Treatment of High-Risk Neuroblastoma
Standard Treatment Options for High-Risk Neuroblastoma
Chemotherapy, surgery, SCT, radiation therapy, cis-retinoic acid, anti-GD2 antibody ch14.18, and interleukin-2/GM-CSF
Local control (surgery and radiation therapy)
Treatment Options Under Clinical Evaluation
Current Clinical Trials
The Children's Oncology Group (COG) high-risk group assignment criteria are described in Table 8.Table 8. Children’s Oncology Group (COG) Neuroblastoma High-Risk Group Assignment Schema Used for COG-P9641 and COG-A3961 Studiesa
|INSS Stage||Age||MYCN Status||INPC Classification||DNA Ploidyb|
|2A/2Bc||≥365 d–21 y||Amplified||Unfavorable||-|
|≥365 d–21 y||Nonamplified||Unfavorable||-|
|≥365 d–21 y||Amplified||Any||-|
|≥548 d–21 y||Any||Any||-|
|INPC = International Neuroblastoma Pathologic Classification; INSS = International Neuroblastoma Staging System.|
|aThe COG-P9641 and COG-A3961 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, DI = 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 2A/2B symptomatic patients with spinal cord compression, neurologic deficits, or other symptoms are treated with immediate chemotherapy for four cycles.|
|dINSS stage 3 or stage 4 patients with clinical symptoms as listed above receive immediate chemotherapy.|
|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.|
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 posttreatment in a European study.
For children with high-risk neuroblastoma, long-term survival with current treatments is about 54%. Children with aggressively treated, high-risk neuroblastoma may develop late recurrences, some more than 5 years after completion of therapy.[3,4]Standard Treatment Options for High-Risk Neuroblastoma
Outcomes for patients with high-risk neuroblastoma remain poor despite recent improvements in survival in randomized trials.
The standard treatment option for high-risk neuroblastoma is the following:
- A regimen of chemotherapy, surgery, stem cell transplant (SCT), and radiation therapy, cis-retinoic acid, anti-GD2 antibody ch14.18, and interleukin-2/granulocyte-macrophage colony-stimulating factor (GM-CSF).
Treatment for patients with high-risk disease is generally divided into the following three phases:
- Induction (includes chemotherapy and surgical resection).
- Consolidation (hematopoietic stem cell rescue/transplantation [HSCT]).
- Maintenance (immunotherapy and retinoid).
The backbone of the most commonly used induction therapy includes dose-intensive cycles of cisplatin and etoposide alternating with vincristine, cyclophosphamide, and doxorubicin. Topotecan was added to this regimen based on the anti-neuroblastoma activity seen in relapsed patients. Response to therapy at the end of induction chemotherapy correlates with EFS at the completion of high-risk therapy. After a response to chemotherapy, resection of the primary tumor is usually attempted.Consolidation phase
The consolidation phase of high-risk regimens involves myeloablative chemotherapy and HSCT, which attempts to eradicate minimal residual disease using lethal doses of chemotherapy and 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 HSCT (31% to 47%) versus conventional chemotherapy (22% to 31%).[8-10] Previously, total-body irradiation had been used in HSCT conditioning regimens. Most current protocols use either carboplatin/etoposide/melphalan or busulfan/melphalan as conditioning for HSCT. Two or more sequential cycles of myeloablative chemotherapy and stem cell rescue given in a tandem fashion has been shown to be feasible for patients with high-risk neuroblastoma.[11,12]
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. (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) and persistently metaiodobenzylguanidine-positive bony metastatic sites is often performed before, during, or after myeloablative therapy. The optimal dose of radiation therapy has not been determined. Radiation of metastatic disease sites is determined on an individual case basis.
Preliminary outcomes for proton radiation therapy of high-risk neuroblastoma primary tumors have been published.Maintenance phase
Differentiation therapy is used to treat potential minimal residual disease following HSCT. After recovery from myeloablative chemotherapy and stem cell rescue, patients are treated with the differentiating agent oral 13-cis-retinoic acid for 6 months. Immunotherapy is given along with differentiated therapy in the post-HSCT differentiation therapy regimen. Antibodies developed to target GD2, present on the surface of neuroblastoma cells, are used. For high risk-patients in remission following HSCT, chimeric anti-GD2 antibody ch14.18 combined with GM-CSF and interleukin-2 are given in concert with retinoic acid and have been shown to improve EFS.[15,16]
Evidence (all treatments):
- A randomized study was performed comparing high-dose therapy with purged autologous bone marrow transplant (ABMT) versus three cycles of intensive consolidation chemotherapy. In addition, patients on this study were subsequently randomly assigned to stop therapy or to receive 6 months of 13-cis-retinoic acid.; [Level of evidence: 1iiA]
- The 5-year EFS was significantly better in the ABMT arm (30%), compared with the consolidation chemotherapy arm (19%; P = .04). There was no significant difference in 5-year OS (39% vs. 30%; P = .39). However, in patients who survived more than 3 years, a significant benefit is seen in OS with ABMT.
- Patients who received 13-cis-retinoic acid had a higher 5-year EFS than patients who received no maintenance therapy (42% vs. 31%), although the difference was not significant. For patients who participated in both random assignments, the 5-year OS from the time of the second randomization for patients assigned ABMT and cis-retinoic acid was 59% and 41% for patients assigned to ABMT without cis-retinoic acid. Patients assigned to consolidation chemotherapy and cis-retinoic acid showed a 5-year survival of 38% and 36% for patients receiving consolidation chemotherapy and no cis-retinoic acid. However, these patients were selected for having completed ABMT without developing progressive disease.
- In a separate study, there was no advantage to purging harvested stem cells of neuroblastoma cells before transplantation.
- In a COG phase III trial following HSCT, patients were randomly assigned to receive anti-GD2 monoclonal antibody (ch14.18) administered with GM-CSF and interleukin-2.
- Immunotherapy together with cis-retinoic acid (EFS, 66%) was superior to standard cis-retinoic acid maintenance therapy (EFS, 46%). As a result, immunotherapy post-HSCT is considered the standard of care in COG trials for high-risk disease.
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 following 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.[18-23]
- Radiation therapy to consolidate local control after surgical resection is often given.; [Level of evidence: 3iiA]
- In stage 4 patients older than 18 months, it is controversial as to whether there is any advantage to gross-total resection of the primary tumor mass after chemotherapy.[20-23]
The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
- COG-ANBL12P1 (NCT01798004) (Busulfan, Melphalan, and Stem Cell Transplant After Chemotherapy in Treating Patients With Newly Diagnosed High-Risk Neuroblastoma): The International Society of Paediatric Oncology European Neuroblastoma Group (SIOPEN) has shown that the busulfan/melphalan (BuMel) conditioning regimen is better than CEM (carboplatin, etoposide, melphalan). However it has not been used with the COG induction regimen. The primary objective of this study is to examine the toxicity profile of BuMel in the context of COG therapy, with specific focus on the incidence and severity of pulmonary and hepatic toxicity.
- COG-ANBL0032 (Isotretinoin With Monoclonal Antibody, Interleukin-2, and Sargramostim Following SCT in Treating Patients With Neuroblastoma): The COG is studying, now in a nonrandomized fashion, the use of monoclonal antibody therapy with GM-CSF and interleukin-2 combined with cis-retinoic acid following chemotherapy.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with neuroblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
- 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]
- Maris JM: Recent advances in neuroblastoma. N Engl J Med 362 (23): 2202-11, 2010. [PUBMED Abstract]
- 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]
- 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]
- 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]
- 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]
- Cheung NK, Heller G, Kushner BH, et al.: Stage IV neuroblastoma more than 1 year of age at diagnosis: major response to chemotherapy and survival durations correlated strongly with dose intensity. Prog Clin Biol Res 366: 567-73, 1991. [PUBMED Abstract]
- 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]
- 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]
- 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]
- Granger M, Grupp SA, Kletzel M, et al.: Feasibility of a tandem autologous peripheral blood stem cell transplant regimen for high risk neuroblastoma in a cooperative group setting: a Pediatric Oncology Group study: a report from the Children's Oncology Group. Pediatr Blood Cancer 59 (5): 902-7, 2012. [PUBMED Abstract]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- George RE, Li S, Medeiros-Nancarrow C, et al.: High-risk neuroblastoma treated with tandem autologous peripheral-blood stem cell-supported transplantation: long-term survival update. J Clin Oncol 24 (18): 2891-6, 2006. [PUBMED Abstract]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]