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Current Management of Neuroblastoma

The University College London Hospitals and Great Ormond Street Hospital for Children, London, United Kingdom

Correspondence: Mark N. Gaze, M.D., F.R.C.P., Ed., F.R.C.R., The Meyerstein Institute of Oncology, The Middlesex Hospital, Mortimer Street, London, W1N 8AA, United Kingdom. Telephone: +44-171-636-8333, ext. 4348; Fax: +44-171-436-0160.

	Abstract

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Neuroblastoma is one of the more common pediatric cancers. Although there have undoubtedly been major advances in therapy over recent decades, there is still room for significant improvements in outcome to be made. Neuroblastoma is a disease with a variable outlook, encompassing a spectrum—from patients with disease which may undergo spontaneous regression, through those who may be cured with limited treatment, to others whose disease is refractory even to the most aggressive management strategies. Great progress has been made toward understanding the basic biology of the disease, which allows reliable allocation of individual patients to good, intermediate, or poor prognostic groups and aids selection of appropriate therapeutic approaches. Unfortunately, attempts to improve the outcome of patients with adverse prognostic factors have been less effective.

This paper reviews the clinical and biological features of neuroblastoma which determine outcome, and outlines current management policies. Some experimental approaches involving translational research which seek to exploit the unique biology of neuroblastoma are discussed. Although currently unproven, such new treatments are undergoing clinical evaluation and may yet offer new hope for patients with this enigmatic disease.

Key Words. Bone marrow transplantation • Chemotherapy • Neuroblastoma • Prognostic factors • Radiation therapy • Targeted radionuclide therapy

	Introduction

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Neuroblastoma, the most common extracranial solid tumor of childhood, is an embryonal tumor of the sympathetic nervous system. It accounts for about 7%-8% of all pediatric malignant disease [1]. It is the most common tumor in infancy and becomes less frequent in each succeeding year. About half the cases occur under the age of three years. Neuroblastoma in adult life is well recognized but very rare. The male:female ratio is equal.

	Pathology

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Neuroblastoma, along with rhabdomyosarcoma, Ewing's sarcoma, and lymphoma, is one of the "small, round, blue cell tumors of childhood." It is a highly cellular tumor, with masses of small, round, or occasionally ovoid cells with scanty cytoplasm and darkly staining nuclei. Typically, rosettes containing a tangle of neurofibrillary material are visible. Immunohistochemical techniques are used to distinguish neuroblastoma from other tumors. It is preferable if a panel of antibodies is used for diagnosis [2], as none of the antigens expressed ( Table 1) is completely specific for neuroblastoma. Some tumors, called ganglioneuroblastoma, also contain mature ganglion cells in addition to undifferentiated neuroblastoma cells. These are usually treated in the same way as pure neuroblastoma. The benign variant, called ganglioneuroma, is more often encountered in older children, and more commonly in the thorax. Histological subtype, as described in the Shimada and Joshi classifications, is of prognostic significance [3, 4]. There is now an International Neuroblastoma Pathology Classification [5]. Over the last ten years, International Criteria have been developed for the diagnosis, staging, and assessment of response to treatment [6, 7]. More recently, the same international study group has achieved consensus on the need to develop stratification of patients into prognostic groups—the International Neuroblastoma Risk Groups (INRG)—on the basis of pathology and other biological markers [8].

	Biochemistry

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The principal catecholamine metabolites ( Table 2) are valuable tumor markers in the diagnosis and surveillance of patients with neuroblastoma. They can be detected and quantified in urine. Urinary catecholamine metabolites may be used for screening healthy babies for neuroblastoma. Unfortunately, screening programs cannot be recommended as they have not led to a reduction in neuroblastoma mortality [9, 10].

	Molecular Biology

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Amplification of the N-myc oncogene located on chromosome 2 at 2p23-24, is one of the more powerful prognostic indicators in neuroblastoma [25, 26]. It is found in between one-quarter and one-third of patients, more commonly in association with advanced disease. A relationship has been found in cell lines between N-myc amplification and sensitivity to treatment [27]. It is possible that N-myc may exert its effect through the regulation of expression of the multidrug resistance-associated protein gene (MRP) [28].

Assessment of DNA ploidy by flow cytometry can also be of significance. Patients under two years of age whose tumors are hyperdiploid or aneuploid appear to have a better outcome than those with diploid characteristics [29].

Lack of expression of the cell surface glycoprotein CD44 is also associated with a poor prognosis. CD44 expression seems to correlate with trk-A expression in patients with a favorable outcome [30], but appears to be independent of N-myc amplification [31].

	Diagnosis

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The gold standard for the diagnosis of neuroblastoma is examination of tumor tissue by histopathology and immunohistochemistry. However, as initial surgery is not indicated in patients with advanced disease who require systemic therapy, International Neuroblastoma Diagnostic Criteria (INDC) have been established which permit a reliable diagnosis to be made without a biopsy [6]. A diagnosis of neuroblastoma is established if bone marrow contains unequivocal tumor cells (e.g., syncytia or clusters of cells positive on immunocytology) and urine contains increased urinary catecholamine metabolites. This may be defined by urinary VMA and/or HVA levels greater than three standard deviations above the mean per milligram creatinine for the age of the patient. The age is important here, as normal levels are highest in neonates and gradually diminish over the first two years of life. Both the VMA and HVA levels should be measured. Normalization per milligram of creatinine makes a timed collection unnecessary and avoids potential false negatives due to dilute urine.

Although histopathological confirmation may not be essential in these circumstances, it is still desirable to obtain tissue for biological studies. This is because biological information is not merely of prognostic relevance [8], but may, more importantly, be used to guide treatment [26]. In those patients for whom the diagnosis of metastatic neuroblastoma is certain before biopsy on the basis of bone marrow examination and urinary catecholamine metabolite studies, tumor tissue can be obtained for biological studies, including histopathological assessment, at the time of insertion of an indwelling venous access catheter. This is a reasonable way of maximizing valuable prognostic information while keeping the number of anesthetic sessions to a minimum.

	Clinical Features

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Most patients with neuroblastoma present with symptoms caused directly by the primary tumor or metastases ( Table 3). Only about one-third of patients have localized disease at presentation; two-thirds have metastases. Some may have symptoms caused by excess catecholamine production or by the nonspecific effect of disseminated malignancy. A significant minority of patients with no symptoms are detected during a routine examination or because of screening. Neuroblastoma may be congenital and may occasionally be detected antenatally.

	Staging

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	Prognostic Factors

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Recently, the significance of the family of tyrosine kinase receptors for nerve growth factor and other neurotrophic factors has been recognized. mRNA expression of trk-A, trk-B, and trk-C, among others, can be quantified and correlated with outcome [44-46]. trk-A and trk-C expression is more common in infants and low-stage patients, and is related to a favorable outcome. In contrast, trk-B expression is associated with N-myc amplification, and related to a poor outcome.

It is clear that while the principal clinical risk indicators, age and stage, predict much, a good deal more can be gained by the incorporation of molecular factors into risk assessment [47]. As, however, many of the poor prognostic factors are not independent but go hand in hand, it is not necessary to measure every possible factor. A judicious selection from among those available should be sufficient to provide a good indication of the likely clinical outcome.

To provide reliable data on the relative importance of the many biological prognostic features in neuroblastoma, it is necessary to perform a multivariate analysis of all of these features and their relationship to treatment and outcome in many thousands of patients. This will require international collaboration. Unfortunately, although all collaborative pediatric oncology groups currently measure some factors routinely at presentation, there are insufficient complete data sets for that analysis to be performed now. The same international group [6] which formulated the INSS and the International Neuroblastoma Response Critera (INRC) is working toward the creation of INRG [8]. The hypothesis for the INRG study is that, when coupled with INSS stage and age, select biological variables will define three distinct risk categories, each requiring different therapy. The objectives of the INRG study are first to determine by multivariate analyses which and what combination of biological variables are most powerful in changing predictive outcome of INSS stage- and age-related categories, and second to establish an international cooperative network for re-evaluating the INRG when new biological features with prognostic potential or newer therapy become available.

Finally, in relation to prognosis, it should not be forgotten that treatment is one of the most important prognostic variables. Certain biological factors which seem to be of significance in relation to the outcome of one type of treatment may no longer have any significance if newer therapies prove to be more effective.

	Treatment Policies

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Stage at diagnosis is the principal criterion for determining treatment policy. Other factors, however, such as age and biological features, should be taken into account when planning treatment.

	Early Disease

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Patients with stage 1 and stage 2A disease have localized tumors which are usually suitable for curative surgery. Adjuvant treatment with radiotherapy or chemotherapy is not indicated, even if there is microscopic residual disease [48, 49]. Unfavorable histology and diploidy predict for local recurrence [50]. Careful follow-up is therefore necessary, as local recurrence or distant metastasis may rarely occur and require salvage treatment.

	More Advanced Operable Disease

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Treatment of patients with lymph node involvement, that is, stage 2B and some stage 3 cases, is again principally surgical. The need for adjuvant treatment depends on age. In infants younger than six months, chemotherapy is controversial. In older children, chemotherapy is definitely warranted, using a schedule such as "OPEC," which comprises vincristine, cisplatin, etoposide and cyclophosphamide [51]. In these patients, it is often preferable to use chemotherapy as the initial treatment with the aim of reducing the tumor bulk, making complete removal more likely and the operation safer. Data from the Pediatric Oncology Group (POG) in patients with stage 2B and 3 disease have shown that while complete resection is not associated with a significantly better event-free survival than incomplete resection, patients with favorable Shimada histology have a significantly better event-free survival rate at two years—92%—compared with only 58% for unfavorable cases [52].

Irradiation of the tumor bed to eradicate residual disease is controversial. In a retrospective review of patients with Children's Cancer Study Group (CCSG) Stage II disease, no significant benefit was seen in irradiated patients [53]. A POG randomized trial was designed to evaluate the place of radiotherapy in addition to chemotherapy in patients over one year of age found to have nodal disease at resection of the primary tumor [54]. In irradiated patients, significantly improved local control and survival rates were seen. The chemotherapy schedule used in this study was less intensive than that now considered standard, and it remains possible that results with more intensive chemotherapy might be as good as those in the combined modality arm of the trial. As patients with biologically favorable tumors generally have a good prognosis [53, 55], even in the presence of residual disease, it is reasonable not to give radiotherapy to patients with biologically favorable stage 2B and 3 tumors, with or without residual disease after chemotherapy and surgery. Despite the adverse effects in young children, radiotherapy should be considered in the management of patients with biologically unfavorable stage 2B and 3 tumors with residual disease [26].

	Stage 4S Disease

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Infants with stage 4S disease have, in general, a good prognosis, and treatment is not always necessary, as the tumor may regress spontaneously as a result of programmed cell death. If the disease is not causing distressing or life-threatening symptoms, it is possible to follow a policy of observation in the hope of spontaneous regression due to apoptosis. Sometimes limited, nonintensive chemotherapy is called for if there are major symptoms such as massive hepatomegaly causing respiratory distress. Alternatively, low-dose irradiation may precipitate regression. Rarely, tumors in such patients may be found to have adverse biological features such as N-myc amplification. In these circumstances, the prognosis is poor, and full, intensive treatment is indicated.

	Inoperable Disease

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Patients with advanced disease, that is, those with stage 4 or inoperable stage 3 disease ( Fig. 1) should receive initial chemotherapy with "OPEC" or a similar schedule. If chemotherapy has rendered the stage 3 tumor operable, it should be removed. In stage 4 patients, surgery to remove residual primary tumor should also be considered if there has been a complete remission at metastatic sites.

View larger version (95K): [in this window] [in a new window]   Figure 1. Contrast enhanced CT scan of a child with stage 3 abdominal neuroblastoma at presentation, showing a large leftsided retroperitoneal tumor crossing the midline and encasing the aorta.

	Megatherapy

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Intensive treatments, or "megatherapy," combining high-dose myeloablative chemotherapy and/or total-body irradiation (TBI) with either autologous bone marrow transplantation (ABMT) or peripheral blood stem cell reinfusion are often used in advanced disease. The rationale is that if undetectable minimal residual disease can be eradicated, then the otherwise inevitable relapse is prevented. Residual cells which have survived initial chemotherapy may be resistant to drugs at conventional doses, but still sensitive to similar drugs which at higher dose levels can bypass inadequate membrane transport and saturate detoxification pathways and DNA repair mechanisms. Single-agent high-dose melphalan, which was evaluated in ENSG trial 1, is one of the more commonly used schedules [59, 60]. Although radiation, usually in the form of TBI, has been investigated with high-dose chemotherapy and ABMT for neuroblastoma, the results are no better than when chemotherapy alone is used, yet the acute and late side effects are greater. Allogeneic transplantation is not associated with improved results.

It is difficult to be certain of the true value of megatherapy. It certainly seems to prolong time to relapse; whether it truly improves long-term disease-free survival is less clear. The European Blood and Marrow Transplant Group has registry data on more than 1,000 patients with neuroblastoma who have received myeloablative therapy [61]. Overall, survival at five years is 33%, but relapses may still be seen later. When patients relapsed after initial ABMT, salvage was not possible, but ABMT did salvage 15% of patients in second or subsequent relapse who had not previously undergone ABMT. The principal factor indicating a poor outcome for transplantation in stage 4 patients over the age of one year is persistent skeletal or bone marrow involvement.

	Targeted Therapy

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Targeted radiotherapy involves the use of compounds labeled with radionuclides which preferentially localize in or around tumor deposits. Biological differences between normal and malignant cells are exploited to achieve the required differential distribution. Clinical results of radioimmunotherapy using the labeled monoclonal antibody UJ13A [62, 63] and the anti-GD2 antibody 3F8 [64] in neuroblastoma have been disappointing. Targeting with nonradiolabeled antibodies may also be used [65]. While not necessarily improving bulky disease, such treatment may have a role post-megatherapy with the aim of controlling minimal residual disease and thus improving long-term event-free survival.

The pharmaceutical mIBG, an analog of the adrenergic neuron-blocking drugs guanethidine and bretylium, is taken up into neuroblastoma cells and normal tissues of sympathetic nervous origin by an active transport process [66] involving the epinephrine transporter molecule [67]. When radiolabeled, mIBG can be used for both imaging and treatment of neuroblastoma ( Fig. 2) and other neural crest tumors.

View larger version (101K): [in this window] [in a new window]   Figure 2. Post-therapy 131I-mIBG scan (right: anterior view, left: posterior view) of a child with stage 4 neuroblastoma showing uptake in the left adrenal primary tumor and in multiple bone metastases.

	Differentiating Agents

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A variety of agents have been shown to have noncytotoxic biological effects on neuroblastoma cells in vitro. For example, drugs such as interferon and retinoids [72, 73] may induce differentiation, and betulinic acid [74] can cause apoptosis. These agents offer possible therapeutic pathways for control of neuroblastoma. In the randomized Children's Cancer Group study CCG-3891, 255 high-risk patients were randomized after completion of conventional therapy to receive 13-cis-retinoic acid or no further treatment. The three-year event-free survival rate for those receiving retinoids was 47% compared with only 25% (p = 0.013) for those receiving no treatment [75]. In the ENSG trial 4, 177 patients with advanced neuroblastoma in complete or good partial remission were randomized to receive either 13-cis-retinoic acid or a placebo as maintenance therapy. This trial has now closed, and results will be analyzed in 1998 when follow-up data are more mature. Other isomers of retinoic acid may be suitable for clinical evaluation [76].

	Palliative Care

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Sadly, despite advances in treatment, the majority of patients with advanced neuroblastoma are still destined to die from their disease. While those patients who relapse after minimal initial treatment for early disease may still be salvaged, patients relapsing after intensive therapy for advanced disease are very rarely cured by second-line treatment. Nonetheless, judicious use of chemotherapy and radiotherapy can be beneficial in terms of symptom control and prolongation of life, and supportive measures can often enhance the quality of life of terminally ill children.

	Palliative Anticancer Treatment

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The use of oral etoposide, given daily for three weeks with a seven-day interval between courses, can sometimes produce disease stabilization even in heavily pretreated patients, although the response rate is disappointing [77]. As the capsules are very large and may be difficult to administer to children, the liquid intravenous preparation is preferred, although its unpleasant taste must be disguised. The principal side effects are myelosupression and alopecia.

Some new cytotoxic drugs are always undergoing evaluation in the pediatric setting in phase I and II clinical trials. The likelihood of benefit for an individual patient is small, and these drugs are most often tried when a family, unwilling to accept the grave prognosis, is desperate for every avenue to be explored. The anti-DNA-topoisomerase I drug irinotecan is due to enter clinical studies in patients with neuroblastoma in the United Kingdom soon [78].

External beam radiotherapy can be valuable in the care of terminally ill children with recurrent or refractory neuroblastoma. It is most widely used for the relief of pain from bone metastases. A single 8Gy fraction usually results in a rapid and lasting benefit. In some cases, however, symptoms may recur at the same site, in which case retreatment can be considered. A fractionated regimen, such as 20Gy in five daily treatments, may be considered preferable in some circumstances, such as for the relief of spinal cord compression or extensive orbital disease.

Over the last decade, ¹³¹I-mIBG therapy has found a definite place in the palliation of symptoms of advanced neuroblastoma. Response rates varying between 16% and 58% have been reported [79-81]. While many patients show no objective tumor reduction, pain relief is often dramatic, making noncurative treatment worthwhile [82].

	Conclusions

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Much progress has been made in the management of neuroblastoma over recent decades, yet there is still scope for improvement. We know more about the peculiar biology of neuroblastoma than we do about any other childhood cancer. We are on the threshold of an era in which determination of the biological characteristics of the tumor in an individual patient not only allows us to make an accurate estimate of the prognosis in that case but can guide us to select the best treatment schedule for that particular patient. A greater understanding of the underlying biology of neuroblastoma is opening up new therapeutic horizons where treatments are specifically tailored to attack cells with certain molecular features.

Further progress in the introduction and evaluation of new treatments depends critically on continuing collaborative translational research led by the various national and international groups such as CCG, POG, SIOP, SFOP, and the UKCCSG, which have already achieved so much [28, 83].

	References

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