Treatment of Stage 4S Neuroblastoma
Many patients with stage 4S neuroblastoma do not require therapy. However, tumors with unfavorable biology or patients who are symptomatic due to 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. (Refer to the Treatment of High-Risk Neuroblastoma section of this summary for more information about the treatment of stage 4S high-risk neuroblastoma.)
|INSS Stage||Age||MYCN Status||INPC Classification||DNA Ploidyb||Risk Group|
|INPC = International Neuroblastoma Pathologic Classification; INSS = International Neuroblastoma Staging System.|
|aThe COG-P9641, COG-A3961, and COG-A3973 trials established the current standard of care for neuroblastoma patients in terms of risk group assignment and treatment strategies.|
|bDNA Ploidy: DNA Index (DI) > 1 is favorable, = 1 is unfavorable; hypodiploid tumors (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.|
Treatment Options for Stage 4S Neuroblastoma
There is no standard approach to the treatment of stage 4S neuroblastoma.
Treatment options for stage 4S neuroblastoma include the following:
Resection of primary tumor is not associated with improved outcome.[2-4] 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 transplantation.
Observation with supportive care (asymptomatic patients with favorable tumor biology)
Chemotherapy (symptomatic patients, very young infants, or those with unfavorable biology)
Infants diagnosed with International Neuroblastoma Staging System (INSS) stage 4S neuroblastoma, particularly those with hepatomegaly or those younger than 2 months, have the potential for rapid clinical deterioration and may benefit from early initiation of therapy. It has been difficult to identify infants with stage 4S disease who will benefit from chemotherapy. Several clinical trials have evaluated the presence of symptoms in patients with 4S disease, including the following:
- In 45 patients with stage 4S neuroblastoma diagnosed in the first month of life, 16 patients developed dyspnea caused by massive liver enlargement; one-half of them did not survive.
- A review of 35 patients with INSS stage 4S disease described 13 patients younger than 4 weeks, all of whom had liver involvement. Of the seven who died, all presented with hepatomegaly at birth and all deaths were due to hepatomegaly or related complications. Of the infants who were aged 1 month to 12 months (n = 22), 21 had hepatomegaly, and there were three deaths (14%). Deaths were due to infection, disseminated intravascular coagulation, and radiation nephritis. One death was related to hepatomegaly. A scoring system to measure signs and symptoms of deterioration or compromise was developed to better assess this group. This scoring system has been evaluated retrospectively and was predictive of the clinical course and has been applied prospectively. It was also helpful in directing the management of patients with INSS 4S disease.[7,8]
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 lower 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 those with unfavorable biology):
- Eighty stage 4S patients were enrolled on COG-P9641.
- Overall, the 5-year event-free survival (EFS) was 77% and the overall survival (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 alone, and 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 lower survival of patients with stage 4S disease; however, the use of chemotherapy on COG-P9641 was restricted to specific clinical situations with a recommended number of cycles.
- Also, on COG-P9641, asymptomatic infants with biologically favorable (MYCN-nonamplified) INSS stage 4S disease did not receive chemotherapy until the development of progressive disease or clinical symptoms.
- Infants who became symptomatic had disease-related organ failure and infectious complications resulting in an inferior OS compared with those who received immediate chemotherapy (4–8 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).
- On COG-ANBL0531, the 2-year OS rate for INSS stage 4S patients was 81%, which is lower than reported on COG-P9641 and thought to reflect the expanded eligibility allowing enrollment of patients who were too ill to undergo diagnostic biopsy. These patients would have been excluded from prior COG trials.
- 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 CT. A pretreatment symptom score was used to determine initial treatment; observation was recommended for infants with low symptom scores (n = 86) and chemotherapy for infants with high symptom scores (n = 37). The chemotherapy recommended for patients with high symptom scores included two to four 3-day courses of carboplatin and etoposide, and 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 between the outcome in 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 in patients with unresectable primary tumors and patients with resectable primary tumors (97% vs. 100%) and patients with negative or with positive skeletal scintigraphy without radiologic abnormalities (100% vs. 97%).
Treatment Options Under Clinical Evaluation
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
(Response and Biology-Based Risk Factor–Guided Therapy in Treating Younger Patients With Non–High-Risk Neuroblastoma):
- For all newly diagnosed INRG MS (4S) patients younger than 18 months, the following occurs:
- Patients younger than 3 months with existing or evolving hepatomegaly or who are symptomatic are entered onto 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 onto 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.
- For all newly diagnosed INRG MS (4S) patients younger than 18 months, the following occurs:
- 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]
- 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]
- 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]
- 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]
- 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]
- Gigliotti AR, Di Cataldo A, Sorrentino S, et al.: Neuroblastoma in the newborn. A study of the Italian Neuroblastoma Registry. Eur J Cancer 45 (18): 3220-7, 2009. [PUBMED Abstract]
- 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]
- 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]
- 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]
- 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]