Neuroblastoma

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56 Neuroblastoma

Katherine K. Matthay, MD, Marnee M. Spierer, MD, Michael P. La Quaglia, MD, FACS, FAAP, FRCS (Ed Hon), Suzanne L. Wolden, MD

Epidemiology, Screening, Etiology, and Genetics

Neuroblastoma is the most common extracranial solid tumor in children and the most common malignancy of infants. Approximately 650 new cases are diagnosed annually in the United States, with an incidence of 0.9 per 100,000.¹ The tumor accounts for 8% to 10% of all childhood cancers and is slightly more common in boys than in girls, with a male-to-female ratio of 1.1 : 1. Review of more than 3000 patients registered on studies at Pediatric Oncology Group (POG) institutions from 1990 to 2000 and at Children’s Cancer Group (CCG) institutions from 1991 to 1995 show the median age at diagnosis is 17.3 months; 40.1% are younger than 1 year of age, 89.4% are younger than 5 years of age, and 97.8% are younger than 10 years of age.²

Neuroblastoma arises from primitive adrenergic neuroblasts of neural crest tissue. This tissue forms columns that are the precursors of spinal ganglia, dorsal spinal nerve roots, and chromaffin cells of the adrenal medulla. Thus, the majority of neuroblastoma cases occur in an anatomic distribution consistent with the location of neural crest tissue. The location of tumors at the time of diagnosis varies with age (Table 56-1). The adrenal gland is the most common location for the development of neuroblastoma, accounting for 35% of cases (Figure 56-1). Paraspinal ganglia in the low thoracic and abdominal chains constitute 30% of all cases, the posterior mediastinum accounts for 19%, and pelvic and cervical ganglia account for 2% or fewer.³ It has been reported that microscopic neuroblastic nodules, resembling neuroblastoma in situ, were found frequently at autopsy in infants younger than 3 months of age who died of unrelated causes.⁴ Initially, this was believed to mean the incidence of neuroblastoma was much higher during early infancy, but these tumors regressed spontaneously and were never clinically detected. However, studies have demonstrated that these nodules occur uniformly in all fetuses, peak between 17 and 20 weeks of gestation, and gradually regress by the time of birth or shortly thereafter.⁵ Thus, the development and subsequent regression of neuroblastoma nodules most likely represents a normal embryologic event, and the development of clinically detectable neuroblastoma is a consequence of a disruption of this process.

Table 56-1 Primary Sites of Neuroblastoma According to Age

FIGURE 56-1 • Axial computed tomography scan with contrast showing a typical primary adrenal tumorin a patient with high-risk neuroblastoma.The extensive tumor encases the major blood vessels and us ubseparable form the para-aortic lymph nodes. Adjacent organs are displaces but not invaded.

Screening Studies

The most extensive data regarding neuroblastoma screening come from Japan, Germany, and a combined Canadian and U.S. study. Neuroblastoma screening has been in place in Japan since 1981. During a 12-year screening period, the incidence rate in infants younger than 1 year of age rose from 28 to 260 per million, but there was no reduction in the incidence rate in children older than 1 year of age.⁶ The Japanese have also noted a reduction in overall mortality since the inception of mass screening.⁷ However, this reduced mortality may reflect the improving treatments that have arisen during the same time and not be a true reflection of the benefits of screening. In Canada, they have also seen an increase in the incidence of early stage disease in children less than 1 year of age.⁸ There has been no reduction in the incidence of advanced stage disease in children older than 1 year of age or in the mortality from neuroblastoma based on population screening at 3 weeks and 6 months of age in Canada.⁹ Screening at 1 year of age in Germany also did not reduce the incidence of advanced-stage disease in children or the mortality of children diagnosed with neuroblastoma.¹⁰ In addition, the psychological affect of false-positive tests and the potential risk incurred by interventions performed on clinically insignificant tumors has not been fully quantified, but could be significant. Many of the tumors detected by mass screening have now been observed, and more than one-third spontaneously regress.¹¹ Thus the benefits of mass screening seem limited and do not appear to warrant the costs.

Genetics

The cause of neuroblastoma is unknown in most cases. No prenatal or postnatal exposure to drugs, chemicals, or radiation has unequivocally demonstrated an increased incidence of neuroblastoma.¹²^,¹³ Genetics, however, play an extremely important role. A case control study in France (ESCALE) showed a positive association between congenital malformation and neuroblastoma, particularly in infants less than one year of age.¹⁴ Familial neuroblastoma is also well described and presents at an earlier median age (9 months versus 22 months for sporadic cases). At least 20% of patients with familial neuroblastoma have bilateral or multifocal disease.¹⁵ Genetic studies of hereditary disease have been impeded by the rarity of the condition and the small size of pedigrees caused by the lethality of neuroblastoma in early childhood. A family history of neuroblastoma is obtained in only approximately 1% of patients. Studies of such families suggest locus heterogeneity; no commonly mutated gene has been identified, and the penetrance appears to be low.¹⁶ Genetic loci in different families include germline mutations in PHOX2B, seen in patients with associated abnormalities such as congenital hypoventilation syndrome or Hirschsprung disease, and abnormalities of the short arm of 16.¹⁷^–²⁰ Neuroblastoma has also been seen occasionally in patients with constitutional chromosomal rearrangements, including deletions overlapping putative tumor suppressor loci at chromosome bands 1p36 and 11q14-23.²¹^–²³ Thus neuroblastoma predisposition is genetically heterogeneous, and initiation of tumorigenesis may require multiple alterations. A recent study using whole-genome single-nucleotide polymorphism analysis revealed a common genetic variation at chromosome band 6p22 that is associated with susceptibility to neuroblastoma, particularly with high-risk disease.²⁴ Very recently, a number of studies have appeared showing that germline mutations or amplifications in the ALK gene are found in approximately 10% of sporadic neuroblastoma and germline mutations in the majority of heritable neuroblastoma.²⁵

Understanding neuroblastoma on the cellular and molecular level has helped to risk-stratify patients in terms of treatment options and predictability of response. Genetic gains and losses have proven to be critical in determination of prognosis. For example, MYCN oncogene amplification, loss of chromosomal material on 1p and 11q, and overall chromosomal ploidy (see later discussion) correlate with outcome and are therefore included in the risk stratification that dictates current treatment.

Deletion of the distal short arm of chromosome 1 (1p) was the first described genetic mutation in neuroblastoma tumors and is the most consistently reported abnormality, occurring in 70% to 80% of the karyotyped near-diploid tumors.²⁶ This most likely represents a deletion (and loss of heterozygosity [LOH]) of a tumor suppressor gene and is found more commonly in advanced disease. Homogeneous staining regions (HSRs) and double-minute chromatin bodies (dmins) are a manifestation of gene amplification. Both of these are derived from the distal short arm of chromosome 2 (2p), which contains the proto-oncogene MYCN.²⁷

MYCN amplification occurs in roughly 25% of primary neuroblastoma cases, 5% to 10% in patients with low stages of disease and stage IV-S, and 30% to 40% in patients with advanced disease.²⁸ The MYCN proto-oncogene is derived from the c-myc viral oncogene and, as mentioned previously, is located on 2p, thus correlating with the cytogenetic abnormalities of HSRs and dmins. If it is going to occur, MYCN amplification is almost always present by the time of diagnosis. This suggests that it is an intrinsic property of a subset of aggressive tumors with a poor prognosis.²⁷ The development of an overexpressing TH-MYCN transgenic mouse that spontanously develops neuroblastoma is further evidence of a role of this oncogene in tumorigenesis.²⁹ Molecular studies have shown a strong correlation between 1p LOH and MYCN, suggesting these two genetic events may be related.²⁶

Chromosomal ploidy is another marker of prognosis that is particularly useful in infants younger than 18 months of age. Near-diploid or pseudodiploid tumors have near-normal nuclear DNA content but often have structural chromosomal abnormalities, including MYCN amplification. Hyperdiploid or near-triploid tumors typically lack MYCN amplification and 1p deletion and therefore have an excellent prognosis.³⁰^,³¹

Telomerase activity has been correlated with MYCN amplification and poor outcomes while increased expression of high-affinity nerve growth factor receptor (gp140TRK-A) has been associated with favorable outcomes. Conversely, the lack of expression of gp140TRK-A has been associated with MYCN amplification and poor survival.²⁷

Pathologic Conditions

Neuroblastoma is a classic “small round blue cell” tumor. Others include Ewing sarcoma, non-Hodgkin lymphoma, primitive neuroectodermal tumors, and rhabdomyosarcoma. Histologic subtypes, including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma, represent different points along the maturation pathway in order of increasing differentiation. The typical neuroblastoma is composed of small, uniform cells containing dense, hyperchromatic nuclei and scant cytoplasm. The presence of neuritic processes (neuropil) is pathognomonic. Homer-Wright pseudorosettes, neuroblasts surrounding areas of eosinophilic neuropil, are seen in 15% to 50% of cases. Ganglioneuromas are composed primarily of mature ganglion cells, neuropil, and Schwann cells, and behave in a benign fashion. Ganglioneuroblastomas have histopathologic characteristics of both neuroblastomas and ganglioneuromas. Because histopathologic features may vary within any single tumor, multiple sections must be examined.³²^,³³ Distinguishing neuroblastomas from other small round blue cell tumors requires special techniques including immunohistochemistry and electron microscopy. Neuroblastoma stains with monoclonal antibodies that recognize neuron-specific enolase, synaptophysin, and neurofilament. Electron microscopy reveals neurosecretory granules that contain catecholamines, microfilaments, and parallel arrays of microtubules within the neuropil.³⁴

Although many different classification systems have been used to help define the prognosis for neuroblastoma, the International Neuroblastoma Pathology Commmittee (INPC) defined and tested a modification of the Shimada system, now widely accepted and validated.³² It is divided into favorable and unfavorable prognostic groups based on histologic category, age, amount of Schwann cell stroma, degree of differentiation; and the mitosis-karyorrhexis index. Each of these features are also independently prognostic.³⁵ In addition, nodular versus diffuse histologic pattern is noting macro nodules, which tend to be associated with a poor prognosis compared with intermixed nodules. Characteristics of the INPC system are listed in Table 56-2.

Table 56-2 The Shimada System

Clinical Presentation

As mentioned previously, primary tumor location varies with age (see Table 56-1). Extent of disease is also age-dependent; the majority of children younger than 1 year of age have localized disease at the time of diagnosis, whereas the majority of children older than 1 year of age have disseminated disease (Table 56-3). Signs and symptoms of neuroblastoma depend on location of the primary tumor but can also reflect lymph node status and metastatic spread. Bone marrow, bone, liver, and skin are the most common sites for hematogenous spread. Rarely, disease spreads to the lungs and brain. Table 56-4 lists the associated signs and symptoms for each anatomic area of disease. Because of the type of catecholamines secreted from most neuroblastomas, hypertension, flushing, and tachycardia are uncommon symptoms. Other rare paraneoplastic symptoms are secretory diarrhea, resulting from secretion of vasoactive intestinal peptide,³⁶ and opsoclonus-myoclonus ataxia syndrome, most likely resulting from antineuronal antibodies that cross-react with cerebellar tissue.³⁷

Table 56-3 Extent of Disease at Diagnosis According to Age

Table 56-4 Signs and Symptoms of Disease Based on Anatomic Location of Primary Tumor and Metastases

Primary Site	Signs and Symptoms
Abdomen	• Abdominal distension and discomfort • Large, irregular, firm palpable mass, often crossing midline

Cervical

• Unilateral neck mass causing Horner syndrome

• Often misdiagnosed as infection and diagnosed after incision and drainage

Thoracic

• Often diagnosed incidentally on CXR that is done to evaluate infection or trauma

• Respiratory compromise

• Superior vena cava syndrome if tumor is large

Pelvis

• Bowel and bladder disturbances

Paraspinal location in cervical, abdominal, thoracic, or pelvic areas

• Tumor may have a “dumbbell” configuration; the tumor extends through the neural foramina and presents with a mass lesion in the spinal canal that may cause spinal cord compression

Metastatic Disease General

• Fever, weight loss, weakness, failure to thrive

Liver

• Respiratory compromise caused by upward pressure on diaphragm (Pepper syndrome); frequently in infants

Bone

• Pain

• Refusal to walk

• Skull masses

• Proptosis with orbital ecchymosis (raccoon eyes) caused by retrobulbar and orbital infiltration

Skin

• Nontender, blue-tinged nodules (blueberry muffin sign); seen in infants with stage IV-S tumors

Bone marrow

• Pancytopenia resulting in infection, pallor, lethargy, bleeding

• Bone pain

Brain

• Typically meningeal, may have suture separation

Paraneoplastic Syndromes

• Opsoclonus-myoclonus-truncal ataxia syndrome (myoclonic jerking and random eye movements); associated with early stage neuroblastoma and may persist after cure

• Diarrhea associated with hypokalemia and dehydration caused by tumor secretion of VIP, most common in ganglioneuroblastomas and ganglioneuromas

Diagnostic and Staging Studies

Diagnosing and staging neuroblastomas requires several imaging modalities. The primary tumor is typically imaged with plain films or ultrasound of the abdomen and thorax and computed tomography (CT) or magnetic resonance imaging (MRI). The classic sign seen on an abdominal plain film is calcification within a suprarenal soft tissue mass. Calcifications are seen in roughly 85% of patients. A mediastinal mass will be evident on the thoracic plain film. Both CT and MRI provide accurate three-dimensional (3-D) measurements of tumor volume and can assess resectability.

In terms of regional and distant disease, CT and MRI can assess nodal disease, hepatic metastases, and intraspinal extension. CT and MRI are also useful in determining whether metastases to the skull, orbit, mandible, or brain are present. Conventional radiographs may be used to assess painful bone metastases, but the standard and most sensitive agent for detection of osteomedullary involvement is ¹²³I-metaiodobenzylguanidine (MIBG) scan, which concentrates as well in primary tumors and soft tissue metastases. MIBG is a guanethidine derivative and an analogue of norepinephrine, and therefore specifically taken up and stored in tumors of sympathetic origin, which express the norepinephrine transporter.³⁸ Because of the high specificity and sensitivity in neuroblastoma, ¹²³I-MIBG has superseded the use of technetium bone scans for the detection of skeletal metastases in the majority of children with neuroblastoma tumors, which take up the chemical in greater than 90% of cases, and has been recommended by the last international consensus conference as a standard element of staging and response evaluation.³⁹^,⁴⁰ A ^99mTc bone scan is indicated for detection of bone metastases in the occasional patient whose tumor does not take up MIBG. ¹⁸F-deoxyglucose positron emission tomography is also a useful complementary imaging modality that reflects the metabolic activity of primary and metastatic lesions, but its exact role in staging and response is still under investigation.⁴¹^,⁴² Metastatic lesions are most often located in the periorbital region, in the metaphyses of long bones, and in the axial skeleton. Complete staging includes two bilateral posterior iliac crest bone marrow aspirates and biopsies. A single positive result is sufficient for the documentation of bone marrow involvement.³⁹

Excess catecholamines are produced in nearly 90% of cases. Therefore, part of the neuroblastoma workup includes measuring urine catecholamines and their metabolites, specifically norepinephrine, vanillylmandelic acid, 3-methoxy-4-hydroxylphenylglycol, or homovanillic acid. Urine or serum dopamine may be measured. Urinary catecholamines are often given as ratios to urinary creatinine.⁴³

According to the international criteria for diagnosing, staging, and assessing response to treatment, the diagnosis of neuroblastoma is established under one of the following circumstances: (1) An unequivocal pathologic diagnosis is made from tumor tissue by light microscopy (with or without immunohistology, electron microscopy, increased urine or serum catecholamines or metabolites), or (2) Bone marrow aspirate or trephine biopsy contains unequivocal tumor cells and urine or serum catecholamines or metabolites are increased.³⁹

Staging and Prognostic Factors

Several different staging systems have been used in neuroblastoma. The Evans and D’Angio classification, historically used by the CCG classification, is the original system. It is based on the extent of the primary tumor and the presence or absence of distant disease. It includes stages I, II, III, IV, and IV-S.⁴⁴ The POG used an alternative staging system that included initial resectability of the primary and lymph node status, although the importance of lymph node involvement in neuroblastoma is unclear. It includes stages A, B, C, D, and D-S.⁴⁵^,⁴⁶ The differences between these two systems can be substantial, depending on the stage. Therefore, a group of investigators met at two international conferences to arrive at a consensus regarding neuroblastoma staging. Criteria for diagnosing, staging, and assessing response to treatment was set forth, and the International Neuroblastoma Staging System (INSS) is now generally accepted as the standard staging system (Table 56-5). To interpret the literature, it is important to recognize the similarities between the INSS and the other two major staging systems. Stage 1 is similar to stages I and A. Stage 4 is essentially the same as stages IV and D, and stage 4S is the same as IV-S and D-S. The greatest disagreement concerns the middle stages (II and III; B and C). Therefore, the INSS divided stage 2 into 2A (incompletely excised tumor) and 2B (ipsilateral lymph node involvement) to evaluate whether patients with 2B disease behave more like stage 2A patients or stage 3 patients. In addition to revising staging, the INSS delineated standard definitions of response to treatment (Table 56-6). These revisions and standard definitions were designed to make interpreting the literature and making management decisions uniform.³⁹

Table 56-5 International Neuroblastoma Staging System

STAGE 1: Localized tumor with complete gross excision, with or without microscopic residual disease; representative ipsilateral lymph nodes negative for tumor (nodes adherent to and removed with the primary tumor may be positive)

STAGE 2A: Localized tumor with incomplete gross excision; representative nonadherent lymph nodes negative for tumor microscopically

STAGE 2B: Localized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumor; enlarged contralateral lymph nodes must be negative microscopically

STAGE 3: Unresectable unilateral tumor infiltrating across the midline,* with or without regional lymph node involvement; or localized unilateral tumor with contralateral regional lymph node involvement; or midline tumor with bilateral extension by infiltration (unresectable) or by lymph node involvement

STAGE 4: Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, or other organs (except as defined in stage 4S)

STAGE 4S: Localized primary tumor (as defined for stage 1, 2A, or 2B), with dissemination limited to skin, liver, and/or bone marrow ^† (limited to infants <1 year of age)

* The midline is defined as the vertebral column. Tumors originating on one side and crossing the midline must infiltrate to or beyond the opposite side of the vertebral column.

† Marrow involvement in stage 4S should be minimal (i.e., <10% of total nucleated cells identified as malignant on bone marrow biopsy or on marrow aspirate). More extensive marrow involvement is considered to be stage 4. The metaiodobenzylguanidine scan (if performed) should be negative in the marrow.

From Brodeur GM, Seeger RC, Barrett A, et al: International criteria for diagnosis, staging and response to treatment in patients with neuroblastoma, J Clin Oncol 6:1874–1881, 1988; and Brodeur GM, Pritchard J, Berthold F, et al: Revisions in the international criteria neuroblastoma diagnosis, staging and response to treatment, J Clin Oncol 11:1466–1477, 1993.

Table 56-6 INSS Classification of Responses to Therapy

Response	Metastatic Sites/Markers	Primary Tumor
Complete response (CR)	No tumor	No tumor; catecholamines normal
Very good partial response (VGPR)	Decreased by 90%-99%	No tumor; catecholamines normal; residual ⁹⁹Tc
Partial response (PR)	Decreased by >50%	All measurable sites decreased by >50%
	Bones and bone marrow	Number of positive bone sites decreased by >50%; no more than one positive bone marrow site allowed*
Mixed response (MR)	No new lesions	>50% reduction of any measurable lesion (primary or metastases) with <50% reduction in any other; <25% increase in any existing lesion
No response (NR)	No new lesions	<50% reduction but <25% increase in any existing lesion
Progressive disease (PD)	Any new lesion	Increase of any measurable lesion by >25%; previous negative marrow biopsy positive for tumor

INSS, International Neuroblastoma Staging System.

* One positive marrow aspirate or biopsy allowed for PR if this response represents a decrease from the number of positive sites at diagnosis.

From Brodeur GM, Pritchard J, Berthold F et al: Revisions in the international criteria neuroblastoma diagnosis, staging and response to treatment, J Clin Oncol 11:1466–1477, 1993.

A more recent international consensus conference was held in 2005 to further refine the staging and risk classification for neuroblastoma. This International Neuroblastoma Risk Group (INRG) Task Force proposed a simpler staging, based on whether or not a tumor had image-defined risk factors for surgery (L1: no risk factors; L2: risk factors present),⁴⁷ and whether or not there was metastatic disease.⁴⁸ In addition, further refinements were made to the response criteria, to incorporate semiquantitative scoring for the MIBG scan⁴⁹^,⁵⁰ and standardization of bone marrow disease using immunocytology and real time–polymerase chain reaction.⁵¹^,⁵²

Treatment for neuroblastoma is based on risk stratification. Therefore, it is essential to understand the clinical and biologic variables predictive of disease outcome. The most important clinical risk factors are disease stage and age at diagnosis. Infants younger than 18 months have a more favorable outcome compared with older children with the same disease stage, as shown in a retrospective analysis of 3666 patients (1986 to 2001) from patients in the Children’s Oncology Group (COG) with documented follow-up data. Using a cut-off of 460 days of age, the 4-year event-free survival (EFS) for those younger than 460 days was 82% versus 42% for those older than 460 days (P < 0.0001); using a cut-off of 573 days, the 4-year EFS was 74% and 38%, respectively (P < 0.0001). The 18-month (547-day) cut off was chosen for convenience, because the difference in EFS was slight over the range of 15 to 18 months. MYCN gene amplification and stage 4 were also more frequent in the older patients, but even after adjustment for these factors, age remained significant.⁵³ Similarly, several biologic variables have prognostic significance. A new histopathologic classification, the INPC, based on the original Shimada system, is now the international standard. Like the Shimada system, this classifies patients into favorable and unfavorable groups based on age, amount of Schwann cell stroma, degree of differentiation, and mitotic-karyorrhectic index (see Table 56-2). Further analyses of an international database of 8800 neuroblastoma patients showed that each of the components of the INPC had independent prognostic significnace within a given age group.³⁵ Serum markers including ferritin, neuron-specific enolase, lactate dehydrogenase, and GD2 each have prognostic value (increased levels associated with worse prognosis); however, they are not currently used in risk stratification because their multivariate importance is less significant than other factors. Unfavorable genetic prognostic markers that are most significant in multivariable analysis include MYCN gene amplification, diploidy, and11q LOH. Other genetic changes with prognostic value in univariate analysis include 1p LOH, TRKA expression, and 17q additions, though these are not currently used in risk stratification.³⁵

Standard Therapeutic Approaches

Treatment for neuroblastoma may include surgery, radiation therapy, and chemotherapy and myeloablative therapy with autologous hematopoietic cell transplant (AHCT). The degree to which each is used is based on the risk-stratified group to which the patient belongs. General descriptions of the roles of all three modalities are presented, followed by detailed discussion on the subject of risk-stratified treatment.

Surgery

Surgery is used to establish the diagnosis, provide tissue for biologic studies, determine stage, establish vascular access for chemotherapy, and accomplish therapeutic excision of the primary tumor and involved regional lymph nodes. The operative approach depends on the initial risk evaluation, which in turn is a function of tumor location, mobility, relationship to major vessels and nerves, ability to control blood supply, presence of distant metastases, and overall prognosis. More recently, image-defined risk factors have been used to determine resectability.⁵⁴ These risk factors are based in the main on vascular or neural encasement as determined by imaging studies. In patients with high-risk disease, initial surgery is directed toward diagnosis, staging, vascular access, and adequate tissue sampling for diagnostic studies. Biopsy of the liver at the time of initial surgery is proposed for patients with abdominal tumors without clinical evidence of metastatic disease.²

Sacrifice of vital structures to achieve resection at diagnosis should be avoided. Patients with low- or intermediate-risk disease may undergo initial resection of the primary site and regional involved lymphatics, or receive neoadjuvant chemotherapy followed by attempted resection.

Nonadherent, intracavitary lymph nodes should be sampled, including lymph nodes superior and inferior to the primary tumor. Lymph nodes adherent to the primary tumor have little relevance in predicting outcome but should be removed if grossly involved. High-risk patients always receive neoadjuvant chemotherapy prior to primary site resection as this increases the chance of complete removal and reduces the risk of complications, especially nephrectomy.⁵⁵ In high-risk patients, gross total resection of the primary tumor site and involved regional lymphatics seems to be associated with improved outcome, and especially improved local control (LC).⁵⁶^–⁵⁷

Radiation Therapy

Neuroblastoma is a relatively radiosensitive tumor. Data collected on neuroblastoma cell line show a D0 of 1.04 Gy and an n of 1.36, which is much more radiosensitive than other mammalian tumors.⁵⁸ However, despite its radiosensitivity in the laboratory, its clinical response to irradiation is variable, which may be attributed to its variation in genomic amplification of MYCN.⁵⁹ Radiation therapy is indicated mainly for high-risk disease, including bulky, unresectable, residual, and metastatic disease, or for palliation of painful recurrent lesions. In rare cases, radiation may be used for intermediate- or low-risk neuroblastoma, including symptomatic spinal cord compression unresponsive to chemotherapy, or life-threatening respiratory distress or abdominal distention in an infant with 4S neuroblastoma resulting from hepatomegaly. Doses have ranged from 15 to 30 Gy in 1.5 to 4 Gy per fraction. The role of radiation therapy for patients with locoregional disease is not clearly defined. A study by Paulino and colleagues⁶⁰ evaluated locoregional control in infants with neuroblastoma who received radiation therapy. They reported 53 children younger than 1 year old who were retrospectively staged according to the INSS guidelines; 8 had stage 1, 7 stage 2A, 6 stage 2B, 15 stage 3, 6 stage 4, and 11 stage 4S. The primary tumor was located in the adrenal gland in 26 (49%), abdomen and nonadrenal in 14 (26%), thorax in 9 (17%), neck in 2 (4%), and pelvis in 2 (4%). All patients, except 11 with stage 4S and 4 with stage 4, had resection of the primary tumor. Postoperative doses ranged from 15 to 25 Gy, whereas preoperative doses ranged from 12 to 31 Gy using a median fraction size of 1.5 Gy. Chemotherapy was employed in 22 of 53 patients (42%). The 5-year overall survival (OS), freedom from progression (FFP), and LC rates were 79%, 81%, and 88%, respectively. INSS stage was a prognostic factor for OS and FFP. There were no isolated locoregional relapses. The 15-year musculoskeletal toxicity rate was 47.3% for those receiving radiation and 3.3% for the group who did not receive radiation. The authors concluded that most LN+ infants achieve locoregional control without radiation and infants younger than 6 months of age who received radiation were the most susceptible to musculoskeletal abnormalities.⁶⁰

Treatment Technique

As with all radiation treatment planning, every attempt should be made to minimize exposure to normal tissues. For high-risk patients who require radiation to the primary site, gross target volume (GTV) is defined as the tumor remaining prior to attempted surgical resection as defined by CT, MRI, or MIBG scans. Uninvolved draining lymph node regions, including next-echelon lymph node regions, are not covered because it is rare to have an isolated next-echelon nodal failure.⁶¹ Primary tumors are often large and frequently expand into a body cavity, displacing normal structures, without infiltrating them. The primary tumor shrinks after induction chemotherapy, and then, after surgical resection, the normal structures now occupy the space previously occupied by the tumor mass. These normal structures do not need to be included in the GTV. Clinical target volume (CTV) typically includes a 1 to 1.5 cm margin on the GTV, and planning target volume (PTV) depends on patient immobilization but is approximately 0.5 cm on the CTV. CT-based treatment planning is recommended for treatment of the primary site. In many cases, anterior and posterior beams are best suited for sparing normal tissue, but in select cases 3-D conformal or intensity-modulated radiation therapy (IMRT) may be beneficial. Caution is advised with respect to IMRT in the thoracic region where there are significant heterogeneities and where tumor movement is difficult to track. Dose constraints to the contralateral kidney, the lung, and the liver are extremely important, and in girls, dose to the ovaries should be considered. Because the primary tumors are near midline, it is important to include an entire vertebral body in the PTV to prevent scoliosis.

High-risk patients typically have several sites of bony metastatic sites on presentation. On current COG protocols, only those with persistent active disease as shown on the pre–stem cell transplant evaluation are irradiated. Alternatively, patients with painful metastasis may also require radiation therapy for palliation. In general, the PTV for metastatic sites is the GTV as defined by MIBG, CT, or MRI with a 1.5 to 2 cm margin.

Neuroblastoma frequently metastasizes to the skull, often diffusely involving the calvarium and skull base. Although radiating the sites of metastatic disease may improve LC, irradiating the brain in young patients is undesirable. Memorial Sloan-Kettering Cancer Center recently published their results with regard to technique, outcome, and toxicities with brain-sparing whole-skull radiotherapy.⁶²

Dose

Historically, radiation was given to all patients except those with Stage I tumors. Doses less than 20 Gy were found to be acceptable for LC, although today the majority of those patients would not receive radiation therapy.⁶³ In the most recently completed COG study (A3973)⁶⁴ dose to both the primary site and metastatic sites was 21.6 Gy in 12 daily fractions (1.8 Gy qd). Another acceptable regimen is 21 Gy in 14 twice-daily fractions (1.5 Gy bid). Because of the high rates of local recurrence, particularly following an incomplete resection, in the ongoing COG study (ANBL0532),⁶⁵ patients undergoing incomplete resections will receive the standard dose (21.6 Gy) to the postinduction chemotherapy, preoperative tumor volume followed by a boost of 14.4 Gy to the gross residual volume for a total dose of 36 Gy.

For patients who require radiation therapy for palliation of pain, it is essential to use a dose that will control pain for the remainder of the patient’s life. As with all fractionation decisions, it largely depends on volume. Small portals can safely be treated with larger doses per fraction without complication. Doses of 16 to 20 Gy in 4-Gy fractions can produce a durable response. Larger portals will likely require a lower dose per fraction to a higher total dose.

For infants with stage 4S disease with respiratory distress secondary to hepatomegaly, radiation therapy may be indicated.⁶⁶ Effective doses are 2 to 6 Gy in single or multiple fractions and the entire liver need not be included in the treatment portal. This scheme may be repeated if necessary (liver may be slow to respond) as long as the kidney is shielded. Radiation (alone or with surgery) may also be used for spinal cord compression secondary to dumbbell extension of the primary tumor; however, studies have shown that chemotherapy alone is equally efficacious with fewer long-term side effects. Doses range from 7.5 Gy to 30 Gy.⁶⁷^–⁷⁰ Total-body irradiation (TBI) can be used for patients undergoing transplant. Doses are 7.5 to 12 Gy in 3 to 6 fractions.⁷¹ Rare patients who develop parenchymal brain metastases, have a significant risk for the development of leptomeningeal disease. At Memorial Sloan-Kettering Cancer Center, a retrospective query identified 29 children with high-risk neuroblastoma treated since 1987 who received radiation therapy for central nervous system (CNS) relapse. All patients received appropriate initial therapies before demonstrating CNS recurrence. At the time of relapse, 16 patients received craniospinal irradiation (CSI) and 13 received focal radiation therapy that did not address the entire neuraxis. CSI was delivered to a median dose of 21.6 Gy, and 12 patients received a boost to a median dose of 25.4 Gy. The majority of those who underwent CSI also received intra-Ommaya radioimmunotherapy with 131I-8H9 or 131I-3F8. At a median follow-up of 21 months after CNS relapse, 12 patients in the CSI group are alive without evidence of CNS disease. All 13 patients in the non-CSI cohort died at a median of 8.8 months.⁷²

Chemotherapy

Chemotherapy is the principal modality used in intermediate- and high-risk patients. Cyclophosphamide, platinum derivatives, doxorubicin, camptothecins and the epipodophyllotoxins have proven effective in several phase II studies and have thus become the backbone of induction therapy.⁷³^–⁷⁷ Recent pilot studies in relapse patients show activity of temozolomide alone or with irinotecan, leading to an ongoing phase II study in the COG.⁷⁸^–⁸⁰

Risk-Stratified Therapy

The COG Risk Stratification System (Table 56-7) uses patient age, INSS stage, DNA index (DI), INPC and MYCN amplification to assign patients to low-, intermediate-, and high-risk groups, which determine treatment. Further refinement has been added for intermediate-risk patients by intensifyng treatment in cases in which there is unbalanced loss of 11q.

Table 56-7 Neuroblastoma Risk Groups Based on Clinical and Biologic Tumor Features

Low-Risk Neuroblastoma

Children with localized neuroblastoma and favorable tumor biology may be cured with surgery alone, and, unlike other tumors, complete resection is unnecessary in these patients. Chemotherapy and radiation are reserved for progressive or recurrent disease or local disease-related symptoms such as spinal cord compression or respiratory distress. The CCG reported on the outcome of Evans stages I to II neuroblastoma treated with surgery as primary therapy. Patients were also assigned an INSS stage—All Evans stage I patients were INSS stage 1; nearly half of Evans stage II patients were also INSS stage 1, with the other half being INSS stage 2b; few were INSS stage 2a. EFS and OS for all stage I patients were 93% and 99% and for stage II patients were 81% and 98%. Additional therapy (radiation, surgery, or chemotherapy) was needed in only 10% of stage I patients and 20% of stage II patients.⁸¹ These results have been confirmed again in a large COG study, P9641.⁸² In this study, radiation was reserved for the rare situation in which patients with symptomatic spinal cord compression or hepatomegaly causing respiratory distress did not respond rapidly enough to chemotherapy. In addition, radiation therapy was given to patients with recurrent local-regional disease of unfavorable biology who received a partial response (PR) after treatment with courses I and II (eight cycles) of chemotherapy with or without subsequent operation. For children with disease other than stage 4S, the dose was 21 Gy in 14 daily fractions. For children with stage 4S disease, the dose was 4.5 Gy in three daily fractions. The target volume included the gross residual disease with a 2-cm margin. For patients who underwent an operative procedure prior to radiation therapy, the volume was the preoperative tumor, regardless of the extent of resection.

MYCN amplification is rare in localized neuroblastoma. The best method to manage low-risk patients who are MYCN-amplified remains controversial. In the aforementioned CCG study, seven patients had MYCN amplification. Four were INSS stage 1 and three were INSS stage 2b. Four of these patients relapsed 2 to 22 months from diagnosis and three died from progression of disease 8 to 25 months after relapse. For stage II patients, MYCN amplification, Shimada unfavorable, age older than 2 years, or positive lymph nodes predicted for a lower OS. However, because most patients were salvaged, multimodality therapy was recommended only for those with progressive disease.⁸¹ The POG reported that the presence of MYCN amplification in localized neuroblastoma did not necessarily portend an adverse outcome. Only 2% of stage A (three patients) and 7% of stage B (three patients) were MYCN amplified. Four of the six were without evidence of disease for 16 to 38 months or more. Two patients died of their disease; both had unfavorable histology (UH) and one had diploid DNA. The authors concluded that the prognostic significance of MYCN amplification may vary according to histologic features.⁸³ A more recent study using the INRG database included 87 children with stage 1 or 2 neuroblastoma and tumor MYCN amplification. The 5-year EFS and OS were 53% and 72%, compared with 2573 stage 1 and 2 patients without MYCN amplification, whose 5-year EFS and OS were 90% and 98%, respectively.⁸⁴

Patients with INSS stage 4S usually fall into the low-risk category with the exception of those patients with MYCN-amplified tumors, who are high-risk, or with either a UH or DI of 1, who are intermediate-risk. Although these patients have metastatic disease on presentation, spontaneous regression occurs frequently. The OS was 92% in a prospective CCG study of 80 patients, where cytotoxic therapy was only given to patients who were symptomatic.⁸⁵ Other cooperative groups had similar results, with an OS of 85% to 88%, and worse outcome for the rare patients with tumors that had MYCN gene amplification, diploidy, and UH. Unfavorable clinical features were age less than 2 months, and patients who were symptomatic.³⁰^,⁸⁶

Patients with 4S neuroblastoma who have unfavorable biologic factors have a poorer prognosis and are now considered intermediate- or high-risk. The CCG recently reported on outcome and prognostic factors in infants treated prospectively with supportive care only or, in symptomatic patients, with low-dose cytotoxic therapy (radiation, chemotherapy, or a combination of the two). The 5-year EFS and OS were 86% and 92%, respectively. Of these patients, 55% received supportive care only, and their 5-year OS was 100% compared with 81% survival in those patients who were symptomatic and required treatment. Infants younger than 2 months old at diagnosis with rapidly progressive abdominal disease accounted for five of the six deaths. Such infants may benefit from more intensive treatment.⁸⁵^,⁸⁶

Although not yet standardized, recommended management for 4S disease begins with a diagnostic biopsy only, as resection of the primary tumor does not influence outcome.^30,^85,⁸⁷ Patients with favorable biology are then observed for symptoms. Special attention is paid to infants younger than 2 months old. If respiratory compromise occurs, moderately intensive chemotherapy is used, with radiation therapy reserved for those who do not respond to chemotherapy. Lastly, patients with 4S disease with intraspinal involvement are managed with chemotherapy. Several retrospective studies and a French prospective study have shown that chemotherapy alone is a safe and effective therapy for intraspinal disease.⁶⁷^–⁷⁰

Intermediate-Risk Neuroblastoma

Patients in this risk group have regionally advanced disease (stage 3 or stage 4 younger than 12-18 months of age) and are MYCN non-amplified. CCG-3881 was a prospective study of intermediate intensity chemotherapy for patients with Evans stage III disease and favorable biology at any age, or unfavorable biology and age less than 12 months; 92% of these patients fit the criteria for INSS stage 3, and 63% met the criteria for intermediate-risk disease. The patients were treated with chemotherapy including cyclophosphamide, doxorubicin, cisplatin, and etoposide followed by radiation for any gross residual disease following delayed surgery. The EFS rate at 4 years was 100% for patients with favorable biology regardless of age and 90% for those younger than 1 year of age with one unfavorable characteristic such as UH or MYCN amplification. The EFS for Evans stage III patients who were 1 year of age or older with unfavorable biology was 54%, despite more intensive therapy. In multivariate analysis, only age and MYCN status had independent prognostic value.⁸⁸ These patients with the EFS of 54% and a portion of the patients with the EFS of 90% are thus appropriately now considered high-risk. Stage 4 patients less than 1 year of age were also treated in CCG-3881; before 1991, all stage 4 infants were treated in a similar fashion; after 1991, all infants whose tumors were MYCN-amplified were transferred to the more dose intensive high-risk protocol. The 3-year EFS and OS for all 134 infants were 63% and 71%, respectively. The MYCN-nonamplified infants (true intermediate risk) had 93% EFS, whereas the MYCN-amplified infants (high risk) had 10% EFS.⁸⁹ These findings dramatically illustrate the prognostic significance of MYCN amplification status and support the need to stratify these infants into different risk groups.

The role of radiation therapy for intermediate-risk disease remains controversial; studies have provided conflicting results. The POG found the percent of patients achieving a complete response (CR), EFS, and OS were significantly higher in the group that received chemotherapy and radiation as compared to chemotherapy alone in patients with POG stage C neuroblastoma.⁹⁰ However, the population was a mixture of intermediate- and high-risk patients, and the chemotherapy regimen was very modest in this study, consisting of only cyclophosphamide and doxorubicin. Conversely, a randomized controlled trial conducted by de Bernardi and colleagues demonstrated no difference in relapse rates among those patients who received radiation therapy for residual disease and those who did not.⁹¹

A recently completed phase III study of combination chemotherapy in 467 patients with intermediate-risk neuroblastoma showed that therapy could be markedly reduced from 9 months to 3 months in the majority of patients. All patients received carboplatin, cyclophosphamide, doxorubicin, and etoposide. Patients who did not achieve a CR after four cycles with favorable biology had surgery to remove or debulk residual disease. Patients with unfavorable biology or residual tumor after the first four cycles, received four additional cycles of chemotherapy and then undergo debulking surgery if they do not achieve a CR. The indications for radiation were (1) progressive clinical deterioration despite chemotherapy or surgery, or both; (2) stage 4s infants with respiratory compromise; (3) stage 3 or 4 patients with progressive neurologic decline from cord compression; (4) PR after eight cycles of chemotherapy and surgery in patients with unfavorable biology; and (5) PR after surgery for local recurrence greater than 3 months after completing protocol therapy. The radiation dose was 24 Gy in 1.5-Gy fractions; 4S patients with respiratory distress could receive 4.5 Gy to the liver in three fractions. The radiation volume included viable gross or microscopic residual disease determined by CT, MRI, or MIBG imaging with 2-cm margins.⁹²

The current ongoing COG study (http://www.cancer.gov/clinicaltrials/COG-ANBL0531) further reduces cytotoxic therapy in a risk-based fashion, so that the most favorable patients in the intermediate group will receive only two cycles of chemotherapy. Toddlers age 12 to 18 months of age with stage 4 disease who have no tumor MYCN amplification or other unfavorable biologic features have now been shown to have an outcome similar to infant stage 4 who are less than 12 months, and therefore may be treated as intermediate risk.³¹^,⁹³

Radiation is indicated only for patients with disease symptoms threatening organ function not relieved by chemotherapy. Patients with significant respiratory distress secondary to massive hepatomegaly can be treated with 4.5 Gy to the liver in three daily fractions. Patients with spinal cord compression can be treated with 9 Gy in five daily fractions if younger than 3 years of age or 21.6 Gy in 12 daily fractions. Radiation therapy is not indicated to local sites for consolidation even in the cases of viable gross or microscopic disease remaining after surgery and chemotherapy. Similarly, radiation therapy is not indicated for nonmetastatic disease progression.

High-Risk Neuroblastoma

Survival rates for patients in this risk group have improved but remain unacceptably low despite aggressive treatment. The 4-year survival rate among the 507 stage 4 patients older than 1 year of age who were treated in the CCG studies from 1978 to 1985 was 9% compared with 30% among the 675 patients treated from 1991 to 1995.⁹⁴ The improvement may be attributable to chemotherapy dose intensification or to the increasing use of high-dose myeloablative therapy with autologous or allogenic bone marrow transplantation. The CCG completed a randomized control trial that demonstrated intensive induction chemotherapy and radiation therapy followed by myeloablative chemotherapy, total body radiation, and purged autologous bone marrow transplantation (ABMT) is superior to conventional chemotherapy as consolidation therapy in children with high-risk neuroblastoma. The 3-year EFS rates were 34% and 22%, respectively. Furthermore, all patients who completed cytotoxic therapy without disease progression were then randomized to receive treatment with 13-cis-retinoic acid for 6 months or no further therapy. The 3-year EFS from time of second randomization for those patients who received 13-cis retinoic acid was 46%, as compared with 29% who received no further therapy.⁷⁵ A long-term follow-up analysis continued to show that EFS for patients randomized to ABMT was significantly higher than those randomized to chemotherapy, with 5-year EFS of 30% versus 19% (P = 0.04). The 5-year EFS (42% versus 31% ) from time of second randomization was higher for cis-RA than for no further therapy, although not significant. OS at 5 years was significantly higher for each randomization by test of proportions (P < 0.01).⁹⁵ Two other randomized trials in Europe compared myeloablative therapy with either no further treatment or with a low-dose oral maintenance chemotherapy, and both showed a significant advantage for the myeloablative chemotherapy.⁹⁶^,⁹⁷ The most recently completed COG study (A3973), achieved similar EFS with less toxicity using a myeloablative chemotherapy regimen without total body radiation and using peripheral blood stem cells rather than bone marrow. This randomized trial showed the lack of advantage for EFS by purging the stem cells with immunomagnetic beads, compared with unpurged stem cells.⁹⁸

Current treatment approaches include intensive induction chemotherapy, myeloablative consolidation chemotherapy with stem cell rescue, and targeted therapy for residual disease. The goal of induction therapy is to induce maximum reduction in tumor bulk. Most induction therapies currently employ combinations of four to six agents, including platinum compounds, cyclophosphamide or ifosfamide, anthracylines, vincristine, and epipodophyllotoxins. Some studies have shown that response rates are the greatest with high-dose intensities, specifically high doses of platinum compounds.⁹⁹^,¹⁰⁰ The efficacy of induction therapy is typically assessed at the time of second-look surgery and is measured as a CR or a PR. Those who have a CR or very good PR (VGPR) have a better chance of cure, although some patients with a PR can be converted to a CR with high-dose myeloablative therapy.¹⁰¹ However, many of the recent attempts to improve response with dose-intensive induction have not improved the CR or VGPR rate using stringent restaging including ¹²³I-MIBG scans to detect residual disease.¹⁰² The European Neuroblastoma Study Group recently performed a randomized control trial comparing two identical induction regimens that differ only in the rapidity of delivery. This directly tested the hypothesis that an increased dose intensity of induction chemotherapy improves response rate and OS twofold. This randomized trial of 262 patients with stage 4 neuroblastoma showed that increasing the dose intensity twofold resulted in improved 5-year EFS (18% versus 30%; P = 0.02), but not in OS.¹⁰³ However, the overall lack of improvement in EFS in this group compared with other contemporary high-risk trials belies the apparent benefit.

The goal of subsequent therapy is to consolidate the response by eliminating any remaining tumor. This is usually accomplished with myeloablative chemotherapy with or without TBI and AHCT.² Historically, autologous bone marrow was used as myeloablative rescue; however, using autologous peripheral blood stem cells is now a more common practice to reduce the risk of tumor cell contamination and to increase the rapidity of engraftment. EFS at 3 years ranges from 38% to 62% in the most recent POG and CCG trials.^74,¹⁰⁴^–¹⁰⁶ Investigations are underway to evaluate the efficacy of two myeloablative consolidations, known as “tandem transplants,” rather than one. George et al.¹⁰⁷ reported the limited institution experience with tandem transplantation. Ninety seven high-risk patients were treated with five cycles of chemotherapy followed by two courses of myeloablative therapy and hematopoietic cell rescue. Progression-free survival at 3, 5, and 7 years for all patients was 55%, 47%, and 45% respectively. Although the majority (93%) underwent both courses of ablation, seven patients received only one course. The outcome appeared promising, so a large cooperative randomized study was undertaken by the COG to compare single versus double high-dose regimens, which opened in 2007.⁶⁵

External-beam radiation therapy is generally used as consolidative treatment to initial sites of bulk disease, including the primary site and large or persistent metastatic deposits. Specific indications for radiation therapy vary for different protocols. Excellent LC rates have been achieved when delivering 21 Gy to the primary site and regional lymph nodes after resection.¹⁰⁸^–¹¹⁰ Bone metastases should be irradiated when they are persistent after chemotherapy or even after a CR if they were initially high volume (i.e., >3 cm). In the most recently completed COG study (A3973)⁶⁴ and in the current, ongoing COG study (ANBL0532),⁶⁵ radiation is given following myeloblative stem cell transplant to all areas of residual soft tissue disease. Volumes are defined by the CT immediately prior to surgical resection (the presurgical resection volume), regardless of extent and timing of the surgical resection or response to chemotherapy. If the primary tumor was grossly resected at diagnosis, the radiation therapy is given to the primary site based on the initial diagnostic tumor volume. In A3973, dose to both the primary site and metastatic sites was 21.6 Gy in 12 daily fractions. Because of the high rates of local recurrence, particularly following an incomplete resection, in ANBL0532 patients undergoing incomplete resections will receive the standard dose of 21.6 Gy to the postinduction chemotherapy, preoperative tumor volume followed by a boost of 14.4 Gy to the gross residual volume for a total dose of 36 Gy.

Targeted radiopharmaceuticals are also under investigation as an alternative means of delivering specific radiotherapy to metastatic tumor sites, either for refractory disease or as part of a myeloablative regimen. Targeted radioisotope therapy using anti-GD2 antibody or MIBG for delivery of radiation in the form of ¹³¹iodine has been tested extensively in clinical trials in relapsed neuroblastoma. Cheung et al.¹¹¹ have reported on the use of ¹³¹I-3F8 (anti-GD2 antibody) for treatment of refractory neuroblastoma with documented responses. They have also treated newly diagnosed patients using ¹³¹I-3F8 in high doses followed by bone marrow rescue and further treatment with cold antibody after transplant.¹¹¹

¹³¹I-MIBG, a norepinephrine analogue taken up by the norepinephrine transporter on neuroblastoma, has been widely shown in European and U.S. studies to elicit approximately a 30% to 40% response rate for refractory neuroblastoma.¹¹²^–¹¹⁴ A phase 1 dose escalation trial of ¹³¹I-MIBG reported by Matthay et al.¹¹⁵ determined the maximal marrow nonablative dose (444 MBq/kg) and the maximal practical high dose with hematopoietic cell rescue (666 MBq/kg). In 30 patients, there was a 37% response rate and no significant toxicity other than hematologic. A follow-up phase II study of 164 patients who failed to achieve a partial or CR with prior therapy or who relapsed after high-dose therapy has since been completed.¹¹⁴ Use of 18 mCi/kg (666 MBq/kg) of ¹³¹I-MIBG supported by AHCT produced an overall response of 37% in this heavily pretreated cohort. A subsequqent study of two consecutive doses of ¹³¹I-MIBG therapy administered in rapid succession followed by HCT has recently been reported to show minimal toxicity and thus the ability to intensify ¹³¹I-MIBG dosing.⁹⁵

The results in these relapsed patients argue strongly for the incorporation of ¹³¹I-MIBG therapy into regimens that include chemotherapeutic agents. Given the demonstration that haematopoiesis can be successfully restored after high-dose ¹³¹I-MIBG therapy, the combination of ¹³¹I-MIBG therapy with high-dose chemotherapy has been tested in several pilot studies, providing evidence of feasibility and engraftment with this approach.¹¹⁶ Subsequently, a phase I study incorporated escalating doses of ¹³¹I-MIBG followed by carboplatin, etoposide, and melphalan with hematopoietic stem cell infusions.¹¹⁷ The combination appeared feasible and effective at a dose of 12 mCi/kg of ¹³¹I-MIBG and chemotherapy doses minimally decreased from those feasible without the MIBG. Dose adjustments were required for patients with decreased renal function, associated with an increased risk of veno-occlusive disease. A phase II study is now underway in New Approaches to Neuroblastoma Therapy and a pilot study for newly diagnosed patients in the COG.

Several institutions have investigated the role of intraoperative radiation therapy (IORT) as an acceptable alternative to external-beam radiation as a way to deliver a high dose to the primary tumor site with minimal toxicity to normal structures.¹¹⁸^–¹²¹ Gillis and colleagues from the University of California–San Francisco recently updated their data. Thirty-one patients with newly diagnosed high-risk neuroblastoma were treated with IORT as part of multimodality therapy. IORT to the primary site and associated lymph nodes achieved excellent LC at a median follow-up of 44 months. The 3-year estimate of the local recurrence rate was 15%, less than that of most previously published series. Only 1 of 22 patients who had undergone gross total resection developed recurrence at the primary tumor site. The 3-year estimate of LC, progression-free survival, and OS was 85%, 47%, and 60%, respectively. Side effects attributable to either the disease process or multimodality treatment were observed in seven patients who developed either hypertension or vascular stenosis. These late complications resulted in the death of two patients. The authors concluded that IORT at the time of primary resection achieved comparable control and survival rates while avoiding many side effects associated with external-beam radiotherapy in young children. Although complications were observed, additional analysis is needed to determine the relative contributions of the disease process and specific components of the multimodality treatment to these adverse events.¹²²

After myeloablative therapy and local radiotherapy, microscopic residual disease frequently causes disease recurrence. The goal for using targeted therapy for residual disease is to eliminate any residual tumor cells that are chemoresistant. Although many patients are in a clinical and radiographic CR after consolidation, microscopic residual disease often remains, and thus many patients relapse. One agent that has proven effective is 13-cis-retinoic acid.⁷⁵ Immunotherapy is being investigated as a means of targeting residual disease after induction and consolidation therapy in randomized trials in both the United States and Europe. Anti-GD2 antibodies, the murine monoclonal antibodies 3F8 and GD2a, and the human-mouse chimeric monoclonal antibody ch14.18 have shown the most promise.¹²³^,¹²⁴

Recurrent Disease

Current approaches under investigation for treating recurrent or refractory neuroblastoma include novel cytotoxic agents, targeted delivery of radiopharmaceuticals (see previous discussion), retinoids, antiangiogenic agents, and other biologic agents’ genetic pathways. Investigation of novel cytotoxic agents has shown significant activity in phase I and II studies of the camptothecins, irinotecan ¹²⁵ and topotecan,¹²⁶^–¹²⁸ and of temozolomide.⁸⁰ Several studies have also been initiated or completed showing activity of these agents in combination therapy. Thus, topotecan with cyclophosphamide is now a recognized active combination in neuroblastoma that appears slightly superior to topotecan alone,¹²⁹ and combinations of irinotecan and temozolomide have appeared promising in pilot studies and are currently under further investigation.⁷⁶^,¹³⁰ Further enhancement of the temozolomide is being sought by adding O6BG, which may help to overcome resistance by inactivation of the DNA repair protein methylguanine-DNA methyltransferase.¹³¹ In addition to 13-cis-retinoic acid, new retinoids are being developed to treat recurrent or refractory disease. Fenretinide is one such compound that induces apoptosis even in cells resistant to 13-cis-retinoic acid.¹³²^,¹³³ Phase I and II trials of oral fenretinide have been completed in the United States and Italy, and new studies of better absorbed formulations are underway.¹³⁴^–¹³⁷ Lastly, as mentioned in the section on high-risk disease, immune-mediated therapy, including anti-GD2 antibodies, the murine monoclonal antibodies 3F8 and GD2a, and the human-mouse chimeric monoclonal antibody ch14.18 and a humanized version, Hu14.18, are currently under investigation for their role in recurrent or refractory disease.¹³⁸^–¹⁴⁰ New immunocytokines with an anti-GD2 combined with IL2, which showed superior activity to naked antibody in preclinical studies, have completed phase I trials.¹⁴¹ Currently, agents targeting molecular pathways, such as Trk inhibitors, histone deacetylase inhibitors,¹⁴² antiangiogenic agents such as bevacizumab,¹⁴³ and inhibitors of the IGF1R¹⁴⁴ are under investigation either alone or as radiosensitizers, based on preclinical testing.