Neuroblastoma Treatment (PDQ®) 2/2 —Health Professional Version - National Cancer Institute

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

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.[48] 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.[49] 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

1. Cotterill SJ, Pearson AD, Pritchard J, et al.: Clinical prognostic factors in 1277 patients with neuroblastoma: results of The European Neuroblastoma Study Group 'Survey' 1982-1992. Eur J Cancer 36 (7): 901-8, 2000. [PUBMED Abstract]
2. Moroz V, Machin D, Faldum A, et al.: Changes over three decades in outcome and the prognostic influence of age-at-diagnosis in young patients with neuroblastoma: a report from the International Neuroblastoma Risk Group Project. Eur J Cancer 47 (4): 561-71, 2011. [PUBMED Abstract]
3. Look AT, Hayes FA, Shuster JJ, et al.: Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 9 (4): 581-91, 1991. [PUBMED Abstract]
4. Schmidt ML, Lukens JN, Seeger RC, et al.: Biologic factors determine prognosis in infants with stage IV neuroblastoma: A prospective Children's Cancer Group study. J Clin Oncol 18 (6): 1260-8, 2000. [PUBMED Abstract]
5. Berthold F, Trechow R, Utsch S, et al.: Prognostic factors in metastatic neuroblastoma. A multivariate analysis of 182 cases. Am J Pediatr Hematol Oncol 14 (3): 207-15, 1992. [PUBMED Abstract]
6. 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]
7. Attiyeh EF, London WB, Mossé YP, et al.: Chromosome 1p and 11q deletions and outcome in neuroblastoma. N Engl J Med 353 (21): 2243-53, 2005. [PUBMED Abstract]
8. Spitz R, Hero B, Simon T, et al.: Loss in chromosome 11q identifies tumors with increased risk for metastatic relapses in localized and 4S neuroblastoma. Clin Cancer Res 12 (11 Pt 1): 3368-73, 2006. [PUBMED Abstract]
9. 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]
10. 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]
11. Park JR, Kreissman SG, London WB, et al.: A phase III randomized clinical trial (RCT) of tandem myeloablative autologous stem cell transplant (ASCT) using peripheral blood stem cell (PBSC) as consolidation therapy for high-risk neuroblastoma (HR-NB): a Children's Oncology Group (COG) study. [Abstract] J Clin Oncol 34 (Suppl 15): A-LBA3, 2016. Also available onlineExit Disclaimer. Last accessed February 11, 2019.
12. Bagatell R, Beck-Popovic M, London WB, et al.: Significance of MYCN amplification in international neuroblastoma staging system stage 1 and 2 neuroblastoma: a report from the International Neuroblastoma Risk Group database. J Clin Oncol 27 (3): 365-70, 2009. [PUBMED Abstract]
13. Canete A, Gerrard M, Rubie H, et al.: Poor survival for infants with MYCN-amplified metastatic neuroblastoma despite intensified treatment: the International Society of Paediatric Oncology European Neuroblastoma Experience. J Clin Oncol 27 (7): 1014-9, 2009. [PUBMED Abstract]
14. Cohn SL, Pearson AD, London WB, et al.: The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol 27 (2): 289-97, 2009. [PUBMED Abstract]
15. 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]
16. Kushner BH, Cheung NK: Treatment reduction for neuroblastoma. Pediatr Blood Cancer 43 (6): 619-21, 2004. [PUBMED Abstract]
17. Kushner BH, Kramer K, LaQuaglia MP, et al.: Liver involvement in neuroblastoma: the Memorial Sloan-Kettering Experience supports treatment reduction in young patients. Pediatr Blood Cancer 46 (3): 278-84, 2006. [PUBMED Abstract]
18. Navarro S, Amann G, Beiske K, et al.: Prognostic value of International Neuroblastoma Pathology Classification in localized resectable peripheral neuroblastic tumors: a histopathologic study of localized neuroblastoma European Study Group 94.01 Trial and Protocol. J Clin Oncol 24 (4): 695-9, 2006. [PUBMED Abstract]
19. Schmidt ML, Lal A, Seeger RC, et al.: Favorable prognosis for patients 12 to 18 months of age with stage 4 nonamplified MYCN neuroblastoma: a Children's Cancer Group Study. J Clin Oncol 23 (27): 6474-80, 2005. [PUBMED Abstract]
20. London WB, Castleberry RP, Matthay KK, et al.: Evidence for an age cutoff greater than 365 days for neuroblastoma risk group stratification in the Children's Oncology Group. J Clin Oncol 23 (27): 6459-65, 2005. [PUBMED Abstract]
21. George RE, London WB, Cohn SL, et al.: Hyperdiploidy plus nonamplified MYCN confers a favorable prognosis in children 12 to 18 months old with disseminated neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 23 (27): 6466-73, 2005. [PUBMED Abstract]
22. Brodeur GM, Pritchard J, Berthold F, et al.: Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 11 (8): 1466-77, 1993. [PUBMED Abstract]
23. 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 (12): 1874-81, 1988. [PUBMED Abstract]
24. Park JR, Bagatell R, Cohn SL, et al.: Revisions to the International Neuroblastoma Response Criteria: A Consensus Statement From the National Cancer Institute Clinical Trials Planning Meeting. J Clin Oncol 35 (22): 2580-2587, 2017. [PUBMED Abstract]
25. Gauguet JM, Pace-Emerson T, Grant FD, et al.: Evaluation of the utility of (99m) Tc-MDP bone scintigraphy versus MIBG scintigraphy and cross-sectional imaging for staging patients with neuroblastoma. Pediatr Blood Cancer 64 (11): , 2017. [PUBMED Abstract]
26. Bagatell R, McHugh K, Naranjo A, et al.: Assessment of Primary Site Response in Children With High-Risk Neuroblastoma: An International Multicenter Study. J Clin Oncol 34 (7): 740-6, 2016. [PUBMED Abstract]
27. 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]
28. 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]
29. Adkins ES, Sawin R, Gerbing RB, et al.: Efficacy of complete resection for high-risk neuroblastoma: a Children's Cancer Group study. J Pediatr Surg 39 (6): 931-6, 2004. [PUBMED Abstract]
30. Castel V, Tovar JA, Costa E, et al.: The role of surgery in stage IV neuroblastoma. J Pediatr Surg 37 (11): 1574-8, 2002. [PUBMED Abstract]
31. La Quaglia MP, Kushner BH, Su W, et al.: The impact of gross total resection on local control and survival in high-risk neuroblastoma. J Pediatr Surg 39 (3): 412-7; discussion 412-7, 2004. [PUBMED Abstract]
32. Simon T, Häberle B, Hero B, et al.: Role of surgery in the treatment of patients with stage 4 neuroblastoma age 18 months or older at diagnosis. J Clin Oncol 31 (6): 752-8, 2013. [PUBMED Abstract]
33. Englum BR, Rialon KL, Speicher PJ, et al.: Value of surgical resection in children with high-risk neuroblastoma. Pediatr Blood Cancer 62 (9): 1529-35, 2015. [PUBMED Abstract]
34. von Allmen D, Davidoff AM, London WB, et al.: Impact of Extent of Resection on Local Control and Survival in Patients From the COG A3973 Study With High-Risk Neuroblastoma. J Clin Oncol 35 (2): 208-216, 2017. [PUBMED Abstract]
35. Mullassery D, Farrelly P, Losty PD: Does aggressive surgical resection improve survival in advanced stage 3 and 4 neuroblastoma? A systematic review and meta-analysis. Pediatr Hematol Oncol 31 (8): 703-16, 2014. [PUBMED Abstract]
36. Irtan S, Brisse HJ, Minard-Colin V, et al.: Image-defined risk factor assessment of neurogenic tumors after neoadjuvant chemotherapy is useful for predicting intra-operative risk factors and the completeness of resection. Pediatr Blood Cancer 62 (9): 1543-9, 2015. [PUBMED Abstract]
37. Wolden SL, Gollamudi SV, Kushner BH, et al.: Local control with multimodality therapy for stage 4 neuroblastoma. Int J Radiat Oncol Biol Phys 46 (4): 969-74, 2000. [PUBMED Abstract]
38. Katzenstein HM, Kent PM, London WB, et al.: Treatment and outcome of 83 children with intraspinal neuroblastoma: the Pediatric Oncology Group experience. J Clin Oncol 19 (4): 1047-55, 2001. [PUBMED Abstract]
39. De Bernardi B, Pianca C, Pistamiglio P, et al.: Neuroblastoma with symptomatic spinal cord compression at diagnosis: treatment and results with 76 cases. J Clin Oncol 19 (1): 183-90, 2001. [PUBMED Abstract]
40. Simon T, Niemann CA, Hero B, et al.: Short- and long-term outcome of patients with symptoms of spinal cord compression by neuroblastoma. Dev Med Child Neurol 54 (4): 347-52, 2012. [PUBMED Abstract]
41. McGirt MJ, Chaichana KL, Atiba A, et al.: Incidence of spinal deformity after resection of intramedullary spinal cord tumors in children who underwent laminectomy compared with laminoplasty. J Neurosurg Pediatr 1 (1): 57-62, 2008. [PUBMED Abstract]
42. Kraal K, Blom T, van Noesel M, et al.: Treatment and outcome of neuroblastoma with intraspinal extension: A systematic review. Pediatr Blood Cancer 64 (8): , 2017. [PUBMED Abstract]
43. Angelini P, Plantaz D, De Bernardi B, et al.: Late sequelae of symptomatic epidural compression in children with localized neuroblastoma. Pediatr Blood Cancer 57 (3): 473-80, 2011. [PUBMED Abstract]
44. De Bernardi B, Quaglietta L, Haupt R, et al.: Neuroblastoma with symptomatic epidural compression in the infant: the AIEOP experience. Pediatr Blood Cancer 61 (8): 1369-75, 2014. [PUBMED Abstract]
45. Papathanasiou ND, Gaze MN, Sullivan K, et al.: 18F-FDG PET/CT and 123I-metaiodobenzylguanidine imaging in high-risk neuroblastoma: diagnostic comparison and survival analysis. J Nucl Med 52 (4): 519-25, 2011. [PUBMED Abstract]
46. Kushner BH, Kramer K, Modak S, et al.: Sensitivity of surveillance studies for detecting asymptomatic and unsuspected relapse of high-risk neuroblastoma. J Clin Oncol 27 (7): 1041-6, 2009. [PUBMED Abstract]
47. Owens C, Li BK, Thomas KE, et al.: Surveillance imaging and radiation exposure in the detection of relapsed neuroblastoma. Pediatr Blood Cancer 63 (10): 1786-93, 2016. [PUBMED Abstract]
48. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
49. Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004. [PUBMED Abstract]

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 theANBL1232 (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]

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. 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] Similar outcomes were seen in a nonrandomized clinical trial in Japan.[4]

Chemotherapy with or without surgery

Chemotherapy with or without surgery is used to treat symptomatic disease or unresectable progressive disease after surgery.

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.

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.[5] 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, with 81% of patients demonstrating spontaneous regression while avoiding surgical intervention.[5]
   • 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%.

Evidence (observation following biopsy or partial resection):

1. 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.[6] 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 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	Asymptomaticcwithout 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. 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]
5. 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]
6. 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]

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 (only for emergency 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 (only for emergency 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. Pertinent studies are reviewed below.

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 as described below.[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 (only for emergency therapy)

Radiation therapy for intermediate-risk patients is emergency therapy reserved for patients with the following:

• Symptomatic life-threatening or organ-threatening tumor that does not respond rapidly to chemotherapy and/or surgery; and/or
• Progressive disease.

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]

Treatment of High-Risk Neuroblastoma

In This Section

• Treatment Options for High-Risk Neuroblastoma
  • Chemotherapy, surgery, tandem cycles of myeloablative therapy and SCT, radiation therapy, and dinutuximab, with IL-2/GM-CSF and isotretinoin
  • Surgery and radiation therapy (local control)
• Treatment Options Under Clinical Evaluation
  • Current Clinical Trials

The previously used Children's Oncology Group (COG) neuroblastoma high-risk group assignment criteria are described in Table 13.

Table 13. Children’s Oncology Group (COG) Neuroblastoma High-Risk Group Assignment Schema

INSS Stage	Age	MYCN Status	INPC Histology	DNA Ploidya	Other
DI = DNA index; INPC = International Neuroblastoma Pathologic Classification; INSS = International Neuroblastoma Staging System.
aDNA 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).
bINSS stage 2A/2B symptomatic patients with spinal cord compression, neurologic deficits, or other symptoms are treated with immediate chemotherapy for four cycles.
cINSS stage 3 or stage 4 patients with clinical symptoms as listed above receive immediate chemotherapy.
2A/2Bb	Any	Amplified	Any	Any	Any degree of resection
3c	≥547d	Nonamplified	Unfavorable	Any
	Any	Amplified	Any	Any
4c	<365 d	Amplified	Any	Any
	365 d to <547 d	Amplified	Any	Any
	365 d to <547 d	Any	Any	DI =1
	365 d to <547 d	Any	Unfavorable	Any
	≥547 d	Any	Any	Any
4S	<365 d	Amplified	Any	Any	Asymptomatic or symptomatic

Table 14 shows the International Neuroblastoma Risk Group (INRG) classification for high-risk neuroblastoma used in ongoing COG studies, including ANBL1531 (NCT03126916).

Table 14. International Neuroblastoma Risk Group (INRG) Pretreatment Classification Schema for High-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		Any, except GN maturing or GNB intermixed		Amplified			K (high)
L2
	Age ≥18 mo	GNB nodular neuroblastoma	Poorly differentiated or undifferentiated	Amplified			N (high)
M
	Age <18 mo			Amplified			O (high)
	Age ≥18 mo						P (high)
MS
	Age <18 mo			NA	Yes		Q (high)
				Amplified			R (high)

Approximately 8% to 10% of infants with stage 4S disease will have MYCN-amplified tumors and are usually treated on high-risk protocols. The overall event-free survival (EFS) and overall survival (OS) for infants with stage 4 and 4S disease and MYCN-amplification were only 30% at 2 to 5 years after treatment in a European study.[2]

For children with high-risk neuroblastoma, long-term survival with current treatments is about 54%.[3] Children with aggressively treated, high-risk neuroblastoma may develop late recurrences, some more than 5 years after completion of therapy.[4,5]

A study from the INRG database found 146 patients with distant metastases limited to lymph nodes, termed stage 4N, who tended to have favorable-biology disease and a good outcome (5-year OS, 85%), which suggests that for this special subgroup of high-risk, stage 4 patients, less-intensive therapy might be considered.[6]

Treatment Options for High-Risk Neuroblastoma

Outcomes for patients with high-risk neuroblastoma remain poor despite recent improvements in survival in randomized trials.

Treatment options for high-risk neuroblastoma typically include the following:

1. A regimen of chemotherapy, surgery, tandem cycles of myeloablative therapy and stem cell transplant (SCT), radiation therapy, and dinutuximab with interleukin-2 (IL-2)/granulocyte-macrophage colony-stimulating factor (GM-CSF) and isotretinoin.

Chemotherapy, surgery, tandem cycles of myeloablative therapy and SCT, radiation therapy, and dinutuximab, with IL-2/GM-CSF and isotretinoin

Treatment for patients with high-risk disease is generally divided into the following three phases:

• Induction (includes chemotherapy and surgical resection).
• Consolidation (tandem cycles of myeloablative therapy and SCT and radiation therapy to the site of the primary tumor and residual metastatic sites).
• Postconsolidation (immunotherapy and retinoid).

Induction phase

The backbone of the most commonly used induction therapy includes dose-intensive cycles of cisplatin and etoposide alternating with vincristine, cyclophosphamide, and doxorubicin.[7] Topotecan and cyclophosphamide were added to this regimen on the basis of the antineuroblastoma activity seen in relapsed patients.[8] Response to therapy after four cycles of chemotherapy or at the end of induction chemotherapy correlates with EFS at the completion of high-risk therapy.[9,10]

After a response to chemotherapy, resection of the primary tumor is usually attempted. Whether a gross-total resection is beneficial either before or after induction chemotherapy is controversial.[11]

• The COG A3973 (NCT00004188) study had central surgical review of 220 patients who underwent attempted gross-total resection after induction chemotherapy. By the surgeon’s estimate, the degree of resection was determined to be 90% or greater versus less than 90%, but only 63% concordance with central review of imaging was found. Nevertheless, the surgeon’s assessment of 90% or greater resection versus less than 90% resection predicted EFS of 46% versus 38% (P = .01), respectively, and cumulative incidence of local relapse of 8.5% versus 20%, respectively. OS was not significantly different (49% vs. 57%, P = .3). The author's conclusion supports continued efforts to achieve greater than 90% resection in order to decrease local recurrence.[12][Level of evidence: 3iiA]
• A single-center retrospective study of 87 children with high-risk neuroblastoma demonstrated no significant benefit of gross-total resection compared with near-total (>90%) resection.[13][Level of evidence: 3iiD] However, the results suggest that greater than 90% resection is associated with improved OS compared with less than 90% resection.

Consolidation phase

The consolidation phase of high-risk regimens involves myeloablative chemotherapy and SCT, which attempts to eradicate minimal residual disease (MRD) using otherwise lethal doses of ablative chemotherapy rescued by autologous stem cells (collected during induction chemotherapy) to repopulate the bone marrow. Several large randomized controlled studies have shown an improvement in 3-year EFS for treatment with SCT (31% to 47%) versus conventional chemotherapy (22% to 31%).[14-16] Previously, total-body irradiation had been used in SCT conditioning regimens. Most current protocols use tandem chemotherapy and SCT or carboplatin/etoposide/melphalan or busulfan/melphalan as conditioning for SCT and use radiation only to the primary site and sometimes to areas of incompletely resolved metastases.[17][Level of evidence: 3iA]

Evidence (myeloablative chemotherapy and stem cell rescue):

1. A large European multicenter randomized trial demonstrated that after induction with cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide, busulfan/melphalan resulted in an improved EFS, without an effect on OS and severe adverse events, compared with carboplatin/etoposide/melphalan.[18][Level of evidence: 1iiA]
2. Two sequential cycles of myeloablative chemotherapy and stem cell rescue given in a tandem fashion was shown to be feasible for patients with high-risk neuroblastoma.[19]
3. A randomized clinical study (COG-ANBL0532) testing the efficacy of two cycles versus one cycle of myeloablative chemotherapy with stem cell rescue has been completed.[20] Children older than 18 months with stage 4 neuroblastoma who had received six cycles of induction chemotherapy were then randomly assigned to receive a single autologous SCT with carboplatin/etoposide/melphalan or tandem transplants with cyclophosphamide/thiotepa followed by reduced-dose carboplatin/etoposide/melphalan. After tumor bed radiation therapy, patients were randomly assigned on a second trial to receive isotretinoin alone or isotretinoin with dinutuximab and immune enhancement.
   • The 3-year EFS was 61% for tandem transplants and 48% for single autologous SCT (P = .008). The 3-year OS was 74% for tandem autologous SCTs and 69% for single autologous SCT (P = .19).
   • For patients who were randomly assigned to not receive dinutuximab, the 3-year EFS was 74% for tandem SCTs and 56% for single autologous SCT (P = .003); for patients who received dinutuximab, the 3-year OS was 84% for tandem SCTs and 74% for single SCT (P = .03).

(Refer to the Autologous Hematopoietic Cell Transplantation section in the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation.)

Radiation to the primary tumor site (whether or not a complete excision was obtained) is indicated after myeloablative therapy. Treatment of persistently metaiodobenzylguanidine (MIBG)-positive metastatic sites after induction therapy is often performed after myeloablative therapy. The optimal dose of radiation therapy has not been determined, although nonrandomized, retrospective studies suggest doses of 30 Gy to 36 Gy to the primary site improve local control if there is gross residual disease before SCT.[21] Radiation of metastatic disease sites is determined on an individual basis or according to protocol guidelines for patients enrolled in studies.

Metastatic bone relapse in neuroblastoma often occurs at anatomic sites of previous disease. Metastatic sites identified at diagnosis that did not receive radiation during frontline therapy appeared to have a higher risk of involvement at first relapse relative to previously irradiated metastatic sites.[22] These observations support the current paradigm of irradiating metastases that persist by MIBG uptake after induction chemotherapy in high-risk patients. In cases where diffuse bone metastases remain after induction chemotherapy, high-dose chemotherapy is followed by re-assessment before consolidative radiation therapy. Irradiation of more than 50% of the bone marrow is not advised.

Preliminary outcomes of proton radiation therapy to treat high-risk neuroblastoma primary tumors have been published, demonstrating acceptable efficacy and toxicity.[23]

Postconsolidation phase

Postconsolidation therapy is designed to treat potential MRD after SCT.[24] For high-risk patients in remission after SCT, dinutuximab combined with GM-CSF and IL-2 are given in concert with isotretinoin and have been shown to improve EFS.[25,26]

Evidence (all treatments):

1. A randomized study compared high-dose therapy and purged autologous bone marrow transplant (ABMT) with three cycles of intensive consolidation chemotherapy. In addition, after the completion of either chemotherapy or ABMT, patients on this study were randomly assigned to stop therapy or to receive 6 months of isotretinoin.[14]; [24][Level of evidence: 1iiA] The EFS and OS results described below reflect outcome from the time of each randomization.
   • The 5-year EFS was significantly better in the ABMT arm (30%), than in the consolidation chemotherapy arm (19%; P = .04). There was no significant difference in 5-year OS between the two arms (39% vs. 30%; P = .08).[24]
   • Patients who received isotretinoin had a higher 5-year EFS than did patients who received no maintenance therapy (42% vs. 31%), although the difference was not significant (P = .12). OS was higher for patients randomly assigned to receive isotretinoin (50%) than it was for those who stopped therapy (39%), but this difference was not significant (P = .10).[24]
2. An updated Cochrane review evaluated three randomized clinical trials comparing ABMT with standard chemotherapy.[14-16,24,27]
   • EFS was significantly better for ABMT, but there was no statistically significant difference in OS.
3. A retrospective, single-institution, nonrandomized trial compared patients who received GM-CSF and 3F8 anti-GD2 antibody therapy after either autologous SCT or conventional chemotherapy.[28] The patients were a mixture of those referred for initial treatment or further therapy, and included refractory and relapsed patients, some of whom had received autologous SCT at referring institutions. In the autologous SCT group, there was a significantly longer time from first chemotherapy or from autologous SCT to initiation of GM-CSF and 3F8 anti-GD2 antibody treatment. The autologous SCT group also had significantly more ultra–high-risk patients.
   • A trend for better EFS with GM-CSF and 3F8 anti-GD2 antibody therapy and autologous SCT was observed (65% vs. 51%, P = .128), but there was no statistically significant difference in OS between patients who were treated with chemotherapy alone and those who were treated with autologous SCT.
4. In a separate prospective, randomized study, there was no advantage to purging harvested stem cells of neuroblastoma cells before transplantation.[29]
5. A review of 147 allogeneic transplant cases submitted to the Center for International Blood and Marrow Transplant Research found no advantage for allogeneic transplant over autologous transplant, even if the allogeneic transplant recipient had received a previous autologous transplant.[30]
6. In a COG phase III trial after SCT, patients were randomly assigned to receive dinutuximab administered with GM-CSF and IL-2 in conjunction with isotretinoin, versus isotretinoin alone.[25]
   • Immunotherapy together with isotretinoin (EFS, 66%) was superior to standard isotretinoin maintenance therapy (EFS, 46%). As a result, immunotherapy post-SCT is considered the standard of care in COG trials for high-risk disease.[25] As a result of the COG studies, dinutuximab has been approved by the U.S. Food and Drug Administration.

Surgery and radiation therapy (local control)

The potential benefit of aggressive surgical approaches in high-risk patients with metastatic disease to achieve complete tumor resection, either at the time of diagnosis or after chemotherapy, has not been unequivocally demonstrated.

• Several studies have reported that complete resection of the primary tumor at diagnosis improved survival; however, the outcome in these patients may be more dependent on the biology of the tumor, which itself may determine resectability, than on the extent of surgical resection.[31-33]
• Radiation therapy to consolidate local control after surgical resection is often given.[34,35]; [36][Level of evidence: 3iiA] In one study (ANBL0532 [NCT00567567]), 21.6 Gy of radiation therapy was delivered to the tumor bed on the basis of the postinduction preoperative imaging, with a boost of 14.4 Gy to areas larger than 1 cm present after surgery. A retrospective study also confirmed the improvement in local control for children with high-risk neuroblastoma and gross residual disease using radiation therapy doses of 30 Gy to 36 Gy.[21]
• In stage 4 patients older than 18 months, controversy exists about whether there is any advantage to gross-total resection of the primary tumor after chemotherapy.[12,32,33,37]

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:

• ANBL1531 (NCT03126916) (A Phase III Study of 131I-MIBG or Crizotinib Added to Intensive Therapy for Children With Newly Diagnosed High-Risk Neuroblastoma): The standard current COG therapy has been described above; it consists of induction chemotherapy, consolidation with surgery and tandem SCT, and postconsolidation radiation therapy with isotretinoin and dinutuximab immune-enhanced immunotherapy. During the 4-week initial induction chemotherapy cycle, patients will be screened for the ALK gene aberration (occurs in approximately 10%–15% of high-risk patients). Before the second cycle of induction chemotherapy, the treatment arm assignment occurs. Most patients enrolled will be MIBG avid and lack the ALKaberration, and will be randomly assigned to one of the following three treatment arms:
  1. Arm A consists of standard COG therapy as described above.
  2. Arm B consists of standard COG therapy but with an MIBG cycle added after the third cycle of induction chemotherapy.
  3. Arm C consists of the same treatment as arm B but the consolidation ablative therapy for SCT will be a single transplant with busulfan/melphalan, rather than the COG standard tandem transplant.
  Patients with the ALK gene mutation or ALK amplification will receive nonrandomized COG current standard induction chemotherapy with the ALK inhibitor crizotinib added, followed by further therapy on the standard COG treatment plan.
  Patients with MIBG nonavid, ALK nonaberrant tumors will receive standard current chemotherapy as in arm A above.
• ANBL 17P1 (NCT03786783) (A Pilot Induction Regimen Incorporating Chimeric 14.18 Antibody [Dinutuximab] and Sargramostim [GM-CSF] for the Treatment of Newly Diagnosed High-Risk Neuroblastoma): The need for innovative therapies for children with high-risk neuroblastoma remains critical because many children with high-risk disease experience progressive disease during induction therapy, have persistent metastatic disease, or relapse after the completion of therapy. Recent studies conducted in patients with recurrent or refractory neuroblastoma have demonstrated objective clinical responses after treatment with the combination of an anti-GD2 monoclonal antibody plus chemotherapy and GM-CSF. This limited-institution protocol will evaluate whether the addition of the anti-GD2 monoclonal antibody dinutuximab and GM-CSF to standard induction chemotherapy during cycles 3 to 5 for patients with newly-diagnosed neuroblastoma is safe and tolerable.

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. Canete A, Gerrard M, Rubie H, et al.: Poor survival for infants with MYCN-amplified metastatic neuroblastoma despite intensified treatment: the International Society of Paediatric Oncology European Neuroblastoma Experience. J Clin Oncol 27 (7): 1014-9, 2009. [PUBMED Abstract]
3. Maris JM: Recent advances in neuroblastoma. N Engl J Med 362 (23): 2202-11, 2010. [PUBMED Abstract]
4. Cotterill SJ, Pearson AD, Pritchard J, et al.: Late relapse and prognosis for neuroblastoma patients surviving 5 years or more: a report from the European Neuroblastoma Study Group "Survey". Med Pediatr Oncol 36 (1): 235-8, 2001. [PUBMED Abstract]
5. Mertens AC, Yasui Y, Neglia JP, et al.: Late mortality experience in five-year survivors of childhood and adolescent cancer: the Childhood Cancer Survivor Study. J Clin Oncol 19 (13): 3163-72, 2001. [PUBMED Abstract]
6. Morgenstern DA, London WB, Stephens D, et al.: Metastatic neuroblastoma confined to distant lymph nodes (stage 4N) predicts outcome in patients with stage 4 disease: A study from the International Neuroblastoma Risk Group Database. J Clin Oncol 32 (12): 1228-35, 2014. [PUBMED Abstract]
7. Kushner BH, LaQuaglia MP, Bonilla MA, et al.: Highly effective induction therapy for stage 4 neuroblastoma in children over 1 year of age. J Clin Oncol 12 (12): 2607-13, 1994. [PUBMED Abstract]
8. Park JR, Scott JR, Stewart CF, et al.: Pilot induction regimen incorporating pharmacokinetically guided topotecan for treatment of newly diagnosed high-risk neuroblastoma: a Children's Oncology Group study. J Clin Oncol 29 (33): 4351-7, 2011. [PUBMED Abstract]
9. Decarolis B, Schneider C, Hero B, et al.: Iodine-123 metaiodobenzylguanidine scintigraphy scoring allows prediction of outcome in patients with stage 4 neuroblastoma: results of the Cologne interscore comparison study. J Clin Oncol 31 (7): 944-51, 2013. [PUBMED Abstract]
10. Yanik GA, Parisi MT, Shulkin BL, et al.: Semiquantitative mIBG scoring as a prognostic indicator in patients with stage 4 neuroblastoma: a report from the Children's oncology group. J Nucl Med 54 (4): 541-8, 2013. [PUBMED Abstract]
11. De Ioris MA, Crocoli A, Contoli B, et al.: Local control in metastatic neuroblastoma in children over 1 year of age. BMC Cancer 15: 79, 2015. [PUBMED Abstract]
12. von Allmen D, Davidoff AM, London WB, et al.: Impact of Extent of Resection on Local Control and Survival in Patients From the COG A3973 Study With High-Risk Neuroblastoma. J Clin Oncol 35 (2): 208-216, 2017. [PUBMED Abstract]
13. Englum BR, Rialon KL, Speicher PJ, et al.: Value of surgical resection in children with high-risk neuroblastoma. Pediatr Blood Cancer 62 (9): 1529-35, 2015. [PUBMED Abstract]
14. Matthay KK, Villablanca JG, Seeger RC, et al.: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group. N Engl J Med 341 (16): 1165-73, 1999. [PUBMED Abstract]
15. Berthold F, Boos J, Burdach S, et al.: Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial. Lancet Oncol 6 (9): 649-58, 2005. [PUBMED Abstract]
16. Pritchard J, Cotterill SJ, Germond SM, et al.: High dose melphalan in the treatment of advanced neuroblastoma: results of a randomised trial (ENSG-1) by the European Neuroblastoma Study Group. Pediatr Blood Cancer 44 (4): 348-57, 2005. [PUBMED Abstract]
17. Elborai Y, Hafez H, Moussa EA, et al.: Comparison of toxicity following different conditioning regimens (busulfan/melphalan and carboplatin/etoposide/melphalan) for advanced stage neuroblastoma: Experience of two transplant centers. Pediatr Transplant 20 (2): 284-9, 2016. [PUBMED Abstract]
18. Ladenstein R, Pötschger U, Pearson ADJ, et al.: Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial. Lancet Oncol 18 (4): 500-514, 2017. [PUBMED Abstract]
19. Seif AE, Naranjo A, Baker DL, et al.: A pilot study of tandem high-dose chemotherapy with stem cell rescue as consolidation for high-risk neuroblastoma: Children's Oncology Group study ANBL00P1. Bone Marrow Transplant 48 (7): 947-52, 2013. [PUBMED Abstract]
20. Park JR, Kreissman SG, London WB, et al.: A phase III randomized clinical trial (RCT) of tandem myeloablative autologous stem cell transplant (ASCT) using peripheral blood stem cell (PBSC) as consolidation therapy for high-risk neuroblastoma (HR-NB): a Children's Oncology Group (COG) study. [Abstract] J Clin Oncol 34 (Suppl 15): A-LBA3, 2016. Also available onlineExit Disclaimer. Last accessed February 11, 2019.
21. Casey DL, Kushner BH, Cheung NV, et al.: Dose-escalation is needed for gross disease in high-risk neuroblastoma. Pediatr Blood Cancer 65 (7): e27009, 2018. [PUBMED Abstract]
22. Polishchuk AL, Li R, Hill-Kayser C, et al.: Likelihood of bone recurrence in prior sites of metastasis in patients with high-risk neuroblastoma. Int J Radiat Oncol Biol Phys 89 (4): 839-45, 2014. [PUBMED Abstract]
23. Hattangadi JA, Rombi B, Yock TI, et al.: Proton radiotherapy for high-risk pediatric neuroblastoma: early outcomes and dose comparison. Int J Radiat Oncol Biol Phys 83 (3): 1015-22, 2012. [PUBMED Abstract]
24. Matthay KK, Reynolds CP, Seeger RC, et al.: Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children's oncology group study. J Clin Oncol 27 (7): 1007-13, 2009. [PUBMED Abstract]
25. Yu AL, Gilman AL, Ozkaynak MF, et al.: Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med 363 (14): 1324-34, 2010. [PUBMED Abstract]
26. Cheung NK, Cheung IY, Kushner BH, et al.: Murine anti-GD2 monoclonal antibody 3F8 combined with granulocyte-macrophage colony-stimulating factor and 13-cis-retinoic acid in high-risk patients with stage 4 neuroblastoma in first remission. J Clin Oncol 30 (26): 3264-70, 2012. [PUBMED Abstract]
27. Yalçin B, Kremer LC, Caron HN, et al.: High-dose chemotherapy and autologous haematopoietic stem cell rescue for children with high-risk neuroblastoma. Cochrane Database Syst Rev 8: CD006301, 2013. [PUBMED Abstract]
28. Kushner BH, Ostrovnaya I, Cheung IY, et al.: Lack of survival advantage with autologous stem-cell transplantation in high-risk neuroblastoma consolidated by anti-GD2 immunotherapy and isotretinoin. Oncotarget 7 (4): 4155-66, 2016. [PUBMED Abstract]
29. Kreissman SG, Seeger RC, Matthay KK, et al.: Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial. Lancet Oncol 14 (10): 999-1008, 2013. [PUBMED Abstract]
30. Hale GA, Arora M, Ahn KW, et al.: Allogeneic hematopoietic cell transplantation for neuroblastoma: the CIBMTR experience. Bone Marrow Transplant 48 (8): 1056-64, 2013. [PUBMED Abstract]
31. DeCou JM, Bowman LC, Rao BN, et al.: Infants with metastatic neuroblastoma have improved survival with resection of the primary tumor. J Pediatr Surg 30 (7): 937-40; discussion 940-1, 1995. [PUBMED Abstract]
32. Castel V, Tovar JA, Costa E, et al.: The role of surgery in stage IV neuroblastoma. J Pediatr Surg 37 (11): 1574-8, 2002. [PUBMED Abstract]
33. Simon T, Häberle B, Hero B, et al.: Role of surgery in the treatment of patients with stage 4 neuroblastoma age 18 months or older at diagnosis. J Clin Oncol 31 (6): 752-8, 2013. [PUBMED Abstract]
34. Haas-Kogan DA, Swift PS, Selch M, et al.: Impact of radiotherapy for high-risk neuroblastoma: a Children's Cancer Group study. Int J Radiat Oncol Biol Phys 56 (1): 28-39, 2003. [PUBMED Abstract]
35. Casey DL, Kushner BH, Cheung NK, et al.: Local Control With 21-Gy Radiation Therapy for High-Risk Neuroblastoma. Int J Radiat Oncol Biol Phys 96 (2): 393-400, 2016. [PUBMED Abstract]
36. Gatcombe HG, Marcus RB Jr, Katzenstein HM, et al.: Excellent local control from radiation therapy for high-risk neuroblastoma. Int J Radiat Oncol Biol Phys 74 (5): 1549-54, 2009. [PUBMED Abstract]
37. Adkins ES, Sawin R, Gerbing RB, et al.: Efficacy of complete resection for high-risk neuroblastoma: a Children's Cancer Group study. J Pediatr Surg 39 (6): 931-6, 2004. [PUBMED Abstract]

Treatment of INSS Stage 4S and INRG Stage MS Neuroblastoma

In This Section

• Treatment Options for Stage 4S/MS Neuroblastoma
  • Observation with supportive care
  • Chemotherapy
• Treatment Options Under Clinical Evaluation
  • Current Clinical Trials

International Neuroblastoma Staging System (INSS) stage 4S patients are younger than 12 months and have an INSS stage 1 or stage 2 primary tumor, whereas International Neuroblastoma Risk Group (INRG) stage MS patients are younger than 18 months with any stage of primary tumor. Both staging systems have the same definition of limited pattern of metastases.

Many patients with stage 4S neuroblastoma do not require therapy. However, tumors with unfavorable biology or patients who are symptomatic because of evolving hepatomegaly and organ compromise are at increased risk of death and are treated with low-dose to moderate-dose chemotherapy. Eight percent to 10% of these patients will have MYCNamplification and are treated with high-risk protocols.[1]

The previously used Children's Oncology Group (COG) neuroblastoma 4S group assignment criteria are described in Table 15.

Table 15. Children’s Oncology Group (COG) Neuroblastoma Stage 4S Group Assignment Schema Used for COG-P9641, COG-A3961, and COG-A3973 Studiesa

ENLARGE

INSS Stage	Age	MYCN Status	INPC Classification	DNA Ploidyb	Other	Risk Group
DI = DNA index; INPC = International Neuroblastoma Pathologic Classification; INSS = International Neuroblastoma Staging System.
aThe COG-P9641 (NCT00003119), COG-A3961 (NCT00003093), and COG-A3973 (NCT00004188) 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 4S infants with favorable biology and clinical symptoms are treated with immediate chemotherapy until asymptomatic or according to protocol guidelines. 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.
4Sc	<365 d	Nonamplified	Favorable	DI >1	Asymptomatic	Low
	<365 d	Nonamplified	Any	DI =1	Asymptomatic or symptomatic	Intermediate
	<365 d	Nonamplified	Unfavorable	Any	Asymptomatic or symptomatic	Intermediate
	<365 d	Missing	Missing	Missing	Too sick for biopsy	Intermediate
	<365 d	Nonamplified	Any	Any	Symptomatic	Intermediate
	<365 d	Amplified	Any	Any	Asymptomatic or symptomatic	High

Table 16 shows the INRG classification for stage 4S neuroblastoma used in ongoing COG studies.

Table 16. International Neuroblastoma Risk Group (INRG) Pretreatment Classification Schema for Stage 4S Neuroblastomaa

ENLARGE

INRG Stage		Histologic Category	Grade of Tumor Differentiation	MYCN	11q Aberration	Ploidy	Pretreatment Risk Group
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]
MS
	Age <18 mo			NA	No		C (very low)
					Yes		Q (high)
				Amplified			R (high)

Treatment Options for Stage 4S/MS Neuroblastoma

There is no standard approach to the treatment of stage 4S neuroblastoma.

Treatment options for stage 4S neuroblastoma include the following:

1. Observation with supportive care (for asymptomatic patients with favorable tumor biology).
2. Chemotherapy (for symptomatic patients, very young infants, or patients with unfavorable biology).

Resection of primary tumor is not associated with improved outcome.[3-5] Rarely, infants with massive hepatic 4S neuroblastoma develop cirrhosis from the chemotherapy and/or radiation therapy that is used to control the disease and may benefit from orthotopic liver transplant.[6]

Observation with supportive care

Observation with supportive care is used to treat asymptomatic patients with favorable tumor biology.

The treatment of children with stage 4S disease is dependent on clinical presentation.[3,4] Most patients do not require therapy unless bulky disease is causing organ compromise and risk of death.

Chemotherapy

Chemotherapy is used to treat symptomatic patients, very young infants (diagnosed before age 2 months), or patients with unfavorable biology. Patients with evidence of rapid tumor growth in the first several weeks of life require immediate intervention with chemotherapy to avoid potentially irreversible abdominal compartment syndrome and hepatic and/or renal failure.[7]

Infants diagnosed with INSS stage 4S neuroblastoma, particularly those with hepatomegaly or those younger than 3 months, have the potential for rapid clinical deterioration and may benefit from early initiation of therapy.[7] It has been difficult to identify infants with stage 4S disease who will benefit from chemotherapy.

A scoring system to measure signs and symptoms of deterioration or compromise was developed to better assess this group of stage 4S patients.[8] This scoring system has been evaluated retrospectively, was predictive of the clinical course, and has been applied prospectively to guide the management of patients with INSS stage 4S disease.[8,9] The scoring system has been modified based on the ANBL0531 results in the youngest infants discussed above to guide chemotherapeutic intervention for 4S in infants.[7]

Various chemotherapy regimens (cyclophosphamide alone, carboplatin/etoposide, cyclophosphamide/doxorubicin/vincristine) have been used to treat symptomatic patients. The approach is to administer the chemotherapy only as long as symptoms persist to avoid toxicity, which contributes to poorer survival. Additionally, lower doses of chemotherapy are often recommended for very young or low-weight infants, along with granulocyte colony-stimulating factors after each cycle of chemotherapy.

Evidence (chemotherapy for symptomatic patients, very young infants, or patients with unfavorable biology):

1. The COG ANBL0531 (NCT00499616) trial prospectively studied a subset of 4S patients who had MYCN-nonamplified tumors with impaired or impending organ dysfunction or unfavorable biology (unfavorable histology and/or diploid DNA index). Forty-nine patients were enrolled, of which 41 were symptomatic and 28 had unfavorable biology. Patients were assigned to receive two, four, or eight cycles of chemotherapy on the basis of the tumor biology, age of the patient, and symptoms.[7][Level of evidence: 3iiiA]
   • The 3-year overall survival (OS) was 81.4%. Eight of the nine deaths occurred in patients younger than 2 months at diagnosis. Five deaths were related to acute complications of rapidly progressing hepatomegaly (i.e., abdominal compartment syndrome, renal failure, respiratory failure, coagulopathy, and infection). Patients younger than 40 days at diagnosis had more than 13 times the risk of dying compared with patients older than 47 days. The study was amended after the five deaths to mandate immediate chemotherapy for patients with 4S disease younger than 2 months at diagnosis with evolving hepatomegaly. No deaths related to complications of hepatomegaly occurred in the subsequent infants enrolled, including 18 infants who were younger than 2 months.
   • This study confirmed the inferior outcome of patients with unfavorable biology compared with symptomatic patients with favorable biology. Both of the patients with late death died as a result of metastatic disease and had unfavorable biology.
   • Resection of the primary tumor was not mandated in this study, with only 16 patients having a greater than 50% resection of the primary tumor. Symptomatic patients without a biopsy were eligible for enrollment in the trial to encourage rapid treatment and avoid risky procedures. The trial allowed patients with symptomatic 4S disease to avoid biopsy and thus, biological characterization until the patient's condition improved and biopsy was considered safe.
     Emergent surgical abdominal decompression can be used to avoid respiratory deterioration and improve ventilation.[10,11]
2. Eighty stage 4S patients were enrolled on the COG-P9641 trial.[12]
   • Overall, the 5-year event-free survival (EFS) was 77%, and the OS was 91%.
   • The 5-year EFS was 63% and OS was 84% for the 41 patients with asymptomatic stage 4S neuroblastoma treated with surgery or biopsy alone; the EFS was 95% and OS was 97% for the 39 patients treated with surgery and chemotherapy (EFS P = .0016; OS P = .1302). Previously, chemotherapy toxicity was thought to be responsible for the poorer survival of patients with stage 4S disease; however, the use of chemotherapy on the COG-P9641 trial was restricted to specific clinical situations with a recommended number of cycles.
3. Also, on the COG-P9641 trial, asymptomatic infants with biologically favorable (MYCN-nonamplified) INSS stage 4S disease did not receive chemotherapy until the development of progressive disease or clinical symptoms.[12]
   • Infants who became symptomatic had disease-related organ failure and infectious complications resulting in an inferior OS compared with those who received immediate chemotherapy (four to eight cycles of therapy). The 3-year OS for infants who did not receive chemotherapy was 84% versus 97% for infants who received chemotherapy (P = .1321).
4. On the COG-ANBL0531 trial, the 2-year OS rate for INSS stage 4S patients was 81%, which is lower than that reported in other cooperative trials such as COG-P9641.[7,13] Many patients enrolled on the ANBL0531 study were more ill than patients entered on previous trials, in part because tumor biopsy was not required in symptomatic infants. Previous trials mainly included asymptomatic patients and most had favorable biology. Treatment on ANBL0531 was allocated on the basis of symptoms, age, and tumor biology.
5. A prospective study was performed in 125 infants with stage 4S MYCN-nonamplified tumors or INSS stage 3 primary tumors and/or positive bone scintigraphy not associated with changes in the cortical bone documented on plain radiographs and/or computed tomography. A pretreatment symptom score was used to determine initial treatment; observation was recommended for infants with low symptom scores (n = 86) and chemotherapy was recommended for infants with high symptom scores (n = 37). The chemotherapy for patients with high symptom scores included two to four 3-day courses of carboplatin and etoposide; if symptoms persisted or progressive disease developed, up to four 5-day courses of cyclophosphamide, doxorubicin, and vincristine were administered. One-half of the patients underwent complete or partial resection of the primary tumor.[9]
   • There was no difference in the 2-year EFS and OS between asymptomatic and symptomatic patients (EFS, 87% vs. 88%; OS, 98% vs. 97%), although many of the investigators preferred to give chemotherapy in the presence of a low symptom score.
   • For infants with low symptom scores, there was no difference in the outcome between the initially untreated infants (n = 56; OS, 93%) and treated infants (n = 30; OS, 86%).
   • The OS was 90% for infants presenting with high symptom scores.
   • 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%).

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):
  • For all newly diagnosed INRG MS patients younger than 18 months, the following occurs:
    • Patients younger than 3 months with existing or evolving hepatomegaly or who are symptomatic are entered in the trial, and chemotherapy begins immediately. Full staging must be completed within 1 month; a tumor biopsy is not performed until the patient is stable.
    • Patients aged 3 to 12 months who are symptomatic are entered in the trial, and chemotherapy begins immediately. Tumor biopsy is performed after the patient is stable.
    • Patients aged 12 to 18 months who are symptomatic have a tumor biopsy before starting chemotherapy.
    • Patients aged 3 to 18 months who are asymptomatic and patients younger than 3 months who are asymptomatic and have no evolving hepatomegaly have a tumor biopsy followed by close observation initially, to continue for 3 years.
      Patients with INRG MS tumors that have unfavorable histology or unfavorable genomic features with or without symptoms are treated according to a response-based algorithm to determine length of treatment. For INRG MS patients under observation without chemotherapy, an objective scoring system is used to monitor them for clinical changes and initiate therapy. For patients with complete resolution of symptoms and at least a 50% reduction in primary tumor volume (partial response), chemotherapy is discontinued, and observation continues for 3 years after completion of therapy. If the disease progresses, the patient leaves this study.

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. Canete A, Gerrard M, Rubie H, et al.: Poor survival for infants with MYCN-amplified metastatic neuroblastoma despite intensified treatment: the International Society of Paediatric Oncology European Neuroblastoma Experience. J Clin Oncol 27 (7): 1014-9, 2009. [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. Guglielmi M, De Bernardi B, Rizzo A, et al.: Resection of primary tumor at diagnosis in stage IV-S neuroblastoma: does it affect the clinical course? J Clin Oncol 14 (5): 1537-44, 1996. [PUBMED Abstract]
4. Katzenstein HM, Bowman LC, Brodeur GM, et al.: Prognostic significance of age, MYCN oncogene amplification, tumor cell ploidy, and histology in 110 infants with stage D(S) neuroblastoma: the pediatric oncology group experience--a pediatric oncology group study. J Clin Oncol 16 (6): 2007-17, 1998. [PUBMED Abstract]
5. Nickerson HJ, Matthay KK, Seeger RC, et al.: Favorable biology and outcome of stage IV-S neuroblastoma with supportive care or minimal therapy: a Children's Cancer Group study. J Clin Oncol 18 (3): 477-86, 2000. [PUBMED Abstract]
6. Steele M, Jones NL, Ng V, et al.: Successful liver transplantation in an infant with stage 4S(M) neuroblastoma. Pediatr Blood Cancer 60 (3): 515-7, 2013. [PUBMED Abstract]
7. Twist CJ, Naranjo A, Schmidt ML, et al.: Defining Risk Factors for Chemotherapeutic Intervention in Infants With Stage 4S Neuroblastoma: A Report From Children's Oncology Group Study ANBL0531. J Clin Oncol : JCO1800419, 2018. [PUBMED Abstract]
8. Hsu LL, Evans AE, D'Angio GJ: Hepatomegaly in neuroblastoma stage 4s: criteria for treatment of the vulnerable neonate. Med Pediatr Oncol 27 (6): 521-8, 1996. [PUBMED Abstract]
9. 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]
10. Keene DJ, Minford J, Craigie RJ, et al.: Laparostomy closure in stage 4S neuroblastoma. J Pediatr Surg 46 (1): e1-4, 2011. [PUBMED Abstract]
11. Harper L, Perel Y, Lavrand F, et al.: Surgical management of neuroblastoma-related hepatomegaly: do material and method really count? Pediatr Hematol Oncol 25 (4): 313-7, 2008. [PUBMED Abstract]
12. 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]
13. Park JR, Bagatell R, London WB, et al.: Children's Oncology Group's 2013 blueprint for research: neuroblastoma. Pediatr Blood Cancer 60 (6): 985-93, 2013. [PUBMED Abstract]

Treatment of Recurrent Neuroblastoma

In This Section

• Prognostic Factors for Recurrent Neuroblastoma
• Recurrent Neuroblastoma in Patients Initially Classified as Low Risk
  • Locoregional recurrence
  • Metastatic recurrence or disease refractory to standard treatment
• Recurrent Neuroblastoma in Patients Initially Classified as Intermediate Risk
  • Locoregional recurrence
  • Metastatic recurrence
• Recurrent Neuroblastoma in Patients Initially Classified as High Risk
• Recurrent Neuroblastoma in the Central Nervous System
• Treatment Options Under Clinical Evaluation for Recurrent or Refractory Neuroblastoma
  • Current Clinical Trials

Tumor growth resulting from maturation should be differentiated from tumor progression by performing a biopsy and reviewing histology. Patients may have persistent maturing disease with metaiodobenzylguanidine (MIBG) uptake that does not affect outcome, particularly patients with low-risk and intermediate-risk disease.[1] An analysis of 23 paired MIBG and positron emission tomography (PET) scans in 14 patients with refractory or recurrent high-risk neuroblastoma treated with iodine I 131-MIBG (131I-MIBG) found that the MIBG scan was more sensitive than fluorine F 18-fludeoxyglucose (18F-FDG) PET for detecting metastatic bone lesions, although there was a trend for 18F-FDG PET to be more sensitive for soft tissue lesions.[2]

Subclonal ALK mutations or other MAPK pathway lesions may be present at diagnosis, with subsequent clonal expansion at relapse. Consequently, serial sampling of progressive tumors may lead to the identification of potentially actionable mutations.[3,4] Modern comprehensive molecular analysis comparing primary and relapsed neuroblastoma from the same patients revealed extensive clonal enrichment and several newly discovered mutations, with many tumors showing new or clonal-enriched mutations in the RAS-MAPK pathway. This was true for patients with both high-risk and low-risk tumors at diagnosis.[5,6]

If neuroblastoma recurs in a child originally diagnosed with high-risk disease, the prognosis is usually poor despite additional intensive therapy.[7-10] However, it is often possible to gain many additional months of life for these patients with alternative chemotherapy regimens.[11,12] Clinical trials are appropriate for these patients and may be offered. Information about ongoing clinical trials is available from the NCI website.

Prognostic Factors for Recurrent Neuroblastoma

The International Neuroblastoma Risk Group Project performed a survival-tree analysis of clinical and biological characteristics (defined at diagnosis) associated with survival after relapse in 2,266 patients with neuroblastoma entered on large clinical trials in well-established clinical trials groups around the world.[7]

• Overall survival (OS) in the entire relapsed population was 20%.
• Among patients with all stages of disease at diagnosis, MYCN amplification predicted a poorer prognosis, measured as 5-year OS.
• Among patients diagnosed with International Neuroblastoma Staging System (INSS) stage 4 without amplification, age older than18 months and high lactate dehydrogenase (LDH) level predicted poor prognosis.
• Among patients with MYCN amplification, those diagnosed with stage 1 and stage 2 have a better prognosis than do those diagnosed with stage 3 and stage 4.
• Among patients with MYCN-nonamplified tumors who are not stage 4, patients with hyperdiploidy had a better prognosis than did patients with diploidy in those younger than 18 months, while among those older than 18 months, patients with differentiating tumors fared much better than did patients with undifferentiated and poorly differentiated tumors.

Significant prognostic factors determined at diagnosis for postrelapse survival include the following:[7]

• Age.
• INSS stage.
• MYCN status.
• Time from diagnosis to first relapse.
• LDH level, ploidy, and histologic grade of tumor differentiation (to a lesser extent).

Although the OS after recurrence in children presenting with high-risk neuroblastoma is generally extremely poor, patients with high-risk neuroblastoma at first relapse after complete remission or minimal residual disease (MRD) in whom relapse was a single site of soft tissue mass (a few children also had bone marrow or bone disease at relapse) had a 5-year OS of 35% in one single-institution study. All patients underwent surgical resection of the soft tissue disease. MYCN amplification and multifocal soft tissue disease were associated with a worse postprogression survival.[13]

The Children’s Oncology Group (COG) experience with recurrence in patients with low-risk and intermediate-risk neuroblastoma showed that most patients can be salvaged. The COG reported a 3-year event free survival (EFS) of 88% and an OS of 96% in intermediate-risk patients and a 5-year EFS of 89% and OS of 97% in low-risk patients.[14,15] Moreover, in most patients originally diagnosed with low-risk or intermediate-risk disease, local recurrence or recurrence in the 4S pattern may be treated successfully with observation alone, surgery alone, or with moderate-dose chemotherapy, without myeloablative therapy and stem cell transplant.

Recurrent Neuroblastoma in Patients Initially Classified as Low Risk

Locoregional recurrence

Treatment options for locoregional recurrent neuroblastoma initially classified as low risk include the following:

1. Surgery followed by observation or chemotherapy.
2. Chemotherapy that may be followed by surgery.

Local or regional recurrent cancer is resected if possible.

Patients with favorable biology and regional recurrence more than 3 months after completion of planned treatment are observed if resection of the recurrence is total or near total (≥90% resection). Those with favorable biology and a less-than-near-total resection are treated with chemotherapy.

Infants younger than 1 year at the time of locoregional recurrence whose tumors have any unfavorable biologic properties are observed if resection is total or near total. If the resection is less than near total, these same infants are treated with chemotherapy. Chemotherapy may consist of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide, or cyclophosphamide and topotecan. The cumulative dose of each agent is kept low to minimize long-term effects from the chemotherapy regimen as used in previous COG trials (COG-P9641 and COG-A3961).

Older children with local recurrence with either unfavorable International Neuroblastoma Pathology Classification at diagnosis or MYCN gene amplification have a poor prognosis and may be treated with surgery, aggressive combination chemotherapy, or they may be offered entry into a clinical trial.

Evidence (surgery followed by observation or chemotherapy):

1. A COG study of low-risk patients with stages 1, 2A, 2B, and 4S neuroblastoma enrolled 915 patients, 800 of whom were asymptomatic and treated with surgery alone followed by observation. The other patients received chemotherapy with or without surgery.[15]
   • About 10% of patients developed progressive or recurrent tumor. Most recurrences were treated on study with surgery alone or moderate chemotherapy with or without surgery, and most patients were salvaged, as demonstrated by the EFS (89%) and OS (97%) rates at 5 years.

Metastatic recurrence or disease refractory to standard treatment

Treatment options for metastatic recurrent neuroblastoma initially classified as low risk include the following:

1. Observation.
2. Chemotherapy.
3. Surgery followed by chemotherapy.
4. High-risk therapy.

Metastatic recurrent or progressive neuroblastoma in an infant initially categorized as low risk and younger than 1 year at recurrence may be treated according to tumor biology, as defined in the previous COG trials (COG-P9641 and COG-A3961):

1. If the biology is completely favorable, metastasis is in a 4S pattern, and the recurrence or progression is within 3 months of diagnosis, the patient is observed systematically.
2. If the metastatic progression or recurrence occurs more than 3 months after diagnosis or not in a 4S pattern, then the primary tumor is resected, if possible, and chemotherapy is given.
   Chemotherapy may consist of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low to minimize long-term effects from the chemotherapy regimen, as used in previous COG trials (COG-P9641 and COG-A3961).

Any child initially categorized as low risk who is older than 1 year at the time of metastatic recurrent or progressive disease and whose recurrence is not in the stage 4S pattern usually has a poor prognosis and is treated as follows:

1. High-risk therapy.

Patients with metastatic recurrent neuroblastoma are treated like patients with newly diagnosed high-risk neuroblastoma. (Refer to the Treatment Options for High-Risk Neuroblastoma section of this summary for more information.)

Recurrent Neuroblastoma in Patients Initially Classified as Intermediate Risk

The treatment options for locoregional and metastatic recurrence in patients with intermediate-risk neuroblastoma are derived from the results of the COG-A3961 trial. Among 479 patients with intermediate-risk neuroblastoma treated on the COG-A3961 clinical trial, 42 patients developed disease progression. The rate was 10% of those with favorable biology and 17% of those with unfavorable biology. Thirty patients had locoregional recurrence, 11 patients had metastatic recurrence, and 1 patient had both types of recurrent disease. Six of the 42 patients died of disease, while 36 patients were salvaged. Thus, most patients with intermediate-risk neuroblastoma and disease progression may be salvaged.[14]

Locoregional recurrence

Treatment options for locoregional recurrent neuroblastoma initially classified as intermediate risk include the following:

1. Surgery (complete resection).
2. Surgery (incomplete resection) followed by chemotherapy.

The current standard of care is based on the experience from the COG intermediate-risk treatment plan (COG-A3961). Locoregional recurrence of neuroblastoma with favorable biology that occurs more than 3 months after completion of chemotherapy may be treated surgically. If resection is less than near total, then additional chemotherapy may be given. Chemotherapy may consist of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low to minimize long-term effects from the chemotherapy regimen, as used in a previous COG trial (COG-A3961).

Metastatic recurrence

Treatment options for metastatic recurrent neuroblastoma initially classified as intermediate risk include the following:

1. High-risk therapy.

Patients with metastatic recurrent neuroblastoma are treated like patients with newly diagnosed high-risk neuroblastoma. (Refer to the Treatment Options for High-Risk Neuroblastoma section of this summary for more information.)

Recurrent Neuroblastoma in Patients Initially Classified as High Risk

Any recurrence in patients initially classified as high risk signifies a very poor prognosis.[7] Clinical trials may be considered. Palliative care should also be considered as part of the patient's treatment plan.

An analysis of several trials included 383 patients with neuroblastoma whose tumor recurred or progressed on COG modern-era early-phase trials. The 1-year progression-free survival (PFS) rate was 21%, and the 4-year PFS rate was 6%, while the OS rates were 57% at 1 year and 20% at 4 years. Less than 10% of patients experienced no subsequent recurrence or progression. MYCN amplification predicted worse PFS and OS rates.[16] Although the OS after recurrence in children presenting with high-risk neuroblastoma is generally extremely poor, patients with high-risk neuroblastoma at first relapse after complete remission or MRD in whom relapse was a single site of soft tissue mass (a few children also had bone marrow or bone disease at relapse) had a 5-year OS of 35% in one single-institution study.[13]

Treatment options for recurrent or refractory neuroblastoma in patients initially classified as high risk include the following:

1. Chemotherapy combined with immunotherapy.
   • Temozolomide, irinotecan, and dinutuximab.[17]
2. 131I-MIBG. 131I-MIBG alone, in combination with other therapy, or followed by stem cell rescue.
3. ALK inhibitors. Crizotinib, or other ALK inhibitors, for patients with ALK mutations.[18]
4. Chemotherapy.
   • Topotecan in combination with cyclophosphamide or etoposide.[19]
   • Temozolomide with irinotecan.

Chemotherapy combined with immunotherapy produces the best response rate and response duration of treatments for high-risk patients with disease progression.

Evidence (chemotherapy combined with immunotherapy):

1. In the ANBL1221 (NCT01767194) trial, patients in first relapse or progression were randomly assigned to receive either temozolomide/irinotecan/dinutuximab or temozolomide/irinotecan/temsirolimus.[17]
   • Of the 17 patients treated with the combination that included dinutuximab, 9 patients (53%) had an objective response, compared with 1 of 18 patients treated with the regimen that contained temsirolimus.

Evidence (131I-MIBG):

1. For children with recurrent or refractory neuroblastoma, 131I-MIBG is an effective palliative agent and may be considered alone or in combination with chemotherapy (with stem cell rescue) in a clinical research trial.[20-25]; [26,27][Level of evidence: 3iiiA]
2. A North American retrospective study of more than 200 patients treated with 131I-MIBG therapy compared children who had recurrence or progression of disease with children who had stable or persistent disease since diagnosis.[28]
   • The rate of immediate progression after 131I-MIBG therapy was lower and OS at 2 years was better (65% vs. 39%) in patients with stable, persistent disease.
3. Tandem consolidation using 131I-MIBG, vincristine, and irinotecan with autologous stem cell transplant (SCT) followed by busulfan/melphalan with autologous SCT was retrospectively reported in eight patients and resulted in three complete responses, two partial responses, and one minor response.[27]
4. Single autologous SCT with escalating dose 131I-MIBG and carboplatin/etoposide/melphalan was studied in additional patients.[29]
   • After induction chemotherapy, 27 refractory patients and 15 progressing patients were treated, resulting in four responses. Eight patients with partial response to induction were treated, resulting in three responses.
   • The 12% incidence of sinusoidal obstructive syndrome was dose limiting.

Evidence (chemotherapy):

1. Topotecan in combination with cyclophosphamide or etoposide has been used in patients with recurrent disease who did not receive topotecan initially.[30,31]; [19][Level of evidence: 1A]
2. The combination of irinotecan and temozolomide had a 15% response rate in one study.[32][Level of evidence: 2A]
3. High-dose carboplatin, irinotecan, and/or temozolomide has been used in relapsed patients resistant or refractory to regimens containing topotecan.[31]
4. A retrospective study reported on 74 patients who received 92 cycles of ifosfamide, carboplatin, and etoposide; it included 37 patients who received peripheral blood stem cell rescue after responding to this drug combination.[33]
   • Disease regressions (major and minor responses) were achieved in 14 of 17 patients (82%) with a new relapse, 13 of 26 patients (50%) with refractory neuroblastoma, and 12 of 34 patients (35%) who were treated for progressive disease during chemotherapy (P = .005).
   • Grade 3 toxicities were rare.

Allogeneic transplant has a historically low success rate in recurrent or progressive neuroblastoma. In a retrospective registry study, allogeneic SCT after a previous autologous SCT appeared to offer no benefit. Disease recurrence remains the most common cause of treatment failure.[34]

Clinical trials of novel therapeutic approaches, such as a vaccine designed to induce host antiganglioside antibodies that can replicate the antineoplastic activities of intravenously administered monoclonal antibodies, are currently under investigation. Patients also receive a beta-glucan treatment, which has a broad range of immunostimulatory effects and synergizes with anti-GD2/GD3 monoclonal antibodies. In a phase I study of 15 children with high-risk neuroblastoma, the therapy was tolerated without any dose-limiting toxicity.[35] Long-term PFS has been reported in patients who achieve a second or later complete or very good partial remission followed by consolidation with anti-GD2 immunotherapy and isotretinoin with or without maintenance therapy. This includes patients who had previously received anti-GD2 immunotherapy and isotretinoin.[36]

Recurrent Neuroblastoma in the Central Nervous System

Central nervous system (CNS) involvement, although rare at initial presentation, may occur in 5% to 10% of patients with recurrent neuroblastoma. Because upfront treatment for newly diagnosed patients does not adequately treat the CNS, the CNS has emerged as a sanctuary site leading to relapse.[37,38] CNS relapses are almost always fatal, with a median time to death of 6 months.

Treatment options for recurrent neuroblastoma in the CNS include the following:

1. Surgery and radiation therapy.
2. Novel therapeutic approaches.

Current treatment approaches generally include eradicating bulky and microscopic residual disease in the CNS and minimal residual systemic disease that may herald further relapses. Neurosurgical interventions serve to decrease edema, control hemorrhage, and remove bulky tumor before starting therapy.

Compartmental radioimmunotherapy using intrathecal radioiodinated monoclonal antibodies has been tested in patients with recurrent metastatic CNS neuroblastoma after surgery, craniospinal radiation therapy, and chemotherapy.[12]

Treatment Options Under Clinical Evaluation for Recurrent or Refractory Neuroblastoma

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 are examples of national and/or institutional clinical trials that are currently being conducted:

• APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
  Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).
• ADVL1312 (NCT02095132) (A Phase I/II Study of AZD1775 [MK-1775] in Combination With Oral Irinotecan in Children, Adolescents, and Young Adults With Relapsed or Refractory Solid Tumors): Wee1 is a tyrosine kinase that is activated in response to DNA damage and plays a role in chemoresistance and tolerance of oncogene-induced cellular stress. The Wee1 inhibitor AZD1775 (MK-1775) was developed to overcome this checkpoint and render cells more sensitive to chemotherapy, and it may be more effective in tumors with high levels of the MYC or MYCN oncogene.
• ADVL1621 (NCT02332668) (A Phase I/II Study of Pembrolizumab [MK-3475] in Children With Advanced Melanoma or a PD-L1–Positive Advanced, Relapsed or Refractory Solid Tumor or Lymphoma): Part 1 of this study will find the maximum tolerated dose, confirm the dose, and find the recommended phase II dose for pembrolizumab therapy. Part 2 of the study will further evaluate the safety and efficacy at the pediatric phase II recommended dose.
• ENCIT-01 (NCT02311621) (A Phase I Feasibility and Safety Study of Cellular Immunotherapy for Recurrent/Refractory Neuroblastoma Using Autologous T-cells Lentivirally Transduced to Express CD171-Specific Chimeric Antigen Receptors [CAR]):Patients with recurrent or refractory neuroblastoma are resistant to conventional chemotherapy. For this reason, the investigators are attempting to use T cells obtained directly from the patient, which can be genetically modified to express a CAR. The CAR enables the T cell to recognize and kill the neuroblastoma cell through the recognition of CD171, a protein expressed on the surface of the neuroblastoma cell. This is a phase I study designed to determine the maximum tolerated dose of the CAR T cells.
• NANT2015-02 (NCT03107988) (Phase I Study of Lorlatinib [PF-06463922], an Oral Small Molecule Inhibitor of ALK/ROS1, for Patients With ALK-Driven Relapsed or Refractory Neuroblastoma): This is a pediatric dose-finding study of a third-generation ALK inhibitor. Lorlatinib is sensitive to ALK mutations, while crizotinib is resistant. An expansion study to include more children is also being planned.
• N2011-01 (NCT02035137) (Randomized Phase II Pick-the-Winner Study of 131I-MIBG, 131I-MIBG With Vincristine and Irinotecan, or 131I-MIBG With Vorinostat for Resistant/Relapsed Neuroblastoma): This study will compare three treatment regimens containing MIBG, including their effects on tumor response and associated side effects, to determine whether one therapy is better than the other for people diagnosed with relapsed or persistent neuroblastoma.

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

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2. Taggart DR, Han MM, Quach A, et al.: Comparison of iodine-123 metaiodobenzylguanidine (MIBG) scan and [18F]fluorodeoxyglucose positron emission tomography to evaluate response after iodine-131 MIBG therapy for relapsed neuroblastoma. J Clin Oncol 27 (32): 5343-9, 2009. [PUBMED Abstract]
3. Schleiermacher G, Javanmardi N, Bernard V, et al.: Emergence of new ALK mutations at relapse of neuroblastoma. J Clin Oncol 32 (25): 2727-34, 2014. [PUBMED Abstract]
4. Padovan-Merhar OM, Raman P, Ostrovnaya I, et al.: Enrichment of Targetable Mutations in the Relapsed Neuroblastoma Genome. PLoS Genet 12 (12): e1006501, 2016. [PUBMED Abstract]
5. Eleveld TF, Oldridge DA, Bernard V, et al.: Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations. Nat Genet 47 (8): 864-71, 2015. [PUBMED Abstract]
6. Schramm A, Köster J, Assenov Y, et al.: Mutational dynamics between primary and relapse neuroblastomas. Nat Genet 47 (8): 872-7, 2015. [PUBMED Abstract]
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8. Pole JG, Casper J, Elfenbein G, et al.: High-dose chemoradiotherapy supported by marrow infusions for advanced neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 9 (1): 152-8, 1991. [PUBMED Abstract]
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10. Lau L, Tai D, Weitzman S, et al.: Factors influencing survival in children with recurrent neuroblastoma. J Pediatr Hematol Oncol 26 (4): 227-32, 2004. [PUBMED Abstract]
11. Saylors RL 3rd, Stine KC, Sullivan J, et al.: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 19 (15): 3463-9, 2001. [PUBMED Abstract]
12. Kramer K, Kushner BH, Modak S, et al.: Compartmental intrathecal radioimmunotherapy: results for treatment for metastatic CNS neuroblastoma. J Neurooncol 97 (3): 409-18, 2010. [PUBMED Abstract]
13. Murphy JM, Lim II, Farber BA, et al.: Salvage rates after progression of high-risk neuroblastoma with a soft tissue mass. J Pediatr Surg 51 (2): 285-8, 2016. [PUBMED Abstract]
14. 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]
15. 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]
16. London WB, Bagatell R, Weigel BJ, et al.: Historical time to disease progression and progression-free survival in patients with recurrent/refractory neuroblastoma treated in the modern era on Children's Oncology Group early-phase trials. Cancer 123 (24): 4914-4923, 2017. [PUBMED Abstract]
17. Mody R, Naranjo A, Van Ryn C, et al.: Irinotecan-temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (COG ANBL1221): an open-label, randomised, phase 2 trial. Lancet Oncol 18 (7): 946-957, 2017. [PUBMED Abstract]
18. Mossé YP, Lim MS, Voss SD, et al.: Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children's Oncology Group phase 1 consortium study. Lancet Oncol 14 (6): 472-80, 2013. [PUBMED Abstract]
19. London WB, Frantz CN, Campbell LA, et al.: Phase II randomized comparison of topotecan plus cyclophosphamide versus topotecan alone in children with recurrent or refractory neuroblastoma: a Children's Oncology Group study. J Clin Oncol 28 (24): 3808-15, 2010. [PUBMED Abstract]
20. DuBois SG, Groshen S, Park JR, et al.: Phase I Study of Vorinostat as a Radiation Sensitizer with 131I-Metaiodobenzylguanidine (131I-MIBG) for Patients with Relapsed or Refractory Neuroblastoma. Clin Cancer Res 21 (12): 2715-21, 2015. [PUBMED Abstract]
21. Polishchuk AL, Dubois SG, Haas-Kogan D, et al.: Response, survival, and toxicity after iodine-131-metaiodobenzylguanidine therapy for neuroblastoma in preadolescents, adolescents, and adults. Cancer 117 (18): 4286-93, 2011. [PUBMED Abstract]
22. Matthay KK, Yanik G, Messina J, et al.: Phase II study on the effect of disease sites, age, and prior therapy on response to iodine-131-metaiodobenzylguanidine therapy in refractory neuroblastoma. J Clin Oncol 25 (9): 1054-60, 2007. [PUBMED Abstract]
23. Matthay KK, Tan JC, Villablanca JG, et al.: Phase I dose escalation of iodine-131-metaiodobenzylguanidine with myeloablative chemotherapy and autologous stem-cell transplantation in refractory neuroblastoma: a new approaches to Neuroblastoma Therapy Consortium Study. J Clin Oncol 24 (3): 500-6, 2006. [PUBMED Abstract]
24. Matthay KK, Quach A, Huberty J, et al.: Iodine-131--metaiodobenzylguanidine double infusion with autologous stem-cell rescue for neuroblastoma: a new approaches to neuroblastoma therapy phase I study. J Clin Oncol 27 (7): 1020-5, 2009. [PUBMED Abstract]
25. DuBois SG, Chesler L, Groshen S, et al.: Phase I study of vincristine, irinotecan, and ¹³¹I-metaiodobenzylguanidine for patients with relapsed or refractory neuroblastoma: a new approaches to neuroblastoma therapy trial. Clin Cancer Res 18 (9): 2679-86, 2012. [PUBMED Abstract]
26. Johnson K, McGlynn B, Saggio J, et al.: Safety and efficacy of tandem 131I-metaiodobenzylguanidine infusions in relapsed/refractory neuroblastoma. Pediatr Blood Cancer 57 (7): 1124-9, 2011. [PUBMED Abstract]
27. French S, DuBois SG, Horn B, et al.: 131I-MIBG followed by consolidation with busulfan, melphalan and autologous stem cell transplantation for refractory neuroblastoma. Pediatr Blood Cancer 60 (5): 879-84, 2013. [PUBMED Abstract]
28. Zhou MJ, Doral MY, DuBois SG, et al.: Different outcomes for relapsed versus refractory neuroblastoma after therapy with (131)I-metaiodobenzylguanidine ((131)I-MIBG). Eur J Cancer 51 (16): 2465-72, 2015. [PUBMED Abstract]
29. Yanik GA, Villablanca JG, Maris JM, et al.: 131I-metaiodobenzylguanidine with intensive chemotherapy and autologous stem cell transplantation for high-risk neuroblastoma. A new approaches to neuroblastoma therapy (NANT) phase II study. Biol Blood Marrow Transplant 21 (4): 673-81, 2015. [PUBMED Abstract]
30. Simon T, Längler A, Harnischmacher U, et al.: Topotecan, cyclophosphamide, and etoposide (TCE) in the treatment of high-risk neuroblastoma. Results of a phase-II trial. J Cancer Res Clin Oncol 133 (9): 653-61, 2007. [PUBMED Abstract]
31. Kushner BH, Kramer K, Modak S, et al.: Differential impact of high-dose cyclophosphamide, topotecan, and vincristine in clinical subsets of patients with chemoresistant neuroblastoma. Cancer 116 (12): 3054-60, 2010. [PUBMED Abstract]
32. Bagatell R, London WB, Wagner LM, et al.: Phase II study of irinotecan and temozolomide in children with relapsed or refractory neuroblastoma: a Children's Oncology Group study. J Clin Oncol 29 (2): 208-13, 2011. [PUBMED Abstract]
33. Kushner BH, Modak S, Kramer K, et al.: Ifosfamide, carboplatin, and etoposide for neuroblastoma: a high-dose salvage regimen and review of the literature. Cancer 119 (3): 665-71, 2013. [PUBMED Abstract]
34. Hale GA, Arora M, Ahn KW, et al.: Allogeneic hematopoietic cell transplantation for neuroblastoma: the CIBMTR experience. Bone Marrow Transplant 48 (8): 1056-64, 2013. [PUBMED Abstract]
35. Kushner BH, Cheung IY, Modak S, et al.: Phase I trial of a bivalent gangliosides vaccine in combination with β-glucan for high-risk neuroblastoma in second or later remission. Clin Cancer Res 20 (5): 1375-82, 2014. [PUBMED Abstract]
36. Kushner BH, Ostrovnaya I, Cheung IY, et al.: Prolonged progression-free survival after consolidating second or later remissions of neuroblastoma with Anti-GD2 immunotherapy and isotretinoin: a prospective Phase II study. Oncoimmunology 4 (7): e1016704, 2015. [PUBMED Abstract]
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Changes to this Summary (02/12/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This summary was comprehensively reviewed and extensively revised.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of neuroblastoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Neuroblastoma Treatment are:

• Christopher N. Frantz, MD (Alfred I. duPont Hospital for Children)
• Andrea A. Hayes-Jordan, MD, FACS, FAAP (University of North Carolina - Chapel Hill School of Medicine)
• Karen J. Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
• Nita Louise Seibel, MD (National Cancer Institute)
• Stephen J. Shochat, MD (St. Jude Children's Research Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Neuroblastoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389190]

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• Updated: February 12, 2019