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

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Treatment of Low-Risk Neuroblastoma

In This Section

• Treatment Options for Low-Risk Neuroblastoma
  • Surgery followed by observation
  • Chemotherapy with or without surgery
  • Observation without biopsy
• Treatment Options Under Clinical Evaluation
  • Current Clinical Trials

Low-risk neuroblastoma represents nearly one-half of all newly diagnosed patients. The success of previous Children's Oncology Group (COG) clinical trials has contributed to the continued reduction in therapy for select patients with neuroblastoma.

The previously used COG neuroblastoma low-risk group assignment criteria are described in Table 7.

Table 7. Children’s Oncology Group (COG) Neuroblastoma Low-Risk Group Assignment Schema Used for COG Studiesa

INSS Stage	Age	MYCN Status	INPC Histology	DNA Ploidyb	Other
DI = DNA index; INPC = International Neuroblastoma Pathologic Classification; INSS = International Neuroblastoma Staging System.
aThe COG-P9641 (NCT00003119) (low risk) and COG-A3961 (NCT00003093) (intermediate risk) trials established the current standard of care for neuroblastoma patients in terms of risk group assignment and treatment strategies.
bDNA ploidy: DI >1 is favorable, DI =1 is unfavorable; a hypodiploid tumor (with DI <1) will be treated as a tumor with a DI >1 (DI <1 [hypodiploid] to be considered favorable ploidy).
cINSS stage 2A/2B symptomatic patients with spinal cord compression, neurologic deficits, or other symptoms are treated with immediate chemotherapy for four cycles.
d2A/2B tumors must be >50% resected to be classified as low risk. Tumors <50% resected are classified as intermediate risk.
eINSS stage 4S infants with favorable biology and clinical symptoms are treated with immediate chemotherapy until asymptomatic (2–4 cycles). Clinical symptoms include the following: respiratory distress with or without hepatomegaly or cord compression and neurologic deficit or inferior vena cava compression and renal ischemia; or genitourinary obstruction; or gastrointestinal obstruction and vomiting; or coagulopathy with significant clinical hemorrhage unresponsive to replacement therapy.
1	Any	Any	Any	Any
2A/2Bc, d	Any	Nonamplified	Any	Any	Resection ≥50%, asymptomatic
4Se	<365 d	Nonamplified	Favorable	DI >1	Asymptomatic

Table 8 shows the International Neuroblastoma Risk Group (INRG) classification schema for very low-risk or low-risk neuroblastoma used in current COG studies, including the ANBL1232 (NCT02176967) study for low-risk and intermediate-risk patients.

Table 8. International Neuroblastoma Risk Group (INRG) Pretreatment Classification Schema for Very Low-Risk or Low-Risk Neuroblastomaa

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.[1]
L1/L2		GN maturing, GNB intermixed					A (very low)
L1		Any, except GN maturing or GNB intermixed		NA			B (very low)
L2
	Age <18 mo	Any, except GN maturing or GNB intermixed		NA	No		D (low)
	Age ≥18 mo	GNB nodular neuroblastoma	Differentiating	NA	No		E (low)
M
	Age <18 mo			NA		Hyperdiploid	F (low)
MS
	Age <18 mo			NA	No		C (very low)

(Refer to the Treatment of Stage 4S Neuroblastoma section of this summary for more information about the treatment of patients with stage 4S neuroblastoma.)

Treatment Options for Low-Risk Neuroblastoma

For patients with localized disease that appears to be resectable (either based on the absence of image-defined risk factors [L1] or on the surgeon's expertise), the tumor should be resected by an experienced surgeon. If the biology is confirmed to be favorable, residual disease after surgery is not considered a risk factor for relapse and chemotherapy is not indicated. Several studies have shown that patients with favorable biology and residual disease have excellent outcomes, with event-free survival (EFS) exceeding 90% and overall survival (OS) ranging from 99% to 100%.[2,3] Some patients with presumed neuroblastoma have been observed without biopsy; this strategy is being studied further by the COG in the ANBL1232 (NCT02176967) trial.[4,5]

Treatment options for low-risk neuroblastoma include the following:

1. Surgery followed by observation.
2. Chemotherapy with or without surgery (for symptomatic disease or unresectable progressive disease after surgery).
3. Observation without biopsy (for perinatal neuroblastoma with small adrenal tumors). The COG experience with observation of apparent neuroblastoma without diagnostic biopsy is limited and under investigation.
4. Radiation therapy (only for emergency therapy).

Surgery followed by observation

Treatment for patients categorized as low risk (refer to Table 7) may be surgery alone.

Evidence (surgery followed by observation):

1. Results from the COG-P9641 study showed that surgery alone, even without complete resection, can cure nearly all patients with stage 1 neuroblastoma and the vast majority of patients with asymptomatic, favorable-biology, International Neuroblastoma Staging System (INSS) stage 2A and stage 2B disease.[3]
2. Similar outcomes were seen in a nonrandomized clinical trial in Japan.[6]

Chemotherapy with or without surgery

Chemotherapy with or without surgery is used to treat the following:

• Symptomatic disease. Chemotherapy is also reserved for low-risk patients (e.g., INSS stage 1 or L1) who are symptomatic (e.g., spinal cord compression). The chemotherapy consists of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative chemotherapy dose of each agent is kept low to minimize long-term effects.[3] Symptomatic patients with stage 2A/2B or 4S disease are categorized as intermediate risk and receive chemotherapy.
• Unresectable progressive disease after surgery.

Evidence (chemotherapy):

1. The COG-P9641 study was one of the first COG studies to test risk stratification based on consensus-derived factors. In this phase III nonrandomized trial, 915 patients underwent an initial operation to obtain tissue for diagnosis and biology studies and for maximal safe primary tumor resection. Chemotherapy was reserved for patients with, or at risk of, symptomatic disease, with less than 50% tumor resection at diagnosis or with unresectable progressive disease after surgery alone.[3]
   • Stage 1: Patients with stage 1 disease achieved a 5-year EFS of 93% and a 5-year OS of 99%.
   • Stage 2A and 2B: Asymptomatic patients with stage 2A and 2B disease (n = 306) who were observed after initial operation had a 5-year EFS of 87% and an OS rate of 96%. EFS was significantly better for patients with stage 2A than for patients with stage 2B neuroblastoma (92% vs. 85%; P = .0321), but OS did not differ significantly (98% vs. 96%; P = .2867). The primary study objective (to achieve a 3-year OS of 95% for asymptomatic patients with stage 2A and 2B disease) was met.
     Patients with stage 2B disease had a lower EFS and OS for those with unfavorable histology (EFS, 72%; OS, 86%) or diploid tumors (EFS, 75%; OS, 84%) or for patients older than 18 months. Outcomes for patients with stage 2B, diploid tumors, and unfavorable histology were particularly poor (EFS, 54%; OS, 70%), with no survivors among the few patients who had additional 1p loss of heterozygosity, and all of the deaths occurred in children older than 18 months.
   • Asymptomatic patients at diagnosis who were observed after initial operation: Of the initial 915 patients, 800 were asymptomatic at diagnosis and observed after their initial operations. Within this group, 11% of patients experienced recurrent or progressive disease. Of the 115 patients who received immediate chemotherapy (median, four cycles; range, one to eight), 81% of the patients had a very good partial response or better. After chemotherapy, 10% of the patients had disease recurrence or progression.
     For patients treated with surgery alone, the 5-year EFS rate was 89%, and the OS estimate was 97%; for patients treated with surgery and immediate chemotherapy, the 5-year EFS rate was 91%, and the OS estimate was 98%.
   • MYCN amplification: The impact of MYCN-amplified tumors was analyzed in patients with stage I disease. For patients with MYCN-nonamplified tumors, the 5-year EFS was 93%, and OS was 99%; for MYCN-amplified tumors, the 5-year EFS was 70% (P = .0042), and OS was 80% (P < .001).

Observation without biopsy

Observation without biopsy has been used to treat perinatal neuroblastoma with small adrenal tumors.

A COG study determined that selected small INSS stage 1 or stage 2 adrenal masses, presumed to be neuroblastoma, detected in infants younger than 6 months by screening or incidental ultrasonography may safely be observed without a definitive histologic diagnosis being obtained and without surgical intervention, thus avoiding potential complications of surgery in the newborn.[4] Patients are observed frequently to detect any tumor growth or spread that would indicate a need for intervention. Additional studies, including an expansion of criteria allowing observation without surgery, are underway in the COG ANBL1232 (NCT02176967) study (refer to Table 9).

Evidence (observation without biopsy):

1. The COG-ANBL00P2 study reported that expectant observation is safe in patients younger than 6 months with solid adrenal tumors smaller than 3.1 cm (or cystic tumors smaller than 5 cm) and INSS stage 1 disease.[4]
   • Eighty-one percent of patients demonstrated spontaneous regression and avoided surgical intervention.
   • Eighty-three of 87 eligible patients were observed without biopsy or resection; only 16 patients (19%) ultimately underwent surgery.
   • Three-year EFS (for a neuroblastoma event) was 97.7%, and OS was 100%.

Controversy exists about the need to attempt resection, whether at the time of diagnosis or later, in asymptomatic infants aged 12 months or younger with apparent stage 2B and stage 3 MYCN-nonamplified and favorable-biology disease. In a German clinical trial, some of these patients were observed after biopsy or partial resection without chemotherapy or radiation therapy, and many patients did not progress locally and never underwent an additional resection.[5] This cohort is also being evaluated in the COG ANBL1232 (NCT02176967) study (refer to the Treatment Options Under Clinical Evaluation section of this summary for more information). Infants younger than 18 months who have L2 tumors with favorable biology are being observed after tumor biopsy.

Treatment Options Under Clinical Evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

• ANBL1232 (NCT02176967) (Response and Biology-Based Risk Factor–Guided Therapy in Treating Younger Patients With Non–High-Risk Neuroblastoma): This phase III trial is studying how well response and biology-based, risk factor–guided therapy works in treating younger patients with non–high-risk neuroblastoma. Table 9 describes the treatment assignments for patients with low-risk neuroblastoma on the ANBL1232 trial. Many patients with low-risk and intermediate-risk neuroblastoma are not being studied on a COG trial but are registered on ANBL00B1 (NCT00904241), the neuroblastoma biology study, to keep track of outcomes.

  Table 9. ANBL1232 Treatment Assignment for Low-Risk Neuroblastoma

  INRG Stage	Biology (Histology and Genomicsa)	Age	Other	Treatment
  INRG = International Neuroblastoma Risk Group.
  aGenomic features include MYCN gene amplification, segmental chromosome aberrations (somatic copy number loss at 1p, 3p, 4p, or 11q, or somatic copy number gain at 1p, 2p, or 17q), and DNA index.
  bFavorable genomic features are defined by one or more whole-chromosome gains or hyperdiploid tumor (DNA index >1) in the absence of segmental chromosome aberrations as defined above.
  cAsymptomatic is defined as no life-threatening symptoms and no impending neurologic or other sequelae (e.g., epidural or intraspinal tumors with existing or impending neurologic impairment, periorbital or calvarial-based lesions with existing or impending cranial nerve impairment, or anatomic or mechanical compromise of critical organ function by tumor [abdominal compartment syndrome, urinary obstruction, etc.]).
  L1		<12 months	<5 cm in diameter; confirmatory study if nonadrenal	Observe on study without biopsy
  L2	Favorable histology and genomicsb	<18 months	Asymptomaticc	Observe on study
  MS	Any histology and genomics	<3 months	Existing or evolving hepatomegaly or symptomatic	Immediate treatment, response-based chemotherapy, as per protocol
  	Favorable histology and genomicsb	<3 months	Asymptomaticc without existing or evolving hepatomegaly	Observe per clinical scoring system
  	Favorable histology and genomicsb	3–18 months	Asymptomaticc	Observe per clinical scoring system
  			Symptomatic	Response-based chemotherapy, as per protocol

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Pinto NR, Applebaum MA, Volchenboum SL, et al.: Advances in Risk Classification and Treatment Strategies for Neuroblastoma. J Clin Oncol 33 (27): 3008-17, 2015. [PUBMED Abstract]
2. Matthay KK, Perez C, Seeger RC, et al.: Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children's Cancer Group study. J Clin Oncol 16 (4): 1256-64, 1998. [PUBMED Abstract]
3. Strother DR, London WB, Schmidt ML, et al.: Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children's Oncology Group study P9641. J Clin Oncol 30 (15): 1842-8, 2012. [PUBMED Abstract]
4. Nuchtern JG, London WB, Barnewolt CE, et al.: A prospective study of expectant observation as primary therapy for neuroblastoma in young infants: a Children's Oncology Group study. Ann Surg 256 (4): 573-80, 2012. [PUBMED Abstract]
5. Hero B, Simon T, Spitz R, et al.: Localized infant neuroblastomas often show spontaneous regression: results of the prospective trials NB95-S and NB97. J Clin Oncol 26 (9): 1504-10, 2008. [PUBMED Abstract]
6. Iehara T, Hamazaki M, Tajiri T, et al.: Successful treatment of infants with localized neuroblastoma based on their MYCN status. Int J Clin Oncol 18 (3): 389-95, 2013. [PUBMED Abstract]

Treatment of Intermediate-Risk Neuroblastoma

In This Section

• Treatment Options for Intermediate-Risk Neuroblastoma
  • Chemotherapy with or without surgery
  • Surgery and observation (in infants)
  • Radiation therapy
• Treatment Options Under Clinical Evaluation
  • Current Clinical Trials

The previously used Children's Oncology Group (COG) neuroblastoma intermediate-risk group assignment criteria are described in Table 10. They are mostly derived from the COG-A3961 (NCT00003093) study and were used in the COG ANBL0531 (NCT00499616) study.

Table 10. Children’s Oncology Group (COG) Neuroblastoma Intermediate-Risk Group Assignment Schema Used for the COG-A3961 Studya

INSS Stage	Age	MYCN Status	INPC Histology	DNA Ploidyb	Other
DI = DNA index; INPC = International Neuroblastoma Pathologic Classification; INSS = International Neuroblastoma Staging System.
aThe COG-P9641 (NCT00003119) (low risk) and COG-A3961 (NCT00003093) (intermediate risk) trials established the current standard of care for non–high-risk neuroblastoma patients in terms of risk group assignment and treatment strategies.
bDNA ploidy: DI >1 is favorable, DI =1 is unfavorable; a hypodiploid tumor (with DI <1) will be treated as a tumor with a DI >1 (DI <1 [hypodiploid] to be considered favorable ploidy).
cINSS stage 3 or stage 4 patients with clinical symptoms as listed above receive immediate chemotherapy.
dINSS stage 4S infants with favorable biology and clinical symptoms are treated with immediate chemotherapy until asymptomatic (2–4 cycles). Clinical symptoms include the following: respiratory distress with or without hepatomegaly or cord compression and neurologic deficit or inferior vena cava compression and renal ischemia; or genitourinary obstruction; or gastrointestinal obstruction and vomiting; or coagulopathy with significant clinical hemorrhage unresponsive to replacement therapy.
2A/2B	Any	Nonamplified	Any	Any	Resection ≥50%, symptomatic
	Any	Nonamplified	Any	Any	Resection <50%
	Any	Nonamplified	Any	Any	Biopsy only
3c	<547 d	Nonamplified	Any	Any
	≥547 d	Nonamplified	Favorable	Any
4c	<365 d	Nonamplified	Any	Any
	365 d to <547 d	Nonamplified	Favorable	DI >1
4Sd	<365 d	Nonamplified	Any	DI =1	Asymptomatic or symptomatic
	<365 d	Missing	Missing	Missing	Too sick for biopsy
	<365 d	Nonamplified	Any	Any	Symptomatic
	<365 d	Nonamplified	Unfavorable	Any	Asymptomatic or symptomatic

The COG-A3961 (NCT00003093) intermediate-risk study results,[1] associated with results from European studies, were used to redefine the intermediate-risk groupings used in the ANBL0531 (NCT00499616) trial.[2] Modifications of the ANBL0531 risk grouping for the ongoing ANBL00B1 (NCT00904241) biology study are shown in Table 10.

Table 11 shows the International Neuroblastoma Risk Group (INRG) classification for intermediate-risk neuroblastoma used in ongoing COG studies.

Table 11. International Neuroblastoma Risk Group (INRG) Pretreatment Classification Schema for Intermediate-Risk Neuroblastomaa

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.[3]
L2
	Age <18 mo	Any, except GN maturing or GNB intermixed		NA	Yes		G (intermediate)
	Age ≥18 mo	GNB nodular neuroblastoma	Poorly differentiated or undifferentiated	NA	Yes		H (intermediate)
				NA	No		H (intermediate)
M
	Age <12 mo			NA		Diploid	I (intermediate)
	Age 12 to <18 mo			NA		Diploid	J (intermediate)

(Refer to the Treatment of Stage 4S Neuroblastoma section of this summary for more information about the treatment of patients with stage 4S neuroblastoma.)

Treatment Options for Intermediate-Risk Neuroblastoma

Treatment options for intermediate-risk neuroblastoma include the following:

1. Chemotherapy with or without surgery.
2. Surgery and observation (in infants).
3. Radiation therapy (if needed).

Chemotherapy with or without surgery

Patients categorized as intermediate risk have been successfully treated with surgery and four to eight cycles of neoadjuvant chemotherapy (carboplatin, cyclophosphamide, doxorubicin, and etoposide; the cumulative dose of each agent is kept low to minimize long-term effects from the chemotherapy regimen) (COG-A3961, ANBL0531 [NCT00499616]). As a rule, patients whose tumors had unfavorable biology received eight cycles of chemotherapy, compared with four cycles for patients whose tumors had favorable biology. The COG-A3961 phase III trial demonstrated that therapy could be significantly reduced for patients with intermediate-risk neuroblastoma while maintaining outstanding survival.[1] A nonrandomized clinical trial in Japan also reported excellent outcomes for infants with stage 3 neuroblastoma without MYCN amplification.[4] The COG ANBL0531 (NCT00499616) study successfully further reduced the duration and intensity of chemotherapy for multiple subsets of children with intermediate-risk tumors.

In cases of abdominal neuroblastoma thought to involve the kidney, nephrectomy is not undertaken before a course of chemotherapy has been given.[5]

Whether initial chemotherapy is indicated for all intermediate-risk infants with localized neuroblastoma requires further study.

Evidence (chemotherapy with or without surgery):

1. In North America, the COG-A3961 study investigated a risk-based neuroblastoma treatment plan that assigned all patients to a low-, intermediate-, or high-risk group on the basis of age, International Neuroblastoma Staging System (INSS) stage, and tumor biology (i.e., MYCN gene amplification, International Neuroblastoma Pathology Classification system, and DNA ploidy). The intermediate-risk group was subsequently studied in the COG ANBL0531 (NCT00499616) trial.
   The A3961 study investigated an overall reduction in treatment compared with previous treatment plans in patients with unresectable, localized, MYCN-nonamplified tumors and infants with stage 4 MYCN-nonamplified disease. The intermediate-risk group received four to eight cycles of moderate-dose neoadjuvant chemotherapy (carboplatin, cyclophosphamide, doxorubicin, and etoposide), additional surgery in some instances, and avoided radiation therapy. Of the 464 patients with intermediate-risk tumors (stages 3, 4, and 4S), 69.6% had favorable features, defined as hyperdiploidy and favorable histology, and were assigned to receive four cycles of chemotherapy.[1]
   The ANBL0531 (NCT00499616) study treated a similar MYCN-nonamplified, age- and stage-defined group of 404 children and reduced the duration and intensity of chemotherapy for several subsets of patients. The study added stage 4 patients with favorable biology who were aged 12 to 18 months.[2]
   • In the A3961 study, the administration of neoadjuvant chemotherapy facilitated at least a partial resection of 99.6% of the previously unresectable tumors. No significant difference was noted in overall survival (OS) according to the degree of resection accomplished (complete vs. incomplete) in either study.
   • Less than 3% of patients in the A3961 and ANBL0531 studies received local radiation therapy, and only the patients with progressive hepatic enlargement or spinal cord compression received radiation therapy in the latter study. In the A3961 study, the 3-year event-free survival (EFS) rate was 88%, and the OS rate was 95%. In the subsequent ANBL0531 study, the 3-year EFS rate was 83%, and the OS rate was 95%.[2]
   • The 3-year EFS rate was 92% for patients with stage 3 disease with favorable histopathology (n = 269); 90% for patients with stage 4S disease and unfavorable biology, including diploidy or unfavorable histology (n = 31); and 81% for infants with stage 4 disease (n = 176) (P < .001 for stages 3 and 4S vs. stage 4).
   • Only infants were stratified by ploidy; those with diploid tumors received eight versus four cycles of chemotherapy. The 3-year OS rate estimates were 98% for stage 3 disease, 97% for stage 4S disease, and 93% for stage 4 disease (P = .002 for stages 3 and 4S vs. stage 4). Infants with diploidy had a poorer outcome (P = .03), as did all patients with diploidy studied, when combined (P = .03).
   • There was no difference in OS in patients with favorable biologic features between those who received eight cycles of chemotherapy (100%) for persistent disease and those who received four cycles (96%).
   • There was no unexpected toxicity.
2. 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. Chemotherapy was given at diagnosis to 57 infants with organs threatened by the 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, because of age or organ involvement, were observed without chemotherapy.[6]
   • Three-year OS was excellent (95%) for infants receiving chemotherapy.
   • Further surgery was avoided in 33 infants, and chemotherapy was avoided in 72 infants.
   • The 3-year OS rate for the infants who were observed without treatment was 99%. The metastases-free survival rate was 94% for infants with unresected tumors and did not differ from the rate for infants treated with surgery or chemotherapy (median follow-up, 58 months).
   • Forty-four of 93 infants with unresected tumors experienced spontaneous regression (17 were complete regressions), and 39 infants experienced progression.
   • 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.
3. Moderate-dose chemotherapy has been shown to be effective in the prospective Infant Neuroblastoma European Study (EURO-INF-NB-STUDY-1999-99.1); about one-half of the infants with unresectable, nonmetastatic neuroblastoma and no MYCN amplification underwent a safe surgical resection and avoided long-term adverse effects.[7][Level of evidence: 3iiA]
   • The 5-year OS rate was 99%, and the EFS rate was 90% (median follow-up, 6 years).
   • In this study, infants who underwent surgical resection had a better EFS than did those who did not have surgery.
4. A prospective International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) trial treated infants with MYCN nonamplified stage 2 or stage 3 unresectable neuroblastoma, as well as those aged 12 to 18 months who had favorable International Neuroblastoma Pathology Classification.[8][Level of evidence: 3iiD]
   • The EFS rate was 98% with conventional chemotherapy.
   • These results are similar to results from the COG-A3961 trial.
5. In two European prospective trials of infants with disseminated neuroblastoma without MYCN gene amplification, infants with INSS stage 3 primary or positive skeletal scintigraphy without radiologic bone metastasis (identified mostly by metaiodobenzylguanidine scan, but a few with just technetium Tc 99m bone scan) were not started on chemotherapy unless life-threatening or organ-threatening symptoms developed. When given, chemotherapy consisted of short-dose and standard-dose chemotherapy.[9]
   • OS was 100% in the 41 patients who did not have INSS stage 4S, regardless of initial chemotherapy.
   • In infants with overt metastases to the skeleton, lung, and central nervous system (by radionuclide scan, but not by plain x-ray or computed tomography [CT] scan), the 2-year OS rate was 96% (n = 45).
   • No patients died of surgery-related or chemotherapy-related complications on either protocol.

Surgery and observation (in infants)

The need for chemotherapy in all asymptomatic infants with stage 3 or stage 4 disease is controversial, as some European studies have shown favorable outcomes with surgery and observation.[9]

Evidence (surgery and observation in infants):

1. In a French study, infants classified as stage 4 because of a primary tumor infiltrating across the midline (INSS 3 primary with metastases limited to 4S category) or positive bone scintigraphy not associated with changes in the cortical bone documented on plain radiographs and/or CT were reported to have a better outcome with less aggressive chemotherapy than were other stage 4 infants (EFS, 90% vs. 27%).[10] However, a much higher proportion of those with radiologically demonstrated cortical bone lesions also had tumors with MYCN amplification.[10]
2. Building on the French study, SIOPEN conducted a prospective trial of 125 infants (n = 41 with INSS 3 primary tumors or positive scintigraphy) with disseminated neuroblastoma without MYCN amplification to determine whether these patients could be observed in the absence of symptoms. However, treating physicians did not always follow the wait-and-see strategy.[9]
   • There was no significant difference in 2-year OS between patients with unresectable primary tumors and patients with resectable primary tumors (97% vs. 100%) and between patients with negative and positive skeletal scintigraphy without radiologic abnormalities (100% vs. 97%).
3. A German prospective clinical trial enrolled 340 infants aged 1 year or younger whose tumors were stage 1, 2, or 3, verified histologically, and lacked MYCN amplification. Of the 190 infants who underwent resection, 8 infants had stage 3 disease. A total of 93 infants whose tumors were not resectable without high-risk surgery, because of age or organ involvement, were observed without chemotherapy, which included 21 stage 3 patients. Fifty-seven infants, including 41 stage 3 patients, were treated with chemotherapy to control threatening symptoms.[6]
   • Three-year OS was excellent for the entire group of infants with unresected tumors (99%), infants receiving chemotherapy (95%), and infants with resected tumors (98%) (P = .45).

Radiation therapy

Radiation therapy for children with intermediate-risk disease is reserved for patients with progressive disease during treatment with chemotherapy or progressive unresectable disease after treatment with chemotherapy.

In a prospective randomized COG trial that tested reduced-intensity chemotherapy for patients with intermediate-risk neuroblastoma, only 12 of 479 patients (2.5%) received local radiation therapy (21 Gy). One patient had stage 4S disease, five patients had stage 3 disease, and six patients had stage 4 disease. Radiation therapy was administered for clinical deterioration despite initial therapy (eight patients), residual macroscopic disease and unfavorable biologic features (three patients), or relapse after therapy (one patient).[1,11,12]

Treatment Options Under Clinical Evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

• ANBL1232 (NCT02176967) (Response and Biology-Based Risk Factor–Guided Therapy in Treating Younger Patients With Non–High-Risk Neuroblastoma): This phase III trial is studying how well response and biology-based, risk factor–guided therapy works in treating younger patients with non–high-risk neuroblastoma. Table 12 describes the treatment assignments for patients with intermediate-risk neuroblastoma on the ANBL1232 trial. Many intermediate-risk patients will not be eligible for this study; these patients can be registered and tracked on the COG biology study ANBL00B1 (NCT00904241).

  Table 12. ANBL1232 Treatment Assignment for Intermediate-Risk Neuroblastoma

  INRG Stage	Biology (Histology and Genomicsa)	Age	Other	Treatment
  aGenomic features include MYCN gene amplification, segmental chromosome aberrations (somatic copy number loss at 1p, 3p, 4p, or 11q, or somatic copy number gain at 1p, 2p, or 17q), and DNA index.
  bFavorable genomic features are defined by one or more whole-chromosome gains or hyperdiploid tumor (DNA index >1) in the absence of segmental chromosome aberrations as defined above.
  cAsymptomatic is defined as no life-threatening symptoms and no impending neurologic or other sequelae (e.g., epidural or intraspinal tumors with existing or impending neurologic impairment, periorbital or calvarial-based lesions with existing or impending cranial nerve impairment, or anatomic or mechanical compromise of critical organ function by tumor [abdominal compartment syndrome, urinary obstruction, etc.]).
  dUnfavorable genomic features are defined by the presence of any segmental chromosome aberration (somatic copy number loss at 1p, 3p, 4p, or 11q, or somatic copy number gain at 1p, 2p, or 17q) or diploid tumor (DNA index = 1). This includes copy neutral loss of heterozygosity.
  eOnly patients with MYCN-nonamplified tumors are eligible for the ANBL1232 study.
  L2	Favorable histology and genomicsb	<18 months	Asymptomaticc	Observe on study
  MS	Favorable histology and genomicsb	3–18 months	Asymptomaticc	Observe per clinical scoring system
  			Symptomatic	Response-based chemotherapy, as per protocol
  	Unfavorabled/unknown histology and genomicse	<18 months		Response-based chemotherapy, as per protocol
  INRG = International Neuroblastoma Risk Group.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Baker DL, Schmidt ML, Cohn SL, et al.: Outcome after reduced chemotherapy for intermediate-risk neuroblastoma. N Engl J Med 363 (14): 1313-23, 2010. [PUBMED Abstract]
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