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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of neuroblastoma. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board.
Information about the following is included in this summary:
This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal evidence ranking system in developing their level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.
This summary is also available in a patient version, which is written in less-technical language, and in Spanish.
The National Cancer Institute (NCI) provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.
Cancer in children and adolescents is rare. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will enable them to achieve optimal survival and quality of life. (Refer to the PDQ summaries on Supportive Care for specific information about supportive care for children and adolescents with cancer).
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. [1] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.
In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. Childhood and adolescent cancer survivors require close follow-up since cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors).
Neuroblastoma is predominantly a tumor of early childhood, with two-thirds of the cases presenting in children younger than 5 years. Neuroblastoma originates in the adrenal medulla or the paraspinal sites where sympathetic nervous system tissue is present. These tumors can be divided into low-, intermediate-, and high-risk groups as illustrated in the Stage Information section of this summary. Low- and intermediate-risk patients usually have localized disease or are infants younger than 18 months. In rare cases, neuroblastoma can be discovered prenatally by fetal ultrasonography. [2] The most common presentation of neuroblastoma is an abdominal mass. The most common symptoms in high-risk patients are due to a tumor mass or to bone pain from metastases. Proptosis and periorbital ecchymosis are common in these high-risk patients and arise from retrobulbar metastasis. Extensive bone marrow metastasis may result in pancytopenia. Abdominal distention with respiratory compromise due to massive liver metastases may occur in infants. Because they originate in paraspinal ganglia, neuroblastomas may invade through neural foramina and compress the spinal cord extradurally, causing paralysis. Horner syndrome may be caused by neuroblastoma in the stellate ganglion, and children with Horner syndrome without apparent cause should be examined for neuroblastoma and other tumors. [3] Fever, anemia, and hypertension are occasionally found. Multifocal (multiple primaries) neuroblastoma occurs rarely, usually in infants, and generally has a good prognosis. [4] On rare occasions, children may have severe, watery diarrhea due to the secretion of vasoactive intestinal peptide by the tumor, or may have protein-losing enteropathy with intestinal lymphangiectasia. [5]
Children with neuroblastoma rarely present with paraneoplastic neurologic findings, including cerebellar ataxia or opsoclonus/myoclonus. [6] The opsoclonus/myoclonus syndrome appears to be caused by an immunologic mechanism that is not yet fully defined. [7] [8] Unlike most other neuroblastomas, the primary tumor is typically diffusely infiltrated with lymphocytes. [9] Patients who present with this syndrome often have neuroblastomas with favorable biological features and are likely to survive, though tumor-related deaths have been reported. Neurologic dysfunction is most often a presenting symptom but may arise long after removal of the tumor. Opsoclonus/myoclonus syndrome is frequently associated with pervasive and permanent neurologic and cognitive deficits, including psychomotor retardation. [8] [10] [11] Some patients may clinically respond to removal of the neuroblastoma, but improvement may be slow and partial; symptomatic treatment is often necessary. Adrenocorticotropic hormone (ACTH) treatment is thought to be effective, but some patients do not respond to ACTH. [7] [10] Various drugs, plasmapheresis, intravenous gamma-globulin, and rituximab have been reported to be effective in selected cases. [10] [12] [13] The long-term neurologic outcome may be superior in patients treated with chemotherapy, possibly because of its immunosuppressive effects. [6] [12] The use of immunosuppressive therapy with and without intravenous gamma-globulin in the treatment of patients with neuroblastoma and opsoclonus/myoclonus syndrome is currently under study by the Children's Oncology Group (COG) (COG-ANBL00P3).
The diagnosis of neuroblastoma requires the involvement of pathologists who are familiar with childhood tumors. Some neuroblastomas cannot be differentiated, via conventional light microscopy, from other small round blue cell tumors of childhood, such as lymphomas, primitive neuroectodermal tumors, and rhabdomyosarcomas. Evidence for sympathetic neuronal differentiation may be demonstrated by immunohistochemistry, electron microscopy, or by finding elevated levels of serum catecholamines (e.g., dopamine and norepinephrine) or urine catecholamine metabolites, such as vanillylmandelic acid (VMA) or homovanillic acid (HVA). The minimum criterion for a diagnosis of neuroblastoma, as has been established by international agreement, is that it must be based on one of the following: (1) an unequivocal pathologic diagnosis made from tumor tissue by light microscopy (with or without immunohistology, electron microscopy, or increased levels of serum catecholamines or urinary catecholamine metabolites); or (2) the combination of bone marrow aspirate or trephine biopsy containing unequivocal tumor cells (e.g., syncytia or immunocytologically-positive clumps of cells) and increased levels of serum catecholamines or urinary catecholamine metabolites, as described above. [14]
Approximately 70% of patients with neuroblastoma have metastatic disease at diagnosis. The prognosis for patients with neuroblastoma is related to their age at diagnosis, clinical stage of disease, and, in patients older than 1 year, regional lymph node involvement. Other conventional prognostic variables include the site of the primary tumor and tumor histology. [15] [16] [17] [18] (Refer to the Cellular Classification section of this summary for more information.) Biological prognostic variables are also used to help determine treatment.
Children of any age with localized neuroblastoma and infants younger than 1 year with advanced disease and favorable disease characteristics have a high likelihood of long-term, disease-free survival. [15] [19] Older children with advanced-stage disease, however, have a significantly decreased chance for cure, despite intensive therapy. Long-term disease-free survival with aggressive chemotherapy, including stem cell rescue and cis-retinoic acid, is approximately 30%. [20]
The clinical characteristics of neuroblastoma in adolescents are similar to those observed in children. The only exception is that bone marrow involvement occurs less frequently, and there is a greater frequency of metastases in unusual sites such as lung or brain. [21] Neuroblastoma in an adolescent or an adult has a worse long-term prognosis regardless of stage or site and, in many cases, a more prolonged course when treated with standard doses of chemotherapy. High-dose chemotherapy and surgery have been shown to achieve a minimal disease state in more than 50% of these patients. Other modalities, such as local radiation therapy and the use of agents with confirmed activity, may improve the poor prognosis. [22] [23]
Neuroblastoma is an embryonal cancer; it is thought to arise from partially committed primordial cells during fetal or early childhood development. Little is known about the events that predispose to the developments of neuroblastoma. Epidemiologic studies and genetic studies of hereditary diseases have not provided insight into the etiology. No commonly mutated gene has been identified. In a genome-wide association study of 1032 patients with neuroblastoma, a significant association was observed between common genetic variation at chromosome 6p22 and susceptibility to neuroblastoma. [24]
A number of biologic variables have been studied in children with this tumor. [25] Treatment decisions may be based on important factors such as Shimada classification, tumor cell chromosome number, amplification of the MYCN oncogene within tumor tissue, unbalanced 11q loss of heterozygosity (LOH), and LOH for chromosome 1p. [18] [19] [26] [27] [28] [29] [30] [31] An open biopsy is usually needed to obtain adequate tissue for determination of these biological characteristics.
Many biological characteristics of tumors are not currently used in determining therapy; however, as clinical research matures, these characteristics may be found useful as therapeutic targets or as clinically important prognostic factors. Amplification of the MYCN gene is associated with deletion of chromosome 1p and gain of the long arm of chromosome 17(17q), the latter of which independently predicts a poor prognosis. [32] In contrast to MYCN gene amplification, the degree of expression of the MYCN gene in the tumor does not predict prognosis. [33] Other biological prognostic factors that have been extensively investigated include tumor cell telomere length, telomerase activity, and RNA; [34] [35] urinary VMA, HVA, and their ratio; [36] dopamine; CD44 expression; TrkA gene expression; neuron-specific enolase level, serum lactic dehydrogenase level, and serum ferritin level. [25] High-level expression of the MRP1 drug resistance gene is an independent indicator of decreased survival. [37] The profile of GABAergic receptors expressed in neuroblastoma is predictive of prognosis regardless of age, stage, and MYCN gene amplification. [38] Gene expression profiling may prove useful for prognosis prediction. [39] In addition, reponse to treatment has been associated with outcome. The persistence of neuroblastoma cells in bone marrow during or after chemotherapy, for example, is associated with a poor prognosis. [40] [41]
Based on these biologic factors and an improved understanding of the molecular development of the neural crest cells that give rise to neuroblastoma, the tumors have been categorized into three biological groups. These groups are not used to determine treatment at this time. One type expresses the TrkA neurotrophin receptor, is hyperdiploid, and tends to spontaneously regress. Another type expresses the TrkB neurotrophin receptor, has gained an additional chromosome, 17q, has loss of heterozygosity of 14q or 11q, and is genomically unstable. In a third type, in addition to a gain of 17q, chromosome 1p is lost and the MYCN gene becomes amplified. [42] [43]
Current data do not support neuroblastoma screening. Screening infants for neuroblastoma by assay of urinary catecholamine metabolites was initiated in Japan. [44] A large population-based North American study, in which most infants in Quebec were screened at the ages of 3 weeks and 6 months, has shown that screening detects many neuroblastomas with favorable characteristics [45] [46] that would never have been detected clinically, apparently due to spontaneous regression of the tumors. Another study of infants screened at the age of 1 year shows similar results. [47] Screening at the ages of 3 weeks, 6 months, or 1 year caused no reduction in the incidence of advanced-stage neuroblastoma with unfavorable biological characteristics in older children, nor did it reduce the number of deaths from neuroblastoma in infants screened at any age. [46] [47] No public health benefits have been shown from screening infants for neuroblastoma at these ages.
This phenomenon has been well described in infants, especially in those with the 4S pattern of metastatic spread. [48] (Refer to the Stage Information section of this summary for more information.) Regression generally occurs only in tumors with a near triploid number of chromosomes, no MYCN amplification, and no loss of chromosome 1p. Additional features associated with spontaneous regression [49] [50] include the lack of telomerase expression, [51] [52] the expression of Ha-ras, [53] and the expression of the neurotrophin receptor TrkA, a nerve growth factor receptor.
Recent studies have suggested that selected infants who appear to have asymptomatic, small, low-stage adrenal neuroblastoma detected by screening or as an incidental finding by ultrasound, often have tumors that spontaneously regress and may be observed safely without surgical intervention or tissue diagnosis. [54] [55] [56] The COG is currently studying whether it is feasible to simply observe neonates with small adrenal masses that are presumed to be neuroblastomas (COG ANBL00P2). These masses are usually found during prenatal or incidental ultrasound examination.
(Refer to the PDQ summary on Screening for Neuroblastoma for more information.)
One clinicopathologic staging system involves evaluation of tumor specimens obtained prior to therapy for the amount of stromal development, the degree of neuroblastic maturation, and the mitosis-karyorrhexis index of the neuroblastic cells. [1] [2] Favorable and unfavorable prognoses are defined on the bases of these histologic parameters and on patient age. The prognostic significance of this classification system, and of related systems using similar criteria, has been confirmed in several studies. [1] [2] [3] Neuroblastoma containing many differentiating cells, termed ganglioneuroblastoma, can have nodules of undifferentiated cells whose histology, along with MYCN amplification, determines prognosis. [4] [5]
The treatment section of this document is organized to correspond with the Children’s Oncology Group (COG) risk-based schema for the treatment of neuroblastoma. This schema is based on three factors: patient age at diagnosis, certain biological characteristics of the patient’s neuroblastoma tumor, and the stage of the tumor as defined by the International Neuroblastoma Staging System (INSS). The INSS has replaced the previously used Children’s Cancer Group (CCG) and Pediatric Oncology Group (POG) staging systems. The INSS is described below, and the COG risk-based treatment schema is described in Table 1 in this section.
A thorough evaluation for metastatic disease should be performed prior to therapy initiation. The following investigations are recommended: [1]
INSS combines certain features of the previously used POG and CCG systems [1] [5] and has identified distinct prognostic groups. [1] [5] [6] [7]
In North America, the COG is investigating a risk-based neuroblastoma treatment plan that assigns all patients to a low-, intermediate-, or high-risk group based on age, INSS stage, and tumor biology.
The following table outlines the COG neuroblastoma risk group assignment schema. The risk group assignment determines the treatment plan for each patient. Patients assigned to the low-, intermediate-, and high-risk groups have an overall survival of more than 90%, 70% to 90%, and about 30%, respectively, 3 years after diagnosis. European studies suggest that the inclusion of chromosome 1p status of neuroblastoma cells may improve risk grouping [8] and the clinical significance of additional tumor genetic characteristics including 17q gain, 1p deletion, and 11q deletion are under study. The COG has found unbalanced 11q loss of heterozygosity to be a negative prognostic factor in a subset of children with otherwise biologically favorable neuroblastoma and will study whether these children will benefit from more aggressive therapy. [9] Some controversies exist regarding the treatment of several small subsets of patients and the INSS staging system; [10] [11] [12] risk group assignment and recommended treatment are expected to mature as additional outcome data are analyzed. The risk group for INSS Stage 4, including patients aged 12 to 18 months, for example, was changed for patients with non-MYCN-amplified status in 2005. [13] [14] [15]
| INSS Stage | Age | MYCN Status | Shimada Classification | DNA Ploidya | Risk Group |
|---|---|---|---|---|---|
| 1 | 0–21 y | Any | Any | Any | Low |
| 2A/2Bb | <365 d | Any | Any | Any | Low |
| ≥365 d–21 y | Nonamplified | Any | - | Low | |
| ≥365 d–21 y | Amplified | Favorable | - | Low | |
| ≥365 d–21 y | Amplified | Unfavorable | - | High | |
| 3c | <365 d | Nonamplified | Any | Any | Intermediate |
| <365 d | Amplified | Any | Any | High | |
| ≥365 d–21 y | Nonamplified | Favorable | - | Intermediate | |
| ≥365 d–21 y | Nonamplified | Unfavorable | - | High | |
| ≥365 d–21 y | Amplified | Any | - | High | |
| 4c | <548 d [13] [14] [15] | Nonamplified | Any | Any | Intermediate |
| <548 d | Amplified | Any | Any | High | |
| ≥548 d–21 y | Any | Any | - | High | |
| 4Sd | <365 d | Nonamplified | Favorable | >1 | Low |
| <365 d | Nonamplified | Any | =1 | Intermediate | |
| <365 d | Nonamplified | Unfavorable | Any | Intermediate | |
| <365 d | Amplified | Any | Any | High | |
| aDNA Ploidy: DNA Index (DI) > 1 is favorable, = 1 is unfavorable; hypodiploid tumors (with DI < 1) will be treated as a tumor with a DI > 1 (DI < 1 [hypodiploid] to be considered favorable ploidy). | |||||
| bINSS stage 2A/2B symptomatic patients with spinal cord compression, neurologic deficits, or other symptoms are treated on the LOW RISK NB Study with immediate chemotherapy for four cycles (course 1). | |||||
| cINSS stage 3 or stage 4 patients with clinical symptoms as listed above (or if in the investigator’s opinion it is in the best interest of the patient) will receive immediate chemotherapy. | |||||
| dINSS stage 4S infants with favorable biology and clinical symptoms are treated on the LOW RISK NB Study with immediate chemotherapy until asymptomatic (2–4 cycles). Clinical symptoms defined as: respiratory distress with or without hepatomegaly or cord compression and neurologic deficit or inferior vena cava compression and renal ischemia; or genitourinary obstruction; or gastrointestinal obstruction and vomiting; or coagulopathy with significant clinical hemorrhage unresponsive to replacement therapy. | |||||
The treatments described in this summary are based on the Children’s Oncology Group (COG) Risk Stratification Schema, which is described in the Stage Information section of this summary. The risk of progression of the tumor causing morbidity and mortality is gauged based on the stage of the tumor, the age of the child at diagnosis, and tumor biology. The biological features considered are the Shimada classification, amplification of the MYCN gene, and the number of chromosomes in tumor cells. Treatment information is presented in this format because most children with neuroblastoma in North America are treated according to the COG schema. Accurate determination of biological characteristics, such as Shimada classification, usually requires an open biopsy. The accuracy of staging is increased by performing a metaiodobenzylguanidine (MIBG) scan. Urinary excretion of the catecholamine metabolites vanillylmandelic acid (VMA) and homovanillic acid (HVA) per mg of excreted creatinine should be measured prior to therapy. If elevated, these markers can be used to determine the persistence of disease.
This risk-based neuroblastoma treatment plan assigns each patient to a low-, intermediate-, or high-risk group. (Risk groups are defined in the table in the Stage Information section of this summary.) In patients without metastatic disease, initial surgery is performed to establish the diagnosis, to resect as much of the primary tumor as is safely possible, to accurately stage disease through sampling of regional lymph nodes that are not adherent to the tumor, and to obtain adequate tissue for biological studies.
Treatment for patients categorized as low risk (refer to table) is with surgery alone, but surgery may be combined with 6 to 12 weeks of chemotherapy in some cases. Chemotherapy is reserved for patients who are symptomatic, such as from spinal cord compression or, in stage 4S, respiratory compromise secondary to hepatic infiltration. The chemotherapy consists of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen (COG-P9641).
Patients categorized as intermediate risk (refer to table) are treated with surgery and 12 to 24 weeks of the same chemotherapy regimen described above (COG-3961).
In contrast, patients categorized as high risk (refer to table) are generally treated with aggressive multiagent chemotherapy consisting of very high doses of the drugs listed above but often also including ifosfamide and high-dose cisplatin. After a response to chemotherapy, resection of the primary tumor should be attempted, followed by myeloablative chemotherapy, sometimes total-body irradiation, and autologous stem cell transplantation. Radiation of residual tumor and original sites of metastases is often performed before, during, or after myeloablative therapy. After recovery, patients are treated with oral 13-cis-retinoic acid for 6 months. Both myeloablative therapy and retinoic acid improve outcome in patients categorized as high risk. [1] [2]
Radiation therapy is reserved for patients with symptomatic life-threatening or organ-threatening tumor that does not respond rapidly enough to chemotherapy, or for intermediate-risk patients whose tumor has responded incompletely to both chemotherapy and attempted resection and also has unfavorable biological characteristics. Radiation therapy to the primary site is often recommended for high-risk patients even in cases of complete resection.
As part of the COG treatment plan, specific relapse therapy is defined for low- and intermediate-risk patients determined by patient age at recurrence, stage, and biology of the recurrence.
Immediate treatment should be given for symptomatic spinal cord compression. Neurologic recovery is more likely the less the severity of compromise and the shorter the duration of symptoms. Neurologic outcome appears to be similar whether cord compression is treated with chemotherapy, radiation therapy, or laminectomy. Laminectomy, however, may result in later scoliosis, and chemotherapy is often needed whether or not surgery or radiation is used. [3] [4] [5] The COG neuroblastoma treatment plan recommends immediate chemotherapy for cord compression in patients classified as low or intermediate risk (COG-P9641, COG-A3961). Children with high-risk neuroblastoma whose spinal cord compression worsens on medical therapy may benefit from surgical intervention. [6]
Studies suggest that selected presumed neuroblastomas detected in infants by screening or incidental ultrasound may safely be observed without obtaining a definitive histologic diagnosis and without surgical intervention, thus avoiding potential complications of surgery in the newborn. [7] [8] [9] The experience with tumors detected by mass urinary catecholamine metabolite screening in Japan appears to be applicable to tumors detected by prenatal or perinatal ultrasound in the United States. Twenty-six infants who had presumed Evans stage I, II, or IVS by imaging, urinary VMA and HVA levels of less than 50 μg/mg creatinine, no tumor involvement of great vessels or invasion into the spinal canal, and tumor size smaller than 5 cm, were observed with frequent imaging. Biopsy and tissue diagnosis were not obtained initially. The tumor increased in size in about one-third of the infants and was resected without any apparent increase in stage. All had favorable biological features. In two-thirds of the infants, after observation for 6 to 73 months, no surgery had been performed, the VMA and HVA had normalized, and in several cases the tumors had become undetectable by imaging. [7] The COG is currently investigating systematic observation without surgery for infants with presumed small Evans stage I adrenal neuroblastoma detected by prenatal or perinatal ultrasound.
In North America, the Children’s Oncology Group (COG) is investigating a risk-based neuroblastoma treatment plan that assigns all patients to a low-, intermediate-, or high-risk group based on age, International Neuroblastoma Staging System (INSS) stage, and tumor biology (i.e., MYCN gene amplification, Shimada classification, and DNA ploidy) (COG-P9641). (Risk groups are defined in the table in the Stage Information section of this summary.)
Patients with low-risk neuroblastoma have a cure rate higher than 90%. [1] [2] [3] [4] [5] The following tumors are categorized as low risk (see table):
Low-risk neuroblastomas are generally treated with surgical resection and observation or observation alone (COG-9641).
Stage 2 low-risk tumors are treated with chemotherapy only if less than 50% of the tumor has been resected. In the other low-risk patients, chemotherapy is recommended only for life-threatening or organ-threatening symptoms that cannot be relieved by safe surgical resection of the mass. Such symptoms include respiratory distress, renal or bowel ischemia, spinal cord compression, gastrointestinal or genitourinary obstruction, or coagulopathy (COG-9641). Chemotherapy is given for 6 to 24 weeks and consists of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen (COG-9641). Radiation therapy is reserved for patients with symptomatic life-threatening or organ-threatening tumor that does not respond rapidly enough to chemotherapy.
Studies suggest that selected presumed neuroblastomas detected in infants by screening may be safely observed without surgical intervention and without pathologic diagnosis. [6] [7] The COG is investigating systematic observation without diagnostic surgery for selected infants with presumed INSS stage 1 adrenal neuroblastoma detected by prenatal or perinatal ultrasound (COG-ANBL00P2).
The treatment of children with low-risk stage 4S disease is dependent on clinical presentation. [8] [9] Children who are clinically stable with this special pattern of neuroblastoma may not require therapy. The development of complications, such as functional compromise from massive hepatomegaly, is an indication for intervention, especially in infants younger than 2 to 3 months. [8] [10] [11] In a study of 80 infants with 4S disease, those who were asymptomatic had 100% survival with supportive care only, and patients with symptoms had an 81% survival rate when they received low-dose chemotherapy. [10] Resection of primary tumor is not associated with improved outcome. [8] [9] [10]
The COG neuroblastoma treatment plan also defines the treatment for progression or recurrence of low-risk neuroblastoma. The treatment is dependent on the characteristics of the progression or recurrence. (Refer to the Recurrent Neuroblastoma section of this summary for more information.)
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with neuroblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
In North America, the Children’s Oncology Group (COG) is investigating a risk-based neuroblastoma treatment plan that assigns all patients to a low-, intermediate-, or high-risk group based on age, International Neuroblastoma Staging System (INSS) stage, and tumor biology (i.e., MYCN gene amplification, Shimada classification, and DNA ploidy). (Risk groups are defined in the table in the Stage Information section of this summary.)
Patients with intermediate-risk neuroblastoma generally have a cure rate of 70% to 90%. The following patients are categorized as intermediate risk (see table):
There is considerable variation in outcome, and, therefore, in treatment for children with stage 3 disease (tumor involving both sides of the midline by virtue of either invasion into normal tissues or lymph node metastasis). Infants younger than 1 year have a greater than 80% cure rate while older children have a cure rate of 50% to 70% with current relatively intensive therapy. [4] [5] [6] [7] In one study, those with favorable compared with unfavorable biological features (i.e., Shimada classification and MYCN gene amplification) had event-free survival rates of almost 100% and about 50%, respectively. [8] [9] [10] In cases of abdominal neuroblastoma thought to involve the kidney, nephrectomy should not be undertaken before a trial of chemotherapy has been given. [11]
Patients classified as intermediate risk with stage 3 tumors with favorable or unfavorable Shimada classification are treated with 12 weeks and 24 weeks of chemotherapy, respectively. In patients classified as intermediate risk with favorable biology, radiation therapy is reserved for patients with symptomatic life-threatening or organ-threatening tumor that does not respond rapidly enough to chemotherapy. In patients classified as intermediate risk with unfavorable biologic features, radiation therapy is given if residual viable tumor remains after 24 weeks of chemotherapy and second-look surgery.
Survival of patients with INSS stage 4 disease is strongly dependent on age. Children younger than 1 year at diagnosis have a good chance of long-term survival (i.e., a 5-year disease-free survival rate of 50%–80%), [12] [13] with outcome particularly dependent on tumor cell ploidy (e.g., hyperploidy confers a favorable prognosis while diploidy predicts early treatment failure). [5] [14]
Infants younger than 18 months at diagnosis with INSS stage 4 neuroblastoma who do not have MYCN gene amplification are categorized as intermediate risk. [15] [1] [2] [3] These infants are treated with 12 weeks of chemotherapy if the tumor has both favorable Shimada classification and hyperdiploidy, and if not, these infants are treated with 24 weeks of chemotherapy.
Infants younger than 1 year at diagnosis with INSS stage 4S neuroblastoma without amplification of the MYCN gene, but with unfavorable Shimada classification, diploid DNA, or both, are classified as intermediate risk. These infants are treated with 24 weeks of chemotherapy.
Chemotherapy for intermediate-risk patients consists of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide given for 12 to 24 weeks. The cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen (COG-A3961).
The COG Neuroblastoma Treatment Plan also defines the treatment for progression or recurrence of intermediate-risk neuroblastoma. This treatment depends on the characteristics of the progression or recurrence. (Refer to the Recurrent Neuroblastoma section of this summary for more information.)
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with neuroblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
In North America, the Children’s Oncology Group (COG) investigated a risk-based neuroblastoma treatment plan that assigned all patients to a low-, intermediate-, or high-risk group based on age, International Neuroblastoma Staging System (INSS) stage, and tumor biology (i.e., MYCN gene amplification, Shimada classification, and DNA ploidy) (COG-P9611). (Risk groups are defined in the table in the Stage Information section of this summary.)
The following patients are considered to have high-risk neuroblastoma (see table):
For children with high-risk neuroblastoma, long-term survival ranges from 10% to 40%. Children with aggressively treated, high-risk neuroblastoma may develop late recurrences, some more than 5 years after completion of therapy. [2] [3] A randomized study was performed comparing high-dose therapy with purged autologous hematopoietic stem cell transplantation (HSCT) versus three cycles of intensive consolidation chemotherapy. The 3-year event-free survival (EFS) was significantly better in the HSCT arm (34%) compared with the consolidation chemotherapy arm (18%). Superiority of myeloablative chemotherapy over maintenance therapy was confirmed in another study. [4] In addition, patients on this study were subsequently randomized to stop therapy or to receive 6 months of 13-cis-retinoic acid. [5] Patients who received 13-cis-retinoic acid had significantly better 3-year EFS than patients who received no maintenance therapy. This was true for all patient subgroups. Based on these results, future clinical trials will build upon autologous HSCT and 13-cis-retinoic acid for high-risk neuroblastoma. [5]
The potential benefit of aggressive surgical approaches in high-risk patients with metastatic disease to achieve complete tumor resection, either at the time of diagnosis or following chemotherapy, has not been unequivocally demonstrated. Several studies have 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, which itself may determine resectability, than on the extent of surgical resection. [6] [7] [8] [9] [10] The use of radiation therapy to consolidate local control after surgical resection is recommended. [11]
Patients classified as high risk receive treatment with an aggressive regimen of combination chemotherapy consisting of very high drug doses. Drugs often used include cyclophosphamide, ifosfamide, cisplatin, carboplatin, vincristine, doxorubicin, and etoposide. After a response to chemotherapy, resection of the primary tumor should be attempted, followed by myeloablative chemotherapy and stem cell rescue (i.e., bone marrow and/or peripheral blood stem cell transplantation). The use of purged stem cells is under investigation. Radiation to the primary tumor site should be undertaken whether or not a complete excision was obtained. Radiation of sites of metastatic disease is determined on an individual case basis. After recovery, patients are treated with oral 13-cis-retinoic acid for 6 months. Both myeloablative therapy and postchemotherapy retinoic acid improve outcome in patients categorized as high risk. [5]
The following are examples of national and/or institutional clinical trials that are currently being conducted. For more information about clinical trials, please see the NCI Web site.
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with neuroblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
The prognosis and treatment of recurrent or progressive neuroblastoma depends on many factors including initial stage, tumor biological characteristics at recurrence, the site and extent of the recurrence or progression, previous treatment, and individual patient considerations. In selected patients originally diagnosed with low- or intermediate-risk disease, recurrence may be treated successfully with limited intervention. When neuroblastoma recurs in a child originally diagnosed with high-risk disease and is widespread, the prognosis is usually poor despite additional intensive therapy. [1] [2] [3] The combination of cyclophosphamide plus topotecan has been active in patients with recurrent or refractory disease who have not received topotecan previously. [4] 131-I-metaiodobenzylguanidine (131-I-MIBG) therapy is also active in patients with recurrent or refractory neuroblastoma. [5] Clinical trials are appropriate and should be considered. Information about ongoing clinical trials is available from the NCI Web site.
Central nervous system (CNS) involvement, though rare at initial presentation, may occur in 5% to 10% of patients with recurrent neuroblastoma. Inward compression of the brain from cranial metastases can occur, and rarely meningeal and isolated intracranial metastases occur. Early recognition and treatment of CNS involvement may result in reduced neurologic impairment. [6] [7]
In North America, the Children’s Oncology Group (COG) is investigating a risk-based neuroblastoma treatment plan that assigns all patients to a low-, intermediate-, or high-risk group based on age, International Neuroblastoma Staging System (INSS) stage, and tumor biology (i.e., MYCN gene amplification, Shimada classification, and DNA ploidy). [8] Treatment of recurrent disease is determined by the risk group at the time of diagnosis (refer to the table in the Stage Information section of this summary), extent of disease at recurrence, patient age at recurrence, and the tumor biology at recurrence. If tumor is unavailable for biological studies at recurrence, the biology of the tumor at the time of diagnosis is used to help determine treatment.
(Risk categories are defined in the table in the Stage Information section of this summary.)
Local regional recurrent cancer is resected if possible:
Chemotherapy consists of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen (COG-P9641). Older children with local recurrence with either unfavorable Shimada classification or MYCN gene amplification have a poor prognosis and should be treated with an aggressive regimen of combination chemotherapy consisting of very high doses of the drugs listed above, and often also including ifosfamide and high-dose cisplatin. Both myeloablative therapy and postchemotherapy retinoic acid may improve outcome of newly diagnosed high-risk patients with a poor prognosis. [9] These modalities are commonly employed in the treatment of patients with a recurrence that augurs a poor prognosis.
Metastatic recurrent or progressive neuroblastoma in an infant initially categorized as low risk (see table) and younger than 1 year at recurrence, whether the patient has INSS stage 1, 2, or 4S at the time of diagnosis, is treated according to tumor biology:
Chemotherapy consists of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen (COG-P9641).
Any child initially categorized as low risk who is older than 1 year at the time of metastatic recurrent or progressive disease usually has a poor prognosis and should be treated with an aggressive regimen of combination chemotherapy consisting of very high doses of the drugs listed above, and often also including ifosfamide and high-dose cisplatin. Both myeloablative therapy and postchemotherapy retinoic acid may improve outcome of newly diagnosed patients with a poor prognosis. [9] These modalities are commonly employed in the treatment of patients with a recurrence that augurs a poor prognosis.
(Risk categories are defined in the table in the Stage Information section of the summary.)
Local regional recurrence of neuroblastoma with favorable biology that occurs more than 3 months after completion of 12 weeks of chemotherapy is treated surgically. If resection is less than near total, then 12 additional weeks of chemotherapy is given. Chemotherapy consists of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen (COG-A3961).
If the recurrence is metastatic and/or occurs while on chemotherapy or within 3 months of completing chemotherapy and/or has unfavorable biologic properties, the prognosis is poor and the patient should be treated with an aggressive regimen of combination chemotherapy consisting of very high doses of the drugs listed above, and often also including ifosfamide and high-dose cisplatin. Both myeloablative therapy and postchemotherapy retinoid acid may improve outcome of newly diagnosed patients with a poor prognosis. [9] These modalities are commonly employed in the treatment of patients with a recurrence that augurs a poor prognosis.
(Risk categories are defined in the table in the Stage Information section of this summary.)
Any recurrence in patients initially classified as high risk signifies a poor prognosis. If the tumor has recurred in spite of the administration of aggressive high-dose combination chemotherapy, often with myeloablative therapy plus stem cell rescue, phase I or phase II clinical trials are appropriate and should be considered. [2] The combination of cyclophosphamide and topotecan with or without etoposide has been used in recurrent disease. [4] [10]
The following are examples of national and/or institutional clinical trials that are currently being conducted. For more information about clinical trials, please see the NCI Web site.
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent neuroblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Added Bell et al. as reference 13.
Added text about the etiology of neuroblastoma (cited Maris et al. as reference 24).
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