Treatment of High-Risk Neuroblastoma
Standard Treatment Options for High-Risk Neuroblastoma
Chemotherapy, surgery, SCT, radiation therapy, isotretinoin (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, isotretinoin (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 isotretinoin 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 isotretinoin 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 isotretinoin.; [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 isotretinoin 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 isotretinoin was 59% and 41% for patients assigned to ABMT without isotretinoin. Patients assigned to consolidation chemotherapy and isotretinoin showed a 5-year survival of 38% and 36% for patients receiving consolidation chemotherapy and no isotretinoin. 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 isotretinoin (EFS, 66%) was superior to standard isotretinoin 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 SCT After Chemotherapy in Treating Patients With Newly Diagnosed High-Risk Neuroblastoma): The International Society of Paediatric Oncology European Neuroblastoma Group (SIOPEN) published a comparison of the conditioning regimen busulfan/melphalan (BuMel) versus carboplatin/etoposide/melphalan (CEM), and BuMel showed better survival outcomes. Because BuMel 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.The outcome of this trial will influence the choice of preparative regimens used in the upcoming COG high-risk neuroblastoma trials.
- COG-ANBL09P1 (NCT01175356) (Induction Therapy Including 131I-Metaiodobenzylguanidine [mIBG] and Chemotherapy in Treating Patients With Newly Diagnosed High-Risk Neuroblastoma Undergoing SCT, Radiation Therapy, and Maintenance Therapy With Isotretinoin): This limited-institution study uses the COG induction-phase therapy followed by semiablative mIBG and autologous SCT followed by BuMel myeloablative induction with a second autologous SCT, followed by the standard surgery and radiation and maintenance therapy with isotretinoin.
- 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 isotretinoin 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
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- 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]
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- 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]
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