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]
   
   
3. 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]
   
   
4. 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]
   
   
5. 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]
   
   
6. 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]
   
   
7. 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]
   
   
8. 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]
   
   
9. 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]
   
   
10. 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]
    
    
11. 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]
    
    
12. Paul SR, Tarbell NJ, Korf B, et al.: Stage IV neuroblastoma in infants. Long-term survival. Cancer 67 (6): 1493-7, 1991.  [PUBMED Abstract]
    
    
13. 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]
    
    
14. 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]
    
    
15. 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]
    
    

Treatment of High-Risk Neuroblastoma

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 ¹⁵). (Risk groups are defined in the table ¹⁴ in the Stage Information section of this summary.)

The following patients are considered to have high-risk neuroblastoma (see table ¹⁴):

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 ¹⁹.

• Monoclonal antibody therapy with or without granulocyte-macrophage colony-stimulating factor (GM-CSF) following chemotherapy (COG-ANBL0032 ²⁰).[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 ²¹).

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with neuroblastoma ¹⁸. 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 ¹⁹.

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]
    
    

Recurrent Neuroblastoma

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. When neuroblastoma recurs in a child originally diagnosed with high-risk disease and is widespread, the prognosis is usually poor despite additional intensive therapy.[1-3] The combination of cyclophosphamide plus topotecan has been active in patients with recurrent or refractory disease who have not received topotecan previously.[4] 131-I-metaiodobenzylguanidine (131-I-MIBG) therapy is also active in patients with recurrent or refractory neuroblastoma.[5] Clinical trials are appropriate and should be considered. Information about ongoing clinical trials is available from the NCI Web site ⁶.

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.[6,7]

In North America, the Children’s Oncology Group (COG) is investigating a risk-based neuroblastoma treatment plan that assigns 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).[8] Treatment of recurrent disease is determined by the risk group at the time of diagnosis (refer to the table ¹² in the Stage Information section of this summary), extent of disease at recurrence, patient age at recurrence, and the tumor biology at recurrence. If tumor is unavailable for biological studies at recurrence, the biology of the tumor at the time of diagnosis is used to help determine treatment.

(Risk categories are defined in the table ¹⁴ 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 ¹⁵). Older children with local recurrence with either unfavorable Shimada 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.[9] These modalities are commonly employed in the treatment of patients with a recurrence that augurs a poor prognosis.

Metastatic recurrent or progressive neuroblastoma in an infant initially categorized as low risk (see table ¹²) and younger than 1 year at recurrence, whether the patient has INSS stage 1, 2, or 4S at the time of diagnosis, is treated according to tumor biology:

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 Shimada 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 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.[9] These modalities are commonly employed in the treatment of patients with a recurrence that augurs a poor prognosis.

(Risk categories are defined in the table ¹⁴ in the Stage Information section of the summary.)

Local regional recurrence of neuroblastoma with favorable biology that occurs more than 3 months after completion of 12 weeks of chemotherapy is treated surgically. If resection is less than near total, then 12 additional 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-A3961 ¹⁶).

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.[9] These modalities are commonly employed in the treatment of patients with a recurrence that augurs a poor prognosis.

(Risk categories are defined in the table ¹⁴ in the Stage Information section of this summary.)

Any recurrence in patients initially classified as high risk signifies a 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.[2] The combination of cyclophosphamide and topotecan with or without etoposide has been used in recurrent disease.[4,10]

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 ¹⁹.

• Monoclonal antibody therapy with or without granulocyte-macrophage colony-stimulating factor (GM-CSF) following chemotherapy.[11]



• Targeted radiation therapy with 131-I-metaiodobenzylguanidine (131-I-MIBG).[5]



• Tandem myeloablation and stem cell transplantation.[12,13]



• Inclusion of myeloablative doses of 131-I-MIBG prior to stem cell transplantation (NANT-99-01 ²²).[14]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent neuroblastoma ²³. 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 ¹⁹.

References

1. 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]
   
   
2. 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]
   
   
3. 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]
   
   
4. 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]
   
   
5. 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]
   
   
6. 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]
   
   
7. 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]
   
   
8. 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]
   
   
9. 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]
   
   
10. 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]
    
    
11. Kushner BH, Kramer K, Cheung NK: Phase II trial of the anti-G(D2) monoclonal antibody 3F8 and granulocyte-macrophage colony-stimulating factor for neuroblastoma. J Clin Oncol 19 (22): 4189-94, 2001.  [PUBMED Abstract]
    
    
12. Frappaz D, Michon J, Coze C, et al.: LMCE3 treatment strategy: results in 99 consecutively diagnosed stage 4 neuroblastomas in children older than 1 year at diagnosis. J Clin Oncol 18 (3): 468-76, 2000.  [PUBMED Abstract]
    
    
13. Grupp SA, Stern JW, Bunin N, et al.: Rapid-sequence tandem transplant for children with high-risk neuroblastoma. Med Pediatr Oncol 35 (6): 696-700, 2000.  [PUBMED Abstract]
    
    
14. Matthay KK, Tan JC, Villablanca JG, et al.: Phase I dose escalation of iodine-131-metaiodobenzylguanidine with myeloablative chemotherapy and autologous stem-cell transplantation in refractory neuroblastoma: a new approaches to Neuroblastoma Therapy Consortium Study. J Clin Oncol 24 (3): 500-6, 2006.  [PUBMED Abstract]
    
    

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Changes to this Summary (11/06/2008)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

General Information ²⁷

Added Bell et al. as reference 13 ²⁸.

Added text ²⁹ about the etiology of neuroblastoma (cited Maris et al. as reference 24).

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