Neuroblastoma: Biology and TherapyPublished on Physicians Practice (http://www.physicianspractice.com)

Neuroblastoma: Biology and TherapyReview Article [1] | December 01, 1997By Katherine K. Matthay, MD [2]

Neuroblastoma is the most common extracranial solid tumor of childhood, accounting for 15% ofcancer-related deaths. These tumors have a predilection for young children; 60% of cases occurbefore age 2 years and 97%

ABSTRACT: Neuroblastoma is the most common extracranial solid tumor of childhood,accounting for 15% of cancer-related deaths. These tumors have a predilection for youngchildren; 60% of cases occur before age 2 years and 97% before age 10. Neuroblastomasderive from embryonic neural crest cells of the peripheral sympathetic nervous system.The behavior of this malignancy is characterized by marked clinical heterogeneity,ranging from spontaneous maturation in some patients to inexorable rapid metastaticprogression in others. This article will discuss some of the molecular and biologicalfeatures of neuroblastoma that are associated with these differences in behavior, andhow these features have been used to develop a risk-based approach to therapy.[ONCOLOGY 11(12):1857-1866, 1997]

Introduction

Approximately 500 cases of neuroblastoma are diagnosed annually in the United States. Overallincidence from birth to age 15 is 8.7 cases per million per year. The disease has a strikingpredilection for young children; 60% of cases occur before age 2 years and 97% before age 10.Thus far, no definite environmental risk factors have been determined, although single studies havesuggested a possible increased risk from maternal exposure to alcohol, neurally active drugs,diuretics, and hair coloring and from paternal exposure to electromagnetic fields.The clinical behavior of neuroblastoma varies markedly, ranging from spontaneous maturation insome patients to inexorable rapid metastatic progression in others. This article will explore some ofthe molecular and biological features of neuroblastoma that are associated with these differences inbehavior and the use of these features to develop a risk-based approach to therapy.

Molecular Genetics and Cellular Markers

Chromosome Abnormalities

Deletion of the distal short arm of chromosome 1 was the first described genetic mutation inneuroblastoma tumors and is the most consistently reported abnormality.[1,2] Cytogenetic analysisof near-diploid neuroblastoma tumors and cell lines shows deletion of the distal short arm ofchromosome 1 in 70% of cases. This deletion is found more frequently in patients with advanceddisease and a poor prognosis. However, due to the technical difficulties inherent in karyotyping solidtumors, fewer patients with low-stage disease have been examined, although those tested havelacked the abnormality.To eliminate the need for karyotyping, Fong et al studied DNA by comparing constitutional(lymphocyte) DNA to tumor DNA. They identified loss of heterozygosity at one or more loci onchromosome 1 in 13 of 47 tumors and showed, again, that this abnormality correlates withadvanced, poor-prognosis disease.[1] Subsequent investigation revealed frequent deletions onchromosome 11 and chromosome 14, as well as rearrangements on chromosome 17.[3]More recent screening studies for abnormalities of chromosome number have used comparativegenomic hybridization. This technique summarizes DNA copy number abnormalities by mappingthem to their positions on normal metaphase chromosomes, based on simultaneous hybridization oftumor and normal DNA labeled in different colors to normal metaphase spreads. The ratio of tumorto normal fluorescence intensities along the target chromosomes indicates relative increases anddecreases in DNA copy number throughout the entire tumor genome. In a preliminary study of 29cases from the Children’s Cancer Group (CCG), Plantaz et al showed that chromosome 17 gains were

Page 1 of 12

Neuroblastoma: Biology and TherapyPublished on Physicians Practice (http://www.physicianspractice.com)

the most frequent abnormality in neuroblastoma, seen ingreater than 70% of cases.[4]

MYCN Amplification

One of the other intriguing abnormalities found in neuroblastoma tumors, which has been shown tocorrelate very strongly with outcome, is MYCN amplification, which is found in about 30% of tumors.The MYCN proto-oncogene is derived from the c-myc viral oncogene and is located on the distal armof chromosome 2. The finding of MYCN amplification correlates with the cytogenetic abnormalities ofdouble minutes (small extrachromosmal amplifi- fications of MYCN DNA) and homogeneouslystaining regions (regions of MYCN-amplified DNA that can be integrated into any otherwise normalchromosome). FIGURE 1

Fluorescence in situ hybridization

Amplification of MYCN has now been shown to correlate very closely with advanced-stage diseaseand, within each stage, to be highly predictive of outcome.[5] MYCN may now readily be determinedby traditional Southern blot DNA analysis, the technique of fluorescence in situ hybridization (FISH; Figure 1), immunostaining of tissues for protein expression, and the sensitive polymerase chainreaction (PCR), as well as by comparative genomic hybridization.[4-7]Other genes commonly implicated in cancers, such as the ras family of p53, have not beencommonly affected in neuroblastoma tumors.

Ploidy

Chromosomal ploidy is another marker of prognosis that has proved to be particularly useful ininfants less than 18 months of age. Near-diploid or pseudodiploid tumors have near-normal nuclearDNA content but often have structural chromosomal aberrations, including MYCN amplification. Incontrast, hyperdiploid or near-triploid tumors are most common in infants who have tumors that lack1p deletion or MYCN amplification and have an excellent prognosis. A small subset of infants withdiploid tumors have a much poorer prognosis than those with hyperdiploidy.[8]

Cellular Markers of Differentiation

Several cellular markers of differentiation along neuronal pathways have been shown to haveprognostic importance in neuroblastoma, suggesting that the malignant transformation of these cellsmay result, in part, from inadequate response to the usual inducers of neuronal differentiation.Investigations have demonstrated abnormalities in the nerve growth factor receptors inneuroblastoma cell lines. These studies have shown a significant correlation between the increasedexpression of high-affinity nerve growth factor receptor (gp140TRK-A) and tumors with single-copy MYCN and a favorable outcome, as well as a correlation between lack of expression of the nervegrowth factor receptors and both MYCN amplification and poor survival.[9]

Telomerase

Another determinant of malignant progression may be telomerase, an RNA-protein complex thatprevents cell senescence by maintaining chromosomal telomeres. Telomerase is expressed innormal germ-line but not most somatic cells, and it appears to be necessary for immortalization ofmalignant cells.Telomerase activity has recently been reported to correlate with both MYCN amplification and stagein neuroblastoma.[10] We have now examined a large group of primary neuroblastomas for RNAlevels of telomerase and have shown correlations with both stage and event-free survival, with

Page 2 of 12

Neuroblastoma: Biology and TherapyPublished on Physicians Practice (http://www.physicianspractice.com)

poorer event-free survival in patients whose tumors show higher telomerase expression.[11]

Prognostic Factors and Risk Groups

TABLE 1

Clinical Factors in Neuroblastoma Analyzed Singly

In addition to the many molecular genetic determinants of malignant progression, many moregeneral laboratory, pathologic, and clinical markers have been shown to correlate with prognosis(Table 1). Shimada has developed a powerful classification system that combines age withhistopathologic grading (based on the amount of neural stroma), mitotic-karyorrhectic index, anddifferentiation, as well as diffuse vs nodular appearance. This prognostic classification, whichappears to be independent of MYCN amplification, has been verified in both retrospective andprospective CCG studies.[12,13]A number of serum markers have also shown to be prognostic for outcome, probably because, inpart, they are surrogate markers of tumor burden. These include serum levels of lacticdehydrogenase (LDH), ferritin, GD2 ganglioside, and chromogranin.The most important clinical risk factors are disease stage and age at diagnosis, with age less than 1year conferring the most favorable prognosis. Other clinical risk factors that may have some adverseimportance include bone metastases, bone marrow metastases, and primary site in the abdomen (asopposed to the more favorable sites of the pelvis or thorax).[2,14-18]

Screening and Diagnosis

Given the high incidence of neuroblastoma in infancy, newborn urinary screening forcatecholamines, excreted in 80% to 90% of cases, has been suggested as a cost-effective way todetect this tumor. Interestingly, the results of screening at birth and 6 months reported thus farsuggest that most of the cases detected by this method are biologically favorable tumors with a highrate of spontaneous regression. Although screening has revealed an increased incidence in infancy,the survival or stage distribution of cases in children over age 1 year is not substantially affected,suggesting that this method does not detect the more malignant tumors at an early stage.[2]Approximately half of children who present with neuroblastoma already have disseminated disease.The most common symptoms are pain due to either primary tumor or to bone and bone marrowinvolvement, an abdominal mass, weight loss, anorexia, and irritability. Metastases to the orbit arecommon with resulting proptosis, while mediastinal primaries may be accompanied by Horner’ssyndrome. Rare presentations of neuroblastoma due to paraneoplastic phenomena include secretory

Page 3 of 12

Neuroblastoma: Biology and TherapyPublished on Physicians Practice (http://www.physicianspractice.com)

diarrhea (due to secretion of vasoactive intestinal peptide) or opsoclonus, myoclonus, and ataxia(which is possibly due to cross-reacting antineuronal antibodies elicited by the tumor, which causeacute cerebellar encephalopathy and result in this syndrome in about 3% of patients).Primary tumors arise in the abdomen in 70% of patients, often in the adrenal gland and next mostfrequently in the chest. Bone marrow and bone are the most common sites of metastases, while lungand central nervous system metastases are very rare (less than 5%).[2] TABLE 2

Clinical Evaluation of Neuroblastoma

Diagnostic evaluation of neuroblastoma requires tissue for both diagnosis and prognosis, sincehistologic grading, as well as molecular genetic studies, are essential for management decisions.Urinary catecholamine determinations and serum ferritin and LDH levels are useful both in assessingprognosis and as a baseline for disease monitoring (Table 2).Metastatic and staging evaluation includes, at a minimum, a computed tomographic (CT) ormagnetic resonance imaging (MRI) scan of the primary, bone scan, bilateral bone marrow aspirateand biopsy, and, optimally, an iodine-123- or iodine-131-metaiodobenzylguanidine (MIBG) scan(Table 2). Meta-iodobenzylguanidine is a derivative of guanethidine, similar in structure tonorepinephrine, that specifically concentrates in neuroblastoma and pheochromocytoma. It is 90%sensitive for tumor detection, and has the advantage of imaging equally well in soft-tissue, bone,and bone marrow tumors, with no uptake in normal bone, thus preventing the confusion with normalepiphyses that can occur with technetium scans.[19,20] Additional sensitivity for bone marrowmetastases can be achieved with immunocytologic testing using either immunofluorescence orimmunoperoxidase stain, which can detect as little as 0.001% tumor infiltration, includingunsuspected bone marrow tumor in patients with otherwise low-stage disease.[21,22]

Staging Systems

TABLE 3

International Neuroblastoma Staging System

Several different staging systems have been used to help plan treatment for neuroblastoma: (1) theoriginal and widely used classification of Evans, also used by the CCG; (2) the St. Jude Children'sResearch Hospital system, now revised and utilized by the Pediatric Oncology Group (POG); and (3)the International Union Against Cancer (UICC) tumor-node-metastasis (TNM) system. All threesystems have prognostic value. An international consensus group has arrived at a new synthesis ofthese systems, the International Neuroblastoma Staging System (INSS; see Table 3). Theinternational system is being tested further prospectively in order to facilitate internationalcomparisons of treatments.[19,20]

Risk-Based Therapy

Risk Classification

TABLE 4

Page 4 of 12

Neuroblastoma: Biology and TherapyPublished on Physicians Practice (http://www.physicianspractice.com)

Risk Groups for Neuroblastoma

Treatment of neuroblastoma must be tailored to both the extent of disease and the biological riskcharacteristics. A working division into risk groups, shown in Table 4, categorizes patients into threegroups requiring different treatment intensities.Further study using multivariate analysis may result in greater refinement of a combined anatomicand biological staging system. However, the current working classification used by the CCG hassucceeded in identifying those children who have an excellent prognosis when given little or notherapy and those who have a guarded prognosis even with very aggressive treatment.

Low-Risk Group

The low-risk group is comprised of patients with INSS stage 1, 2, or 4s disease and usually favorablebiological characteristics. These patients require minimal therapy, usually surgery alone, unless theyhave local disease-related symptoms, such as cord compression from a paraspinal tumor orrespiratory distress from liver infiltration by a tumor in the intraventricular system (Figure 2). FIGURE2

Infant with stage 4s neuroblastoma

Both retrospective and now prospective studies have confirmed that surgery alone is sufficienttherapy for stage 1 and 2 neuroblastoma. A retrospective CCG analysis showed that the survival rateamong patients with stage 2 disease was greater than 90% regardless of measurable postoperativeresidual tumor.[15] This has been confirmed in prospective studies conducted by both the POG andCCG.The overall survival rate for more than 200 children with stage 2 disease treated with initial surgicalmanagement is greater than 95% regardless of other biological features, with only 13% of patientsrequiring any chemotherapy for symptoms. Even the 15% of patients who have a local tumorrecurrence after surgery can usually be treated effectively with moderate-intensity chemotherapy or

Page 5 of 12

Neuroblastoma: Biology and TherapyPublished on Physicians Practice (http://www.physicianspractice.com)

local radiation.[unpublished CCG data]Neither radiation nor chemotherapy has been shown to contribute to survival in the low-risk group asa whole. The only exceptions are children over 1 year old at diagnosis who have stage 2 disease withtumor MYCN amplification. In previous studies, these children showed rapid progression anddissemination without aggressive therapy; therefore, it is now recommended that they receive veryaggressive therapy on the treatment protocols for high-risk patients.Children with stage 4s neuroblastoma also had a 90% overall 3-year survival in the most recentlycompleted CCG study, CCG-3881. However, approximately half of these children required a shortcourse of chemotherapy with cyclophosphamide (Cytoxan, Neosar), and some received hepaticirradiation for respiratory distress. The rare patient with MYCN amplification progressed rapidly, andtherefore, will be treated as a high-risk patient in the future.[23,24]

Intermediate-Risk Group

The recently completed CCG-3881 study for intermediate-risk patients treated all infants with stage3 disease; children over 1 year old with stage 3 disease and favorable Shimada classification, normalferritin (less than 143 ng/mL), and single-copy MYCN; and infants with stage 4 disease andnonamplified MYCN with a 9-month course of chemotherapy, surgery, and local radiation to residualdisease. The 3-year event-free survival rate for the stage 3 patients was 96%. Event-free survival didnot differ between the infants and the children greater than 1 year old with favorable-biologytumors, nor between the infants with unfavorable biological features and those with no unfavorablebiological features.In the past, the subset of stage 3 patients greater than1 year old at diagnosis had an event-freesurvival of only 30% to 40%. In CCG-3881, stage 4 infants had a 75% 3-year event-free survivaloverall, but if only patients with known nonamplified MYCN were considered (N = 72), the 3-yearevent-free survival was 95%.The excellent outcome for these intermediate-risk patients has led to the goal of decreasing cost andlate sequelae in this group by decreasing the overall cumulative dose and duration of therapywithout compromising dose intensity. Thus, in the next intermediate-risk protocol (a combined effortof the CCG and POG), patients will be treated with only four cycles (12 weeks) of combinationchemotherapy, all administered in the outpatient setting; the only exception will be children witheither unfavorable Shimada classification or diploidy, who will receive eight cycles. The stage 3 and 4patients with MYCN amplification will be considered high risk regardless of age, and will be treatedon a different protocol.[16,23,24]

High-Risk Disease

FIGURE 3

Historical comparison of survival

The high-risk group consists mainly of patients with stage 4 disease who are greater than 1 year oldat diagnosis, but also includes the following subgroups: stage 3 children greater than1 year old witheither MYCN amplification or unfavorable Shimada features; stage 2 patients greater than 1 yearwith MYCN amplification; and stage 3, 4, and 4s infants with MYCN amplification. These patientscontinue to respond poorly even to very dose-intensive therapy, although incremental advanceshave certainly been made over the past decade.As shown in Figure 3, the 4-year survival rate among the 507 stage 4 patients greater than 1 yearold who were treated in the CCG studies from 1978 to 1985 was 9%, as compared with a rate of 30%among the 675 patients treated from 1991 to 1995 (P < .001).[24] Some of this improvement maybe attributable to increases in the dose intensity of therapy; a meta-analysis by Cheung and

Page 6 of 12

Neuroblastoma: Biology and TherapyPublished on Physicians Practice (http://www.physicianspractice.com)

co-workers has shown an effect of dose intensity in neuroblastoma similar to that reported in othercancers.[25] The improvement may also be the result of the increasing use of high-dosemyeloablative therapy with autologous or allogeneic bone marrow transplantation (BMT).[26-33]Nonrandomized Studies—Between 1988 and 1993, the CCG completed three concurrent studiesof high-risk neuroblastoma: CCG-321P1, which tested allogeneic BMT; CCG-321P2, 1 year ofchemotherapy; and CCG-321P3, autologous purged BMT. All three studies treated patients with fiveto six cycles of induction chemotherapy consisting of cisplatin (Platinol), doxorubicin,cyclophosphamide, and etoposide (VePesid). After undergoing surgery for local control and receivingirradiation to residual disease sites, patients received ablative chemotherapy and total-bodyirradiation (TBI) with BMT or were continued on four-drug induction chemotherapy for a total of 13cycles.Several important conclusions can be drawn from these nonrandomized studies:1. Allogeneic BMT was not shown to be superior to autologous purged BMT and, in fact, had a highertoxic death rate and an equal relapse rate.[29]2. With a median follow-up of 5 years, the event-free survival at 5 years from the time of autologousBMT for 147 patients is 37%. FIGURE 4

Event-free survival

3. In a retrospective nonrandomized comparison of all of the stage 4 patients who continued toreceive chemotherapy vs those who went on to receive purged autologous BMT, the event-freesurvival rate was significantly better for those receiving autologous BMT (40% vs 19%; Figure 4).[18]This retrospective analysis involved 207 children greater than 1 year at diagnosis with stage 4neuroblastoma treated on CCG protocol 321P2 (described above). By the end of five to sevencourses of chemotherapy, 159 patients were event-free; 67 of these patients went on to receiveautologous BMT, while 74 continued chemotherapy for a total of 1 year. The relative risk of an eventafter autologous BMT was only 58% of that with chemotherapy (P = .01). An even more significantadvantage for autologous BMT was seen among patients who were only in partial, as opposed tocomplete, remission at the end of induction and for those who with tumor MYCN amplification.Other Comparisons of Autologous BMT and Chemotherapy—Previous smaller studiescomparing autologous marrow transplantation to chemotherapy had yielded conflicting results, withPinkerton reporting the only randomized trial showing a significant improvement with autologousBMT.[32] This report included a total of only 65 patients, however.A retrospective comparison by the POG of 116 patients achieving complete or partial remission didnot show any significant difference in outcome for the 32 patients who underwent BMT prior toprogression.[34] The Study Group of Japan reported a 50% event-free survival rate in anonrandomized group of patients given myeloablative therapy with autologous BMT, as comparedwith a 39% rate in those who received chemotherapy.[31]Overall, autologous BMT appears to be at least as effective as intensive chemotherapy and mayprovide an advantage in some extremely high-risk subgroups. However, a definitive conclusioncannot be made until the results of a recently completed CCG randomized prospective trialcomparing outcomes among unselected high-risk patients from the time of diagnosis becomeavailable.Another ongoing phase I dose-escalation study of a non-TBI-containing myeloablative regimen hasthus far shown event-free survival comparable to that seen in the previous 321P3 study (55% at 2years from autologous BMT). This phase I study has further verified the earlier suggestion fromKushner and co-workers[28] that higher-dose local irradiation to tumor sites may prevent primarysite relapse, a common problem in previous CCG protocols. However, the relapse rate for patientstransplanted after first disease progression has continued to be high; the current event-free survivalrate at 2 years post-transplantation is only 15%. This is similar to the poor outcome observed inEuropean studies, as reported by Ladenstein and colleaguesl.[27]

Page 7 of 12

Neuroblastoma: Biology and TherapyPublished on Physicians Practice (http://www.physicianspractice.com)

Recently Completed and Ongoing Trials

CCG Trial in High-Risk Disease

The most recently completed CCG trial in high-risk disease was designed to answer, in a prospective,randomized fashion, the relative importance of ablative therapy with purged autologous BMT vsintensive consolidation. The study accrued 550 high-risk patients in 4-1/2 years, with approximatelyone-third of patients randomized to each arm and the other one-third nonrandomly assigned toconsolidation chemotherapy if they refused to be randomized. A second randomization, done at theend of chemotherapy consolidation or autologous BMT, assigned patients to receive or not to receive6 months of 13-cis-retinoic acid (isotretinoin [Accutane]). In vitro and some in vivo studies havereported this differentiating agent to have efficacy against neuroblastoma.The outcome of this study, still blinded for analysis, will help determine the future role ofmyeloablative therapy, as well as the potential utility of differentiating agents, in high-riskneuroblastoma. Current and future studies will examine repetitive stem-cell transplants, moreintensive induction therapies, and the use of alternative stem-cell sources.

Source and Purity of Stem Cells for Ablative Therapy

The source and purity of the stem cells used for ablative therapy in neuroblastoma have been thefocus of concern. Immunocytology techniques have shown that as many as 70% of patients havebone marrow tumor at diagnosis and 50% have circulating tumor cells in peripheral blood. Even afterseveral cycles of induction chemotherapy, 25% of patients still have some detectable tumor by bonemarrow immunocytology and 7% have circulating tumor cells.[22]Such cells in bone marrow have the potential for tumorigenicity. This has been inferred from studiesshowing the development of tumor cell lines from harvested bone marrow and by reports of miliarylung metastases following autologous BMT,[35] and has been demonstrated more definitively by thegene-marking studies of Rill and co-workers.[36] In these gene-marking studies, autologousunpurged but histologically tumor-free marrow was transfected with the neomycin resistance geneand then reinfused into patients, some of whom subsequently relapsed with neuroblastoma tumorsexpressing the marker.More recently, testing of peripheral blood stem-cell collections and bone marrow with PCR hasconfirmed the problem of contamination with tumor cells, even in CD34-selected preparations. Thesignificance of such low-level contamination is still undetermined but will be examined in futurestudies. Such contamination suggests the need for effective methods to purge both peripheral bloodstem cells and bone marrow prior to reinfusion.[37]

Novel Therapeutic Approaches for Metastatic Disease

Dose-intensive therapy, with or without stem-cell support, is rapidly approaching the limits oftoxicity, both in terms of acute and late effects. Novel approaches that are more tumor-specific andless toxic are required to make further progress in metastatic neuroblastoma. Approaches underinvestigation that show some promise in the laboratory and in preliminary phase I and II studiesinclude immunologic modulators, including tumor-specific antibody, antibody given withgran_ulocyte colony-stimulating factor (GM-CSF, filgrastim [Neupogen]) or interleukin-2 (IL-2[Leukine]), fusion proteins of antibody with cytokines, and tumor vaccines; tumor-targeted therapyutilizing radiolabeled antibody or MIBG; and tumor-differentiating agents.

Immunologic Modulators

Phase I and II studies of anti-GD2 antibodies have shown some modest antitumor efficacy in patientswith relapsed neuroblastoma.[38,39] Both the murine monoclonal 3F8 and 14G2a (murine), thelatter tested with IL-2 and with GM-CSF, have shown some tumor responses, as well as in vitrostimulation of antibody-dependent cellular cytotoxicity (ADCC). More recently, Yu and co-workershave completed a phase II trial of the human chimeric anti-GD2 antibody, CH14.18 with GM-CSF,which again shows some responses, most frequently in bone marrow tumor.[40]

Targeted Therapy

Targeted therapy using antibody or MIBG for the delivery of radiation in the form of iodine-131 hasalso been tested in clinical trials. Cheung and co-workers have documented responses toiodine-131-3F8 among patients with refractory neuroblastoma,[41] and are currently conducting a

Page 8 of 12

Neuroblastoma: Biology and TherapyPublished on Physicians Practice (http://www.physicianspractice.com)

study in which newly diagnosed patients are receiving iodine-131-3F8 in ablative doses followed bybone marrow rescue, with further treatment with cold antibody post-transplant.Iodine-131-MIBG has been widely tested in Europe for refractory neuroblastoma and, more recently,for initial therapy in patients with regional disease. We have conducted a phase I dose escalationtrial of iodine-131-MIBG at the University of California (San Francisco) and have determined themaximal non-marrow-ablative dose and the maximal practical ablative dose with stem-cellrescue.[42] In 30 patients, we observed a 37% response rate and no significant toxicity other thanhematologic effects. Future studies will utilize combinations of ablative chemotherapy withiodine-131-MIBG.

Differentiating Agents

Differentiating agents are another approach for circumventing the undesirable effects of cytotoxicagents. For many years, laboratory studies have shown the capacity for either spontaneous orinduced differentiation and growth arrest of neuroblastoma cell lines in culture.Currently, various derivatives of retinoic acid are the differentiating compounds in clinical testing.One such derivative, 13-cis-retinoic acid, has been reported to cause remissions in refractorypatients, and a recently completed phase II trial showed a 10% response rate in relapsedneuroblastoma.[43-45] The recently completed randomized CCG-3891 study randomized all patientsat the end of consolidation therapy to receive 13-cis-retinoic acid or no further therapy; results ofthis trial are pending.Other retinoids currently in phase I investigation include all-trans-retinoic acid (ATRA [Vesanoid])combined with interferon-alfa (Intron A, Roferon-A), 9-cis-retinoic acid, and fenretinide, anotheranalog that causes growth arrest and apoptosis in vitro, even in cell lines shown to be resistant totrans-retinoic acid.

Conclusions

Substantial advances are occurring in the elucidation of the molecular pathogenesis ofneuroblastoma, as well as in the definition of clinical prognostic groups. In addition, modest butsignificant improvements in the treatment of metastatic disease have been achieved by increasingdose intensity with the use of hematopoietic support. However, in order to overcome chemotherapyresistance, new therapeutic approaches are required using tumor-targeting, differentiating, orapoptotic agents; stimulation of host immune response; or genetic manipulation. References: 1. Fong C, Dracopoli NC, White PS et al: Loss of heterozygosity for the short arm of chromosome 1 inhuman neuroblastomas: Correlation with N-myc amplification. Proc Natl Acad Sci USA 86:3753-3757,1989.

2. Matthay KK: Neuroblastoma in, Pochedly C (ed): Neoplastic Diseases in Childhood, pp 725-768.Chur, Switzerland, Harwood Academic, 1994.

3. Suzuki T, Yokota J, Mugishima H, et al: Frequent loss of heterozygosity on chromosome 14q inneuroblastoma. Cancer Res 49:1095-1098, 1989.

4. Plantaz D, Mohapatra G, Matthay KK, et al: Gain of the chromosome 17 is the most frequentabnormality detected in neuroblastoma by CGH. Am J Pathol 150:1-9, 1997.

5. Seeger RC, Brodeur GM, Sather H, et al: Association of multiple copies of the N-myc oncogene withrapid progression of neuroblastomas. N Engl J Med 313:1111-1116, 1985.

6. Shapiro DN, Valentine MB, Rowe ST, et al: Detection of N-myc gene amplification by fluorescencein situ hybridization: Diagnostic utility for neuroblastoma. Am J Pathol 142:1339-1346, 1993.

7. Crabbe DCG, Peters J, Seeger RC: Rapid detection of MYCN gene amplification in neuroblastomasusing the polymerase chain reaction. Diag Mol Path 1:229-234, 1993.

8. Look AT, Hayes FA, Schuster JJ, et al: Clinical relevance of tumor cell ploidy and N-myc gene

Page 9 of 12

Neuroblastoma: Biology and TherapyPublished on Physicians Practice (http://www.physicianspractice.com)

amplification in childhood neuroblastoma: A Pediatric Oncology Group study. J Clin Oncol 9:581-591,1991.

9. Suzuki T, Bogenmann E, Shimada H, et al: Lack of high affinity nerve growth factor receptors inaggressive neuroblastomas. J Natl Cancer Inst 85:377-384, 1993.

10. Hiyama E, Hiyama K, Yokoyama T, et al: Correlating telomerase activity levels with humanneuroblastoma outcomes. Nature Med 1(3):249-255, 1995.

11. Reynolds CP, Zuo JJ, Wang H, et al: Telomerase in primary neuroblastomas. Prog Clin Biol Res,1997 (in press).

12. Shimada H, Stram DO, Chatten J, et al: Identification of subsets of neuroblastomas by combinedhistopathologic and N-myc analysis. J Natl Cancer Inst 87:1470-1476, 1995.

13. Chatten J, Shimada H, Sather HN, et al: Prognostic value of histopathology in advancedneuroblastoma: A report from the Childrens Cancer Study Group. Hum Pathol 19:1187-1198, 1988.

14. Haase GM, O’Leary MC, Stram DO, et al: Pelvic neuroblastoma: Implications for a new favorablesubgroup: A Childrens Cancer Group experience. Ann Surg Oncol 2:516-523, 1995.

15. Matthay KK, Sather HN, Seeger RC, et al: Excellent outcome of stage II neuroblastoma isindependent of residual disease and radiation therapy. J Clin Oncol 7:236-244, 1989.

16. Matthay K, Seeger R, Haase G, et al: Treatment and outcome for stage III neuroblastoma basedon prospective biologic staging. Med Pediatr Oncol 23:173, 1994.

17. Matthay KK, Lukens J, Stram D, et al: Prognosis for stage IV neuroblastoma less than one year atdiagnosis: A prospective Childrens Cancer Group Study. Proc Am Soc Clin Oncol 14:446, 1995.

18. Stram DO, Matthay KK, O’Leary M, et al: Consolidation chemoradiotherapy and autologous bonemarrow transplantation vs continued chemotherapy for metastatic neuroblastoma: A report of twoconcurrent Children’s Cancer Group studies. J Clin Oncol 14:2417-2426, 1996.

19. Brodeur GM, Seeger RC, Barrett A, et al: International criteria for diagnosis, staging, andresponse to treatment in patients with neuroblastoma. J Clin Oncol 6:1874-1881, 1988.

20. Brodeur GM, Pritchard J, Berthold F, et al: Revisions of the international criteria forneuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 11:1466-1477, 1993.

21. Moss TJ, Reynolds CP, Sather HN, et al: Prognostic value of immunocytologic detection of bonemarrow metastases in neuroblastoma. N Engl J Med 324:219-226, 1991.

22. Matthay KK, Reynolds CP, Stram DO, et al: Quantitative tumor cell content of bone marrow andblood as an early predictor of response in high risk neuroblastoma: A CCG study (abstraact1844). Proc Am Soc Clin Oncol 16:512a, 1997.

23. Haase GM, Atkinson JB, Stram DO, et al: Surgical management and outcome in non-metastaticneuroblastoma: Comparison of the Childrens Cancer Group and the International Staging Systems. JPediatr Surg 30:289-295, 1995.

24. Matthay K, Lukens J, Stram D, et al: Improving survival from 1978-1995 using risk basedtreatment for neuroblastoma: Children’s Cancer Group (CCG). Med Pediatr Oncol 27:220, 1996.

25. Cheung NKV, Heller G: Chemotherapy dose intensity correlates strongly with response, mediansurvival, and median progression-free survival in metastatic neuroblastoma. J Clin Oncol 1050-1058,1991.

26. Graham-Pole J, Casper J, Elfenbein G, et al: High-dose chemoradiotherapy supported by marrow

Page 10 of 12

Neuroblastoma: Biology and TherapyPublished on Physicians Practice (http://www.physicianspractice.com)

infusions for advanced neuroblastoma: A Pediatric Oncology Group study. J Clin Oncol 9:152-158,1991.

27. Ladenstein R, Lasset C, Hartmann O, et al: Impact of megatherapy on survival after relapse fromstage 4 neuroblastoma in patients over 1 year of age at diagnosis: A report from the European Groupfor Bone Marrow Transplantation. J Clin Oncol 11:2230-2341, 1993.

28. Kushner BH, O’Reilly RJ, Mandell LR, et al: Myeloablative combination chemotherapy without totalbody irradiation for neuroblastoma. J Clin Oncol 9:274-279, 1991.

29. Matthay KK, Seeger RC, Reynolds CP, et al: Allogeneic vs autologous purged bone marrowtransplantation for neuroblastoma. J Clin Oncol 12:2382-2389, 1994.

30. Matthay KK, Stram DO, Selch ME, et al: Patterns of relapse after autologous purged bone marrowtransplantation for neuroblastoma: A Childrens Cancer Group Study. J Clin Oncol 11:2226-2233,1993.

31. Ohnuma N, Takahashi H, Kaneko M, et al: Treatment combined with bone marrow transplantationfor advanced neuroblastoma: An analysis of patients who were pretreated intensively with theprotocol of the Study Group of Japan. Med Pediatr Oncol 24:181-187, 1995.

32. Pinkerton CR: ENSG 1 randomized study of high-dose melphalan in neuroblastoma. Bone MarrowTransplant 3(suppl):112-113, 1991.

33. Philip T, Zucker JM, Bernard JL, et al: Improved survival at 2 and 5 years in the LMCE1 unselectedgroup of 72 children with stage IV neuroblastoma older than 1 year of age at diagnosis: Is curepossible in a small subgroup? J Clin Oncol 9:1037-1044, 1991.

34. Schuster JJ, Cantor AB, McWilliams N, et al: The prognostic significance of autologous bonemarrow transplant in advanced neuroblastoma. J Clin Oncol 9:1045-1049, 1991.

35. Kalra R, Zoger S, Matthay KK: Miliary spread of neuroblastoma: Radiological case of the month. Arch Pediatr Adolesc Med 149:194-195, 1995.

36. Rill DR, Santana VM, Roberts M, et al: Direct demonstration that autologous bone marrowtransplantation for solid tumors can return a multiplicity of tumorigenic cells. Blood 84:380-383,1994.

37. Reynolds CP, Seeger RC, Vo DD, et al: Model system for removing neuroblastoma cells from bonemarrow using monoclonal antibodies and magnetic immunobeads. Cancer Res 46:5882-5886, 1986.

38. Frost JD, Hank JA, Reaman GH, et al: A phase I/IB trial of murine monoclonal anti-GD2 antibody‘14.G2a plus interleukin-2 in children with refractory neuroblastoma: A report of the ChildrenÕsCancer Group. Cancer 80:317-33, 1997.

39. Handgretinger R, Anderson K, Lang P, et al: A phase I study of human/mouse chimericantiganglioside GD2 antibody ch14.18 in patients with neuroblastoma. Eur J Cancer 31A:261-267,1995.

40. Yu AL, Batova A, Avarado C, et al: Usefulness of a chimeric anti-GD2 (Ch 14-18) and GM-CSF forrefractory neuroblastoma: A POG phase II study (abstract). Proc Am Soc Clin Oncol 16:513a, 1997.

41. Cheung NK, Kushner BH, Yeh SJ, et al: 3F8 monoclonal antibody treatment of patients with stageIV neuroblastoma: A phase II study. Prog Clin Biol Res 385:319-328, 1994.

42. Matthay KK, Desantes K, Hasegawa B, et al: Phase I dose escalation of131I-metaiodo-benzylguanidine (MIBG) with autologous bone marrow support in refractoryneuroblastoma. J Clin Oncol in press, 1997.

Page 11 of 12

Neuroblastoma: Biology and TherapyPublished on Physicians Practice (http://www.physicianspractice.com)

43. Villablanca JG, Khan AA, Avramis VI, et al: Phase I trial of 13-cis-retinoic acid in children withneuroblastoma following bone marrow transplantation. J Clin Oncol 134:894-901, 1995.

44. Reynolds CP, Kane DJ, Einhorn PA, et al: Response of neuroblastoma to retinoic acid in vitro andin vivo. Prog Clin Biol Res 366:203-211, 1991.

45. Finklestein JZ, Krailo MD, Lenarsky C, et al: 13-Cis-retinoic acid in the treatment of children withmetastatic neuroblastoma unresponsive to conventional chemotherapy: Report from the ChildrensCancer Study Group. Med Pediatr Oncol 20:307-311, 1992.

Source URL: http://www.physicianspractice.com/neuroblastoma-biology-and-therapy

Links:[1] http://www.physicianspractice.com/review-article[2] http://www.physicianspractice.com/authors/katherine-k-matthay-md

Page 12 of 12