Neuroblastoma

Summary Type: Treatment
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about the treatment of childhood neuroblastoma.


Neuroblastoma

General Information

This cancer treatment information summary provides an overview of the prognosis, diagnosis, classification, and treatment of neuroblastoma.

The National Cancer Institute 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. These summaries are updated regularly according to the latest published research findings by an Editorial Board of pediatric oncology specialists.

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 Supportive Care summaries 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.

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 Late Effects of Treatment for Childhood Cancer summary for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.

Presentation of Neuroblastoma

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 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. Fever, anemia, and hypertension are occasionally found. Multifocal (multiple primaries) neuroblastoma occurs rarely, usually in infants, and generally has a good prognosis.3 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.4,.

Opsoclonus/Myoclonus Syndrome

Children with neuroblastoma rarely present with paraneoplastic neurologic findings, including cerebellar ataxia or opsoclonus/myoclonus.5, The opsoclonus/myoclonus syndrome appears to be caused by an immunologic mechanism that is not yet fully defined.6,7 Unlike most other neuroblastomas, the primary tumor is typically diffusely infiltrated with lymphocytes.8 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.7,9,10 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.6,9 Various drugs, plasmapheresis, and intravenous gamma-globulin have been reported to be effective in selected cases.9,11 The long-term neurologic outcome may be superior in patients treated with chemotherapy, possibly because of its immunosuppressive effects.5,11, 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.12,

Diagnosis

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.13,

Prognosis

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.14,15,16,17 (Refer to the Cellular Classification section of this summary for more information.) Biological prognostic variables also are used to help determine treatment.

Age

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.14,18 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%.19,

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.20 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.21,22,

Biologic factors

A number of biologic variables have been studied in children with this tumor.23 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, and loss of heterozygosity for chromosome 1p.17,18,24,25,26,27,28,29 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 MYCN 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.30 In contrast to MYCN gene amplification, the degree of expression of the MYCN gene in the tumor does not predict prognosis.31 Other biological prognostic factors that have been extensively investigated include tumor cell telomere length, telomerase activity, and RNA;32,33 urinary vanillylmandelic acid, homovanillic acid, and their ratio; dopamine; CD44 expression; TrkA gene expression; neuron-specific enolase level, serum lactic dehydrogenase level, and serum ferritin level.23 High-level expression of the MRP1 drug resistance gene is an independent indicator of decreased survival.34 The profile of GABAergic receptors expressed in neuroblastoma is predictive of prognosis regardless of age, stage, and MYCN amplification.35 Gene expression profiling may prove useful for prognosis prediction.36 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.37,38,

Unique Aspects of Neuroblastoma

Biologically discrete types of neuroblastoma

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 3 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. 39,40,

Neuroblastoma screening

Current data do not support neuroblastoma screening. Screening infants for neuroblastoma by assay of urinary catecholamine metabolites was initiated in Japan.41 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 42,43 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.44 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.43,44 No public health benefits have been shown from screening infants for neuroblastoma at these ages.

Spontaneous regression of neuroblastoma

This phenomenon has been well described in infants, especially in those with the 4S pattern of metastatic spread.45 (Refer to the Stage Information 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 46,47 include the lack of telomerase expression,48,49 the expression of Ha-ras,50 and the expression of the neurotrophin receptor TrkA, a nerve growth factor receptor.

Low-stage neuroblastoma in the fetus and newborn

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.51,52,53 The Children’s Oncology Group (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 for more information.)



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.

2 Jennings RW, LaQuaglia MP, Leong K, et al.: Fetal neuroblastoma: prenatal diagnosis and natural history. J Pediatr Surg 28 (9): 1168-74, 1993.

3 Hiyama E, Yokoyama T, Hiyama K, et al.: Multifocal neuroblastoma: biologic behavior and surgical aspects. Cancer 88 (8): 1955-63, 2000.

4 Citak C, Karadeniz C, Dalgic B, et al.: Intestinal lymphangiectasia as a first manifestation of neuroblastoma. Pediatr Blood Cancer 46 (1): 105-7, 2006.

5 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.

6 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.

7 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.

8 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.

9 Pranzatelli MR: The neurobiology of the opsoclonus-myoclonus syndrome. Clin Neuropharmacol 15 (3): 186-228, 1992.

10 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.

11 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.

12 de Alarcon PA, Children's Oncology Group: Phase II Randomized Study of Cyclophosphamide and Prednisone With or Without Immune Globulin in Pediatric Patients With Neuroblastoma-Associated Opsoclonus-Myoclonus-Ataxia Syndrome, COG-ANBL00P3, Clinical trial, Active.

13 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.

14 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.

15 Evans AE, Albo V, D'Angio GJ, et al.: Factors influencing survival of children with nonmetastatic neuroblastoma. Cancer 38 (2): 661-6, 1976.

16 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.

17 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.

18 Brodeur GM, Azar C, Brother M, et al.: Neuroblastoma. Effect of genetic factors on prognosis and treatment. Cancer 70 (6 Suppl): 1685-94, 1992.

19 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.

20 Conte M, Parodi S, De Bernardi B, et al.: Neuroblastoma in adolescents: the Italian experience. Cancer 106 (6): 1409-17, 2006.

21 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.

22 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.

23 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.

24 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.

25 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.

26 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.

27 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.

28 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.

29 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.

30 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.

31 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.

32 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.

33 Ohali A, Avigad S, Ash S, et al.: Telomere length is a prognostic factor in neuroblastoma. Cancer 107 (6): 1391-9, 2006.

34 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.

35 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.

36 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.

37 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.

38 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.

39 Maris JM, Matthay KK: Molecular biology of neuroblastoma. J Clin Oncol 17 (7): 2264-79, 1999.

40 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.

41 Sawada T: Past and future of neuroblastoma screening in Japan. Am J Pediatr Hematol Oncol 14 (4): 320-6, 1992.

42 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.

43 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.

44 Schilling FH, Spix C, Berthold F, et al.: Neuroblastoma screening at one year of age. N Engl J Med 346 (14): 1047-53, 2002.

45 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.

46 Reynolds CP: Ras and Seppuku in neuroblastoma. J Natl Cancer Inst 94 (5): 319-21, 2002.

47 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.

48 Hiyama E, Hiyama K, Yokoyama T, et al.: Correlating telomerase activity levels with human neuroblastoma outcomes. Nat Med 1 (3): 249-55, 1995.

49 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.

50 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.

51 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.

52 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.

53 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.

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.1,2,3 Neuroblastoma containing many differentiating cells, termed ganglioneuroblastoma, can have nodules of undifferentiated cells whose histology, along with MYCN amplification, determines prognosis.4,5,



1 Shimada H, Ambros IM, Dehner LP, et al.: The International Neuroblastoma Pathology Classification (the Shimada system). Cancer 86 (2): 364-72, 1999.

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.

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.

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.

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.

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 3 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.

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.

International Neuroblastoma Staging System

INSS combines certain features of the previously used POG and CCG systems 1 5 and has identified distinct prognostic groups.1,5,6,7,

  • 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 (i.e., 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 to be stage 4 disease. The results of the MIBG (metaiodobenzylguanidine) scan, if performed, should be negative for disease in the bone marrow.

Children’s Oncology Group Neuroblastoma Risk Grouping

In North America, the COG is investigating a risk-based neuroblastoma treatment plan that assigns all patients to low-risk, intermediate-risk, and high-risk groups 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-risk, intermediate-risk, 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;10,11,12 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 2005.13,14,15,

Table 1: Children’s Oncology Group Neuroblastoma Risk Group Assignment Schema

INSS Stage Age MYCN Status Shimada Classification DNA Ploidy Risk Group* INSS 2A/2B symptomatic patients with spinal cord compression, neurologic deficits, or other symptoms are treated on the LOW RISK NB Study with immediate chemotherapy for 4 cycles (Course 1).** INSS 4S infants with favorable biology and clinical symptoms are treated on the LOW RISK NB Study with immediate chemotherapy until asymptomatic (2 to 4 cycles). Clinical symptoms defined as: respiratory distress with or without hepatomegaly or cord compression and neurologic deficit or inferior vena cava compression and renal ischemia; or genitourinary obstruction; or gastrointestinal obstruction and vomiting; or coagulopathy with significant clinical hemorrhage unresponsive to replacement therapy.*** INSS 3 or 4 patients with clinical symptoms as listed above (or if in the investigator’s opinion it is in the best interest of the patient) will receive immediate chemotherapy.10-21y AnyAnyAnyLow2A/2B*<365dAny AnyAnyLow≥365d-21y NonAmpAny-Low≥365d-21yAmpFav-Low ≥365d-21y Amp Unfav-High3*** <365dNonAmp AnyAnyIntermediate<365dAmpAnyAnyHigh≥365d-21y NonAmp Fav-Intermediate≥365d-21y NonAmp Unfav-High≥365d-21y AmpAny-High4***<548d 13,14,15,NonAmpAnyAnyIntermediate<548dAmpAnyAnyHigh≥548d-21yAnyAny-High4S** <365dNonAmpFav>1Low<365dNonAmpAny=1Intermediate<365dNonAmpUnfavAnyIntermediate<365dAmpAnyAny HighBiology Defined By:MYCN Status: Amplified (Amp) versus NonAmplified (NonAmp)Shimada Classification: Favorable (Fav) versus Unfavorable (Unfav)DNA Ploidy: DNA Index (DI) >1 is favorable, = 1 is unfavorable; hypodiploid tumors (with DI <1) will be treated as a tumor with a DI >1 (DNA index <1 [hypodiploid] to be considered favorable ploidy).


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.

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.

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.

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.

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.

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.

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.

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.

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.

10 Kushner BH, Cheung NK: Treatment reduction for neuroblastoma. Pediatr Blood Cancer 43 (6): 619-21, 2004.

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.

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.

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.

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.

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.

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 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 an MIBG (metaiodobenzylguanidine) 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-risk, intermediate-risk, or high-risk group. (Risk groups are defined in Table 1 of 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.

Low Risk

Treatment for patients categorized as low risk (Table 1) 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.1,

Intermediate Risk

Patients categorized as intermediate risk (Table 1) are treated with surgery and 12 to 24 weeks of the same chemotherapy regimen described above.2,

High Risk

In contrast, patients categorized as high risk (Table 1) 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.3,4

Radiation

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.

Relapse Therapy for Low- and Intermediate-Risk Patients

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

Urgent Chemotherapy

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.5,6,7 The COG neuroblastoma treatment plan recommends immediate chemotherapy for cord compression in patients classified as low or intermediate risk.1,2 Children with high-risk neuroblastoma whose spinal cord compression worsens on medical therapy may benefit from surgical intervention.8,

Observation without Surgery of Localized, Presumed Adrenal Neuroblastoma in Infants

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.9,10,11 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.9 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.

The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.



1 Strother DR, Children's Oncology Group: Phase III Study of Primary Surgical Therapy in Children With Low-Risk Neuroblastoma, COG-P9641, Clinical trial, Completed.

2 Baker DL, Children's Oncology Group: Phase III Study of Combination Chemotherapy in Children With Intermediate-Risk Neuroblastoma, COG-A3961, Clinical trial, Completed.

3 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.

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.

5 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.

6 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.

7 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.

8 Sandberg DI, Bilsky MH, Kushner BH, et al.: Treatment of spinal involvement in neuroblastoma patients. Pediatr Neurosurg 39 (6): 291-8, 2003.

9 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.

10 Holgersen LO, Subramanian S, Kirpekar M, et al.: Spontaneous resolution of antenatally diagnosed adrenal masses. J Pediatr Surg 31 (1): 153-5, 1996.

11 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.

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 low-, intermediate-, and high-risk groups based on age, International Neuroblastoma Staging System (INSS) stage, and tumor biology (i.e., MYCN gene amplification, Shimada classification, and DNA ploidy).1 (Risk groups are defined in Table 1 of the Stage Information section of this summary.)

Patients with low-risk neuroblastoma have a cure rate higher than 90%.2,3,4,5,6 The following tumors are categorized as low risk (see Table 1):

  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.1,

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.1 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.1 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.7,8 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.9,10 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.9,11,12 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.11 Resection of primary tumor is not associated with improved outcome.9,10,11

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 section of this summary for more information.)



1 Strother DR, Children's Oncology Group: Phase III Study of Primary Surgical Therapy in Children With Low-Risk Neuroblastoma, COG-P9641, Clinical trial, Completed.

2 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.

3 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.

4 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.

5 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.

6 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.

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.

8 Holgersen LO, Subramanian S, Kirpekar M, et al.: Spontaneous resolution of antenatally diagnosed adrenal masses. J Pediatr Surg 31 (1): 153-5, 1996.

9 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.

10 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.

11 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.

12 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.

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 low-risk, intermediate-risk, and high-risk groups 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 Table 1 of 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 1):

  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.1,2,3,
  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.4,5,6,7 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.8,9,10 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 (e.g., a 5-year disease-free survival rate of 50% to 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 1,2,3 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.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 section of this summary for more information.)



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.

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 G