Home > Health & Wellness > Health Library > Neuroblastoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]
This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. 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 and Palliative 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. 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.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. For neuroblastoma, the 5-year survival rate in the United States has remained stable at approximately 87% for children younger than 1 year and has increased from 37% to 65% in children aged 1 to 14 years. 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 aged 5 years or younger. 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 aged 18 months or younger. In rare cases, neuroblastoma can be discovered prenatally by fetal ultrasonography.
Predisposition to Neuroblastoma
Little is known about the events that predispose to the development of neuroblastoma. Parental exposures have not been definitively linked. In a genome-wide association study of 1,032 patients with neuroblastoma, a significant association was observed between a common genetic variation (polymorphism) at chromosome 6p22 and neuroblastoma. Tumors that arose in patients with this polymorphism tended to be clinically aggressive. Genome-wide association studies in children with neuroblastoma have found a few gene polymorphisms associated with the development of high-risk neuroblastoma and a few other gene polymorphisms associated with the development of low-risk neuroblastoma.[4,5] Germline deletion at the 1p36 or 11q14-23 locus are associated with the development of neuroblastoma and the same deletions are found somatically in sporadic neuroblastomas.[6,7]
About 1% to 2% of patients with neuroblastoma have a family history of neuroblastoma, and these children are on average younger (9 months); about 20% have multifocal primary neuroblastomas. The primary cause of familial neuroblastoma is germline mutation in the ALK gene. Similar somatic mutations and amplification of the ALK gene are found in 8% to12% of sporadic neuroblastomas. The mutations result in constitutive phosphorylation of ALK, which is critical for cell growth of the ALK-mutant neuroblasts. Thus, inhibition of ALK kinase is a potential target for treatment of neuroblastoma, especially in children whose tumors harbor an ALK mutation or ALK gene amplification. Familial neuroblastoma is rarely associated with Ondine's curse (congenital central hypoventilation syndrome) with germline mutation of the PHOX2B gene.
Presentation of Neuroblastoma
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. Fever, anemia, and hypertension are occasionally found. Multifocal (multiple primaries) neuroblastoma occurs rarely, usually in infants, and generally has a good prognosis. 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. Vasoactive intestinal peptide secretion may also occur upon chemotherapeutic treatment, and tumor resection reduces vasoactive intestinal peptide secretion.
Children with neuroblastoma rarely present with paraneoplastic neurologic findings, including cerebellar ataxia or opsoclonus/myoclonus. 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.[16,17,18]
The opsoclonus/myoclonus syndrome appears to be caused by an immunologic mechanism that is not yet fully defined.[16,19] Unlike most other neuroblastomas, the primary tumor is typically diffusely infiltrated with lymphocytes. 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.
Some patients may clinically respond to removal of the neuroblastoma, but improvement may be slow and partial; symptomatic treatment is often necessary. Adrenocorticotropic hormone treatment is thought to be effective, but some patients do not respond to adrenocorticotropic hormone.[17,19] Various drugs, plasmapheresis, intravenous gamma globulin, and rituximab have been reported to be effective in selected cases.[17,21,22,23] The long-term neurologic outcome may be superior in patients treated with chemotherapy, possibly because of its immunosuppressive effects.[15,21] The use of immunosuppressive therapy with and without intravenous gamma globulin in the treatment of patients with neuroblastoma and opsoclonus/myoclonus syndrome is 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:
However, primary tumor tissue is often needed to obtain all the biological data that may be used to determine treatment in current COG clinical trials. There is an absolute requirement for tissue biopsy to determine the International Neuroblastoma Pathology Classification (INPC) (see Cellular Classification section for more information). The INPC was used to determine treatment in the COG risk assignment schema for prior COG studies in patients with stage 2, 3, and 4S tumors. In the risk/treatment group assignment schema for the current COG studies, INPC is used to determine treatment for stage 3 and 4S patients as well as for stage 4 patients aged 18 months or younger. Additionally, a significant number of tumor cells are needed to determine MYCN copy number DNA index and 11q and 1p loss of heterozygosity. For older stage 4 patients, bone marrow with extensive tumor involvement combined with elevated catecholamine metabolites is adequate for study entry.
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, site of the primary tumor, tumor histology, and, in patients older than 1 year, regional lymph node involvement. Biological prognostic variables are also used to help determine treatment (see below).[25,26,27,28] The 5-year overall survival for all infants and children with neuroblastoma has increased from 46% when diagnosed between 1974 and 1989, to 71% when diagnosed between 1999 and 2005; however, this single number can be misleading due to the extremely heterogeneous prognosis based on the neuroblastoma patient's age, stage, and biology. (Refer to the Cellular Classification section of this summary for more information.)
The effect of age at diagnosis on 5-year survival is profound—age younger than 1 year is associated with 90% survival, 1 to 4 years is 68%, 5 to 9 years is 52%, and 10 to 14 years is 66%. Children of any age with localized neuroblastoma and infants aged 18 months and younger with advanced disease and favorable disease characteristics have a high likelihood of long-term, disease-free survival. The prognosis of fetal and neonatal neuroblastoma are similar to that of older infants with neuroblastoma and similar biological features. Older children with advanced-stage disease, however, have a significantly decreased chance for cure, despite intensive therapy. For children aged 18 months and older with stage 4 neuroblastoma, who receive aggressive treatment with surgery and radiation therapy to the primary tumor mass, as well as aggressive chemotherapy with hematopoietic stem cell rescue followed by cis -retinoic acid, long-term survival is approximately 30% to 50%.
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. Neuroblastoma has a worse long-term prognosis in an adolescent or adult compared to a child, regardless of stage or site and, in many cases, a more prolonged course when treated with standard doses of chemotherapy. Aggressive chemotherapy and surgery have been shown to achieve a minimal disease state in more than 50% of these patients.[33,34,35] Other modalities, such as local radiation therapy and the use of agents with confirmed activity, may improve the poor prognosis.[34,35] However, the overall prognosis for older patients is dismal.
A number of biologic variables have been studied in children with this tumor. Treatment decisions are usually based on important factors such as the INPC (refer to the Cellular Classification section of this summary for information about the INPC system), ploidy, amplification of the MYCN oncogene within tumor tissue, unbalanced 11q loss of heterozygosity, and loss of heterozygosity for chromosome 1p.[28,37,38,39,40,41,42,43] In the future, MYCN amplification, 11q23 alleles, and ploidy (along with standardized procedures for evaluation) are expected to be the standard factors used for evaluation of treatment programs, as established by the International Consensus for Neuroblastoma Molecular Diagnostics. An open biopsy is often needed to obtain adequate tissue for determination of these biological characteristics.
Many biological characteristics of tumors are not currently used in determining therapy; however, as 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 not only with deletion of chromosome 1p, but also gain of the long arm of chromosome 17 (17q), the latter of which independently predicts a poor prognosis. In contrast to MYCN gene amplification, the degree of expression of the MYCN gene in the tumor does not predict prognosis. However, high overall MYCN-dependent gene expression and low expression of sympathetic neuron late differentiation genes both predict a poor outcome of neuroblastomas otherwise considered to be at low or intermediate risk of recurrence.ATRX is involved in epigenetic gene silencing and telomere length. ATRX mutation without MYCN amplification is associated with age at diagnosis in adolescents and young adults with metastatic neuroblastoma.
Other biological prognostic factors that have been extensively investigated include tumor cell telomere length, telomerase activity, and telomerase ribonucleic acid;[49,50] urinary VMA, HVA, and their ratio; dopamine; CD44 expression; TrkA gene expression; and serum neuron-specific enolase level, serum lactic dehydrogenase level, and serum ferritin level. High-level expression of the MRP1 drug resistance gene is an independent indicator of decreased survival. The profile of GABAergic receptors expressed in neuroblastoma is predictive of prognosis regardless of age, stage, and MYCN gene amplification. Gene expression profiling may prove useful for prognosis prediction. Whole chromosome copy number changes do not predict recurrence, while segmental chromosome number changes do.[55,56] In addition, response 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.[57,58]
Unique Aspects of Neuroblastoma
Biologically discrete types of neuroblastoma
Based on biologic factors and an improved understanding of the molecular development of the neural crest cells that give rise to neuroblastoma, the tumors have been categorized into three biological types. These types are not used to determine treatment at this time; however, type 1 has a very favorable prognosis, while types 2 and 3 have poor prognoses.
Children whose tumors have lost a copy of 11q are older at diagnosis, and their tumors contain more segmental changes in gene copy number compared with children whose tumors show MYCN amplification.[61,62] Moreover, segmental chromosome changes not detected at diagnosis may be found in neuroblastomas at relapse. This suggests that clinically important tumor progression is associated with accumulation of segmental chromosomal alterations.
Current data do not support neuroblastoma screening. Screening infants for neuroblastoma by assay of urinary catecholamine metabolites was initiated in Japan. 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 [65,66] 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. 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.[66,67] No public health benefits have been shown from screening infants for neuroblastoma at these ages. (Refer to the PDQ summary Neuroblastoma Screening for more information.)
Spontaneous regression of neuroblastoma
This phenomenon has been well described in infants, especially in those with the 4S pattern of metastatic spread. (Refer to the Stage Information section of this summary for more information.) In a German clinical trial, spontaneous regression and/or lack of progression occurred in nearly half of 93 asymptomatic infants aged 12 months or younger with stage 1, 2, or 3 tumors without MYCN amplification; all were observed after partial or no resection. 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 [70,71] include the lack of telomerase expression,[72,73] the expression of Ha-ras, and the expression of the neurotrophin receptor TrkA, a nerve growth factor receptor.
Studies have suggested that selected infants who appear to have asymptomatic, small, low-stage adrenal neuroblastoma detected by screening or during prenatal or incidental ultrasound examination, often have tumors that spontaneously regress and may be observed safely without surgical intervention or tissue diagnosis.[75,76,77]
The International Neuroblastoma Pathologic Classification (INPC) 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.[1,2,3,4] Favorable and unfavorable prognoses are defined on the bases of these histologic parameters. 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] About 25% of reported neuroblastomas diagnosed in the fetus and neonate are cystic; cystic neuroblastomas have lower stages and a higher incidence of favorable biology.
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:
International Neuroblastoma Staging System
INSS combines certain features of the previously used POG and CCG systems [1,8] and has identified distinct prognostic groups.[1,8,9,10]
Children's Oncology Group Neuroblastoma Risk Grouping
In North America, the COG investigated a risk-based neuroblastoma treatment plan that assigned all patients to a low-, intermediate-, or high-risk group based on age, INSS stage, and tumor biology. The relevant biological attributes of the tumor included MYCN status, International Neuroblastoma Pathologic Classification (INPC) histopathology classification, and tumor DNA index. The low-risk group was observed without further treatment unless the patient had life- or organ-threatening tumors. The intermediate-risk group received limited chemotherapy, additional surgery in some instances, and avoided radiation therapy. This study involved an overall reduction in treatment compared to prior treatment plans. The high-risk group was treated with aggressive chemotherapy, second-look surgery, high-dose chemotherapy with stem cell rescue, radiation therapy, and cis -retinoic acid. The outcome for the low- and intermediate-risk groups combined was an event-free survival and overall 3-year survival of 88% and 96%, respectively. There was no unexpected toxicity. These studies (COG-P9641 and COG-A3961) have established a new standard of care for children in North America with neuroblastoma.
Some controversies exist regarding the treatment of several small subsets of patients and the INSS staging system;[12,13,14] risk group assignment and recommended treatment are expected to mature as additional outcome data are analyzed. For example, the risk group for INSS stage 4, including patients aged 12 to 18 months was changed for patients with MYCN-nonamplified status in 2005.[15,16,17] Table 1 describes the risk group assignment criteria used to assign treatment in these studies.
The treatments described in this summary are based on the Children's Oncology Group (COG) group assignment, which is described in the Stage Information section of this summary. Treatment information is presented in this format because most children with neuroblastoma in North America are treated according to the COG schema. The prior COG risk-based neuroblastoma studies established the standard of care. They assigned each patient to a low-, intermediate-, or high-risk group and the basis of the assignment is described in Table 1.
In patients without metastatic disease, the standard of care is to perform an initial surgery 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. Accurate determination of biological characteristics, such as INPC system, usually requires an open biopsy. The accuracy of diagnosis and 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.
There is controversy about the need for immediate diagnostic biopsy in infants aged 3 months and younger with suspected neuroblastoma tumors that are likely to spontaneously regress. Biopsy is not required for infants entered into a COG study of expectant observation of adrenal masses in neonates. In a German clinical trial, 25 infants aged 3 months and younger with presumed neuroblastoma were observed without biopsy for periods of 1 to 18 months prior to biopsy or resection. There were no apparent ill effects of the delay.
There is also controversy about the need for attempted resection, whether at the time of diagnosis or later, in asymptomatic infants aged 12 months or younger with apparent stage 2B and 3 MYCN-nonamplified disease. In a German clinical trial, some of these patients were observed after biopsy or partial resection without chemotherapy or radiation, and many did not progress locally and never received additional resection.
Treatment for patients categorized as low risk (refer to Table 1 in the Stage Information section of this summary) may be surgery alone, but surgery may be combined with 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).
The COG study COG-P9641 demonstrated excellent survival in patients with asymptomatic, low-risk, stage 2A or 2B disease with favorable histology.
Observation without surgery for localized, suspected adrenal neuroblastoma in infants
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.[4,5,6] 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. The COG is investigating systematic observation without surgery for infants with presumed small Evans stage I adrenal neuroblastoma detected by prenatal or perinatal ultrasound.
Patients categorized as intermediate risk (refer to Table 1 in the Stage Information section of this summary) have been successfully treated with surgery and 12 to 24 weeks of the same chemotherapy regimen described above (COG-A3961). As a rule, patients whose tumors have unfavorable biology receive twice as many cycles of chemotherapy as those with favorable biology.
Whether initial chemotherapy is indicated for all intermediate-risk infants with localized neuroblastoma is controversial. A German prospective clinical trial enrolled 340 infants aged 1 year or younger whose tumors were stage 1, 2, or 3, histologically verified, and lacked MYCN amplification. Forty-four of 93 infants with unresected tumors experienced spontaneous regression (17 were complete regressions) and 39 infants experienced progression. The 3-year overall survival (OS) rate was 99%, and the metastases-free survival rate was 94% for infants with unresected tumors and was not different from infants treated with surgery or chemotherapy (median follow-up, 58 months). The investigators suggested that a wait-and-see strategy is appropriate for infants with localized neuroblastoma because regressions have been observed after the first year of life.
Moderate-dose chemotherapy has been shown to be effective in the prospective Infant Neuroblastoma European Study (INES 99.1 [EURO-INF-NB-STUDY-1999-99.1]), where about half of the infants with unresectable, nonmetastatic neuroblastoma and no MYCN amplification underwent a safe surgical resection and avoided long-term adverse effects. The 5-year OS rate was 99% and the event-free survival (EFS) rate was 90% (median follow-up, 6 years). In this study, infants undergoing surgical resection had a better EFS than those who did not have surgery.[Level of evidence: 3iiA]
In contrast, patients categorized as high risk (refer to Table 1 of the Stage Information section of the summary) are generally treated with dose-intensive 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 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.[8,9]; [Level of evidence: 1iiA] Compared to retinoic acid alone, chimeric anti-GD2 antibody ch14.18 combined with granulocyte macrophage-colony stimulating factor and interleukin-2 and given in concert with retinoic acid improves event-free survival for high-risk neuroblastoma patients in remission after stem cell transplant.
Radiation therapy for patients with low- or intermediate-risk neuroblastoma in the completed COG treatment plan was reserved for symptomatic life-threatening or organ-threatening tumor bulk that did not respond rapidly enough to chemotherapy. The common situations where radiation is used in these patients include: 1) infants aged 60 days and younger with stage 4S and marked respiratory compromise from liver metastases that has not responded to chemotherapy, or 2) for symptomatic spinal cord compression that has not responded to initial chemotherapy and/or surgical decompression. In contrast, radiation therapy to the primary site is often recommended for high-risk patients even in cases of complete resection.
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.[12,13,14] The completed COG neuroblastoma treatment plans recommended immediate chemotherapy for cord compression in patients classified as low or intermediate risk. Children with neuroblastoma whose spinal cord compression worsens on medical therapy may benefit from surgical intervention.
Description of International Neuroblastoma Response Criteria
In order to stop therapy after the initially planned number of cycles, certain response criteria, depending on treatment group, must be met. These criteria are defined below:[16,17]
Surveillance for Recurrence of High-Risk Neuroblastoma
Surveillance studies during and following treatment are able to detect asymptomatic and unsuspected relapse in a substantial portion of patients. As an element in an overall surveillance plan, the most reliable test to detect disease progression or recurrence is the 123 I-MIBG scan.[18,19]
Standard Treatment Options
Refer to the Treatment Option Overview section of this summary for more information.
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, International Neuroblastoma Pathology Classification [INPC] system, and DNA index). The low-risk group was observed without further treatment in most cases. Chemotherapy was given for four cycles (12 weeks) to treat patients with life- or organ-threatening neuroblastoma. (Risk Groups are defined in Table 1 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]
Studies suggest that selected presumed neuroblastomas detected in infants by screening may be safely observed without surgical intervention and without pathologic diagnosis.[6,7] A COG trial investigating systematic observation without diagnostic surgery for selected infants with presumed INSS stage 1 adrenal neuroblastoma detected by prenatal or perinatal ultrasound (COG-ANBL00P2) has met its patient accrual goals. Analysis of the trial is pending. There is some controversy whether additional surgical resection should be attempted in infants with localized MYCN-nonamplified tumors after biopsy or partial resection. A German clinical trial observed a group of these patients and some infants did not require further intervention, in part due to spontaneous regression.
The treatment of children with low-risk stage 4S disease is dependent on clinical presentation.[9,10] 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.[9,11,12] 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. Resection of primary tumor is not associated with improved outcome.[9,10,11] In 45 patients with 4S neuroblastoma diagnosed in the first month of life, 16 patients developed dyspnea caused by massive liver enlargement; half of them did not survive.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials 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, International Neuroblastoma Pathology Classification [INPC] system, and DNA ploidy). The intermediate-risk group received limited chemotherapy, additional surgery in some instances, and avoided radiation therapy. This study involved an overall reduction in treatment compared to prior treatment plans. Event-free survival (EFS) and overall survival (OS) rates were 88% and 96%, respectively. There was no unexpected toxicity. These studies (COG-P9641 and COG-A3961) have established a new standard of care for children in North America with neuroblastoma. (Risk groups are defined in Table 1 in the Stage Information section of this summary.)
Chemotherapy is given for four to eight cycles (12 to 24 weeks) and consists of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen. Radiation therapy is reserved for patients with symptomatic life-threatening or organ-threatening tumor that does not respond rapidly enough to chemotherapy and/or surgery.
There is considerable variation in outcome, and, therefore, in treatment for children with stage 3 disease (tumor involving both sides of the midline by virtue of either invasion into normal tissues or lymph node metastasis). Infants aged 1 year and younger have a greater than 80% cure rate while older children have a cure rate of 50% to 70% with current, relatively intensive therapy.[2,3,4,5] In one study, those with favorable compared with unfavorable biological features (i.e., INPC and MYCN gene amplification) had EFS rates of almost 100% and about 50%, respectively.[6,7,8] In cases of abdominal neuroblastoma thought to involve the kidney, nephrectomy should not be undertaken before a trial of chemotherapy has been given.
Whether initial chemotherapy is indicated for all intermediate-risk infants with localized neuroblastoma is controversial. A German prospective clinical trial enrolled 340 infants aged 1 year or younger whose tumors were stage 1, 2, or 3, histologically verified, and lacked amplification of MYCN. Chemotherapy was given at diagnosis to 57 infants with organs threatened by tumor. The tumor was completely resected or nearly so in 190 infants who underwent low-risk surgery. A total of 93 infants whose tumors were not resectable without high-risk surgery due to age or organ involvement were observed without chemotherapy. Further surgery was avoided in 33 infants and chemotherapy was avoided in 72 infants. Some degree of spontaneous tumor regression occurred in nearly half the infants. Overall survival of the 93 infants was 99%.
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%),[11,12] with outcome particularly dependent on MYCN amplification and tumor cell ploidy (e.g., hyperdiploidy confers a favorable prognosis while diploidy predicts early treatment failure).[3,13] Infants aged18 months and younger at diagnosis with INSS stage 4 neuroblastoma who do not have MYCN gene amplification are categorized as intermediate risk.[14,15,16,17] The need for chemotherapy in all asymptomatic infants with stage 4 disease is somewhat controversial. Stage 4 and 4S infants (N = 170) aged 12 months or younger and Stage 4 asymptomatic infants (N = 14) enrolled in an International Society of Pediatric Oncology (SIOP) trial had one of the following characteristics: 1) metastases of the 4S pattern and including positive bone metastases by iodine I 131 metaiodobenzylguanidine (131 I-MIBG) or technetium bone scan without cortical bone abnormality by computer tomography (CT) scan or plain x-ray, or 2) primary tumor stage 3 with 4S metastatic pattern. These infants were observed without initial chemotherapy, and in cases with surgical risk factors, the infants were observed without resection of the primary tumor. Although three infants underwent tumor progression, all survived. Although many were eventually treated with chemotherapy at the investigator's choice, a substantial number of infants received no chemotherapy.
A small, single-institution study suggested that all MYCN-nonamplified INSS stage 3 tumors may be treated with surgical resection followed by observation without chemotherapy.[Level of evidence: 3iiDi]
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, International Neuroblastoma Pathology Classification [INPC] system, and DNA ploidy) (COG-P9641 and COG-A3961). (Low-, intermediate- and high-risk groups are defined in Table 1 in the Stage Information section of this summary.)
For children with high-risk neuroblastoma, long-term survival with current treatments is about 30%. Children with aggressively treated, high-risk neuroblastoma may develop late recurrences, some more than 5 years after completion of therapy.[1,2] 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. In addition, patients on this study were subsequently randomized to stop therapy or to receive 6 months of 13-cis-retinoic acid. 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. The 5-year EFS and overall survival (OS) for patients treated with both HSCT and retinoic acid is 50% and 59%, respectively. The 10-year OS remains greater than 50%. However, these patients were selected for having completed HSCT without developing progressive disease. Based on these results, clinical trials have built upon autologous HSCT and 13-cis -retinoic acid for high-risk neuroblastoma. Compared to retinoic acid alone, the addition of chimeric anti-GD2 antibody ch14.18 combined with granulocyte macrophage-colony stimulating factor and interleukin-2 improves EFS for high-risk neuroblastoma patients in remission after stem cell transplant (SCT) (COG-ANBL0032 and COG-ANBL0931).
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.[7,8,9,10,11] The use of radiation therapy to consolidate local control after surgical resection is recommended.; [Level of evidence: 3iiA]
Assessment of risk for low-stage MYCN-amplified neuroblastoma is controversial because it is so rare. A study of 87 INSS stage 1 and 2 patients pooled from several clinical trial groups demonstrated no effect of age, stage, or initial treatment on outcome. The EFS and OS were 53% and 72%, respectively. Survival was superior in patients whose tumors were hyperdiploid rather than diploid (EFS 82% ± 20% vs. 37% ± 21%; OS 94% ± 11% vs. 54% ± 15%). The overall EFS and OS for infants with stage 4 and 4S disease and MYCN-amplification was only 30% at 2 to 5 years post-treatment in a European study.
Patients classified as high risk receive treatment with an aggressive regimen of combination chemotherapy consisting of very high drug doses, generally termed induction. Drugs often used include cyclophosphamide, ifosfamide, cisplatin, carboplatin, vincristine, doxorubicin, etoposide, and topotecan. COG has completed a pilot study of induction demonstrating the feasibility of substituting two cycles of topotecan and cyclophosphamide for two cycles of vincristine, cyclophosphamide, and doxorubicin. 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). Whether or not harvested stem cells should be purged of neuroblastoma cells has been studied in a randomized fashion. There was no advantage to purging. Two or more sequential cycles of myeloablative chemotherapy and stem cell rescue given in a tandem fashion has been studied and feasibility was established.[7,18] It is now under clinical evaluation in COG. Radiation to the primary tumor site should be undertaken whether or not a complete excision was obtained. The optimal dose of radiation therapy has not been determined. 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.[3,5] For high risk-patients in remission following HSCT, compared to retinoic acid alone, chimeric anti-GD2 antibody ch14.18 combined with granulocyte-macrophage colony stimulating factor and interleukin-2 and given in concert with retinoic acid improves EFS.
Treatment Options Under Clinical Evaluation
The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
Age, International Neuroblastoma Staging System (INSS) stage, MYCN status, and time from diagnosis to first relapse are significant prognostic factors for postrelapse survival. The Children's Oncology Group (COG) experience with recurrence in intermediate-risk neuroblastoma is that the majority of recurrences can be salvaged, as demonstrated by a 3-year event free survival (EFS) of 88% and an overall survival (OS) of 96%. When neuroblastoma recurs in a child originally diagnosed with high-risk disease and is widespread, the prognosis is usually poor despite additional intensive therapy.[1,3,4,5]
In selected patients originally diagnosed with low- or intermediate-risk disease, recurrence may be treated successfully with limited intervention. The combination of cyclophosphamide plus topotecan has been active in patients with recurrent or refractory disease who have not received topotecan previously. Iodine I 131 metaiodobenzylguanidine (131 I-MIBG) therapy is also active in patients with recurrent or refractory neuroblastoma. 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. Because upfront treatment for newly diagnosed patients does not adequately treat the CNS, the CNS has emerged as a sanctuary site leading to relapse.[8,9] CNS relapses have been almost always fatal with a median time to death of 6 months. Current treatment approaches generally include eradicating bulky and microscopic residual disease in the CNS as well as minimal residual systemic disease that may herald further relapses. Neurosurgical interventions serve to decrease edema, control hemorrhage, and remove bulky tumor prior to starting radiation therapy. Compartmental radioimmunotherapy using intrathecal radioiodinated monoclonal antibodies has been tested in patients with recurrent metastatic CNS neuroblastoma following surgery, craniospinal radiation therapy, and chemotherapy.
In North America, the COG investigated a risk-based neuroblastoma treatment plan that assigned all patients to a low-, intermediate-, or high-risk group based on age, INSS stage, and tumor biology (i.e., MYCN gene amplification, International Neuroblastoma Pathology Classification [INPC] system, and DNA ploidy). Treatment of recurrent disease was determined by risk group at the time of diagnosis (refer to Table 1), extent of disease at recurrence, patient age at recurrence, and the tumor biology. If tumor was unavailable for biological studies at recurrence, the biology of the tumor at time of diagnosis was used to help determine treatment.
Recurrent Neuroblastoma in Patients Initially Classified as Low Risk
(Risk categories are defined in Table 1 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 as used in prior COG trials (COG-P9641 and COG-A3961). Older children with local recurrence with either unfavorable INPC 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. 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 1 in the Stage Information section of the summary) and younger than 1 year at recurrence, whether the patient has INSS stage 1, 2, or 4S at the time of diagnosis, may be treated according to tumor biology as defined in the prior COG trials (COG-P9641 and COG-A3961):
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, as used in a prior COG trial (COG-P9641).
Any child initially categorized as low risk who is older than 1 year at the time of metastatic recurrent or progressive disease who is not in the stage 4S pattern 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. These modalities are commonly employed in the treatment of patients with a recurrence that augurs a poor prognosis.
Recurrent Neuroblastoma in Patients Initially Classified as Intermediate Risk
(Risk categories are defined in Table 1 in the Stage Information section of the summary.)
The current standard of care is based on the experience from the COG Intermediate-Risk treatment plan (COG-A3961). Local regional recurrence of neuroblastoma with favorable biology that occurs more than 3 months after completion of 12 weeks of chemotherapy may be treated surgically. If resection is less than near total, then 12 additional weeks of chemotherapy may be given. Chemotherapy consists of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen, as used in a prior COG trial (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 retinoic acid may improve outcome of newly diagnosed patients with a poor prognosis. These modalities are commonly employed in the treatment of patients with a recurrence that augurs a poor prognosis.
Recurrent or Refractory Neuroblastoma in Patients Initially Classified as High Risk
Any recurrence in patients initially classified as high risk signifies a very poor prognosis. Data from three consecutive German high-risk neuroblastoma trials described 253 children relapsing after intensive chemotherapy with autologous stem cell transplantation (SCT) who had a 5-year OS rate of less than 10%. Only 23 of the 253 patients eventually proceeded to a second autologous SCT following retrieval chemotherapy. Among these patients, the 3-year OS rate was 43%, but the 5-year OS rate was less than 20%. This shows that intensive second-line therapy is feasible, although even with intensive therapy and second autologous SCT, only a small minority of relapsed high-risk neuroblastoma patients may benefit.[Level of evidence: 3iiiA] Whether this intense therapeutic approach is better than other salvage therapy approaches is unknown. Topotecan alone and in combination with cyclophosphamide or etoposide has been used in patients with recurrent disease who did not receive topotecan initially.[14,15]; [Level of evidence: 1A] High-dose carboplatin-irinotecan-temozolomide has been used in patients resistant or refractory to regimens containing topotecan. The combination of irinotecan and temozolomide had a 15% response rate in one study.[Level of evidence: 2A]
For children with recurrent or refractory neuroblastoma, 131 I-MIBG is an effective palliative agent and should be considered.; [Level of evidence: 3iiiA]
Additionally, phase I or II clinical trials are appropriate and should be considered.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent neuroblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
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 text to state that ATRX is involved in epigenetic gene silencing and telomere length; ATRX mutation without MYCN amplification is associated with age at diagnosis in adolescents and young adults with metastatic neuroblastoma (cited Cheung et al. as reference 48).
Added Schleiermacher et al. as reference 56.
Revised text to state that before resection of the primary tumor, bone should be assessed by metaiodobenzylguanidine (MIBG) scan, which is applicable to all sites of disease, and by technetium 99 scan if the results of the MIBG scan are negative or unavailable. Also added text to state that additional imaging of isolated or equivocal positive lesions is recommended if the primary tumor does not take up MIBG (cited Taggart et al. as reference 5).
Revised text for stage 4S to state that it is considered localized primary tumor, as defined for stage 1, 2A, or 2B, with dissemination limited to skin, liver, and/or bone marrow (limited to infants younger than 18 months).
Treatment Option Overview
Added text to state that the Children's Oncology Group (COG) study COG-P9641 demonstrated excellent survival in patients with asymptomatic, low-risk, stage 2A or 2B disease with favorable histology (cited Strother et al. as reference 3).
Revised text to state that for children with recurrent or refractory neuroblastoma, 131 I-MIBG is an effective palliative agent and should be considered (cited Johnson et al. as reference 19 and level of evidence 3iiiA).
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of neuroblastoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Neuroblastoma Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
National Cancer Institute: PDQ® Neuroblastoma Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/neuroblastoma/HealthProfessional. Accessed <MM/DD/YYYY>.
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Coping with Cancer: Financial, Insurance, and Legal Information page.
More information about contacting us or receiving help with the Cancer.gov Web site can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the Web site's Contact Form.
For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 8:00 a.m. to 8:00 p.m., Eastern Time. A trained Cancer Information Specialist is available to answer your questions.
The NCI's LiveHelp® online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 8:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer.
Write to us
For more information from the NCI, please write to this address:
Search the NCI Web site
The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use the search box in the upper right corner of each Web page. The results for a wide range of search terms will include a list of "Best Bets," editorially chosen Web pages that are most closely related to the search term entered.
There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.
The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237).
Last Revised: 2012-11-16
How this information was developed to help you make better health decisions.
Healthwise, Healthwise for every health decision, and the Healthwise logo are trademarks of Healthwise, Incorporated.
Call First Nurse 24 Hours a Day for free health care advice, resources and referrals!
Ames: 515-239-6877In Iowa: 800-524-6877
Search health information online in our Mulimedia Health Library.
Mary Greeley consistently delivers high quality patient care.
Patient Privacy |
Net Learning for Employees |
MGMC PACS for Physicians
1111 Duff Avenue Ames, IA 50010 - 515-239-2011 - firstname.lastname@example.org
©2014 Mary Greeley Medical Center - All rights reserved.