Treatment of High-Risk Neuroblastoma
[Note: Refer to the Treatment Option Overview section of this summary for more information.]
In North America, the Children’s Oncology Group (COG) investigated a risk-based neuroblastoma treatment plan that assigned all patients to a low-, intermediate-, or high-risk group based on age, International Neuroblastoma Staging System (INSS) stage, and tumor biology (i.e., MYCN gene amplification, International Neuroblastoma Pathology Classification [INPC] system, and DNA ploidy) (COG-P9641 and COG-A3961). (Low-, intermediate- and high-risk groups are defined in Table 1 in the Stage Information section of this summary.)
For children with high-risk neuroblastoma, long-term survival with current treatments is about 30%. Children with aggressively treated, high-risk neuroblastoma may develop late recurrences, some more than 5 years after completion of therapy.[1,2] A randomized study was performed comparing high-dose therapy with purged autologous hematopoietic stem cell transplantation (HSCT) versus three cycles of intensive consolidation chemotherapy. The 3-year event-free survival (EFS) was significantly better in the HSCT arm (34%) compared with the consolidation chemotherapy arm (18%). Superiority of myeloablative chemotherapy over maintenance therapy was confirmed in another study. In addition, patients on this study were subsequently randomized to stop therapy or to receive 6 months of 13-cis-retinoic acid. Patients who received 13-cis-retinoic acid had significantly better 3-year EFS than patients who received no maintenance therapy. This was true for all patient subgroups. The 5-year EFS and overall survival (OS) for patients treated with both HSCT and retinoic acid is 50% and 59%, respectively. The 10-year OS remains greater than 50%. However, these patients were selected for having completed HSCT without developing progressive disease. Based on these results, clinical trials have built upon autologous HSCT and 13-cis-retinoic acid for high-risk neuroblastoma. Compared to retinoic acid alone, the addition of chimeric anti-GD2 antibody ch14.18 combined with granulocyte macrophage-colony stimulating factor and interleukin-2 improves EFS for high-risk neuroblastoma patients in remission after stem cell transplant (SCT) (COG-ANBL0032 and COG-ANBL0931).
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.[7-11] The use of radiation therapy to consolidate local control after surgical resection is recommended.; [Level of evidence: 3iiA]
Assessment of risk for low-stage MYCN-amplified neuroblastoma is controversial because it is so rare. A study of 87 INSS stage 1 and 2 patients pooled from several clinical trial groups demonstrated no effect of age, stage, or initial treatment on outcome. The EFS and OS were 53% and 72%, respectively. Survival was superior in patients whose tumors were hyperdiploid rather than diploid (EFS 82% ± 20% vs. 37% ± 21%; OS 94% ± 11% vs. 54% ± 15%). The overall EFS and OS for infants with stage 4 and 4S disease and MYCN-amplification was only 30% at 2 to 5 years post-treatment in a European study.Standard Treatment Options
Patients classified as high risk receive treatment with an aggressive regimen of combination chemotherapy consisting of very high drug doses, generally termed induction. Drugs often used include cyclophosphamide, ifosfamide, cisplatin, carboplatin, vincristine, doxorubicin, etoposide, and topotecan. COG has completed a pilot study of induction demonstrating the feasibility of substituting two cycles of topotecan and cyclophosphamide for two cycles of vincristine, cyclophosphamide, and doxorubicin. After a response to chemotherapy, resection of the primary tumor should be attempted, followed by myeloablative chemotherapy and stem cell rescue (i.e., bone marrow and/or peripheral blood stem cell transplantation). Whether or not harvested stem cells should be purged of neuroblastoma cells has been studied in a randomized fashion. There was no advantage to purging. Two or more sequential cycles of myeloablative chemotherapy and stem cell rescue given in a tandem fashion has been studied and feasibility was established.[7,18] It is now under clinical evaluation in COG. Radiation to the primary tumor site should be undertaken whether or not a complete excision was obtained. The optimal dose of radiation therapy has not been determined. Radiation of sites of metastatic disease is determined on an individual case basis. After recovery, patients are treated with oral 13-cis-retinoic acid for 6 months. Both myeloablative therapy and postchemotherapy retinoic acid improve outcome in patients categorized as high risk.[3,5] For high risk-patients in remission following HSCT, compared to retinoic acid alone, chimeric anti-GD2 antibody ch14.18 combined with granulocyte-macrophage colony stimulating factor and interleukin-2 and given in concert with retinoic acid improves EFS.Treatment Options Under Clinical Evaluation
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-ANBL09P1 (Induction Therapy Including 131I-MIBG and Chemotherapy in Treating Patients With Newly Diagnosed High-Risk Neuroblastoma Undergoing SCT, Radiation Therapy, and Maintenance Therapy With Isotretinoin ): This limited-participation pilot study for children with newly diagnosed high-risk neuroblastoma assesses the tolerability and feasibility of an induction regimen containing five cycles of multi-agent chemotherapy and a block of 131I-MIBG/irinotecan/vincristine followed by a consolidation regimen of busulfan/melphalan with autologous stem cell rescue and external-beam radiation therapy.
- COG-ANBL0032 (Isotretinoin With or Without Monoclonal Antibody, Interleukin-2, and Sargramostim Following SCT in Treating Patients With Neuroblastoma): The COG is studying, in a nonrandomized fashion, the use of monoclonal antibody therapy with granulocyte-macrophage colony-stimulating factor and interleukin-2 combined with cis-retinoic acid following chemotherapy.[6,19,20]
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
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- Park JR, Stewart CF, London WB, et al.: A topotecan-containing induction regimen for treatment of high risk neuroblastoma. [Abstract] J Clin Oncol 24 (Suppl 18): A-9013, 505s, 2006.
- Kreissman SG, Villablanca JG, Seeger RC, et al.: A randomized phase III trial of myeloablative autologous peripheral blood stem cell (PBSC) transplant (ASCT) for high-risk neuroblastoma (HR-NB) employing immunomagnetic purged (P) versus unpurged (UP) PBSC: A Children's Oncology Group study. [Abstract] J Clin Oncol 26 (Suppl 15): A-10011, 2008. Also available online. Last accessed March 22, 2013.
- Kletzel M, Katzenstein HM, Haut PR, et al.: Treatment of high-risk neuroblastoma with triple-tandem high-dose therapy and stem-cell rescue: results of the Chicago Pilot II Study. J Clin Oncol 20 (9): 2284-92, 2002. [PUBMED Abstract]
- Cheung NK, Kushner BH, Cheung IY, et al.: Anti-G(D2) antibody treatment of minimal residual stage 4 neuroblastoma diagnosed at more than 1 year of age. J Clin Oncol 16 (9): 3053-60, 1998. [PUBMED Abstract]
- Simon T, Hero B, Faldum A, et al.: Consolidation treatment with chimeric anti-GD2-antibody ch14.18 in children older than 1 year with metastatic neuroblastoma. J Clin Oncol 22 (17): 3549-57, 2004. [PUBMED Abstract]