Neuroblastoma Treatment (PDQ®) 5/7—Health Professional Version - National Cancer Institute

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

Neuroblastoma Treatment (PDQ®)–Health Professional Version

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 for the next COG intermediate-risk clinical trial, ANBL0531 (NCT00499616). 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.[2]
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.

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.[3]

In cases of abdominal neuroblastoma thought to involve the kidney, nephrectomy is not undertaken before a course of chemotherapy has been given.[4]

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).
   This 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 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, P = .37).
   • Only 2.5% of the 479 patients received local radiation therapy. The 3-year event-free survival (EFS) was 88%, and OS was 95%.
   • The 3-year EFS 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 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.[5]
   • 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 MYCNamplification underwent a safe surgical resection and avoided long-term adverse effects.[6][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.[7][Level of evidence: 3iiD]
   • The EFS 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.[8]
   • 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 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.[8]

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%).[9] However, a much higher proportion of those with radiologically demonstrated cortical bone lesions also had tumors with MYCN amplification.[9]
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.[8]
   • 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.[5]
   • 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).[1,10,11]

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]
2. 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]
3. 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]
4. Shamberger RC, Smith EI, Joshi VV, et al.: The risk of nephrectomy during local control in abdominal neuroblastoma. J Pediatr Surg 33 (2): 161-4, 1998. [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. Rubie H, De Bernardi B, Gerrard M, et al.: Excellent outcome with reduced treatment in infants with nonmetastatic and unresectable neuroblastoma without MYCN amplification: results of the prospective INES 99.1. J Clin Oncol 29 (4): 449-55, 2011. [PUBMED Abstract]
7. Kohler JA, Rubie H, Castel V, et al.: Treatment of children over the age of one year with unresectable localised neuroblastoma without MYCN amplification: results of the SIOPEN study. Eur J Cancer 49 (17): 3671-9, 2013. [PUBMED Abstract]
8. De Bernardi B, Gerrard M, Boni L, et al.: Excellent outcome with reduced treatment for infants with disseminated neuroblastoma without MYCN gene amplification. J Clin Oncol 27 (7): 1034-40, 2009. [PUBMED Abstract]
9. Minard V, Hartmann O, Peyroulet MC, et al.: Adverse outcome of infants with metastatic neuroblastoma, MYCN amplification and/or bone lesions: results of the French society of pediatric oncology. Br J Cancer 83 (8): 973-9, 2000. [PUBMED Abstract]
10. 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]
11. Kim C, Choi YB, Lee JW, et al.: Excellent treatment outcomes in children younger than 18 months with stage 4 MYCN nonamplified neuroblastoma. Korean J Pediatr 61 (2): 53-58, 2018. [PUBMED Abstract]