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Neuroblastoma

Table of Contents

GENERAL INFORMATION

CELLULAR CLASSIFICATION

STAGE INFORMATION

Childrens Cancer Group (CCG) staging system

Pediatric Oncology Group (POG) staging system

International Neuroblastoma Staging System (INSS)

TREATMENT OPTION OVERVIEW

LOCALIZED RESECTABLE NEUROBLASTOMA

LOCALIZED UNRESECTABLE NEUROBLASTOMA

REGIONAL NEUROBLASTOMA

DISSEMINATED NEUROBLASTOMA

STAGE IVS NEUROBLASTOMA

RECURRENT NEUROBLASTOMA

GENERAL INFORMATION

This treatment information summary on neuroblastoma is an overview of prognosis, diagnosis, classification, and patient treatment. The National Cancer Institute created the PDQ database to increase the availability of new treatment information and its use in treating patients. Information and references from the most recent published literature are included after review by pediatric oncology specialists.

Cancer in children is rare. A team approach that incorporates the skills of the local physician, pediatric surgeon, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, and social workers is imperative to ensure that patients receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. For advances to be made in treating these patients, therapy should be delivered in the context of a clinical trial at a major medical center that has expertise in treating children. Only through entry of all eligible children into appropriate, well-designed clinical trials will progress be made against these diseases. Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[1]

Neuroblastoma is predominantly a tumor of early childhood, with two thirds of the cases presenting in children younger than 5 years of age. In rare cases, neuroblastoma can be discovered prenatally by fetal ultrasonography.[2] Neuroblastoma originates in the adrenal medulla or the paraspinal sites where sympathetic nervous system tissue is present. The most common symptoms are due to a tumor mass or to bone pain from metastases. Proptosis and periorbital ecchymosis are common and arise from retrobulbar metastasis. Because they originate in paraspinal ganglia, neuroblastomas may invade through neural foramina and compress the spinal cord, causing paralysis. Fever, anemia, and hypertension are found occasionally. Rarely, children may have severe watery diarrhea due to the secretion of vasoactive intestinal peptide by the tumor, cerebellar ataxia, or opsoclonus/myoclonus.[3]

The opsoclonus/myoclonus paraneoplastic syndrome appears to have an immunologic mechanism that is not yet fully defined.[4] Patients who present with this syndrome often have low-grade disease with good survival, but tumor-related deaths have been reported. Opsoclonus/myoclonus has also been associated with pervasive and permanent neurologic disorders, including psychomotor retardation. Neurologic dysfunction may be the presenting symptom or may first occur after removal of the tumor. Some patients may clinically respond to removal of the neuroblastoma, but improvement may be slow and partial; symptomatic treatment is often necessary. Adrenocorticotropic hormone (ACTH) treatment is thought to be the most effective, but some patients are resistant to ACTH.[4,5] Various drugs, plasmapheresis, and gamma-globulin have been reported to be effective in selected cases.[5,6] It has been suggested that the long-term neurologic outcome may be superior in patients treated with chemotherapy.[6]

The diagnosis of neuroblastoma requires the involvement of pathologists who are familiar with childhood tumors. Some neuroblastomas cannot be discriminated from other small round blue cell tumors of childhood (such as lymphomas, primitive neuroectodermal tumor, and rhabdomyosarcoma) without finding evidence of sympathetic neuronal differentiation by immunohistochemistry, electron microscopy, or elevated levels of urine or serum catecholamines or metabolites. The minimum criterion for a diagnosis of neuroblastoma that has been established by international agreement is based on one of the following: 1) An unequivocal pathologic diagnosis made from tumor tissue by light microscopy (with or without immunohistology, electron microscopy, or increased levels of urine or serum catecholamines or metabolites). Catecholamines and metabolites include dopamine, homovanillic acid (HVA), and/or vanillylmandelic acid (VMA). To be considered increased, levels must be greater than 3.0 SD above the mean per milligram creatinine for age, and at least two of these must be measured. 2) Bone marrow aspirate or trephine biopsy containing unequivocal tumor cells (e.g., syncytia or immunocytologically positive clumps of cells) and increased levels of urine or serum catecholamines or metabolites as described above.[7]

Approximately 70% of all patients with neuroblastoma have metastatic disease at diagnosis. The prognosis for patients with neuroblastoma is related to their age at diagnosis, clinical stage of disease, and (in patients older than 1 year of age) regional lymph node involvement. Other conventional prognostic variables include the site of the primary tumor and tumor histology (see Cellular Classification section below).[8-10]

Children of any age with localized neuroblastoma and infants younger than 1 year of age with advanced disease and favorable disease characteristics have a high likelihood of long-term, disease-free survival.[8,11] Older children with advanced-stage disease, however, have a significantly decreased chance for cure despite intensive therapy. As an example, aggressive multiagent chemotherapy has resulted in a 2-year survival rate of approximately 20% in older children with stage IV neuroblastoma.[12,13] Neuroblastoma in the adolescent or adult has a worse long-term prognosis regardless of stage or site and, in many cases, a more prolonged course.[14]

A number of biologic variables have been studied in children with this tumor. Of particular importance are aneuploidy of tumor DNA and amplification of the N-myc oncogene within tumor tissue, since treatment decisions may be based on these factors. Hyperdiploid tumor DNA is associated with a favorable prognosis, especially in infants with neuroblastoma,[15] while N-myc amplification is associated with a poor prognosis, regardless of patient age.[11,15,16] Expression of the gene encoding the high-affinity nerve growth factor receptor (termed TRK-A proto-oncogene), the low-affinity nerve growth factor receptor (termed LNGFR), and HA-ras p21 are each associated with a very good outcome and are inversely related to amplification of the N-myc gene.[17,18] An increased ratio of the excreted catecholamine metabolites (VMA or HVA), lack of expression of glycoprotein CD44 on the tumor cell surface, elevated serum ferritin, serum neuron-specific enolase, and serum lactate dehydrogenase are each associated with poor prognosis.[19-24] Biologic staging consisting of N-myc copy number and age is useful in defining prognosis and treatment of stage III neuroblastoma.[25] Some data support the theory that, in neuroblastomas, high levels of p-glycoprotein, the protein product of the multidrug resistance gene, directly correspond with a poorer outcome following chemotherapy.[26]

Many of the improvements in survival in childhood cancer have been made using new therapies that have attempted to improve on the best available, accepted therapy. Clinical trials in pediatrics are designed to compare potentially better therapy with therapy that is currently accepted. This may be done in a randomized study of two treatment arms or by evaluating a single new treatment and comparing the results with those previously obtained with standard therapy.

The current data do not support neuroblastoma screening. Screening infants for neuroblastoma by assay of urinary catecholamine metabolites was initiated in Japan[27] but remains controversial.[28] A large population-based North American study in which most infants in Quebec were screened at ages 3 weeks and 6 months has shown that screening detects many neuroblastomas with favorable characteristics[29,30] that would never have been detected clinically, apparently because the tumors would have spontaneously regressed. There was no reduction in the incidence of advanced-stage neuroblastomas with unfavorable biological characteristics in older children. This strongly suggests that screening for neuroblastoma at ages 3 weeks and 6 months will not decrease mortality and morbidity.[31] The ongoing collection of population- based mortality data in the Quebec study will allow more definitive conclusions regarding the public health benefits of neuroblastoma screening. For a more extensive discussion of neuroblastoma screening, see the PDQ treatment information summary on Screening for Neuroblastoma.

References:

1. Sanders J, Glader B, Cairo M, et al.: Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99(1): 139-141, 1997.
2. Jennings RW, LaQuaglia MP, Leong K, et al.: Fetal neuroblastoma: prenatal diagnosis and natural history. Journal of Pediatric Surgery 28(9): 1168-1174, 1993.
3. Azizkhan RG, Haase GM: Current biologic and therapeutic implications in the surgery of neuroblastoma. Seminars in Surgical Oncology 9(6): 493-501, 1993.
4. Connolly AM, Pestronk A, Mehta S, et al.: Serum autoantibodies in children opsoclonus-myoclonus syndrome: an analysis of antigenic targets in neural tissues. Journal of Pediatrics 130(6): 878-884, 1997.
5. Pranzatelli MR: The neurobiology of the opsoclonus-myoclonus syndrome. Clinical Neuropharmacology 15(3): 186-228, 1992.
6. 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. Medical and Pediatric Oncology 28(4): 284-288, 1997.
7. Brodeur GM, Pritchard J, Berthold F, et al.: Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. Journal of Clinical Oncology 11(8): 1466-1477, 1993.
8. Adams, GA, Shochat SJ, Smith EI, et al.: Thoracic neuroblastoma: a Pediatric Oncology Group study. Journal of Pediatric Surgery 28(3): 372-378, 1993.
9. Evans AE, Albo V, D'Angio GJ, et al.: Factors influencing survival of children with nonmetastatic neuroblastoma. Cancer 38(2): 661-666, 1976.
10. Hayes FA, Green A, Hustu HO, et al.: Surgicopathologic staging of neuroblastoma: prognostic significance of regional lymph node metastases. Journal of Pediatrics 102(1): 59-62, 1983.
11. Brodeur GM, Azar C, Brother M, et al.: Neuroblastoma: effect of genetic factors on prognosis and treatment. Cancer 70(6, Suppl): 1685-1694, 1992.
12. Bowman LC, Hancock ML, Santana VM, et al.: Impact of intensified therapy on clinical outcome in infants and children with neuroblastoma: the St Jude Children's Research Hospital experience, 1962-1988. Journal of Clinical Oncology 9(9): 1599-1608, 1991.
13. McWilliams NB, Hayes FA, Green AA, et al.: Cyclophosphamide/doxorubicin vs. cisplatin/teniposide in the treatment of children older than 12 months of age with disseminated neuroblastoma: a Pediatric Oncology Group randomized phase II study. Medical and Pediatric Oncology 24(3): 176-180, 1995.
14. Franks LM, Bollen A, Seeger RC, et al.: Neuroblastoma in adults and adolescents: an indolent course with poor survival. Cancer 79(10): 2028-2035, 1997.
15. Look AT, Hayes FA, Shuster JJ, et al.: Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study. Journal of Clinical Oncology 9(4): 581-591, 1991.
16. Tonini GP, Boni L, Pession A, et al.: MYCN oncogene amplification in neuroblastoma is associated with worse prognosis, except in stage 4s: the Italian experience with 295 children. Journal of Clinical Oncology 15(1): 85-93, 1997.
17. Nakagawara A, Arima-Nakagawara M, Scavarda NJ, et al.: Association between high levels of expression of the TRK gene and favorable outcome in human neuroblastoma. New England Journal of Medicine 328(12): 847-854, 1993.
18. Tanaka T, Seeger RC, Tanabe M, et al.: Prognostic prediction in neuroblastomas: clinical significance of combined analysis for Ha-ras p21 expression and N-myc gene amplification. Cancer Detection and Prevention 18(4): 283-289, 1994.
19. Shuster JJ, McWilliams NB, Castleberry R, et al.: Serum lactate dehydrogenase in childhood neuroblastoma: a Pediatric Oncology Group recursive partitioning study. American Journal of Clinical Oncology 15(4): 295-303, 1992.
20. Berthold F, Trechow R, Utsch S, et al.: Prognostic factors in metastatic neuroblastoma: a multivariate analysis of 182 cases. American Journal of Pediatric Hematology/Oncology 14(3): 207-215, 1992.
21. Hann HW, Evans AE, Siegel SE, et al.: Prognostic importance of serum ferritin in patients with stages III and IV neuroblastoma: the Childrens Cancer Study Group experience. Cancer Research 45(6): 2843-2848, 1985.
22. Massaron S, Seregni E, Luksch R, et al.: Neuron-specific enolase evaluation in patients with neuroblastoma. Tumor Biology 19(4): 261-268, 1998.
23. De Bernardi B, Pianca C, Boni L, et al.: Disseminated neuroblastoma (stage IV and IV-S) in the first year of life: outcome related to age and stage. Italian Cooperative Group on Neuroblastoma. Cancer 70(6): 1625-1633, 1992.
24. Combaret V, Gross N, Lasset C, et al.: Clinical relevance of CD44 cell-surface expression and N-myc gene amplification in a multicentric analysis of 121 pediatric neuroblastomas. Journal of Clinical Oncology 14(1): 25-34, 1996.
25. Matthay KK, Perez C, Seeger RC, et al: Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children's Cancer Group study. Journal of Clinical Oncology 16(4): 1256-1264, 1998.
26. Chan HS, Haddad G, Thorner PS, et al: P-glycoprotein expression as a predictor of the outcome of therapy for neuroblastoma. New England Journal of Medicine 325(23): 1608-1614, 1992.
27. Sawada T: Past and future of neuroblastoma screening in Japan. American Journal of Pediatric Hematology/Oncology 14(4): 320-326, 1992.
28. Murphy SB, Cohn SL, Craft AW, et al.: Do children benefit from mass screening for neuroblastoma? Consensus statement from the American Cancer Society workshop on neuroblastoma screening. Lancet 337(8737): 344-346, 1991.
29. Woods WG, Lemieux B, Leclerc JM, et al.: Screening for neuroblastoma (NB) in North America: the Quebec Project. In: Evans AE, Biedler JL, Brodeur GM, et al., Eds.: Advances in Neuroblastoma Research 4. Wiley-Liss, Inc, 1994, pp 377-382.
30. 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): 2363-2371, 1995.
31. Woods WG, Tuchman M, Robison LL, et al.: A population-based study of the usefulness of screening for neuroblastoma. Lancet 348(9043): 1682-1687, 1996.

CELLULAR CLASSIFICATION

One clinicopathologic staging system involves evaluation of tumor specimens for the amount of stromal development, the degree of neuroblastic maturation, and the mitosis-karyorrhexis index of the neuroblastic cells.[1] Favorable and unfavorable prognoses are defined on the bases of these histologic parameters and on patient age. The prognostic significance of this classification system, and of related systems using similar criteria, has been confirmed in several studies.[2,3]

References:

1. Chatten J, Shimada H, Sather HN, et al.: Prognostic value of histopathology in advanced neuroblastoma: a report from the Children Cancer Study Group. Human Pathology 19(10): 1187-1198, 1988.
2. Joshi VV, Chatten J, Sather HN, et al.: Evaluation of the Shimada classification in advanced neuroblastoma with a special reference to the mitosis-karyorrhexis index: a report from the Childrens Cancer Study Group. Modern Pathology 4(2): 139-147, 1991.
3. Joshi VV, Cantor AB, Altshuler G, et al.: Recommendations for modification of terminology of neuroblastic tumors and prognostic significance of Shimada classification. Cancer 69(8): 2183-2196, 1992.

STAGE INFORMATION

There are several staging systems currently used for neuroblastoma. The system used in the treatment section of this document (localized, regional, disseminated, and special) is based on the Childrens Cancer Group (CCG), St. Jude, and the Pediatric Oncology Group (POG) staging systems. An International Neuroblastoma Staging System (INSS) has been proposed, which combines elements of the POG and CCG staging systems. Current protocols use the POG or CCG staging system to assign treatment, but also specify that the INSS stage be defined for all patients. If the INSS is validated in current studies, it will replace previous systems in future protocols. Each of these staging systems is described below.

The CCG uses a clinical staging system based on physical examination, radiographic evaluation, and bone marrow examination.[1] Follow-up of patients staged according to the CCG system has demonstrated the prognostic significance of this staging system.[1]

Stage I: tumor confined to the organ or structure of origin.

Stage II: tumor extending in continuity beyond the organ or structure of

origin but not crossing the midline. Regional lymph nodes on the
homolateral side may be involved.

Stage III: tumor invasively extending in continuity beyond the midline.

Regional lymph nodes may be involved bilaterally.

Stage IV: remote disease involving skeleton, parenchymatous organs, soft

tissues, distant lymph node groups, etc. (See stage IVS.)

Stage IVS: patients who would otherwise be stage I or II but have remote

disease confined to one or more of the following sites only: liver, skin,
or bone marrow (without radiographic evidence of bone metastases on
complete skeletal survey).[2]

Investigators at St. Jude Children's Research Hospital developed a clinical, surgical, and pathologic staging system that places major emphasis on the presence of regional lymph node metastases.[2] From this system evolved the Pediatric Oncology Group (POG) staging system outlined below. The prognostic significance of the POG staging system has been documented in several studies.[3,4] The major differences between the CCG and POG systems are in the staging of patients with involved ipsilateral lymph nodes (stages I and II in CCG, stage C in POG), and in patients with tumors that cross the midline and who have negative nodes (POG stage A or B, CCG stage III).

Stage A: complete gross resection of the primary tumor, with or without

microscopic residual disease. Intracavitary lymph nodes, not adherent to
but removed with the primary, must be histologically free of tumor. Nodes
adherent to the surface of or within the primary tumor may be positive
without upstaging the patient to stage C. If the primary is in the
abdomen or pelvis, the liver must be histologically free of tumor.

Stage B: incomplete gross resection of the primary tumor. Nodes and liver

must be histologically free of tumor.

Stage C: complete or incomplete gross resection of the primary tumor.

Intracavitary nodes not adherent to the primary must be histologically
positive for tumor. Liver must be histologically free of tumor.

Stage D: any dissemination of disease beyond intracavitary nodes (i.e.,

extracavitary nodes, liver, skin, bone marrow, bone, etc.).

Stage DS: infants less than 1 year of age with stage IVS disease (see CCG

staging system).

The INSS combines certain features of both the POG and CCG systems and is under evaluation by both groups.[5,6] It has been shown to identify distinct prognostic groups.[7]

Stage 1: localized tumor with complete gross excision, with or without

microscopic residual disease; representative ipsilateral lymph nodes
negative for tumor microscopically (nodes attached to and removed with the
primary tumor may be positive).

Stage 2A: localized tumor with incomplete gross excision; representative

ipsilateral nonadherent lymph nodes negative for tumor microscopically.

Stage 2B: localized tumor with or without complete gross excision, with

ipsilateral nonadherent lymph nodes positive for tumor. Enlarged
contralateral lymph nodes must be negative microscopically.

Stage 3: unresectable unilateral tumor infiltrating across the midline, with

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

Stage 4: any primary tumor with dissemination to distant lymph nodes, bone,

bone marrow, liver, skin, and/or other organs (except as defined for
stage 4S).

Stage 4S: localized primary tumor (as defined for stage 1, 2A, or 2B), with

dissemination limited to skin, liver, and/or bone marrow (limited to
infants less than 1 year of age). Marrow involvement should be minimal
(i.e., <10% of total nucleated cells identified as malignant by bone
biopsy or by bone marrow aspirate). More extensive bone marrow involvement
would be considered to be stage IV disease. The results of the meta-
iodobenzylguandine (MIBG) scan (if performed) should be negative for
disease in the bone marrow.

References:

1. Evans AE, D'Angio GJ, Sather HN, et al.: A comparison of four staging systems for localized and regional neuroblastoma: a report from the Childrens Cancer Study Group. Journal of Clinical Oncology 8(4): 678-688, 1990.
2. Hayes FA, Green A, Hustu HO, et al.: Surgicopathologic staging of neuroblastoma: prognostic significance of regional lymph node metastases. Journal of Pediatrics 102(1): 59-62, 1983.
3. Castleberry RP, Smith EI, Cantor A, et al.: Surgico-pathologic staging of neuroblastoma. Journal of Clinical Oncology 9(1): 189, 1991.
4. Castleberry RP, Kun LE, Shuster JJ, et al.: Radiotherapy improves the outlook for children older than 1 year with Pediatric Oncology Group stage C neuroblastoma. Journal of Clinical Oncology 9(5): 789-795, 1991.
5. Brodeur GM, Pritchard J, Berthold F, et al.: Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. Journal of Clinical Oncology 11(8): 1466-1477, 1993.
6. Brodeur GM, Seeger RC, Barrett A, et al.: International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma. Journal of Clinical Oncology 6(12): 1874-1881, 1988.
7. Castleberry RP, Shuster JJ, Smith EI, et al.: The Pediatric Oncology Group experience with the international staging system criteria for neuroblastoma. Journal of Clinical Oncology 12(11): 2378-2381, 1994.

TREATMENT OPTION OVERVIEW

For the purposes of treatment presented here, neuroblastoma is categorized as localized resected, localized unresected, regional, disseminated, and special.

Because of the prognostic significance and the therapeutic implications of specific tumor biologic properties (e.g., N-myc amplification and tumor DNA ploidy), it is important that tumor specimens adequate for determination of these factors be obtained prior to treatment. Vanillylmandelic acid and homovanillic acid levels should be obtained prior to therapy. If elevated, these markers can be used to determine the persistence of disease.

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

LOCALIZED RESECTABLE NEUROBLASTOMA

Localized disease includes those with INSS stage 1 disease, Childrens Cancer Group (CCG) stage I, II, or III tumors that have been resected and have negative nodes, Pediatric Oncology Group (POG) stage A disease, and favorable biologic features.[1] These children, of any age, have a cure rate of greater than 90%.[2-4]

Treatment options:

Complete gross resection produces disease-free survivals that are indistinguishable from those obtained with operation plus adjuvant chemotherapy or operation plus radiation therapy.[2-4] Microscopic residual disease in the tumor bed does not adversely affect survival and does not indicate the need for therapy beyond operation. However, in light of other information relating to prognosis, including patient age, the Shimada grade, ferritin, NSE, LDH, and N-myc amplification, further therapy may be indicated.

References:

1. Matthay KK, Perez C, Seeger RC, et al: Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children's Cancer Group study. Journal of Clinical Oncology 16(4): 1256-1264, 1998.
2. Hayes FA, Green A, Hustu HO, et al.: Surgicopathologic staging of neuroblastoma: prognostic significance of regional lymph node metastases. Journal of Pediatrics 102(1): 59-62, 1983.
3. Evans AR, Brand W, de Lorimier A, et al.: Results in children with local and regional neuroblastoma managed with and without vincristine, cyclophosphamide, and imidazolecarboxamide: a report from the Children's Cancer Study Group. American Journal of Clinical Oncology 6(1): 3-8, 1984.
4. Nitschke R, Smith EI, Shochat S, et al.: Localized neuroblastoma treated by surgery: a Pediatric Oncology Group study. Journal of Clinical Oncology 6(8): 1271-1279, 1988.

LOCALIZED UNRESECTABLE NEUROBLASTOMA

Localized unresectable disease includes those with INSS stage 2 disease, Childrens Cancer Group (CCG) stages I, II, or III tumors that are incompletely resected and have negative nodes, and Pediatric Oncology Group (POG) stage B disease. In these patients, there are no metastases to regional lymph nodes, but the tumor is not completely resected. The probability of long-term survival is 75%-90% depending on age of patient, favorable biologic features, and therapy delivered.[1-4]

Treatment options:

The initial management generally consists of subtotal resection or biopsy followed by chemotherapy.[3,5-8] Second-look operation is used subsequently to remove residual tumor, and radiation therapy may be given to patients with residual disease following second-look operation. The chemotherapeutic agents most commonly used include cyclophosphamide and doxorubicin, with cisplatin and either teniposide or etoposide reserved for more resistant tumors. Short-term therapy for 4-6 months is usually adequate. However, in light of other information relating to prognosis, including patient age, the Shimada grade, ferritin, NSE, LDH, and N-myc amplification, either more or less therapy may be indicated.

References:

1. Hayes FA, Green A, Hustu HO, et al.: Surgicopathologic staging of neuroblastoma: prognostic significance of regional lymph node metastases. Journal of Pediatrics 102(1): 59-62, 1983.
2. Ninane J, Pritchard DJ, Morris-Jones PH, et al.: Stage II neuroblastoma: adverse prognostic significance of lymph node involvement. Archives of Disease in Childhood 57(2): 438-442, 1982.
3. Evans AE, Albo V, D'Angio GJ, et al.: Cyclophosphamide treatment of patients with localized and regional neuroblastoma: a randomized study. Cancer 38(2): 655-660, 1976.
4. Matthay KK, Perez C, Seeger RC, et al: Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children's Cancer Group study. Journal of Clinical Oncology 16(4): 1256-1264, 1998.
5. Nitschke R, Smith EI, Altshuler G, et al.: Postoperative treatment of nonmetastatic visible residual neuroblastoma: a Pediatric Oncology Group Study. Journal of Clinical Oncology 9(7): 1181-1188, 1991.
6. McGuire WA, Simmons DL, Grosfeld JL, et al.: Stage II neuroblastoma--does adjuvant irradiation contribute to cure? Medical and Pediatric Oncology 13(3): 117-121, 1985.
7. Haase GM, Wong KY, deLorimier AA, et al.: Improvement in survival after excision of primary tumor in stage III neuroblastoma. Journal of Pediatric Surgery 24(2): 194-200, 1989.
8. Garaventa A, de Bernardi B, Pianca C, et al.: Localized but unresectable neuroblastoma: treatment and outcome of 145 cases. Journal of Clinical Oncology 11(9): 1770-1779, 1993.

REGIONAL NEUROBLASTOMA

Regional neuroblastoma includes those with INSS stage 3 disease, Childrens Cancer Group (CCG) stage II or stage III tumors that have positive nodes, and Pediatric Oncology Group (POG) stage C disease. Infants younger than 1 year of age have a greater than 80% chance of cure while older children have a cure rate of 50%-70% with current, relatively intensive therapy.[1-4] In those cases of abdominal neuroblastoma thought to involve the kidney, nephrectomy should not be undertaken before a trial of chemotherapy has been given.[5]

Treatment options for patients younger than 1 year of age:

1. Surgical resection of the primary tumor may be possible at diagnosis or as a delayed procedure. Complete resection of the primary tumor, either as a primary or secondary procedure, may improve outcome.[6,7] Select groups of patients whose tumors have favorable biologic features may not require treatment other than surgery.[8]

2. Chemotherapy with cyclophosphamide and doxorubicin, cisplatin with teniposide or etoposide or vincristine with cisplatin and teniposide or etoposide for more resistant tumors.[2,3]

1. Surgical resection of the primary tumor may be possible at diagnosis or following tumor reduction with chemotherapy +/- radiation therapy. Complete resection of the primary tumor, either prior to chemotherapy or as a secondary procedure, may improve outcome.[6] Select groups of patients whose tumors have favorable biologic features may not require treatment other than surgery.[8]

2. Aggressive chemotherapy using combinations of cyclophosphamide, doxorubicin, cisplatin, and teniposide or etoposide.[1,2]

3. Radiation therapy to nodal drainage areas may improve outcome.[1]

1. High-dose chemotherapy, radiation therapy, and bone marrow reconstitution for patients with poor prognostic characteristics (e.g., N-myc amplification).[9-11]

2. Aggressive chemotherapy and radiation therapy given simultaneously.

1. Castleberry RP, Kun LE, Shuster JJ, et al.: Radiotherapy improves the outlook for patients older than 1 year with Pediatric Oncology Group stage C neuroblastoma. Journal of Clinical Oncology 9(5): 789-795, 1991.
2. Bowman LC, Castleberry RP, Cantor A, et al.: Genetic staging of unresectable or metastatic neuroblastoma in infants: a Pediatric Oncology Group study. Journal of the National Cancer Institute 89(5): 373-380, 1997.
3. Castleberry RP, Shuster JJ, Altshuler G, et al.: Infants with neuroblastoma and regional lymph node metastases have a favorable outlook after limited postoperative chemotherapy: a Pediatric Oncology Group study. Journal of Clinical Oncology 10(8):1299-1304, 1992.
4. 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. Journal of Clinical Oncology 11(1): 84-90, 1993.
5. Shamberger RC, Smith EI, Joshi VV, et al.: The risk of nephrectomy during local control in abdominal neuroblastoma. Journal of Pediatric Surgery 33(2): 161-164, 1998.
6. Haase GM, Wong KY, deLorimier AA, et al.: Improvement in survival after excision of primary tumor in stage III neuroblastoma. Journal of Pediatric Surgery 24(2): 194-200, 1989.
7. DeCou JM, Bowman LC, Rao BN, et al.: Infants with metastatic neuroblastoma have improved survival with resection of the primary tumor. Journal of Pediatric Surgery 30(7): 937-941, 1995.
8. Kushner BH, Cheung NK, LaQuaglia MP, et al.: International neuroblastoma staging system stage 1 neuroblastoma: a prospective study and literature review. Journal of Clinical Oncology 14(7): 2174-2180, 1996.
9. Hartmann O, Pinkerton CR, Philip T, et al.: Very-high-dose cisplatin and etoposide in children with untreated advanced neuroblastoma. Journal of Clinical Oncology 6(1): 44-50, 1988.
10. Matthay KK, Seeger RC, Reynolds CP, et al.: Allogeneic versus autologous purged bone marrow transplantation for neuroblastoma: a report from the Childrens Cancer Group. Journal of Clinical Oncology 12(11): 2382-2389, 1994.
11. Evans AE, August CS, Kamani N, et al.: Bone marrow transplantation for high risk neuroblastoma at the Children's Hospital of Philadelphia: an update. Medical and Pediatric Oncology 23(4): 323-327, 1994.

DISSEMINATED NEUROBLASTOMA

Disseminated disease includes those with Childrens Cancer Group (CCG) stage IV and Pediatric Oncology Group (POG) stage D disease. Differentiating patients with stage IVS ("special") neuroblastoma from other disseminated disease patients is important; stage IVS patients should be treated as described in the treatment section on stage IVS neuroblastoma. Survival of patients with disseminated disease is strongly dependent on age. Children younger than 1 year of age at diagnosis have a good chance of long-term survival (5-year disease-free survival rate of 50%-80%),[1,2] with outcome particularly dependent on tumor cell ploidy (hyperploidy confers a favorable prognosis while diploidy predicts early treatment failure).[3,4]

For children older than 1 year of age, long-term survival ranges from 10%-40%. A randomized study was performed comparing high-dose therapy with purged autologous bone marrow transplantation versus three cycles of intensive consolidation chemotherapy. The 3 year event-free survival was significantly better in the autologous bone marrow transplantation arm (34%) compared to the consolidation chemotherapy arm (18%).[5] In addition, patients on this study were subsequently randomized to stop therapy or to receive 6 months of 13 cis- retinoic acid.[6] The use of 13 cis-retinoic acid can induce differentiation and growth of neuroblastoma in vitro. Overall, the 3 year event-free survival from the time of the second randomization was 47% for patients receiving 13 cis-retinoic acid and 25% for patients randomized to receive no further therapy. For patients randomized to receive 13 cis-retinoic acid, an apparent advantage in 3 year event-free survival was seen for stage IV patients (40% vs 18%), high-risk stage III patients (77% vs 49%), patients randomized to receive consolidation chemotherapy alone (32% vs 16%), patients randomized to receive autologous bone marrow transplantation (55% vs 39%), and patients with MYCN genomic amplification (39% vs 13%). Based on these results, future clinical trials will build upon autologous stem cell transplantation and cis-retinoic acid for high-risk neuroblastoma.[5,6]

The potential benefit of aggressive surgical approaches to achieve complete tumor resection, either at the time of diagnosis or following chemotherapy, has not been unequivocally demonstrated. Two studies reported that complete resection of the primary tumor at diagnosis improved survival; however, the outcome in these patients may be more dependent on the biology of the tumor than on the extent of surgical resection.[7-9] Consideration should also be given to enrollment of poor-prognosis patients older than 1 year of age in a clinical trial that incorporates new agent testing prior to initiating standard therapy. These studies appear to have no deleterious effect on outcome and have identified ifosfamide, iproplatin, and carboplatin as effective agents in newly diagnosed neuroblastoma.[9]

Treatment options:

1. Intensive conventional chemotherapy, using combinations of cyclophosphamide, doxorubicin, cisplatin, teniposide or etoposide, and vincristine.[2,10-12] Surgery and radiation therapy may be used with chemotherapy, depending on the clinical presentation and course. Post- chemotherapy treatment includes 13 cis-retinoic acid.[5,6]

2. Clinical trials evaluating myeloablative chemotherapy and radiation therapy followed by stem cell reconstitution and 13 cis-retinoic acid.[6,13-16]

3. The use of prolonged isotretinoin treatment following intensive chemotherapy. Neuroblastoma cells in vitro often respond to retinoic acid by differentiation and/or growth inhibition, and several patients treated with retinoic acid have shown prolonged decreases in bone marrow tumor involvement.[6,17] The potential benefit of maintenance therapy with isotretinoin is being tested at CCG institutions, where patients were randomly allocated following their intensive chemotherapy to receive isotretinoin for 6 months or to receive no further therapy.

References:

1. Paul SR, Tarbell NJ, Korf B, et al.: Stage IV neuroblastoma in infants: long-term survival. Cancer 67(6): 1493-1497, 1991.
2. Bowman LC, Hancock ML, Santana VM, et al.: Impact of intensified therapy on clinical outcome in infants and children with neuroblastoma: the St Jude Children's Research Hospital experience, 1962-1988. Journal of Clinical Oncology 9(9): 1599-1608, 1991.
3. Look AT, Hayes FA, Shuster JJ, et al.: Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study. Journal of Clinical Oncology 9(4): 581-591, 1991.
4. Bowman LC, Castleberry RP, Cantor A, et al.: Genetic staging of unresectable or metastatic neuroblastoma in infants: a Pediatric Oncology Group study. Journal of the National Cancer Institute 89(5): 373-380, 1997.
5. Matthay KK, Harris R, Reynolds CP, et al.: Improved event-free survival for autologous bone marrow transplantation (ABMT) vs chemotherapy in neuroblastoma: a phase III randomized Children's Cancer Group (CCG) study. Proceedings of the American Society of Clinical Oncology 17: A2018, 525a, 1998.
6. Reynolds CP, Villablanca JG, Stram DO, et al.: 13-cis-retinoic acid after intensive consolidation therapy for neuroblastoma improves event-free survival: a randomized Childrens Cancer Group (CCG) study. Proceedings of the American Society of Clinical Oncology 17:A5, 2a, 1998.
7. Haase GM, O'Leary MC, Ramsay NK, et al.: Aggressive surgery combined with intensive chemotherapy improves survival in poor-risk neuroblastoma. Journal of Pediatric Surgery 26(9): 1119-1124, 1991.
8. DeCou JM, Bowman LC, Rao BN, et al.: Infants with metastatic neuroblastoma have improved survival with resection of the primary tumor. Journal of Pediatric Surgery 30(7): 937-941, 1995.
9. Shorter NA, Davidoff AM, Evans AE, et al.: The role of surgery in the management of stage IV neuroblastoma: a single institution study. Medical and Pediatric Oncology 24(5): 287-291, 1995.
10. Hartmann O, Pinkerton CR, Philip T, et al.: Very-high-dose cisplatin and etoposide in children with untreated advanced neuroblastoma. Journal of Clinical Oncology 6(1): 44-50, 1988.
11. Kushner BH, LaQuaglia MP, Bonilla MA, et al.: Highly effective induction therapy for stage 4 neuroblastoma in children over 1 year of age. Journal of Clinical Oncology 12(12): 2607-2613, 1994.
12. Pinkerton CR, Zucker JM, Hartmann O, et al.: Short duration, high dose, alternating chemotherapy in metastatic neuroblastoma (ENSG 3C induction regimen). British Journal of Cancer 62(2): 319-323, 1990.
13. Philip T, Zucker JM, Bernard JL, et al.: Improved survival at 2 and 5 years in the LMCE1 unselected group of 72 children with stage IV neuroblastoma older than 1 year of age at diagnosis: is cure possible in a small subgroup? Journal of Clinical Oncology 9(6): 1037-1044, 1991.
14. Matthay KK, Seeger RC, Reynolds CP, et al.: Allogeneic versus autologous purged bone marrow transplantation for neuroblastoma: a report from the Childrens Cancer Group. Journal of Clinical Oncology 12(11): 2382-2389, 1994.
15. McCowage GB, Vowels MR, Shaw PJ, et al.: Autologous bone marrow transplantation for advanced neuroblastoma using teniposide, doxorubicin, melphalan, cisplatin, and total-body irradiation. Journal of Clinical Oncology 13(11): 2789-2795, 1995.
16. Pole JG, Casper J, Elfenbein G, et al.: High-dose chemoradiotherapy supported by marrow infusions for advanced neuroblastoma: a Pediatric Oncology Group study. Journal of Clinical Oncology 9(1): 152-158, 1991.
17. Baker D, Willougby MW, Price JP, et al.: Retinoic acid therapy for poor prognosis neuroblastoma with minimal residual disease. In: D'Angio GJ, Evans AE, Knudson AG, Seeger RC, Eds.: The 5th Symposium on Neuroblastoma Research. Children's Hospital of Philadelphia, 1990, p 119.
18. Shuster JJ, Cantor AB, McWilliams N, et al.: The prognostic significance of autologous bone marrow transplant in advanced neuroblastoma. Journal of Clinical Oncology 9(6): 1045-1049, 1991.
19. Castleberry RP, Cantor AB, Green AA, et al.: Phase II investigational window using carboplatin, iproplatin, ifosfamide, and epirubicin in children with untreated disseminated neuroblastoma: a Pediatric Oncology Group study. Journal of Clinical Oncology 12(8): 1616-1620, 1994.

STAGE IVS NEUROBLASTOMA

Stage IVS ("special") neuroblastoma typically presents in very young infants and has a 2-year survival rate greater than 90%.[1] The International Neuroblastoma Staging System (INSS) has been revised to include, in stage 4S only, infants younger than 1 year of age at diagnosis. Bone marrow disease must also be very limited to qualify for stage 4S (see the Stage Information section above).[2] Stage IVS neuroblastoma has a higher rate of spontaneous regression than other neuroblastomas, often making chemotherapy unnecessary. In specific circumstances, mild chemotherapy may be indicated.

Treatment options:

The treatment of children with stage IVS disease is controversial.[3,4] Children with this special pattern of neuroblastoma may not require therapy, although the development of complications, such as functional compromise from massive hepatomegaly, and is an indication for intervention, especially in infants younger than 2 months of age.[4,5]

Because of the unpredictable clinical course of this entity, these children should be entered into cooperative group studies and observed by a multidisciplinary team of physicians who are prepared to individualize therapy according to the requirements of each case.

References:

1. Nickerson HJ, Nesbit ME, Grosfeld JL, et al.: Comparison of stage IV and IV-S neuroblastoma in the first year of life. Medical and Pediatric Oncology 13(5): 261-268, 1985.
2. Brodeur GM, Pritchard J, Berthold F, et al.: Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. Journal of Clinical Oncology 11(8): 1466-1477, 1993.
3. McWilliams NB: IV-S Neuroblastoma: treatment controversy revisited. Medical and Pediatric Oncology 14(1): 41-44, 1986.
4. Guglielmi M, De Bernardi B, Rizzo A, et al.: Resection of primary tumor at diagnosis in stage IV-S neuroblastoma: does it affect the clinical course? Journal of Clinical Oncology 14(5): 1537-1544, 1996.
5. Hsu LL, Evans AE, D'Angio GJ: Hepatomegaly in neuroblastoma stage 4s: criteria for treatment of the vulnerable neonate. Medical and Pediatric Oncology 27(6): 521-528, 1996.

RECURRENT NEUROBLASTOMA

The prognosis and treatment of recurrent or progressive neuroblastoma depend on the site and extent of the recurrence or progression and on the previous therapy. Recurrence is usually widespread and prognosis poor despite additional intensive therapy.[1] Unlike at initial presentation, central nervous system involvement is common. Most commonly, there is inward compression of the brain from cranial metastases, but meningeal and isolated intracranial metastasis can occur. Early recognition and treatment of central nervous system involvement may result in reduced neurologic impairment. The selection of further treatment depends on many factors, including the site of recurrence and previous treatment as well as individual patient considerations. Clinical trials are appropriate and should be considered.[2-7] Refer to the PDQ Protocol File for ongoing clinical trials for neuroblastoma.

References:

1. Pole JG, Casper J, Elfenbein G, et al.: High-dose chemoradiotherapy supported by marrow infusions for advanced neuroblastoma: a Pediatric Oncology Group study. Journal of Clinical Oncology 9(1): 152-158, 1991.
2. Hayes FA, Green AA: Second complete remission (CR) in children with metastatic neuroblastoma (NB). Proceedings of the American Society of Clinical Oncology 4: C-921, 237, 1985.
3. Philip T, Gentet JC, Carrie C, et al.: Phase II studies of combinations of drugs with high-dose carboplatin in neuroblastoma (800 mg/m2 to 1 g 250/m2): a report from the LMCE group. Progress in Clinical and Biological Research 271: 573-582, 1988.
4. Cheung NK, Lazarus H, Miraldi FD, et al.: Ganglioside GD2 specific monoclonal antibody 3F8: a phase I study in patients with neuroblastoma and malignant melanoma. Journal of Clinical Oncology 5(9): 1430-1440, 1987.
5. Frappaz D, Michon J, Hartmann O. et al.: Etoposide and carboplatin in neuroblastoma: a French Society of Pediatric Oncology phase II study. Journal of Clinical Oncology 10(10): 1592-1601, 1992.
6. Matthay KK, DeSantes K, Hasegawa B, et al.: Phase I dose escalation of 131I-metaiodobenzylguanidine with autologous bone marrow support in refractory neuroblastoma. Journal of Clinical Oncology 16(1): 229-236, 1998.
7. Evans AE, August CS, Kamani N, et al.: Bone marrow transplantation for high risk neuroblastoma at the Children's Hospital of Philadelphia: an update. Medical and Pediatric Oncology 23(4): 323-327, 1994.