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

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

Neuroblastoma Treatment (PDQ®)–Health Professional Version

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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
  • Radiation therapy (for patients with symptoms related to hepatomegaly from metastatic disease)
• 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.

The decision by the INRG Task Force to replace the category of 4S disease with that of the new MS definition was based on reports in which small numbers of infants with L2 primary tumors and 4S metastatic patterns, including patients aged 12 to 18 months, had favorable outcomes.[1,2] A subsequent study of the actual INRG data found that a number of biological characteristics predicted poor outcome of patients aged 12 to 18 months with stage MS disease, and that only those infants with favorable biology had long-term outcomes similar to those with the traditional 4S diagnosis.[2]

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 MYCN amplification and are treated with high-risk protocols.[3]

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.[4]
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).
3. Radiation therapy (rarely for patients with symptoms related to hepatomegaly from metastatic disease).

Resection of primary tumor is not associated with improved outcome.[5-7] 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.[8]

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.[5,6] 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.[9]

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.[9] 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.[10] 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.[10,11] The scoring system has been modified on the basis of the ANBL0531 (NCT00499616) results in the youngest infants discussed above to guide chemotherapeutic intervention for 4S in infants.[9]

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 in order 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, 41 of whom were symptomatic and 28 of whom 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.[9][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.
     Emergent surgical abdominal decompression can be used to avoid respiratory deterioration and improve ventilation.[12,13]
   • 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, and thus studied, patients with symptomatic 4S disease to avoid biopsy and thus, biological characterization until the patient's condition improved and biopsy was considered safe.
2. Eighty stage 4S patients were enrolled on the COG-P9641 trial.[14]
   • 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.[14]
   • 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.[9] 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.[11] 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.
   • 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%).

Radiation therapy (for patients with symptoms related to hepatomegaly from metastatic disease)

In rare cases of marked hepatomegaly in symptomatic MS (4S) infants with neuroblastoma who were unresponsive to chemotherapy, very low-dose radiation therapy has been used. In a series of 41 symptomatic infants with MS disease, radiation therapy was administered to five infants, three of whom died.[9]

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. Monclair T, Brodeur GM, Ambros PF, et al.: The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J Clin Oncol 27 (2): 298-303, 2009. [PUBMED Abstract]
2. Taggart DR, London WB, Schmidt ML, et al.: Prognostic value of the stage 4S metastatic pattern and tumor biology in patients with metastatic neuroblastoma diagnosed between birth and 18 months of age. J Clin Oncol 29 (33): 4358-64, 2011. [PUBMED Abstract]
3. 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]
4. 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]
5. 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]
6. 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]
7. 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]
8. 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]
9. 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 37 (2): 115-124, 2019. [PUBMED Abstract]
10. 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]
11. 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]
12. Keene DJ, Minford J, Craigie RJ, et al.: Laparostomy closure in stage 4S neuroblastoma. J Pediatr Surg 46 (1): e1-4, 2011. [PUBMED Abstract]
13. 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]
14. 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]