Neuroblastoma Treatment (PDQ®) - NCI

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General InformationPredisposition to NeuroblastomaPresentation of Neuroblastoma Opsoclonus/myoclonus syndromeDiagnosisPrognosis Age Biologic factorsUnique Aspects of Neuroblastoma Biologically discrete types of neuroblastoma Neuroblastoma screening Spontaneous regression of neuroblastoma

Cellular Classification

Stage InformationInternational Neuroblastoma Staging SystemChildren’s Oncology Group Neuroblastoma Risk Grouping

Treatment Option OverviewLow-Risk Neuroblastoma Observation without surgery for localized, suspected adrenal neuroblastoma in infantsIntermediate-Risk NeuroblastomaHigh-Risk NeuroblastomaRadiation TherapyChemotherapyDescription of International Neuroblastoma Response CriteriaSurveillance for Recurrence of High-Risk Neuroblastoma

Treatment of Low-Risk NeuroblastomaStandard Treatment OptionsCurrent Clinical Trials

Treatment of Intermediate-Risk NeuroblastomaStandard Treatment OptionsCurrent Clinical Trials

Treatment of High-Risk NeuroblastomaStandard Treatment OptionsTreatment Options Under Clinical EvaluationCurrent Clinical Trials

Recurrent NeuroblastomaRecurrent Neuroblastoma in Patients Initially Classified as Low Risk

Last Modified: 03/29/2012

Neuroblastoma Treatment (PDQ®)Health Professional Version

Local/regional recurrence Metastatic recurrenceRecurrent Neuroblastoma in Patients Initially Classified as Intermediate Risk Local/regional recurrence Metastatic recurrenceRecurrent or Refractory Neuroblastoma in Patients Initially Classified as High Risk Treatment options under clinical evaluationCurrent Clinical Trials

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General Information

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

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has beenslowly increasing since 1975.[1] Children and adolescents with cancer should be referred to medical centers thathave a multidisciplinary team of cancer specialists with experience treating the cancers that occur duringchildhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary carephysician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists,rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receivetreatment, supportive care, and rehabilitation that will enable them to achieve optimal survival and quality of life.

(Refer to the PDQ summaries on Supportive and Palliative Care 1 for specific information about supportive carefor children and adolescents with cancer).

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have beenoutlined by the American Academy of Pediatrics.[2] At these pediatric cancer centers, clinical trials are availablefor most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials isoffered to most patients and families. Clinical trials for children and adolescents with cancer are generallydesigned to compare potentially better therapy with therapy that is currently accepted as standard. Most of theprogress 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 2.

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between1975 and 2002, childhood cancer mortality has decreased by more than 50%. For neuroblastoma, the 5-yearsurvival rate in the United States has remained stable at approximately 87% for children younger than 1 year andhas increased from 37% to 65% in children aged 1 to 14 years.[1] Childhood and adolescent cancer survivorsrequire 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 3 for specific information aboutthe 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 childrenaged 5 years or younger. Neuroblastoma originates in the adrenal medulla or the paraspinal sites wheresympathetic nervous system tissue is present. These tumors can be divided into low-, intermediate-, and high-risk

groups as illustrated in the Stage Information 4 section of this summary. Low- and intermediate-risk patientsusually have localized disease or are infants aged 18 months or younger. In rare cases, neuroblastoma can bediscovered prenatally by fetal ultrasonography.[3]

Predisposition to Neuroblastoma

Little is known about the events that predispose to the development of neuroblastoma. Parental exposures havenot been definitively linked. In a genome-wide association study of 1,032 patients with neuroblastoma, a significantassociation was observed between a common genetic variation (polymorphism) at chromosome 6p22 andneuroblastoma. Tumors that arose in patients with this polymorphism tended to be clinically aggressive.[4]Germline deletion at the 1p36 or 11q14-23 locus are associated with the development of neuroblastoma and thesame deletions are found somatically in sporadic neuroblastomas.[5,6]

About 1% to 2% of patients with neuroblastoma have a family history of neuroblastoma, and these children are onaverage younger (9 months); about 20% have multifocal primary neuroblastomas. The primary cause of familialneuroblastoma is germline mutation in the ALK gene.[7] Similar somatic mutations and amplification of the ALKgene are found in 8% to12% of sporadic neuroblastomas. The mutations result in constitutive phosphorylation ofALK, which is critical for cell growth of the ALK-mutant neuroblasts. Thus, inhibition of ALK kinase is a potentialtarget for treatment of neuroblastoma, especially in children whose tumors harbor an ALK mutation or ALK geneamplification.[8] Familial neuroblastoma is rarely associated with Ondine’s curse (congenital centralhypoventilation syndrome) with germline mutation of the PHOX2B gene.[9]

Presentation of Neuroblastoma

The most common presentation of neuroblastoma is an abdominal mass. The most common symptoms in high-riskpatients are due to a tumor mass or to bone pain from metastases. Proptosis and periorbital ecchymosis arecommon in these high-risk patients and arise from retrobulbar metastasis. Extensive bone marrow metastasis mayresult in pancytopenia. Abdominal distention with respiratory compromise due to massive liver metastases mayoccur in infants. Because they originate in paraspinal ganglia, neuroblastomas may invade through neural foraminaand compress the spinal cord extradurally, causing paralysis. Horner syndrome may be caused by neuroblastomain the stellate ganglion, and children with Horner syndrome without apparent cause should be examined forneuroblastoma and other tumors.[10] Fever, anemia, and hypertension are occasionally found. Multifocal (multipleprimaries) neuroblastoma occurs rarely, usually in infants, and generally has a good prognosis.[11] On rareoccasions, children may have severe, watery diarrhea due to the secretion of vasoactive intestinal peptide (VIP)by the tumor, or may have protein-losing enteropathy with intestinal lymphangiectasia.[12] VIP secretion may alsooccur upon chemotherapeutic treatment, and tumor resection reduces VIP secretion.[13]

Opsoclonus/myoclonus syndrome

Children with neuroblastoma rarely present with paraneoplastic neurologic findings, including cerebellar ataxia oropsoclonus/myoclonus.[14] Neurologic dysfunction is most often a presenting symptom but may arise long afterremoval of the tumor. Opsoclonus/myoclonus syndrome is frequently associated with pervasive and permanentneurologic and cognitive deficits, including psychomotor retardation.[15-17]

The opsoclonus/myoclonus syndrome appears to be caused by an immunologic mechanism that is not yet fullydefined.[15,18] Unlike most other neuroblastomas, the primary tumor is typically diffusely infiltrated withlymphocytes.[19] Patients who present with this syndrome often have neuroblastomas with favorable biologicalfeatures and are likely to survive, though tumor-related deaths have been reported.[15]

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 beeffective, but some patients do not respond to ACTH.[16,18] Various drugs, plasmapheresis, intravenous gamma-globulin (IVIG), and rituximab have been reported to be effective in selected cases.[16,20-22] The long-termneurologic outcome may be superior in patients treated with chemotherapy, possibly because of itsimmunosuppressive effects.[14,20] The use of immunosuppressive therapy with and without IVIG in the treatmentof patients with neuroblastoma and opsoclonus/myoclonus syndrome is under study by the Children's Oncology

Group (COG) (COG-ANBL00P3 5).

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 celltumors of childhood, such as lymphomas, primitive neuroectodermal tumors, and rhabdomyosarcomas. Evidencefor sympathetic neuronal differentiation may be demonstrated by immunohistochemistry, electron microscopy, orby finding elevated levels of serum catecholamines (e.g., dopamine and norepinephrine) or urine catecholaminemetabolites, 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 ofthe following:

1. An unequivocal pathologic diagnosis made from tumor tissue by light microscopy (with or withoutimmunohistology, electron microscopy, or increased levels of serum catecholamines or urinarycatecholamine metabolites).[23]

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 orurinary catecholamine metabolites, as described above.[23]

However, primary tumor tissue is often needed to obtain all the biological data that may be used to determinetreatment in current COG clinical trials. There is an absolute requirement for tissue biopsy to determine the

International Neuroblastoma Pathology Classification (INPC) (see Cellular Classification 6 section for moreinformation). The INPC was used to determine treatment in the COG risk assignment schema for prior COGstudies in patients with stage 2, 3, and 4S tumors. In the risk/treatment group assignment schema for the currentCOG studies, INPC is used to determine treatment for stage 3 and 4S patients as well as for stage 4 patients aged18 months or younger. Additionally, a significant number of tumor cells are needed to determine MYCN copynumber DNA index and 11q and 1p loss of heterozygosity (LOH). For older stage 4 patients, bone marrow withextensive tumor involvement combined with elevated catecholamine metabolites is adequate for study entry.

Prognosis

Approximately 70% of patients with neuroblastoma have metastatic disease at diagnosis. The prognosis forpatients with neuroblastoma is related to their age at diagnosis, clinical stage of disease, site of the primary tumor,tumor histology, and, in patients older than 1 year, regional lymph node involvement. Biological prognostic variables

are also used to help determine treatment (see below 7).[24-27] The 5-year overall survival for all infants andchildren with neuroblastoma has increased from 46% when diagnosed between 1974 and 1989, to 71% whendiagnosed between 1999 and 2005;[28] however, this single number can be misleading due to the extremelyheterogeneous prognosis based on the neuroblastoma patient's age, stage, and biology. (Refer to the Cellular

Classification 6 section of this summary for more information.)

Age

The effect of age at diagnosis on 5-year survival is profound—age younger than 1 year is associated with 90%survival, 1 to 4 years is 68%, 5 to 9 years is 52%, and 10 to 14 years is 66%.[28] Children of any age withlocalized neuroblastoma and infants aged 18 months and younger with advanced disease and favorable diseasecharacteristics have a high likelihood of long-term, disease-free survival.[29] The prognosis of fetal and neonatalneuroblastoma are similar to that of older infants with neuroblastoma and similar biological features.[30] Olderchildren with advanced-stage disease, however, have a significantly decreased chance for cure, despite intensivetherapy. For children aged 18 months and older with stage 4 neuroblastoma, who receive aggressive treatmentwith surgery and radiation therapy to the primary tumor mass, as well as aggressive chemotherapy withhematopoietic stem cell rescue followed by cis-retinoic acid, long-term survival is approximately 30% to 50%.[31]

The clinical characteristics of neuroblastoma in adolescents are similar to those observed in children. The onlyexception is that bone marrow involvement occurs less frequently, and there is a greater frequency of metastasesin unusual sites such as lung or brain.[32] Neuroblastoma has a worse long-term prognosis in an adolescent oradult compared to a child, regardless of stage or site and, in many cases, a more prolonged course when treated

with standard doses of chemotherapy. Aggressive chemotherapy and surgery have been shown to achieve aminimal disease state in more than 50% of these patients.[32-34] Other modalities, such as local radiation therapyand the use of agents with confirmed activity, may improve the poor prognosis.[33,34] However, the overallprognosis for older patients is dismal.

Biologic factors

A number of biologic variables have been studied in children with this tumor.[35] Treatment decisions are usually

based on important factors such as the INPC (refer to the Cellular Classification 6 section of this summary forinformation about the INPC system), ploidy, amplification of the MYCN oncogene within tumor tissue, unbalanced11q LOH, and LOH for chromosome 1p.[27,36-42] In the future, MYCN amplification, 11q23 alleles, and ploidy(along with standardized procedures for evaluation) are expected to be the standard factors used for evaluation oftreatment programs, as established by the International Consensus for Neuroblastoma Molecular Diagnostics.[43]An open biopsy is often 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 clinicalresearch matures, these characteristics may be found useful as therapeutic targets or as clinically importantprognostic factors. Amplification of the MYCN gene is associated not only with deletion of chromosome 1p, butalso gain of the long arm of chromosome 17 (17q), the latter of which independently predicts a poor prognosis.[44]In contrast to MYCN gene amplification, the degree of expression of the MYCN gene in the tumor does not predictprognosis.[45] However, high overall MYCN-dependent gene expression and low expression of sympatheticneuron late differentiation genes both predict a poor outcome of neuroblastomas otherwise considered to be at lowor intermediate risk of recurrence.[46] Other biological prognostic factors that have been extensively investigatedinclude tumor cell telomere length, telomerase activity, and telomerase ribonucleic acid;[47,48] urinary VMA,HVA, and their ratio;[49] dopamine; CD44 expression; TrkA gene expression; serum neuron-specific enolaselevel, serum lactic dehydrogenase level, and serum ferritin level.[35] High-level expression of the MRP1 drugresistance gene is an independent indicator of decreased survival.[50] The profile of GABAergic receptorsexpressed in neuroblastoma is predictive of prognosis regardless of age, stage, and MYCN gene amplification.[51]Gene expression profiling may prove useful for prognosis prediction.[52] Whole chromosome copy numberchanges do not predict recurrence, while segmental chromosome number changes do.[53] In addition, response totreatment has been associated with outcome. The persistence of neuroblastoma cells in bone marrow during orafter chemotherapy, for example, is associated with a poor prognosis.[54,55]

Unique Aspects of Neuroblastoma

Biologically discrete types of neuroblastoma

Based on biologic factors and an improved understanding of the molecular development of the neural crest cellsthat give rise to neuroblastoma, the tumors have been categorized into three biological types. These types are notused to determine treatment at this time; however, type 1 has a very favorable prognosis, while types 2 and 3 havepoor prognoses.

Type 1: Expresses the TrkA neurotrophin receptor, is hyperdiploid, and tends to spontaneously regress.[56,57]

Type 2: Expresses the TrkB neurotrophin receptor and its ligand, has gained an additional copy ofchromosome 17q, has LOH of 14q or 11q, and is genomically unstable.[56,57]

Type 3: Has a gain of chromosome 17q, loss of chromosome 1p, and the MYCN gene becomes amplified.[56,57]

Children whose tumors have lost a copy of 11q are older at diagnosis, and their tumors contain more segmentalchanges in gene copy number compared with children whose tumors show MYCN amplification.[58,59] Moreover,segmental chromosome changes not detected at diagnosis may be found in neuroblastomas at relapse. Thissuggests that clinically important tumor progression is associated with accumulation of segmental chromosomalalterations.[60]

Neuroblastoma screening

Current data do not support neuroblastoma screening. Screening infants for neuroblastoma by assay of urinarycatecholamine metabolites was initiated in Japan.[61] A large population-based North American study, in whichmost infants in Quebec were screened at the ages of 3 weeks and 6 months, has shown that screening detectsmany neuroblastomas with favorable characteristics [62,63] 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 yearshows similar results.[64] Screening at the ages of 3 weeks, 6 months, or 1 year caused no reduction in theincidence of advanced-stage neuroblastoma with unfavorable biological characteristics in older children, nor did itreduce the number of deaths from neuroblastoma in infants screened at any age.[63,64] No public health benefitshave been shown from screening infants for neuroblastoma at these ages. (Refer to the PDQ summary

Neuroblastoma Screening 8 for more information.)

Spontaneous regression of neuroblastoma

This phenomenon has been well described in infants, especially in those with the 4S pattern of metastatic spread.

[65] (Refer to the Stage Information 4 section of this summary for more information.) In a German clinical trial,spontaneous regression and/or lack of progression occurred in nearly half of 93 asymptomatic infants aged 12months or younger with stage 1, 2, or 3 tumors without MYCN amplification; all were observed after partial or noresection.[66] Regression generally occurs only in tumors with a near triploid number of chromosomes, no MYCNamplification, and no loss of chromosome 1p. Additional features associated with spontaneous regression [67,68]include the lack of telomerase expression,[69,70] the expression of Ha-ras,[71] and the expression of theneurotrophin receptor TrkA, a nerve growth factor receptor.

Studies have suggested that selected infants who appear to have asymptomatic, small, low-stage adrenalneuroblastoma detected by screening or during prenatal or incidental ultrasound examination, often have tumorsthat spontaneously regress and may be observed safely without surgical intervention or tissue diagnosis.[72-74]

References

1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challengesfor the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010. [PUBMED Abstract]

2. Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. AmericanAcademy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41,1997. [PUBMED Abstract]

3. Jennings RW, LaQuaglia MP, Leong K, et al.: Fetal neuroblastoma: prenatal diagnosis and natural history. JPediatr Surg 28 (9): 1168-74, 1993. [PUBMED Abstract]

4. Maris JM, Mosse YP, Bradfield JP, et al.: Chromosome 6p22 locus associated with clinically aggressiveneuroblastoma. N Engl J Med 358 (24): 2585-93, 2008. [PUBMED Abstract]

5. Satgé D, Moore SW, Stiller CA, et al.: Abnormal constitutional karyotypes in patients with neuroblastoma: areport of four new cases and review of 47 others in the literature. Cancer Genet Cytogenet 147 (2): 89-98,2003. [PUBMED Abstract]

6. Mosse Y, Greshock J, King A, et al.: Identification and high-resolution mapping of a constitutional 11qdeletion in an infant with multifocal neuroblastoma. Lancet Oncol 4 (12): 769-71, 2003. [PUBMED Abstract]

7. Mossé YP, Laudenslager M, Longo L, et al.: Identification of ALK as a major familial neuroblastomapredisposition gene. Nature 455 (7215): 930-5, 2008. [PUBMED Abstract]

8. George RE, Sanda T, Hanna M, et al.: Activating mutations in ALK provide a therapeutic target inneuroblastoma. Nature 455 (7215): 975-8, 2008. [PUBMED Abstract]

9. Mosse YP, Laudenslager M, Khazi D, et al.: Germline PHOX2B mutation in hereditary neuroblastoma. Am

J Hum Genet 75 (4): 727-30, 2004. [PUBMED Abstract]

10. Mahoney NR, Liu GT, Menacker SJ, et al.: Pediatric horner syndrome: etiologies and roles of imaging andurine studies to detect neuroblastoma and other responsible mass lesions. Am J Ophthalmol 142 (4): 651-9,2006. [PUBMED Abstract]

11. Hiyama E, Yokoyama T, Hiyama K, et al.: Multifocal neuroblastoma: biologic behavior and surgicalaspects. Cancer 88 (8): 1955-63, 2000. [PUBMED Abstract]

12. Citak C, Karadeniz C, Dalgic B, et al.: Intestinal lymphangiectasia as a first manifestation ofneuroblastoma. Pediatr Blood Cancer 46 (1): 105-7, 2006. [PUBMED Abstract]

13. Bourdeaut F, de Carli E, Timsit S, et al.: VIP hypersecretion as primary or secondary syndrome inneuroblastoma: A retrospective study by the Société Française des Cancers de l'Enfant (SFCE). PediatrBlood Cancer 52 (5): 585-90, 2009. [PUBMED Abstract]

14. Matthay KK, Blaes F, Hero B, et al.: Opsoclonus myoclonus syndrome in neuroblastoma a report from aworkshop 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]

15. 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 PediatrOncol 36 (6): 612-22, 2001. [PUBMED Abstract]

16. Pranzatelli MR: The neurobiology of the opsoclonus-myoclonus syndrome. Clin Neuropharmacol 15 (3):186-228, 1992. [PUBMED Abstract]

17. Mitchell WG, Davalos-Gonzalez Y, Brumm VL, et al.: Opsoclonus-ataxia caused by childhoodneuroblastoma: developmental and neurologic sequelae. Pediatrics 109 (1): 86-98, 2002. [PUBMED Abstract]

18. Connolly AM, Pestronk A, Mehta S, et al.: Serum autoantibodies in childhood opsoclonus-myoclonussyndrome: an analysis of antigenic targets in neural tissues. J Pediatr 130 (6): 878-84, 1997. [PUBMED Abstract]

19. 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]

20. 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 Oncol28 (4): 284-8, 1997. [PUBMED Abstract]

21. 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]

22. Corapcioglu F, Mutlu H, Kara B, et al.: Response to rituximab and prednisolone for opsoclonus-myoclonus-ataxia syndrome in a child with ganglioneuroblastoma. Pediatr Hematol Oncol 25 (8): 756-61, 2008. [PUBMED Abstract]

23. Brodeur GM, Pritchard J, Berthold F, et al.: Revisions of the international criteria for neuroblastomadiagnosis, staging, and response to treatment. J Clin Oncol 11 (8): 1466-77, 1993. [PUBMED Abstract]

24. Adams GA, Shochat SJ, Smith EI, et al.: Thoracic neuroblastoma: a Pediatric Oncology Group study. JPediatr Surg 28 (3): 372-7; discussion 377-8, 1993. [PUBMED Abstract]

25. Evans AE, Albo V, D'Angio GJ, et al.: Factors influencing survival of children with nonmetastaticneuroblastoma. Cancer 38 (2): 661-6, 1976. [PUBMED Abstract]

26. Hayes FA, Green A, Hustu HO, et al.: Surgicopathologic staging of neuroblastoma: prognostic significanceof regional lymph node metastases. J Pediatr 102 (1): 59-62, 1983. [PUBMED Abstract]

27. 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]

28. Horner MJ, Ries LA, Krapcho M, et al.: SEER Cancer Statistics Review, 1975-2006. Bethesda, Md:

National Cancer Institute, 2009. Also available online 9. Last accessed March 29, 2012.

29. Gustafson WC, Matthay KK: Progress towards personalized therapeutics: biologic- and risk-directedtherapy for neuroblastoma. Expert Rev Neurother 11 (10): 1411-23, 2011. [PUBMED Abstract]

30. Isaacs H Jr: Fetal and neonatal neuroblastoma: retrospective review of 271 cases. Fetal Pediatr Pathol 26(4): 177-84, 2007 Jul-Aug. [PUBMED Abstract]

31. Matthay KK, Villablanca JG, Seeger RC, et al.: Treatment of high-risk neuroblastoma with intensivechemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children'sCancer Group. N Engl J Med 341 (16): 1165-73, 1999. [PUBMED Abstract]

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

33. Kushner BH, Kramer K, LaQuaglia MP, et al.: Neuroblastoma in adolescents and adults: the MemorialSloan-Kettering experience. Med Pediatr Oncol 41 (6): 508-15, 2003. [PUBMED Abstract]

34. Franks LM, Bollen A, Seeger RC, et al.: Neuroblastoma in adults and adolescents: an indolent course withpoor survival. Cancer 79 (10): 2028-35, 1997. [PUBMED Abstract]

35. Riley RD, Heney D, Jones DR, et al.: A systematic review of molecular and biological tumor markers inneuroblastoma. Clin Cancer Res 10 (1 Pt 1): 4-12, 2004. [PUBMED Abstract]

36. Moroz V, Machin D, Faldum A, et al.: Changes over three decades in outcome and the prognostic influenceof age-at-diagnosis in young patients with neuroblastoma: a report from the International NeuroblastomaRisk Group Project. Eur J Cancer 47 (4): 561-71, 2011. [PUBMED Abstract]

37. Look AT, Hayes FA, Shuster JJ, et al.: Clinical relevance of tumor cell ploidy and N-myc geneamplification in childhood neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 9 (4): 581-91,1991. [PUBMED Abstract]

38. Schmidt ML, Lukens JN, Seeger RC, et al.: Biologic factors determine prognosis in infants with stage IVneuroblastoma: A prospective Children's Cancer Group study. J Clin Oncol 18 (6): 1260-8, 2000. [PUBMED

Abstract]

39. Berthold F, Trechow R, Utsch S, et al.: Prognostic factors in metastatic neuroblastoma. A multivariateanalysis of 182 cases. Am J Pediatr Hematol Oncol 14 (3): 207-15, 1992. [PUBMED Abstract]

40. Matthay KK, Perez C, Seeger RC, et al.: Successful treatment of stage III neuroblastoma based onprospective biologic staging: a Children's Cancer Group study. J Clin Oncol 16 (4): 1256-64, 1998. [PUBMED

Abstract]

41. Attiyeh EF, London WB, Mossé YP, et al.: Chromosome 1p and 11q deletions and outcome inneuroblastoma. N Engl J Med 353 (21): 2243-53, 2005. [PUBMED Abstract]

42. 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]

43. Ambros PF, Ambros IM, Brodeur GM, et al.: International consensus for neuroblastoma moleculardiagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee. Br JCancer 100 (9): 1471-82, 2009. [PUBMED Abstract]

44. Bown N, Cotterill S, Lastowska M, et al.: Gain of chromosome arm 17q and adverse outcome in patientswith neuroblastoma. N Engl J Med 340 (25): 1954-61, 1999. [PUBMED Abstract]

45. Cohn SL, London WB, Huang D, et al.: MYCN expression is not prognostic of adverse outcome inadvanced-stage neuroblastoma with nonamplified MYCN. J Clin Oncol 18 (21): 3604-13, 2000. [PUBMED

Abstract]

46. Fredlund E, Ringnér M, Maris JM, et al.: High Myc pathway activity and low stage of neuronaldifferentiation associate with poor outcome in neuroblastoma. Proc Natl Acad Sci U S A 105 (37): 14094-9,2008. [PUBMED Abstract]

47. Poremba C, Hero B, Goertz HG, et al.: Traditional and emerging molecular markers in neuroblastomaprognosis: the good, the bad and the ugly. Klin Padiatr 213 (4): 186-90, 2001 Jul-Aug. [PUBMED Abstract]

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

49. Strenger V, Kerbl R, Dornbusch HJ, et al.: Diagnostic and prognostic impact of urinary catecholamines inneuroblastoma patients. Pediatr Blood Cancer 48 (5): 504-9, 2007. [PUBMED Abstract]

50. Haber M, Smith J, Bordow SB, et al.: Association of high-level MRP1 expression with poor clinicaloutcome in a large prospective study of primary neuroblastoma. J Clin Oncol 24 (10): 1546-53, 2006. [PUBMED Abstract]

51. Roberts SS, Mori M, Pattee P, et al.: GABAergic system gene expression predicts clinical outcome inpatients with neuroblastoma. J Clin Oncol 22 (20): 4127-34, 2004. [PUBMED Abstract]

52. Wei JS, Greer BT, Westermann F, et al.: Prediction of clinical outcome using gene expression profiling andartificial neural networks for patients with neuroblastoma. Cancer Res 64 (19): 6883-91, 2004. [PUBMED

Abstract]

53. Janoueix-Lerosey I, Schleiermacher G, Michels E, et al.: Overall genomic pattern is a predictor of outcomein neuroblastoma. J Clin Oncol 27 (7): 1026-33, 2009. [PUBMED Abstract]

54. Burchill SA, Lewis IJ, Abrams KR, et al.: Circulating neuroblastoma cells detected by reverse transcriptasepolymerase chain reaction for tyrosine hydroxylase mRNA are an independent poor prognostic indicator instage 4 neuroblastoma in children over 1 year. J Clin Oncol 19 (6): 1795-801, 2001. [PUBMED Abstract]

55. Seeger RC, Reynolds CP, Gallego R, et al.: Quantitative tumor cell content of bone marrow and blood as apredictor of outcome in stage IV neuroblastoma: a Children's Cancer Group Study. J Clin Oncol 18 (24):4067-76, 2000. [PUBMED Abstract]

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

Abstract]

57. Lastowska M, Cullinane C, Variend S, et al.: Comprehensive genetic and histopathologic study revealsthree types of neuroblastoma tumors. J Clin Oncol 19 (12): 3080-90, 2001. [PUBMED Abstract]

58. Carén H, Kryh H, Nethander M, et al.: High-risk neuroblastoma tumors with 11q-deletion display a poor

prognostic, chromosome instability phenotype with later onset. Proc Natl Acad Sci U S A 107 (9): 4323-8,2010. [PUBMED Abstract]

59. Castel V, Villamón E, Cañete A, et al.: Neuroblastoma in adolescents: genetic and clinical characterisation.Clin Transl Oncol 12 (1): 49-54, 2010. [PUBMED Abstract]

60. Schleiermacher G, Janoueix-Lerosey I, Ribeiro A, et al.: Accumulation of segmental alterations determinesprogression in neuroblastoma. J Clin Oncol 28 (19): 3122-30, 2010. [PUBMED Abstract]

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

62. 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]

63. Woods WG, Gao RN, Shuster JJ, et al.: Screening of infants and mortality due to neuroblastoma. N Engl JMed 346 (14): 1041-6, 2002. [PUBMED Abstract]

64. 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]

65. Nickerson HJ, Matthay KK, Seeger RC, et al.: Favorable biology and outcome of stage IV-Sneuroblastoma with supportive care or minimal therapy: a Children's Cancer Group study. J Clin Oncol 18(3): 477-86, 2000. [PUBMED Abstract]

66. Hero B, Simon T, Spitz R, et al.: Localized infant neuroblastomas often show spontaneous regression:results of the prospective trials NB95-S and NB97. J Clin Oncol 26 (9): 1504-10, 2008. [PUBMED Abstract]

67. Reynolds CP: Ras and Seppuku in neuroblastoma. J Natl Cancer Inst 94 (5): 319-21, 2002. [PUBMED Abstract]

68. Ambros PF, Brodeur GM: Concept of tumorigenesis and regression. In: Brodeur GM, Sawada T, TsuchidaY: Neuroblastoma. New York, NY: Elsevier Science, 2000, pp 21-32.

69. Hiyama E, Hiyama K, Yokoyama T, et al.: Correlating telomerase activity levels with humanneuroblastoma outcomes. Nat Med 1 (3): 249-55, 1995. [PUBMED Abstract]

70. Hiyama E, Reynolds CP: Telomerase as a biological and prognostic marker in neuroblastoma. In: BrodeurGM, Sawada T, Tsuchida Y: Neuroblastoma. New York, NY: Elsevier Science, 2000, pp 159-174.

71. Kitanaka C, Kato K, Ijiri R, et al.: Increased Ras expression and caspase-independent neuroblastoma celldeath: possible mechanism of spontaneous neuroblastoma regression. J Natl Cancer Inst 94 (5): 358-68,2002. [PUBMED Abstract]

72. Yamamoto K, Ohta S, Ito E, et al.: Marginal decrease in mortality and marked increase in incidence as aresult of neuroblastoma screening at 6 months of age: cohort study in seven prefectures in Japan. J ClinOncol 20 (5): 1209-14, 2002. [PUBMED Abstract]

73. Okazaki T, Kohno S, Mimaya J, et al.: Neuroblastoma detected by mass screening: the Tumor Board's rolein its treatment. Pediatr Surg Int 20 (1): 27-32, 2004. [PUBMED Abstract]

74. Fritsch P, Kerbl R, Lackner H, et al.: "Wait and see" strategy in localized neuroblastoma in infants: anoption not only for cases detected by mass screening. Pediatr Blood Cancer 43 (6): 679-82, 2004. [PUBMED

Abstract]

Cellular Classification

The International Neuroblastoma Pathologic Classification (INPC) system involves evaluation of tumor specimensobtained prior to therapy for the amount of stromal development, the degree of neuroblastic maturation, and themitosis-karyorrhexis index of the neuroblastic cells.[1-4] Favorable and unfavorable prognoses are defined on thebases of these histologic parameters. The prognostic significance of this classification system, and of relatedsystems using similar criteria, has been confirmed in several studies.[1-3] Neuroblastoma containing manydifferentiating cells, termed ganglioneuroblastoma, can have nodules of undifferentiated cells whose histology,along with MYCN amplification, determines prognosis.[4,5] About 25% of reported neuroblastomas diagnosed inthe fetus and neonate are cystic; cystic neuroblastomas have lower stages and a higher incidence of favorablebiology.[6]

References

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

2. Shimada H, Umehara S, Monobe Y, et al.: International neuroblastoma pathology classification forprognostic evaluation of patients with peripheral neuroblastic tumors: a report from the Children's CancerGroup. Cancer 92 (9): 2451-61, 2001. [PUBMED Abstract]

3. Goto S, Umehara S, Gerbing RB, et al.: Histopathology (International Neuroblastoma PathologyClassification) and MYCN status in patients with peripheral neuroblastic tumors: a report from theChildren's Cancer Group. Cancer 92 (10): 2699-708, 2001. [PUBMED Abstract]

4. Peuchmaur M, d'Amore ES, Joshi VV, et al.: Revision of the International Neuroblastoma PathologyClassification: confirmation of favorable and unfavorable prognostic subsets in ganglioneuroblastoma,nodular. Cancer 98 (10): 2274-81, 2003. [PUBMED Abstract]

5. Kubota M, Suita S, Tajiri T, et al.: Analysis of the prognostic factors relating to better clinical outcome inganglioneuroblastoma. J Pediatr Surg 35 (1): 92-5, 2000. [PUBMED Abstract]

6. Isaacs H Jr: Fetal and neonatal neuroblastoma: retrospective review of 271 cases. Fetal Pediatr Pathol 26(4): 177-84, 2007 Jul-Aug. [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 atdiagnosis, certain biological characteristics of the patient’s neuroblastoma tumor, and the stage of the tumor asdefined by the International Neuroblastoma Staging System (INSS). The INSS has replaced the previously usedChildren’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 10 in this section.

A thorough evaluation for metastatic disease should be performed prior to therapy initiation. The followinginvestigations 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 biopsyspecimens must contain at least 1 cm of marrow, excluding cartilage. Bone marrow sampling may not benecessary for tumors that are otherwise stage 1.[2]

2. Bone should be assessed by metaiodobenzylguanidine (MIBG) scan, which is applicable to all sites ofdisease, and by technetium 99 scan if the results of the MIBG scan are negative or unavailable.[3] Imaging

with 123I-MIBG is optimal for identifying soft tissue and bony metastases and is superior to 18F-FDGpositron emission tomography/computerized tomography (PET/CT) in a prospective comparison.[4] Plainradiographs of positive lesions are recommended.

3. Palpable lymph nodes should be clinically examined and histologically confirmed if indicated for staging.[1]

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. If extension of abdominal disease orpulmonary metastasis is suspected, the chest should be examined by CT scan.

5. Lumbar puncture should be avoided as central nervous system (CNS) metastasis at diagnosis is rare,[5]and lumbar puncture may be associated with an increased incidence of subsequent development of CNSmetastasis.[6]

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

International Neuroblastoma Staging System

INSS combines certain features of the previously used POG and CCG systems [1,7] and has identified distinctprognostic groups.[1,7-9]

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 andremoved with the primary tumor may be positive).

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

Stage 2B: Localized tumor with or without complete gross excision, with ipsilateral nonadherent lymphnodes 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 nodeinvolvement; or localized unilateral tumor with contralateral regional lymph node involvement; or midlinetumor with bilateral extension by infiltration (unresectable) or by lymph node involvement. The midline isdefined as the vertebral column. Tumors originating on one side and crossing the midline must infiltrate to orbeyond 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 MIBGscan, if performed, should be negative for disease in the bone marrow.

Children’s Oncology Group Neuroblastoma Risk Grouping

In North America, the COG investigated a risk-based neuroblastoma treatment plan that assigned all patients to alow-, intermediate-, or high-risk group based on age, INSS stage, and tumor biology. The relevant biologicalattributes of the tumor included MYCN status, International Neuroblastoma Pathologic Classification (INPC)histopathology classification, and tumor DNA index. The low-risk group was observed without further treatmentunless the patient had life- or organ-threatening tumors. The intermediate-risk group received limitedchemotherapy, additional surgery in some instances, and avoided radiation therapy. This study involved an overall

reduction in treatment compared to prior treatment plans.[10] The high-risk group was treated with aggressivechemotherapy, second-look surgery, high-dose chemotherapy with stem cell rescue, radiation therapy, and cis-retinoic acid. The outcome for the low- and intermediate-risk groups combined was an event-free survival andoverall 3-year survival of 88% and 96%, respectively. There was no unexpected toxicity.[10] These studies

(COG-P9641 11 and COG-A3961 12) have established a new standard of care for children in North America withneuroblastoma.

Some controversies exist regarding the treatment of several small subsets of patients and the INSS stagingsystem;[11-13] risk group assignment and recommended treatment are expected to mature as additional outcomedata are analyzed. For example, the risk group for INSS stage 4, including patients aged 12 to 18 months waschanged for patients with MYCN-nonamplified status in 2005.[14-16] Table 1 describes the risk group assignmentcriteria used to assign treatment in these studies.

Table 1. Children’s Oncology Group (COG) Neuroblastoma Low-, Intermediate-, and High-Risk

Group Assignment Schema Used for COG-9641 and COG-A3961 Studiesa

Enlarge 13

INSS Stage Age MYCN Status INPC Classif ication DNA Ploidyb Risk Group

1 0–21 y Any Any Any Low

2A/2Bc <365 d Any Any Any Low

≥365 d–21 y Nonamplified Any - Low

≥365 d–21 y Amplified Favorable - Low

≥365 d–21 y Amplified Unfavorable - High

3d <365 d Nonamplified Any Any Intermediate

<365 d Amplified Any Any High

≥365 d–21 y Nonamplified Favorable - Intermediate

≥365 d–21 y Nonamplified Unfavorable - High

≥365 d–21 y Amplified Any - High

4d <548 d [14-16] Nonamplified Any Any Intermediate


≥548 d–21 y Any Any - High

4Se <365 d Nonamplified Favorable >1 Low

<365 d Nonamplified Any =1 Intermediate

<365 d Nonamplified Unfavorable Any Intermediate


INPC = International Neuroblastoma Pathologic Classification; INSS = International Neuroblastoma Staging System.

aThe COG-9641 and COG-A3961 trials established the current standard of care for neuroblastoma patients in terms of risk group assignment and treatment strategies.

bDNA 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 (DI < 1 [hypodiploid] to beconsidered favorable ploidy).

cINSS stage 2A/2B symptomatic patients with spinal cord compression, neurologic deficits, or other symptoms should be treated with immediate chemotherapy for fourcycles.

dINSS stage 3 or stage 4 patients with clinical symptoms as listed above should receive immediate chemotherapy.

eINSS stage 4S infants with favorable biology and clinical symptoms should be treated with immediate chemotherapy until asymptomatic (2–4 cycles). Clinical symptomsinclude: respiratory distress with or without hepatomegaly or cord compression and neurologic deficit or inferior vena cava compression and renal ischemia; orgenitourinary obstruction; or gastrointestinal obstruction and vomiting; or coagulopathy with significant clinical hemorrhage unresponsive to replacement therapy.

References


2. Russell HV, Golding LA, Suell MN, et al.: The role of bone marrow evaluation in the staging of patientswith otherwise localized, low-risk neuroblastoma. Pediatr Blood Cancer 45 (7): 916-9, 2005. [PUBMED Abstract]

3. Brisse HJ, McCarville MB, Granata C, et al.: Guidelines for imaging and staging of neuroblastic tumors:consensus report from the International Neuroblastoma Risk Group Project. Radiology 261 (1): 243-57,2011. [PUBMED Abstract]

4. Papathanasiou ND, Gaze MN, Sullivan K, et al.: 18F-FDG PET/CT and 123I-metaiodobenzylguanidineimaging in high-risk neuroblastoma: diagnostic comparison and survival analysis. J Nucl Med 52 (4): 519-25,2011. [PUBMED Abstract]

5. DuBois SG, Kalika Y, Lukens JN, et al.: Metastatic sites in stage IV and IVS neuroblastoma correlate withage, tumor biology, and survival. J Pediatr Hematol Oncol 21 (3): 181-9, 1999 May-Jun. [PUBMED Abstract]

6. Kramer K, Kushner B, Heller G, et al.: Neuroblastoma metastatic to the central nervous system. TheMemorial Sloan-kettering Cancer Center Experience and A Literature Review. Cancer 91 (8): 1510-9,2001. [PUBMED Abstract]

7. Brodeur GM, Seeger RC, Barrett A, et al.: International criteria for diagnosis, staging, and response totreatment in patients with neuroblastoma. J Clin Oncol 6 (12): 1874-81, 1988. [PUBMED Abstract]

8. Castleberry RP, Shuster JJ, Smith EI: The Pediatric Oncology Group experience with the internationalstaging system criteria for neuroblastoma. Member Institutions of the Pediatric Oncology Group. J ClinOncol 12 (11): 2378-81, 1994. [PUBMED Abstract]

9. Ikeda H, Iehara T, Tsuchida Y, et al.: Experience with International Neuroblastoma Staging System andPathology Classification. Br J Cancer 86 (7): 1110-6, 2002. [PUBMED Abstract]

10. Baker DL, Schmidt ML, Cohn SL, et al.: Outcome after reduced chemotherapy for intermediate-riskneuroblastoma. N Engl J Med 363 (14): 1313-23, 2010. [PUBMED Abstract]

11. Kushner BH, Cheung NK: Treatment reduction for neuroblastoma. Pediatr Blood Cancer 43 (6): 619-21,2004. [PUBMED Abstract]

12. 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]

13. Navarro S, Amann G, Beiske K, et al.: Prognostic value of International Neuroblastoma PathologyClassification in localized resectable peripheral neuroblastic tumors: a histopathologic study of localizedneuroblastoma European Study Group 94.01 Trial and Protocol. J Clin Oncol 24 (4): 695-9, 2006. [PUBMED

Abstract]

14. Schmidt ML, Lal A, Seeger RC, et al.: Favorable prognosis for patients 12 to 18 months of age with stage 4nonamplified MYCN neuroblastoma: a Children's Cancer Group Study. J Clin Oncol 23 (27): 6474-80,2005. [PUBMED Abstract]

15. London WB, Castleberry RP, Matthay KK, et al.: Evidence for an age cutoff greater than 365 days forneuroblastoma risk group stratification in the Children's Oncology Group. J Clin Oncol 23 (27): 6459-65,2005. [PUBMED Abstract]

16. George RE, London WB, Cohn SL, et al.: Hyperdiploidy plus nonamplified MYCN confers a favorableprognosis in children 12 to 18 months old with disseminated neuroblastoma: a Pediatric Oncology Groupstudy. 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) group assignment,

which is described in the Stage Information 4 section of this summary. Treatment information is presented in thisformat because most children with neuroblastoma in North America are treated according to the COG schema.The prior COG risk-based neuroblastoma studies established the standard of care. They assigned each patient to a

low-, intermediate-, or high-risk group and the basis of the assignment is described in Table 1 10.

In patients without metastatic disease, the standard of care is to perform an initial surgery to establish thediagnosis, to resect as much of the primary tumor as is safely possible, to accurately stage disease throughsampling of regional lymph nodes that are not adherent to the tumor, and to obtain adequate tissue for biologicalstudies. Accurate determination of biological characteristics, such as INPC system, usually requires an openbiopsy. The accuracy of diagnosis and staging is increased by performing a metaiodobenzylguanidine (MIBG)scan.[1] Urinary excretion of the catecholamine metabolites vanillylmandelic acid (VMA) and homovanillic acid(HVA) per mg of excreted creatinine should be measured prior to therapy. If elevated, these markers can be usedto determine the persistence of disease.

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

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

Low-Risk Neuroblastoma

Treatment for patients categorized as low risk (refer to Table 1 10 in the Stage Information section of thissummary) may be surgery alone, but surgery may be combined with chemotherapy in some cases. Chemotherapyis reserved for patients who are symptomatic, such as from spinal cord compression or, in stage 4S, respiratorycompromise 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 11).

Observation without surgery for localized, suspected adrenal neuroblastoma in infants

Studies suggest that selected presumed neuroblastomas detected in infants by screening or incidental ultrasoundmay safely be observed without obtaining a definitive histologic diagnosis and without surgical intervention, thusavoiding potential complications of surgery in the newborn.[3-5] The experience with tumors detected by massurinary catecholamine metabolite screening in Japan appears to be applicable to tumors detected by prenatal orperinatal ultrasound in the United States.[3] The COG is investigating systematic observation without surgery forinfants with presumed small Evans stage I adrenal neuroblastoma detected by prenatal or perinatal ultrasound.

Intermediate-Risk Neuroblastoma

Patients categorized as intermediate risk (refer to Table 1 10 in the Stage Information section of this summary)have been successfully treated with surgery and 12 to 24 weeks of the same chemotherapy regimen described

above (COG-A3961 12). As a rule, patients whose tumors have unfavorable biology receive twice as many cyclesof chemotherapy as those with favorable biology.

Whether initial chemotherapy is indicated for all intermediate-risk infants with localized neuroblastoma is

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

Moderate-dose chemotherapy has been shown to be effective in the prospective Infant Neuroblastoma European

Study (INES 99.1 [EURO-INF-NB-STUDY-1999-99.1 14]), where about half of the infants with unresectable,nonmetastatic neuroblastoma and no MYCN amplification underwent a safe surgical resection and avoided long-term adverse effects. The 5-year OS rate was 99% and the event-free survival (EFS) rate was 90% (medianfollow-up, 6 years). In this study, infants undergoing surgical resection had a better EFS than those who did nothave surgery.[6][Level of evidence: 3iiA]

High-Risk Neuroblastoma

In contrast, patients categorized as high risk (refer to Table 1 10 of the Stage Information section of the summary)are generally treated with dose-intensive multiagent chemotherapy consisting of very high doses of the drugs listedabove but often also including ifosfamide and high-dose cisplatin. After a response to chemotherapy, resection ofthe primary tumor should be attempted, followed by myeloablative chemotherapy and autologous stem celltransplantation. Radiation of residual tumor and original sites of metastases is often performed before, during, orafter myeloablative therapy. After recovery, patients are treated with oral 13-cis-retinoic acid for 6 months. Bothmyeloablative therapy and retinoic acid improve outcome in patients categorized as high risk.[7,8]; [9][Level ofevidence: 1iiA] Compared to retinoic acid alone, chimeric anti-GD2 antibody ch14.18 combined with granulocytemacrophage-colony stimulating factor and interleukin-2 and given in concert with retinoic acid improves event-freesurvival for high-risk neuroblastoma patients in remission after stem cell transplant.[10]

Radiation Therapy

Radiation therapy (RT) for patients with low- or intermediate-risk neuroblastoma in the completed COG treatmentplan was reserved for symptomatic life-threatening or organ-threatening tumor bulk that did not respond rapidlyenough to chemotherapy. The common situations where radiation is used in these patients include: 1) infants aged60 days and younger with stage 4S and marked respiratory compromise from liver metastases that has notresponded to chemotherapy, or 2) for symptomatic spinal cord compression that has not responded to initialchemotherapy and/or surgical decompression. In contrast, radiation therapy to the primary site is oftenrecommended for high-risk patients even in cases of complete resection.

Chemotherapy

Immediate treatment should be given for symptomatic spinal cord compression. Neurologic recovery is more likelythe less the severity of compromise and the shorter the duration of symptoms. Neurologic outcome appears to besimilar 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 isused.[11-13] The completed COG neuroblastoma treatment plans recommended immediate chemotherapy forcord compression in patients classified as low or intermediate risk. Children with neuroblastoma whose spinal cordcompression worsens on medical therapy may benefit from surgical intervention.[14]

Description of International Neuroblastoma Response Criteria

In order to stop therapy after the initially planned number of cycles, certain response criteria, depending ontreatment group, must be met. These criteria are defined below:[15,16]

Complete Response (CR): Total disappearance of tumor, with no evidence of disease. VMA/HVA arenormal.

Very Good Partial Response (VGPR): Primary tumor has decreased by 90% to 99%, and no evidence of

metastatic disease. Urine VMA/HVA are normal. Residual bone scan changes are allowed.

Partial Response (PR): 50% to 90% decrease in the size of all measurable lesions; the number of bonescan positive sites is decreased by greater than 50% and no new lesions are present; no more than onepositive bone marrow site allowed if this represents a reduction in the number of sites originally positive fortumor at diagnosis.

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

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

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

Surveillance for Recurrence of High-Risk Neuroblastoma

Surveillance studies during and following treatment are able to detect asymptomatic and unsuspected relapse in asubstantial portion of patients. As an element in an overall surveillance plan, the most reliable test to detect disease

progression or recurrence is the 123I-MIBG scan.[17,18]

References

1. Vik TA, Pfluger T, Kadota R, et al.: (123)I-mIBG scintigraphy in patients with known or suspectedneuroblastoma: Results from a prospective multicenter trial. Pediatr Blood Cancer 52 (7): 784-90, 2009. [PUBMED Abstract]


3. 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]

4. Holgersen LO, Subramanian S, Kirpekar M, et al.: Spontaneous resolution of antenatally diagnosed adrenalmasses. J Pediatr Surg 31 (1): 153-5, 1996. [PUBMED Abstract]

5. Fritsch P, Kerbl R, Lackner H, et al.: "Wait and see" strategy in localized neuroblastoma in infants: anoption not only for cases detected by mass screening. Pediatr Blood Cancer 43 (6): 679-82, 2004. [PUBMED

Abstract]

6. Rubie H, De Bernardi B, Gerrard M, et al.: Excellent outcome with reduced treatment in infants withnonmetastatic and unresectable neuroblastoma without MYCN amplification: results of the prospectiveINES 99.1. J Clin Oncol 29 (4): 449-55, 2011. [PUBMED Abstract]


8. 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: arandomised controlled trial. Lancet Oncol 6 (9): 649-58, 2005. [PUBMED Abstract]

9. Matthay KK, Reynolds CP, Seeger RC, et al.: Long-term results for children with high-risk neuroblastomatreated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children'soncology group study. J Clin Oncol 27 (7): 1007-13, 2009. [PUBMED Abstract]

10. Yu AL, Gilman AL, Ozkaynak MF, et al.: Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoinfor neuroblastoma. N Engl J Med 363 (14): 1324-34, 2010. [PUBMED Abstract]

11. Katzenstein HM, Kent PM, London WB, et al.: Treatment and outcome of 83 children with intraspinalneuroblastoma: the Pediatric Oncology Group experience. J Clin Oncol 19 (4): 1047-55, 2001. [PUBMED

Abstract]

12. De Bernardi B, Pianca C, Pistamiglio P, et al.: Neuroblastoma with symptomatic spinal cord compression atdiagnosis: treatment and results with 76 cases. J Clin Oncol 19 (1): 183-90, 2001. [PUBMED Abstract]

13. Plantaz D, Rubie H, Michon J, et al.: The treatment of neuroblastoma with intraspinal extension withchemotherapy followed by surgical removal of residual disease. A prospective study of 42 patients--resultsof the NBL 90 Study of the French Society of Pediatric Oncology. Cancer 78 (2): 311-9, 1996. [PUBMED

Abstract]

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


16. Brodeur GM, Seeger RC, Barrett A, et al.: International criteria for diagnosis, staging, and response totreatment in patients with neuroblastoma. J Clin Oncol 6 (12): 1874-81, 1988. [PUBMED Abstract]

17. Kushner BH, Kramer K, Modak S, et al.: Sensitivity of surveillance studies for detecting asymptomatic andunsuspected relapse of high-risk neuroblastoma. J Clin Oncol 27 (7): 1041-6, 2009. [PUBMED Abstract]

18. Papathanasiou ND, Gaze MN, Sullivan K, et al.: 18F-FDG PET/CT and 123I-metaiodobenzylguanidineimaging in high-risk neuroblastoma: diagnostic comparison and survival analysis. J Nucl Med 52 (4): 519-25,2011. [PUBMED Abstract]

Treatment of Low-Risk Neuroblastoma

Standard Treatment Options

In North America, the Children’s Oncology Group (COG) investigated a risk-based neuroblastoma treatment planthat assigned all patients to a low-, intermediate-, or high-risk group based on age, International NeuroblastomaStaging System (INSS) stage, and tumor biology (i.e., MYCN gene amplification, International NeuroblastomaPathology Classification [INPC] system, and DNA index). The low-risk group was observed without furthertreatment in most cases. Chemotherapy was given for four cycles (12 weeks) to treat patients with life- or organ-

threatening neuroblastoma. (Risk Groups are defined in Table 1 15 in the Stage Information section of thissummary.)

Patients with low-risk neuroblastoma have a cure rate higher than 90%.[1-5]

Studies suggest that selected presumed neuroblastomas detected in infants by screening may be safely observedwithout surgical intervention and without pathologic diagnosis.[6,7] A COG trial investigating systematicobservation without diagnostic surgery for selected infants with presumed INSS stage 1 adrenal neuroblastoma

detected by prenatal or perinatal ultrasound (COG-ANBL00P2 16) has met its patient accrual goals. Analysis ofthe trial is pending. There is some controversy whether additional surgical resection should be attempted in infantswith localized MYCN-nonamplified tumors after biopsy or partial resection. A German clinical trial observed agroup of these patients and some infants did not require further intervention, in part due to spontaneous regression.[8]

The treatment of children with low-risk stage 4S disease is dependent on clinical presentation.[9,10] Children whoare clinically stable with this special pattern of neuroblastoma may not require therapy. The development ofcomplications, 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 wereasymptomatic had 100% survival with supportive care only, and patients with symptoms had an 81% survival ratewhen they received low-dose chemotherapy.[11] Resection of primary tumor is not associated with improvedoutcome.[9-11] In 45 patients with 4S neuroblastoma diagnosed in the first month of life, 16 patients developeddyspnea caused by massive liver enlargement; half of them did not survive.[13]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with

neuroblastoma 17. The list of clinical trials can be further narrowed by location, drug, intervention, and othercriteria.

General information about clinical trials is also available from the NCI Web site 18.

References


Abstract]

2. Hayes FA, Green A, Hustu HO, et al.: Surgicopathologic staging of neuroblastoma: prognostic significanceof 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 neuroblastomamanaged with and without vincristine, cyclophosphamide, and imidazolecarboxamide. A report from theChildren'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: aPediatric 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 IIneuroblastoma 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 adrenalmasses. J Pediatr Surg 31 (1): 153-5, 1996. [PUBMED Abstract]


9. Guglielmi M, De Bernardi B, Rizzo A, et al.: Resection of primary tumor at diagnosis in stage IV-Sneuroblastoma: does it affect the clinical course? J Clin Oncol 14 (5): 1537-44, 1996. [PUBMED Abstract]

10. Katzenstein HM, Bowman LC, Brodeur GM, et al.: Prognostic significance of age, MYCN oncogeneamplification, tumor cell ploidy, and histology in 110 infants with stage D(S) neuroblastoma: the pediatriconcology group experience--a pediatric oncology group study. J Clin Oncol 16 (6): 2007-17, 1998. [PUBMED

Abstract]

11. Nickerson HJ, Matthay KK, Seeger RC, et al.: Favorable biology and outcome of stage IV-Sneuroblastoma with supportive care or minimal therapy: a Children's Cancer Group study. J Clin Oncol 18(3): 477-86, 2000. [PUBMED Abstract]

12. Hsu LL, Evans AE, D'Angio GJ: Hepatomegaly in neuroblastoma stage 4s: criteria for treatment of thevulnerable neonate. Med Pediatr Oncol 27 (6): 521-8, 1996. [PUBMED Abstract]

13. Gigliotti AR, Di Cataldo A, Sorrentino S, et al.: Neuroblastoma in the newborn. A study of the ItalianNeuroblastoma Registry. Eur J Cancer 45 (18): 3220-7, 2009. [PUBMED Abstract]

Treatment of Intermediate-Risk Neuroblastoma


In North America, the Children’s Oncology Group (COG) investigated a risk-based neuroblastoma treatment planthat assigned all patients to a low-, intermediate-, or high-risk group based on age, International NeuroblastomaStaging System (INSS) stage, and tumor biology (i.e., MYCN gene amplification, International NeuroblastomaPathology Classification [INPC] system, and DNA ploidy). The intermediate-risk group received limitedchemotherapy, additional surgery in some instances, and avoided radiation therapy. This study involved an overallreduction in treatment compared to prior treatment plans. Event-free survival (EFS) and overall survival (OS)

rates were 88% and 96%, respectively. There was no unexpected toxicity.[1] These studies (COG-P9641 11 and

COG-A3961 12) have established a new standard of care for children in North America with neuroblastoma.

(Risk groups are defined in Table 1 10 in the Stage Information section of this summary.)

Chemotherapy is given for four to eight cycles (12 to 24 weeks) and consists of moderate doses of carboplatin,cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low to minimizepermanent injury from the chemotherapy regimen. Radiation therapy is reserved for patients with symptomaticlife-threatening or organ-threatening tumor that does not respond rapidly enough to chemotherapy and/or surgery.

There is considerable variation in outcome, and, therefore, in treatment for children with stage 3 disease (tumorinvolving both sides of the midline by virtue of either invasion into normal tissues or lymph node metastasis).Infants aged 1 year and younger have a greater than 80% cure rate while older children have a cure rate of 50%to 70% with current, relatively intensive therapy.[2-5] In one study, those with favorable compared withunfavorable biological features (i.e., INPC and MYCN gene amplification) had EFS rates of almost 100% andabout 50%, respectively.[6-8] In cases of abdominal neuroblastoma thought to involve the kidney, nephrectomyshould not be undertaken before a trial of chemotherapy has been given.[9]

Whether initial chemotherapy is indicated for all intermediate-risk infants with localized neuroblastoma iscontroversial. A German prospective clinical trial enrolled 340 infants aged 1 year or younger whose tumors werestage 1, 2, or 3, histologically verified, and lacked amplification of MYCN. Chemotherapy was given at diagnosis to57 infants with organs threatened by tumor. The tumor was completely resected or nearly so in 190 infants who

underwent low-risk surgery. A total of 93 infants whose tumors were not resectable without high-risk surgery dueto age or organ involvement were observed without chemotherapy. Further surgery was avoided in 33 infants andchemotherapy was avoided in 72 infants. Some degree of spontaneous tumor regression occurred in nearly halfthe infants. Overall survival of the 93 infants was 99%.[10]

Survival of patients with INSS stage 4 disease is strongly dependent on age. Children younger than 1 year atdiagnosis have a good chance of long-term survival (i.e., a 5-year disease-free survival rate of 50%–80%),[11,12]with outcome particularly dependent on MYCN amplification and tumor cell ploidy (e.g., hyperdiploidy confers afavorable prognosis while diploidy predicts early treatment failure).[3,13] Infants aged18 months and younger atdiagnosis with INSS stage 4 neuroblastoma who do not have MYCN gene amplification are categorized asintermediate risk.[14-17] The need for chemotherapy in all asymptomatic infants with stage 4 disease is somewhatcontroversial.[18] Stage 4 and 4S infants (N = 170) aged 12 months or younger and Stage 4 asymptomatic infants(N = 14) enrolled in an International Society of Pediatric Oncology (SIOP) trial had one of the followingcharacteristics: 1) metastases of the 4S pattern and including positive bone metastases by iodine I 131

metaiodobenzylguanidine (131I-MIBG) or technetium bone scan without cortical bone abnormality by computertomography (CT) scan or plain x-ray, or 2) primary tumor stage 3 with 4S metastatic pattern. These infants wereobserved without initial chemotherapy, and in cases with surgical risk factors, the infants were observed withoutresection of the primary tumor. Although three infants underwent tumor progression, all survived. Although manywere eventually treated with chemotherapy at the investigator’s choice, a substantial number of infants receivedno chemotherapy.[18]

A small, single-institution study suggested that all MYCN-nonamplified INSS stage 3 tumors may be treated withsurgical resection followed by observation without chemotherapy.[19][Level of evidence: 3iiDi]





References


2. Castleberry RP, Kun LE, Shuster JJ, et al.: Radiotherapy improves the outlook for patients older than 1year with Pediatric Oncology Group stage C neuroblastoma. J Clin Oncol 9 (5): 789-95, 1991. [PUBMED

Abstract]

3. Bowman LC, Castleberry RP, Cantor A, et al.: Genetic staging of unresectable or metastaticneuroblastoma in infants: a Pediatric Oncology Group study. J Natl Cancer Inst 89 (5): 373-80, 1997. [PUBMED Abstract]

4. Castleberry RP, Shuster JJ, Altshuler G, et al.: Infants with neuroblastoma and regional lymph nodemetastases have a favorable outlook after limited postoperative chemotherapy: a Pediatric Oncology Groupstudy. J Clin Oncol 10 (8): 1299-304, 1992. [PUBMED Abstract]

5. 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]


Abstract]

7. Perez CA, Matthay KK, Atkinson JB, et al.: Biologic variables in the outcome of stages I and IIneuroblastoma treated with surgery as primary therapy: a children's cancer group study. J Clin Oncol 18(1): 18-26, 2000. [PUBMED Abstract]

8. Matthay KK, Sather HN, Seeger RC, et al.: Excellent outcome of stage II neuroblastoma is independent ofresidual disease and radiation therapy. J Clin Oncol 7 (2): 236-44, 1989. [PUBMED Abstract]

9. Shamberger RC, Smith EI, Joshi VV, et al.: The risk of nephrectomy during local control in abdominalneuroblastoma. J Pediatr Surg 33 (2): 161-4, 1998. [PUBMED Abstract]


11. Paul SR, Tarbell NJ, Korf B, et al.: Stage IV neuroblastoma in infants. Long-term survival. Cancer 67 (6):1493-7, 1991. [PUBMED Abstract]

12. Bowman LC, Hancock ML, Santana VM, et al.: Impact of intensified therapy on clinical outcome in infantsand children with neuroblastoma: the St Jude Children's Research Hospital experience, 1962 to 1988. J ClinOncol 9 (9): 1599-608, 1991. [PUBMED Abstract]

13. Look AT, Hayes FA, Shuster JJ, et al.: Clinical relevance of tumor cell ploidy and N-myc geneamplification in childhood neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 9 (4): 581-91,1991. [PUBMED Abstract]

14. Schmidt ML, Lukens JN, Seeger RC, et al.: Biologic factors determine prognosis in infants with stage IVneuroblastoma: A prospective Children's Cancer Group study. J Clin Oncol 18 (6): 1260-8, 2000. [PUBMED

Abstract]

15. Schmidt ML, Lal A, Seeger RC, et al.: Favorable prognosis for patients 12 to 18 months of age with stage 4nonamplified MYCN neuroblastoma: a Children's Cancer Group Study. J Clin Oncol 23 (27): 6474-80,2005. [PUBMED Abstract]

16. London WB, Castleberry RP, Matthay KK, et al.: Evidence for an age cutoff greater than 365 days forneuroblastoma risk group stratification in the Children's Oncology Group. J Clin Oncol 23 (27): 6459-65,2005. [PUBMED Abstract]

17. George RE, London WB, Cohn SL, et al.: Hyperdiploidy plus nonamplified MYCN confers a favorableprognosis in children 12 to 18 months old with disseminated neuroblastoma: a Pediatric Oncology Groupstudy. J Clin Oncol 23 (27): 6466-73, 2005. [PUBMED Abstract]

18. De Bernardi B, Gerrard M, Boni L, et al.: Excellent outcome with reduced treatment for infants withdisseminated neuroblastoma without MYCN gene amplification. J Clin Oncol 27 (7): 1034-40, 2009. [PUBMED Abstract]

19. Modak S, Kushner BH, LaQuaglia MP, et al.: Management and outcome of stage 3 neuroblastoma. Eur JCancer 45 (1): 90-8, 2009. [PUBMED Abstract]

Treatment of High-Risk Neuroblastoma

In North America, the Children’s Oncology Group (COG) investigated a risk-based neuroblastoma treatment planthat assigned all patients to a low-, intermediate-, or high-risk group based on age, International NeuroblastomaStaging System (INSS) stage, and tumor biology (i.e., MYCN gene amplification, International Neuroblastoma

Pathology Classification [INPC] system, and DNA ploidy) (COG-P9641 11 and COG-A3961 12). (Low-,

intermediate- and high-risk groups are defined in Table 1 10 in the Stage Information section of this summary.)

For children with high-risk neuroblastoma, long-term survival with current treatments is about 30%. Children withaggressively treated, high-risk neuroblastoma may develop late recurrences, some more than 5 years aftercompletion of therapy.[1,2] A randomized study was performed comparing high-dose therapy with purgedautologous hematopoietic stem cell transplantation (HSCT) versus three cycles of intensive consolidationchemotherapy. The 3-year event-free survival (EFS) was significantly better in the HSCT arm (34%) comparedwith the consolidation chemotherapy arm (18%).[3] Superiority of myeloablative chemotherapy over maintenancetherapy was confirmed in another study.[4] In addition, patients on this study were subsequently randomized tostop therapy or to receive 6 months of 13-cis-retinoic acid.[3] Patients who received 13-cis-retinoic acid hadsignificantly better 3-year EFS than patients who received no maintenance therapy. This was true for all patientsubgroups. The 5-year EFS and overall survival (OS) for patients treated with both HSCT and retinoic acid is 50%and 59%, respectively. The 10-year OS remains greater than 50%.[5] However, these patients were selected forhaving completed HSCT without developing progressive disease. Based on these results, clinical trials have builtupon autologous HSCT and 13-cis-retinoic acid for high-risk neuroblastoma.[3] Compared to retinoic acid alone,the addition of chimeric anti-GD2 antibody ch14.18 combined with granulocyte macrophage-colony stimulatingfactor and interleukin-2 improves EFS for high-risk neuroblastoma patients in remission after stem cell transplant

(SCT) (COG-ANBL0032 19 and COG-ANBL0931 20).[6]

The potential benefit of aggressive surgical approaches in high-risk patients with metastatic disease to achievecomplete tumor resection, either at the time of diagnosis or following chemotherapy, has not been unequivocallydemonstrated. Several studies have reported that complete resection of the primary tumor at diagnosis improvedsurvival; however, the outcome in these patients may be more dependent on the biology of the tumor, which itselfmay determine resectability, than on the extent of surgical resection.[7-11] The use of radiation therapy toconsolidate local control after surgical resection is recommended.[12]; [13][Level of evidence: 3iiA]

Assessment of risk for low-stage MYCN-amplified neuroblastoma is controversial because it is so rare. A study of87 INSS stage 1 and 2 patients pooled from several clinical trial groups demonstrated no effect of age, stage, orinitial treatment on outcome. The EFS and OS were 53% and 72%, respectively. Survival was superior in patientswhose tumors were hyperdiploid rather than diploid (EFS 82% ± 20% vs. 37% ± 21%; OS 94% ± 11% vs. 54% ±15%).[14] The overall EFS and OS for infants with stage 4 and 4S disease and MYCN-amplification was only30% at 2 to 5 years post-treatment in a European study.[15]


Patients classified as high risk receive treatment with an aggressive regimen of combination chemotherapyconsisting of very high drug doses, generally termed induction. Drugs often used include cyclophosphamide,ifosfamide, cisplatin, carboplatin, vincristine, doxorubicin, etoposide, and topotecan. COG has completed a pilotstudy of induction demonstrating the feasibility of substituting two cycles of topotecan and cyclophosphamide fortwo cycles of vincristine, cyclophosphamide, and doxorubicin.[16] After a response to chemotherapy, resection ofthe primary tumor should be attempted, followed by myeloablative chemotherapy and stem cell rescue (i.e., bonemarrow and/or peripheral blood stem cell transplantation). Whether or not harvested stem cells should be purgedof neuroblastoma cells has been studied in a randomized fashion. There was no advantage to purging.[17] Two ormore sequential cycles of myeloablative chemotherapy and stem cell rescue given in a tandem fashion has beenstudied and feasibility was established.[7,18] It is now under clinical evaluation in COG. Radiation to the primarytumor site should be undertaken whether or not a complete excision was obtained. The optimal dose of radiationtherapy has not been determined. Radiation of sites of metastatic disease is determined on an individual casebasis. After recovery, patients are treated with oral 13-cis-retinoic acid for 6 months. Both myeloablative therapyand postchemotherapy retinoic acid improve outcome in patients categorized as high risk.[3,5] For high risk-patients in remission following HSCT, compared to retinoic acid alone, chimeric anti-GD2 antibody ch14.18combined with granulocyte-macrophage colony stimulating factor and interleukin-2 and given in concert withretinoic acid improves EFS.[6]

Treatment Options Under Clinical Evaluation

The following are examples of national and/or institutional clinical trials that are currently being conducted.


COG-ANBL09P1 21 (Induction Therapy Including 131I-MIBG and Chemotherapy in Treating PatientsWith Newly Diagnosed High-Risk Neuroblastoma Undergoing SCT, Radiation Therapy, and Maintenance

Therapy With Isotretinoin ): This limited-participation pilot study for children with newly diagnosed high-riskneuroblastoma assesses the tolerability and feasibility of an induction regimen containing five cycles of

multi-agent chemotherapy and a block of 131I-MIBG/irinotecan/vincristine followed by a consolidationregimen of busulfan/melphalan with autologous stem cell rescue and external-beam radiation therapy.

COG-ANBL0032 19 (Isotretinoin With or Without Monoclonal Antibody, Interleukin-2, and Sargramostim

Following SCT in Treating Patients With Neuroblastoma): The COG is studying, in a nonrandomizedfashion, the use of monoclonal antibody therapy with granulocyte-macrophage colony-stimulating factor andinterleukin-2 combined with cis-retinoic acid following chemotherapy.[6,19,20]





References

1. Cotterill SJ, Pearson AD, Pritchard J, et al.: Late relapse and prognosis for neuroblastoma patientssurviving 5 years or more: a report from the European Neuroblastoma Study Group "Survey". Med PediatrOncol 36 (1): 235-8, 2001. [PUBMED Abstract]

2. Mertens AC, Yasui Y, Neglia JP, et al.: Late mortality experience in five-year survivors of childhood andadolescent 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 versusoral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: arandomised controlled trial. Lancet Oncol 6 (9): 649-58, 2005. [PUBMED Abstract]

5. Matthay KK, Reynolds CP, Seeger RC, et al.: Long-term results for children with high-risk neuroblastomatreated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children'soncology group study. J Clin Oncol 27 (7): 1007-13, 2009. [PUBMED Abstract]

6. Yu AL, Gilman AL, Ozkaynak MF, et al.: Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoinfor neuroblastoma. N Engl J Med 363 (14): 1324-34, 2010. [PUBMED Abstract]

7. George RE, Li S, Medeiros-Nancarrow C, et al.: High-risk neuroblastoma treated with tandem autologousperipheral-blood stem cell-supported transplantation: long-term survival update. J Clin Oncol 24 (18): 2891-6, 2006. [PUBMED Abstract]

8. DeCou JM, Bowman LC, Rao BN, et al.: Infants with metastatic neuroblastoma have improved survivalwith resection of the primary tumor. J Pediatr Surg 30 (7): 937-40; discussion 940-1, 1995. [PUBMED Abstract]

9. Adkins ES, Sawin R, Gerbing RB, et al.: Efficacy of complete resection for high-risk neuroblastoma: aChildren's Cancer Group study. J Pediatr Surg 39 (6): 931-6, 2004. [PUBMED Abstract]

10. 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]

11. La Quaglia MP, Kushner BH, Su W, et al.: The impact of gross total resection on local control and survivalin high-risk neuroblastoma. J Pediatr Surg 39 (3): 412-7; discussion 412-7, 2004. [PUBMED Abstract]

12. Haas-Kogan DA, Swift PS, Selch M, et al.: Impact of radiotherapy for high-risk neuroblastoma: aChildren's Cancer Group study. Int J Radiat Oncol Biol Phys 56 (1): 28-39, 2003. [PUBMED Abstract]

13. Gatcombe HG, Marcus RB Jr, Katzenstein HM, et al.: Excellent local control from radiation therapy forhigh-risk neuroblastoma. Int J Radiat Oncol Biol Phys 74 (5): 1549-54, 2009. [PUBMED Abstract]

14. Bagatell R, Beck-Popovic M, London WB, et al.: Significance of MYCN amplification in internationalneuroblastoma staging system stage 1 and 2 neuroblastoma: a report from the International NeuroblastomaRisk Group database. J Clin Oncol 27 (3): 365-70, 2009. [PUBMED Abstract]

15. Canete A, Gerrard M, Rubie H, et al.: Poor survival for infants with MYCN-amplified metastaticneuroblastoma despite intensified treatment: the International Society of Paediatric Oncology EuropeanNeuroblastoma Experience. J Clin Oncol 27 (7): 1014-9, 2009. [PUBMED Abstract]

16. Park JR, Stewart CF, London WB, et al.: A topotecan-containing induction regimen for treatment of highrisk neuroblastoma. [Abstract] J Clin Oncol 24 (Suppl 18): A-9013, 505s, 2006.

17. Kreissman SG, Villablanca JG, Seeger RC, et al.: A randomized phase III trial of myeloablative autologousperipheral blood stem cell (PBSC) transplant (ASCT) for high-risk neuroblastoma (HR-NB) employingimmunomagnetic purged (P) versus unpurged (UP) PBSC: A Children's Oncology Group study. [Abstract]J Clin Oncol 26 (Suppl 15): A-10011, 2008.

18. 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]

19. Cheung NK, Kushner BH, Cheung IY, et al.: Anti-G(D2) antibody treatment of minimal residual stage 4neuroblastoma diagnosed at more than 1 year of age. J Clin Oncol 16 (9): 3053-60, 1998. [PUBMED Abstract]

20. Simon T, Hero B, Faldum A, et al.: Consolidation treatment with chimeric anti-GD2-antibody ch14.18 inchildren older than 1 year with metastatic neuroblastoma. J Clin Oncol 22 (17): 3549-57, 2004. [PUBMED

Abstract]

Recurrent Neuroblastoma

Age, International Neuroblastoma Staging System (INSS) stage, MYCN status, and time from diagnosis to firstrelapse are significant prognostic factors for postrelapse survival.[1] The Children’s Oncology Group (COG)experience with recurrence in intermediate-risk neuroblastoma is that the majority of recurrences can be salvaged,as demonstrated by a 3-year event free survival (EFS) of 88% and an overall survival (OS) of 96%.[2] Whenneuroblastoma recurs in a child originally diagnosed with high-risk disease and is widespread, the prognosis isusually poor despite additional intensive therapy.[1,3-5]

In selected patients originally diagnosed with low- or intermediate-risk disease, recurrence may be treatedsuccessfully with limited intervention. The combination of cyclophosphamide plus topotecan has been active in

patients with recurrent or refractory disease who have not received topotecan previously.[6] Iodine I 131

metaiodobenzylguanidine (131I-MIBG) therapy is also active in patients with recurrent or refractoryneuroblastoma.[7] Clinical trials are appropriate and should be considered. Information about ongoing clinical trials

is available from the NCI Web site 2.

Central nervous system (CNS) involvement, though rare at initial presentation, may occur in 5% to 10% ofpatients with recurrent neuroblastoma. Because upfront treatment for newly diagnosed patients does notadequately treat the CNS, the CNS has emerged as a sanctuary site leading to relapse.[8,9] CNS relapses havebeen almost always fatal with a median time to death of 6 months. Current treatment approaches generally includeeradicating bulky and microscopic residual disease in the CNS as well as minimal residual systemic disease thatmay herald further relapses. Neurosurgical interventions serve to decrease edema, control hemorrhage, andremove bulky tumor prior to starting radiation therapy. Compartmental radioimmunotherapy using intrathecalradioiodinated monoclonal antibodies has been tested in patients with recurrent metastatic CNS neuroblastomafollowing surgery, craniospinal radiation therapy, and chemotherapy.[10]

In North America, the COG investigated a risk-based neuroblastoma treatment plan that assigned all patients to alow-, intermediate-, or high-risk group based on age, INSS stage, and tumor biology (i.e., MYCN geneamplification, International Neuroblastoma Pathology Classification [INPC] system, and DNA ploidy).[11]

Treatment of recurrent disease was determined by risk group at the time of diagnosis (refer to Table 1 10), extentof disease at recurrence, patient age at recurrence, and the tumor biology. If tumor was unavailable for biologicalstudies at recurrence, the biology of the tumor at time of diagnosis was used to help determine treatment.

Recurrent Neuroblastoma in Patients Initially Classified as Low Risk

(Risk categories are defined in Table 1 10 in the Stage Information section of this summary.)

Local/regional recurrence

Local regional recurrent cancer is resected if possible:

1. Those with favorable biology and regional recurrence more than 3 months after completion of plannedtreatment are observed if resection of the recurrence is total or near total (≥90% resection). Those withfavorable 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 unfavorablebiologic 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. Thecumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen as used

in prior COG trials (COG-P9641 11 and COG-A3961 12). Older children with local recurrence with eitherunfavorable INPC classification or MYCN gene amplification have a poor prognosis and should be treated with anaggressive regimen of combination chemotherapy consisting of very high doses of the drugs listed above, andoften also including ifosfamide and high-dose cisplatin. Both myeloablative therapy and postchemotherapy retinoicacid may improve outcome of newly diagnosed high-risk patients with a poor prognosis.[12] These modalities arecommonly employed in the treatment of patients with a recurrence that augurs a poor prognosis.

Metastatic recurrence

Metastatic recurrent or progressive neuroblastoma in an infant initially categorized as low risk (see Table 1 10 inthe Stage Information section of the summary) and younger than 1 year at recurrence, whether the patient hasINSS stage 1, 2, or 4S at the time of diagnosis, may be treated according to tumor biology as defined in the prior

COG trials (COG-P9641 11 and COG-A3961 12):

1. If the biology is completely favorable, metastasis is in a 4S pattern, and the recurrence or progression iswithin 3 months of diagnosis, the patient is observed systematically.

2. If the metastatic progression or recurrence with completely favorable biology occurs more than 3 monthsafter diagnosis or not in a 4S pattern, then the primary tumor is resected if possible and 12 to 24 weeks ofchemotherapy are given, depending on response.

3. If the tumor in the infant with metastatic recurrence or progression has unfavorable INPC classificationand/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. Thecumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen, as used

in a prior COG trial (COG-P9641 11).

Any child initially categorized as low risk who is older than 1 year at the time of metastatic recurrent orprogressive disease who is not in the stage 4S pattern usually has a poor prognosis and should be treated with anaggressive regimen of combination chemotherapy consisting of very high doses of the drugs listed above, andoften also including ifosfamide and high-dose cisplatin. Both myeloablative therapy and postchemotherapy retinoicacid may improve outcome of newly diagnosed patients with a poor prognosis.[12] These modalities are commonlyemployed in the treatment of patients with a recurrence that augurs a poor prognosis.

Recurrent Neuroblastoma in Patients Initially Classified as Intermediate Risk

(Risk categories are defined in Table 1 10 in the Stage Information section of the summary.)

Local/regional recurrence

The current standard of care is based on the experience from the COG Intermediate-Risk treatment plan (COG-

A3961 12). Local regional recurrence of neuroblastoma with favorable biology that occurs more than 3 monthsafter completion of 12 weeks of chemotherapy may be treated surgically. If resection is less than near total, then12 additional weeks of chemotherapy may be given. Chemotherapy consists of moderate doses of carboplatin,cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low to minimizepermanent injury from the chemotherapy regimen, as used in a prior COG trial (COG-A3961).

Metastatic recurrence

If the recurrence is metastatic and/or occurs while on chemotherapy or within 3 months of completingchemotherapy and/or has unfavorable biologic properties, the prognosis is poor and the patient should be treatedwith 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 postchemotherapyretinoic acid may improve outcome of newly diagnosed patients with a poor prognosis.[12] These modalities arecommonly employed in the treatment of patients with a recurrence that augurs a poor prognosis.

Recurrent or Refractory Neuroblastoma in Patients Initially Classified as High Risk

(Risk categories are defined in Table 1 10 in the Stage Information section of this summary.)

Any recurrence in patients initially classified as high risk signifies a very poor prognosis.[1] Data from threeconsecutive German high-risk neuroblastoma trials described 253 children relapsing after intensive chemotherapywith autologous stem cell transplantation (SCT) who had a 5-year OS rate of less than 10%. Only 23 of the 253patients eventually proceeded to a second autologous SCT following retrieval chemotherapy. Among thesepatients, the 3-year OS rate was 43%, but the 5-year OS rate was less than 20%. This shows that intensivesecond-line therapy is feasible, although even with intensive therapy and second autologous SCT, only a smallminority of relapsed high-risk neuroblastoma patients may benefit.[13][Level of evidence: 3iiiA] Whether thisintense therapeutic approach is better than other salvage therapy approaches is unknown. Topotecan alone and incombination with cyclophosphamide or etoposide has been used in patients with recurrent disease who did notreceive topotecan initially.[14,15]; [16][Level of evidence: 1A] High-dose carboplatin-irinotecan-temozolomide hasbeen used in patients resistant or refractory to regimens containing topotecan.[15] The combination of irinotecanand temozolomide had a 15% response rate in one study.[17][Level of evidence: 2A]

For adolescents and young adults with recurrent or refractory neuroblastoma, 131I-MIBG is a highly effectivesalvage agent and should be considered.[18]

Additionally, phase I or II clinical trials are appropriate and should be considered.

Treatment options under clinical evaluation

The following is an example of a national and/or institutional clinical trial that is currently being conducted.


COG-ANBL1021 22 (Biological Therapy, Sargramostim [GM-CSF], and Isotretinoin in Treating Patients

With Relapsed or Refractory Neuroblastoma): Feasibility/phase II study of Hu14.18-IL2 immunocytokine,GM-CSF, and isotretinoin in patients with relapsed or refractory neuroblastoma.


Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent



References

1. London WB, Castel V, Monclair T, et al.: Clinical and biologic features predictive of survival after relapseof neuroblastoma: a report from the International Neuroblastoma Risk Group project. J Clin Oncol 29 (24):3286-92, 2011. [PUBMED Abstract]


3. Pole JG, Casper J, Elfenbein G, et al.: High-dose chemoradiotherapy supported by marrow infusions foradvanced neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 9 (1): 152-8, 1991. [PUBMED

Abstract]

4. Castel V, Cañete A, Melero C, et al.: Results of the cooperative protocol (N-III-95) for metastatic relapsesand refractory neuroblastoma. Med Pediatr Oncol 35 (6): 724-6, 2000. [PUBMED Abstract]

5. Lau L, Tai D, Weitzman S, et al.: Factors influencing survival in children with recurrent neuroblastoma. JPediatr Hematol Oncol 26 (4): 227-32, 2004. [PUBMED Abstract]

6. Saylors RL 3rd, Stine KC, Sullivan J, et al.: Cyclophosphamide plus topotecan in children with recurrent orrefractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 19 (15): 3463-9, 2001. [PUBMED Abstract]

7. Matthay KK, Yanik G, Messina J, et al.: Phase II study on the effect of disease sites, age, and priortherapy on response to iodine-131-metaiodobenzylguanidine therapy in refractory neuroblastoma. J ClinOncol 25 (9): 1054-60, 2007. [PUBMED Abstract]

8. Kramer K, Kushner B, Heller G, et al.: Neuroblastoma metastatic to the central nervous system. TheMemorial Sloan-kettering Cancer Center Experience and A Literature Review. Cancer 91 (8): 1510-9,2001. [PUBMED Abstract]

9. Matthay KK, Brisse H, Couanet D, et al.: Central nervous system metastases in neuroblastoma: radiologic,clinical, and biologic features in 23 patients. Cancer 98 (1): 155-65, 2003. [PUBMED Abstract]

10. Kramer K, Kushner BH, Modak S, et al.: Compartmental intrathecal radioimmunotherapy: results fortreatment for metastatic CNS neuroblastoma. J Neurooncol 97 (3): 409-18, 2010. [PUBMED Abstract]

11. Goto S, Umehara S, Gerbing RB, et al.: Histopathology (International Neuroblastoma PathologyClassification) and MYCN status in patients with peripheral neuroblastic tumors: a report from theChildren's Cancer Group. Cancer 92 (10): 2699-708, 2001. [PUBMED Abstract]


13. Simon T, Berthold F, Borkhardt A, et al.: Treatment and outcomes of patients with relapsed, high-riskneuroblastoma: results of German trials. Pediatr Blood Cancer 56 (4): 578-83, 2011. [PUBMED Abstract]

14. Simon T, Längler A, Harnischmacher U, et al.: Topotecan, cyclophosphamide, and etoposide (TCE) in thetreatment of high-risk neuroblastoma. Results of a phase-II trial. J Cancer Res Clin Oncol 133 (9): 653-61,2007. [PUBMED Abstract]

15. Kushner BH, Kramer K, Modak S, et al.: Differential impact of high-dose cyclophosphamide, topotecan,and vincristine in clinical subsets of patients with chemoresistant neuroblastoma. Cancer 116 (12): 3054-60,2010. [PUBMED Abstract]

16. London WB, Frantz CN, Campbell LA, et al.: Phase II randomized comparison of topotecan pluscyclophosphamide versus topotecan alone in children with recurrent or refractory neuroblastoma: aChildren's Oncology Group study. J Clin Oncol 28 (24): 3808-15, 2010. [PUBMED Abstract]

17. Bagatell R, London WB, Wagner LM, et al.: Phase II study of irinotecan and temozolomide in children withrelapsed or refractory neuroblastoma: a Children's Oncology Group study. J Clin Oncol 29 (2): 208-13,2011. [PUBMED Abstract]

18. Polishchuk AL, Dubois SG, Haas-Kogan D, et al.: Response, survival, and toxicity after iodine-131-metaiodobenzylguanidine therapy for neuroblastoma in preadolescents, adolescents, and adults. Cancer 117(18): 4286-93, 2011. [PUBMED Abstract]

Changes to this Summary (03/29/2012)

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

General Information 24

Revised text 25 to state that the 5-year overall survival for all infants and children with neuroblastoma hasincreased from 46% when diagnosed between 1974 and 1989, to 71% when diagnosed between 1999 and 2005.

Added Gustafson et al. as reference 29 26.

Stage Information 4

Added text 27 to state that imaging with iodine I 123 metaiodobenzylguanidine(123I-MIBG) is optimal foridentifying soft tissue and bony metastases and is superior to 18F-FDG positron emissiontomography/computerized tomography in a prospective comparison (cited Brisse et al. and Papathanasiou et al. asreferences 3 and 4, respectively).

Treatment Option Overview 28

Added text 29 about a German prospective clinical trial that enrolled 340 infants aged 1 year or younger whosetumors were stage 1, 2, or 3, histologically verified, and lacked MYCN amplification; the 3-year overall survival(OS) rate was 99% and metastases-free survival rate was 94% for infants with unresected tumors and was notdifferent from infants treated with surgery or chemotherapy. The investigators suggested that a wait-and-seestrategy is appropriate for infants with localized neuroblastoma because regressions have been observed after thefirst year of life.

Added text 30 about how moderate-dose chemotherapy has been shown to be effective in the prospective InfantNeuroblastoma European Study, where about half of the infants with unresectable, nonmetastatic neuroblastomaand no MYCN amplification underwent a safe surgical resection and avoided long-term adverse effects (citedRubie et al. as reference 6 and level of evidence 3iiA).

Added Papathanasiou et al. as reference 18 31.

Treatment of High-Risk Neuroblastoma 32

Added text 33 about the COG-ANBL09P1 clinical trial as a treatment option under clinical evaluation.

Recurrent Neuroblastoma 34

Added text 35 to state that age, International Neuroblastoma Staging System stage, MYCN status, and time fromdiagnosis to first relapse are significant prognostic factors for postrelapse survival (cited London et al. asreference 1).

Revised text 36 to state that data from three consecutive German high-risk neuroblastoma trials described 253children relapsing after intensive chemotherapy with autologous stem cell transplantation (SCT) who had a 5-yearOS rate of less than 10%. Only 23 of the 253 patients eventually proceeded to a second autologous SCT followingretrieval chemotherapy. Among these patients, the 3-year OS rate was 43%, but the 5-year OS rate was less than20%.This shows that intensive second-line therapy is feasible, although even with intensive therapy and secondautologous SCT, only a small minority of relapsed high-risk neuroblastoma patients may benefit (cited Kushner etal. as reference 15).

Added text 37 to state that phase I or II clinical trials are appropriate and should be considered.

Added text 38 about the COG-ANBL1021 clinical trial as a treatment option under clinical evaluation.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed,evidence-based information about the treatment of neuroblastoma. It is intended as a resource to inform and assistclinicians who care for cancer patients. It does not provide formal guidelines or recommendations for makinghealth care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board39, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independentreview of the literature and does not represent a policy statement of NCI or the National Institutes of Health

(NIH).

Board members review recently published articles each month to determine whether an article should:

be discussed at a meeting,be cited with text, orreplace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strengthof the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Neuroblastoma Treatment are:

Christopher N. Frantz, MD (Alfred I. duPont Hospital for Children)Michael P. LaQuaglia, MD (Memorial Sloan-Kettering Cancer Center)Karen Jean Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)Nita Louise Seibel, MD (National Cancer Institute)Stephen J. Shochat, MD (St. Jude Children's Research Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's

Contact Form 40. Do not contact the individual Board Members with questions or comments about the summaries.Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. Thesedesignations are intended to help readers assess the strength of the evidence supporting the use of specificinterventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking

system 41 in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot beidentified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularlyupdated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer informationsummary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Neuroblastoma Treatment. Bethesda, MD: National Cancer Institute. Date lastmodified <MM/DD/YYYY>. Available at:http://cancer.gov/cancertopics/pdq/treatment/neuroblastoma/HealthProfessional. Accessed <MM/DD/YYYY>.

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQsummaries only. Permission to use images outside the context of PDQ information must be obtained from theowner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this

summary, along with many other cancer-related images, is available in Visuals Online 42, a collection of over 2,000scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or“under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursementdeterminations. More information on insurance coverage is available on Cancer.gov on the Coping with Cancer:

Financial, Insurance, and Legal Information 43 page.

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Glossary Terms

Level of evidence 1A

Randomized, controlled clinical trial with total mortality as an endpoint. See Levels of Evidence for Adultand Pediatric Cancer Treatment Studies (PDQ®) for more information.

Level of evidence 1iiA

Randomized, controlled, nonblinded clinical trial with total mortality as an endpoint. See Levels ofEvidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Level of evidence 2A

Nonrandomized, controlled clinical trial with total mortality as an endpoint. See Levels of Evidence forAdult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Level of evidence 3iiA

Consecutive case series (not population-based) with total mortality as an endpoint. See Levels ofEvidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Level of evidence 3iiDi

Consecutive case series (not population-based) with event-free survival as an endpoint. See Levels ofEvidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Level of evidence 3iiiA

Nonconsecutive case series with total mortality as an endpoint. See Levels of Evidence for Adult andPediatric Cancer Treatment Studies (PDQ®) for more information.

Table of Links

1 http://cancer.gov/cancerinfo/pdq/supportivecare

2 http://cancer.gov/clinicaltrials

3 http://www.cancer.gov/cancertopics/pdq/treatment/lateeffects/HealthProfessional

4 http://www.cancer.gov/cancertopics/pdq/treatment/neuroblastoma/HealthProfessional/Page3#Section_14

5 http://www.cancer.gov/clinicaltrials/search/view?version=healthprofessional&;cdrid=69271


7 http://www.cancer.gov/cancertopics/pdq/treatment/neuroblastoma/HealthProfessional/#Section_314

8 http://www.cancer.gov/cancertopics/pdq/screening/neuroblastoma/HealthProfessional

9 http://seer.cancer.gov/csr/1975_2006




13 http://www.cancer.gov/cancertopics/pdq/treatment/neuroblastoma/HealthProfessional/Table1




17 http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?Diagnosis=42067&tt=1&format=2&cn=1

18 http://www.cancer.gov/clinicaltrials





23 http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?Diagnosis=43713&tt=1&format=2&cn=1
















39 http://www.cancer.gov/cancertopics/pdq/pediatric-treatment-board

40 http://www.cancer.gov/contact

41 http://www.cancer.gov/cancertopics/pdq/levels-evidence-adult-treatment/HealthProfessional

42 http://visualsonline.cancer.gov

43 http://www.cancer.gov/cancertopics/coping/financial-legal

44 http://www.cancer.gov/help

45 https://livehelp.cancer.gov

46 http://cancer.gov

47 https://cissecure.nci.nih.gov/ncipubs

Documents

Neuroblastoma Treatment (PDQ®) - NCI