Neuroblastoma Treatment (PDQ®)—Health Professional Version - National Cancer Institute 3/7

Neuroblastoma Treatment (PDQ®)—Health Professional Version - National Cancer Institute

Neuroblastoma Treatment (PDQ®)–Health Professional Version

Treatment Option Overview for Neuroblastoma

In This Section

• Children’s Oncology Group (COG) Neuroblastoma Risk Grouping
• International Neuroblastoma Risk Grouping
• Revised International Neuroblastoma Response Criteria (INRC)
• Surgery
• Radiation Therapy
• Treatment of Spinal Cord Compression
• Surveillance During and After Treatment
• Special Considerations for the Treatment of Children With Cancer

Most children with neuroblastoma in North America have been treated according to the Children’s Oncology Group (COG) risk-group assignment, even if they were not enrolled in a COG study. In contrast, in the ongoing COG studies, the International Neuroblastoma Risk Group (INRG) risk grouping is used to assign treatment. Because the older system is still being used by some physicians to plan treatment, the treatments described in this summary are based on both the INRG risk grouping using the International Neuroblastoma Risk Group Staging System (INRGSS) and the 2007 COG risk stratification system that uses the International Neuroblastoma Staging System (INSS), as described in the COG biology study ANBL00B1 (NCT00904241). The COG is in the process of revising the COG risk stratification schema and the next version will be based on the INRGSS.

In the previous COG risk system, each child was assigned to a low-risk, intermediate-risk, or high-risk group (refer to Tables 7, 10, and 13 for more information) on the basis of the following factors:[1-6]

• INSS stage.
• Age.
• International Neuroblastoma Pathologic Classification (INPC).
• Ploidy.
• Amplification of the MYCN oncogene within tumor tissue.[1-6]

Other biological factors that influenced treatment selection in previous COG studies included unbalanced 11q loss of heterozygosity and loss of heterozygosity for chromosome 1p.[7,8] However, in 2012, the COG Neuroblastoma Committee defined favorable genomics, for purposes of risk assignment, as hyperdiploid neuroblastoma cells without segmental copy number aberrations, including no loss of copy number at 1p, 3p, 4p, or 11q and no gain of copy number at 1q, 2p, or 17q. This does not correspond to the INRGSS, which only includes 11q abnormalities; however, the criteria may change in future versions.

Generally, treatment is based on whether the tumor is classified as low, intermediate, or high risk, as follows:

• Low risk. For patients with low-risk tumors, the approach is either observation or resection, with chemotherapy restricted to symptomatic patients with low-risk biology. Five-year overall survival (OS) was 97% in a large COG study.[9] The ongoing COG study is looking at the reduction of therapy in a limited subset of patients with low-risk tumors.
• Intermediate risk. For patients with intermediate-risk tumors, chemotherapy is often given before definitive resection, and the number of chemotherapy cycles is based on clinical and tumor biological risk factors and response to therapy. In recent studies, select patients have been observed without undergoing chemotherapy or attempted resection. The 3-year OS rate for intermediate-risk patients was about 96% in a large COG study.[10] The current focus of ongoing studies is to decrease the intensity of chemotherapy in a limited subset of intermediate-risk children to further diminish side effects.
• High risk. For high-risk patients, treatment has intensified to include chemotherapy, surgery, radiation therapy, myeloablative therapy and stem cell transplant (SCT), isotretinoin, and immunotherapy, resulting in survival rates of about 50%. Statistically significant improvement in survival was observed in a randomized phase III COG study (ANBL0532 [NCT00567567]) with tandem cycles of myeloablative therapy with SCT compared with a single cycle of myeloablative therapy and SCT among patients, all of whom received immunotherapy.[11]

Table 5 describes the treatment options for low-risk, intermediate-risk, high-risk, stage 4S, and recurrent neuroblastoma by INSS-based risk group.

Table 5. Treatment Options for Neuroblastoma

COG Risk-Group Assignment		Treatment Options
COG = Children's Oncology Group; GM-CSF = granulocyte-macrophage colony-stimulating factor; 131I-MIBG = iodine I 131-metaiodobenzylguanidine; SCT = stem cell transplant.
Low-Risk Neuroblastoma		Surgery followed by observation.
		Chemotherapy with or without surgery (for symptomatic disease or unresectable progressive disease after surgery).
		Observation without biopsy(for perinatal neuroblastoma with small adrenal tumors).
		Radiation therapy (only for emergency therapy).
Intermediate-Risk Neuroblastoma		Chemotherapy with or without surgery.
		Surgery and observation (in infants).
		Radiation therapy.
High-Risk Neuroblastoma		A regimen of chemotherapy, surgery, tandem cycles of myeloablative therapy and SCT, radiation therapy, and dinutuximab, with interleukin-2/GM-CSF and isotretinoin.
Stage 4S/MS Neuroblastoma		Observation with supportive care (for asymptomatic patients with favorable tumor biology).
		Chemotherapy (for symptomatic patients, very young infants, or those with unfavorable biology).
		Radiation therapy (rarely for patients with symptoms related to hepatomegaly from metastatic disease).
Recurrent Neuroblastoma	Locoregional recurrence in patients initially classified as low risk	Surgery followed by observation or chemotherapy.
		Chemotherapy that may be followed by surgery.
	Metastatic recurrence in patients initially classified as low risk	Observation (if metastatic disease is in a 4S pattern in an infant).
		Chemotherapy.
		Surgery followed by chemotherapy.
		High-risk therapy.
	Locoregional recurrence in patients initially classified as intermediate risk	Surgery (complete resection).
		Surgery (incomplete resection) followed by chemotherapy.
		Radiation therapy (only for patients with disease progression after chemotherapy and second-look surgery).
	Metastatic recurrence in patients initially classified as intermediate risk	High-risk therapy.
	Recurrence in patients initially classified as high risk	Chemotherapy combined with immunotherapy.
		131I-MIBG alone, in combination with other therapy, or followed by stem cell rescue.
		ALK inhibitors.
		Chemotherapy.
	Recurrence in the central nervous system	Surgery and radiation therapy.
		Novel therapeutic approaches.

Children’s Oncology Group (COG) Neuroblastoma Risk Grouping

The treatment sections of this summary are organized to correspond with the COG risk-based treatment plan that assigned all patients to a low-, intermediate-, or high-risk group. The COG risk-based treatment plan is in use for the ongoing ANBL1232 (NCT02176967)COG study, while the ANBL1531 (NCT03126916) study of high-risk neuroblastoma is based on the INRG risk grouping. This risk-based schema was based on the following factors:

• Patient age at diagnosis.
• Certain biological characteristics of the tumor, which included MYCN status and genomic segmental aberrations, INPC histopathology classification, and tumor DNA index.
• Stage of the tumor as defined by the INSS.

Table 7 (in the Treatment of Low-Risk Neuroblastoma section), Table 10 (in the Treatment of Intermediate-Risk Neuroblastoma section), and Table 13 (in the Treatment of High-Risk Neuroblastoma section) describe the risk-group assignment criteria used to assign treatment in the low-risk COG-P9641 trial, the intermediate-risk COG-A3961 and ANBL0531 (NCT00499616) trials, and the high-risk COG-A3973 and ANBL0532 (NCT00567567) studies.

Assessment of risk for low-stage MYCN-amplified neuroblastoma is controversial because it is so rare. A study of 87 patients with INSS stage 1 and stage 2 neuroblastoma pooled from several clinical trial groups demonstrated no effect of age, stage, or initial treatment on outcome. The event-free survival (EFS) rate was 53% and the OS rate was 72%. Survival was superior in patients whose tumors were hyperdiploid, rather than diploid (EFS, 82% ± 20% vs. 37% ± 21%; OS, 94% ± 11% vs. 54% ± 15%).[12] The overall EFS and OS for infants with stage 4 and 4S disease and MYCN amplification was only 30% at 2 to 5 years after treatment in a European study.[13] The COG considers infants with stage 4 and stage 4S disease with MYCN amplification to be at high risk.[4]

International Neuroblastoma Risk Grouping

The INRG classification schema assigns neuroblastoma patients to one of 16 pretreatment risk groups on the basis of INRG stage, age, histologic category, grade of tumor differentiation, MYCN amplification, 11q aberration (the only segmental chromosomal aberration studied), and ploidy. Four levels of risk were defined according to outcomes among 8,800 patients with high-quality data, as they had been entered in clinical trials (refer to Table 6). In the overall risk grouping, histology is an important risk determinant for all stage L1 and L2 tumors, and grade of differentiation discriminates among neuroblastomas and nodular ganglioneuroblastomas in patients older than 18 months. The goals of the INRG are to develop shared data from the patients in clinical trials and to define risk groups for future trials.[14]

Table 6. International Neuroblastoma Risk Group (INRG) Pretreatment Classification Schemaa

ENLARGE

INRG Stage		Histologic Category	Grade of Tumor Differentiation	MYCN	11q Aberration	Ploidy	Pretreatment Risk Group
GN = ganglioneuroma; GNB = ganglioneuroblastoma; NA = not amplified.
aReprinted with permission. © (2015) American Society of Clinical Oncology. All rights reserved. Pinto N et al.: Advances in Risk Classification and Treatment Strategies for Neuroblastoma, J Clin Oncol 33 (27), 2015: 3008–3017.[15]
L1/L2		GN maturing, GNB intermixed					A (very low)
L1		Any, except GN maturing or GNB intermixed		NA			B (very low)
				Amplified			K (high)
L2
	Age <18 mo="" td="">	Any, except GN maturing or GNB intermixed		NA	No		D (low)
					Yes		G (intermediate)
	Age ≥18 mo	GNB nodular neuroblastoma	Differentiating	NA	No		E (low)
					Yes		H (intermediate)
			Poorly differentiated or undifferentiated	NA			H (intermediate)
				Amplified			N (high)
M
	Age <18 mo="" td="">			NA		Hyperdiploid	F (low)
	Age <12 mo="" td="">			NA		Diploid	I (intermediate)
	Age 12 to <18 mo="" td="">			NA		Diploid	J (intermediate)
	Age <18 mo="" td="">			Amplified			O (high)
	Age ≥18 mo						P (high)
MS
	Age <18 mo="" td="">			NA	No		C (very low)
					Yes		Q (high)
				Amplified			R (high)

Controversy exists regarding the current COG risk grouping system, the INRG Risk Grouping Schema, and the treatment of certain small subsets of patients.[16-18] Risk group definitions of very low-, low-, intermediate-, and high-risk subsets and the recommended treatments are expected to evolve as new biomarkers are identified and additional outcome data are analyzed. For example, the risk group assignment for INSS stage 4 neuroblastoma in patients aged 12 to 18 months changed in 2005 for those whose tumors had single-copy MYCN and all favorable biological features; these patients had been previously classified as high risk, but data from both Pediatric Oncology Group and Children's Cancer Group studies suggested that this subgroup of patients could be successfully treated as intermediate risk.[19-21] Future versions of the INRG are expected to contain more tumor genomic criteria to help assign risk.[15]

Revised International Neuroblastoma Response Criteria (INRC)

In COG clinical trials, before therapy can be stopped after the initially planned number of cycles, certain response criteria, depending on risk group and treatment assignment, must be met.[22-24] The revised INRC depend on the use of three-dimensional (3-D) imaging combined with the following:

• Metaiodobenzylguanidine (MIBG) scan. MIBG scanning for primary tumor, bone, and lymph node or soft tissue metastases.
• Positron emission tomography (PET) scan. PET scans are used instead of MIBG in the 10% of patients with MIBG non-avid tumors.

Technetium Tc 99m (99mTc) bone scans are no longer used, because a retrospective study of 132 patients who received both MIBG and 99mTc scans showed no staging benefit.[25]

Overall response in the revised INRC integrates tumor response of the primary tumor, bone marrow, and soft tissue and bone metastases. Primary and metastatic soft tissue sites are assessed using Response Evaluation Criteria in Solid Tumors (RECIST) and iodine I 123 (123I)-MIBG scans or fluorine F 18-fludeoxyglucose (18F-FDG) PET scans if the tumor is MIBG non-avid. Bone marrow is assessed by histology, immunohistochemistry and cytology, or immunocytology with the help of immunorecognition tools. Bone marrow with less than 5% tumor involvement is classified as minimal disease. Urinary catecholamine levels are not included in response assessment.[24]

The overall INRC response criteria are defined as follows:[22,23]

• Complete Response: No evidence of disease, including resolution of MIBG uptake (or PET scan positivity in MIBG non-avid disease) in any location of soft tissue or bone, with less than 10 mm remaining on 3-D imaging of primary tumor; target lymph nodes less than 10 mm in short dimension; and no histologic tumor in two bone marrow biopsies and two bone marrow aspirates.
• Partial Response: 30% or more decrease in longest diameter of primary site and no new lesions and MIBG (or 18F-FDG PET) stable or improved and at least a 50% reduction in absolute MIBG bone score or a 50% or greater reduction in number of 18F-FDG PET-avid bone lesions.
• Minor Response: Partial response or complete response of at least one component of disease, but at least one other component with stable disease and no component with progressive disease.
• Progressive Disease: Any new lesion; increase in longest diameter in any measurable lesion by 20% and increase of at least 5 mm in longest diameter; previous negative bone marrow now positive for tumor; any new soft tissue lesion that is MIBG (or 18F-FDG PET) avid or positive by biopsy; a new avid bone site; or increase in relative MIBG score of 1.25% or greater.
• Stable Disease: Neither sufficient shrinkage for partial response nor sufficient increase for progressive disease and may have greater than 5% tumor infiltration as defined in minimal disease.

Care should be taken in interpreting the development of metastatic disease in an infant who was initially considered to have stage 1 or 2 disease. If the pattern of metastases in such a patient is consistent with a 4S pattern of disease (involvement of skin, liver, and/or bone marrow, the latter less than 10% involved), these patients are not classified as having progressive/metastatic disease, which would typically be a criterion for removal from protocol therapy. Instead, these patients are managed as stage 4S patients.

Controversy exists regarding the necessity of measuring the primary tumor response in all three dimensions or whether the single longest dimension, as in RECIST tumor response determination, is equally useful.[26] The latter has been adopted for use in the INRC.

Surgery

In patients without metastatic disease, the standard of care is to perform an initial surgery, on the basis of the stage and the risk group, to accomplish the following:

• Obtain tissue for diagnosis.
• Resect as much of the primary tumor as is safely possible. This is most appropriate for low-risk (excluding prenatally diagnosed infants) and intermediate-risk disease.
• Accurately stage disease through sampling of regional lymph nodes that are not adherent to the tumor. This is most appropriate for non–high-risk patients undergoing resection at the time of diagnosis. Lymph node involvement alone is not used to discriminate between L1 and L2 disease.

The COG reported that expectant observation in infants younger than 6 months with small (L1) adrenal masses resulted in an excellent EFS and OS while avoiding surgical intervention in a large majority of patients.[27] According to the surgical guidelines described in the intermediate-risk neuroblastoma clinical trial (ANBL0531 [NCT00499616]), the primary tumor is not routinely resected in patients with 4S neuroblastoma.

In patients with L1 tumors (defined as having no image-defined surgical risk factors), the tumors are resectable and resection is less likely to result in surgical complications. L2 tumors, which have at least one image-defined surgical risk factor, are treated with chemotherapy when deemed too risky to attempt resection, followed by surgery when the tumors have responded. Recent German studies of selected groups of patients have biopsied tissue and observed infants with both L1 and L2 tumors without MYCNamplification, avoiding additional surgery and chemotherapy in most patients.[28]

Whether there is any advantage to gross-total resection of the primary tumor mass after chemotherapy in stage 4 patients older than 18 months remains controversial.[29-34] A meta-analysis of stage 3 versus stage 4 neuroblastoma patients, at all ages combined, found an advantage for gross-total resection (>90%) over subtotal resection in stage 3 neuroblastoma only, not stage 4.[35] Also, a small study suggested that after neoadjuvant chemotherapy, completeness of resection was affected by the number of image-defined risk factors remaining.[36] When an experienced surgeon performed the procedure, a 90% or greater resection of the primary tumor in stage 4 neuroblastoma resulted in a higher local control rate, but did not have a statistically significant impact on OS.[37]

Radiation Therapy

In the current treatment paradigm, radiation therapy for patients with low-risk or intermediate-risk neuroblastoma was reserved for symptomatic life-threatening or organ-threatening tumor bulk that did not respond rapidly enough to chemotherapy. Common situations in which radiation therapy is used in these patients include the following:

• Infants aged 60 days and younger with stage 4S and marked respiratory compromise from liver metastases that has not responded to chemotherapy.[38]
• For infants with spinal cord compression, treatment is generally with chemotherapy or neurosurgical intervention because of the responsiveness of neuroblastoma to chemotherapy and the potentially devastating late effects of radiation therapy in very young children.[39]

Radiation therapy has become part of the standard of care for patients with high-risk disease and is usually delivered after high-dose chemotherapy and stem cell rescue. The basis for this approach initially came from a single-institution report that demonstrated only a 10% primary site relapse with administration of 21 Gy of radiation therapy.[40] Subsequent cooperative group trials have incorporated posttransplant primary tumor bed irradiation, although the optimal dose remains uncertain.

Treatment of Spinal Cord Compression

Spinal cord compression is considered a medical emergency. Patients receive immediate treatment because neurologic recovery is more likely when symptoms are present for a relatively short time before diagnosis and treatment. Recovery also depends on the severity of neurologic defects (weakness vs. paralysis). Neurologic outcome appears to be similar whether cord compression is treated with chemotherapy, radiation therapy, or surgery, although radiation therapy is used less frequently than in the past.

The completed COG low-risk and intermediate-risk neuroblastoma clinical trials recommended immediate chemotherapy for cord compression in low-risk or intermediate-risk patients.[39,41,42] In a single study in this setting looking at the effect of glucocorticoids on neurological outcome, it was associated with improved early symptom relief. However, glucocorticoids did not prevent late residual impairment.[42]

Children with severe spinal cord compression that does not promptly improve or those with worsening symptoms may benefit from neurosurgical intervention. Laminectomy may result in later kyphoscoliosis and may not eliminate the need for chemotherapy.[39,41,42] It was thought that osteoplastic laminotomy, a procedure that does not remove bone, would result in less spinal deformity. Osteoplastic laminotomy may be associated with a lower incidence of progressive spinal deformity requiring fusion, but there is no evidence that functional neurologic deficit is improved with laminoplasty.[43]

The burden of long-term health problems in survivors of neuroblastoma with intraspinal extension is high. In a systematic review of 28 studies of treatment and outcome of patients with intraspinal extension, the severity of the symptoms at diagnosis and the treatment modalities were most associated with the presence of long-term health problems. In particular, the severity of neurological motor deficit was most likely to predict neurological outcome.[44] The severity of motor deficit at diagnosis is associated with spinal deformity and sphincter dysfunction at the end of follow-up, while sphincter dysfunction at diagnosis was correlated with long-term sphincter problems.[45] This supports the initiation of treatment before symptoms have deteriorated to complete loss of neurological function.

In a series of 34 infants with symptomatic epidural spinal cord compression, both surgery and chemotherapy provided unsatisfactory results once paraplegia had been established. The frequency of grade 3 motor deficits and bowel dysfunction increased with a longer symptom duration interval. Most infants with symptomatic epidural spinal cord compression developed sequelae, which were severe in about one-half of patients.[46]

Surveillance During and After Treatment

Surveillance studies during and after treatment are able to detect asymptomatic and unsuspected relapse in a substantial portion of patients. In an overall surveillance plan, which includes urinary vanillylmandelic acid and homovanillic acid testing, one of the most reliable imaging tests to detect disease progression or recurrence is the 123I-MIBG scan.[47,48]

Cross-sectional imaging with computed tomography scans is controversial because of the amount of radiation received and the low proportion of relapses detected with this modality.[49]

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[50] Children and adolescents with cancer are usually 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 following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will enable them to achieve optimal survival and quality of life:

• Primary care physician.
• Pediatric pathologists.
• Pediatric surgeons.
• Pediatric radiation oncologists.
• Pediatric medical oncologists/hematologists.
• Pediatric nurse specialists.
• Social workers.
• Child life professionals.

(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.[51] 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. Other types of clinical trials explore or define novel therapies when there is no standard therapy for a cancer diagnosis. Information about ongoing clinical trials is available from the NCI website.

References

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