Tumor growth due to maturation should be differentiated from tumor progression by performing a biopsy and reviewing histology. Patients may have persistent maturing disease with metaiodobenzylguanidine (mIBG) uptake that does not affect outcome, particularly in patients with low-risk and intermediate-risk disease. In neuroblastoma, subclonal ALK mutations may be present at diagnosis, with subsequent clonal expansion at relapse. Consequently, serial sampling of progressive tumors may be revealing. If neuroblastoma recurs in a child originally diagnosed with high-risk disease, the prognosis is usually poor despite additional intensive therapy.[3-6] However, it is often possible to gain many additional months of life for these patients with alternative chemotherapy regimens.[7,8] Clinical trials are appropriate for these patients and may be offered. Information about ongoing clinical trials is available from the NCI Web site.
Prognostic Factors for Recurrent Neuroblastoma
The International Neuroblastoma Risk Group Project performed a decision-tree analysis of clinical and biological characteristics (defined at diagnosis) associated with survival after relapse in 2,266 patients with neuroblastoma entered on large clinical trials in well-established clinical trials groups around the world.
- Overall survival (OS) in the entire relapse population was 20%.
- Among patients with all stages of disease at diagnosis, MYCN amplification predicted a poorer prognosis, measured as 5-year OS.
- Among patients diagnosed with International Neuroblastoma Staging System (INSS) stage 4 without amplification, age older than18 months and high lactate dehydrogenase (LDH) level predicted poor prognosis.
- Among patients with MYCN amplification, stages 1 and 2 have a better prognosis than stages 3 and 4.
- Among patients with MYCN-nonamplified who are not stage 4, patients with hyperdiploidy had a better prognosis than patients with diploidy in those younger than 18 months, while among those older than 18 months, differentiating tumors did much better than undifferentiated and poorly differentiated tumors.
Significant prognostic factors determined at diagnosis for postrelapse survival include the following:
- INSS stage.
- MYCN status.
- Time from diagnosis to first relapse.
- LDH level, ploidy, and histologic grade of tumor differentiation (to a lesser extent).
The Children’s Oncology Group (COG) experience with recurrence in low-risk and intermediate-risk neuroblastoma is that the majority of recurrences can be salvaged. The COG reported a 3-year event free survival (EFS) of 88% and an OS of 96% in intermediate-risk patients and a 5-year EFS of 89% and OS of 97% in low-risk patients.[9,10] Moreover, in most patients originally diagnosed with low-risk or intermediate-risk disease, local recurrence or recurrence in the 4S pattern may be treated successfully with surgery and/or with moderate dose chemotherapy, without hematopoietic stem cell transplantation.
Recurrent Neuroblastoma in Patients Initially Classified as Low Risk
Treatment options for locoregional recurrent neuroblastoma initially classified as low risk include the following:
- Surgery followed by observation or chemotherapy.
- Chemotherapy that may be followed by surgery.
Local or regional recurrent cancer is resected if possible.
Those with favorable biology and regional recurrence more than 3 months after completion of planned treatment are observed if resection of the recurrence is total or near total (≥90% resection). Those with favorable biology and a less than near-total resection are treated with chemotherapy.
Infants younger than 1 year at the time of locoregional recurrence whose tumors have any unfavorable biologic properties are observed if resection is total or near total. If the resection is less than near total, these same infants are treated with chemotherapy. Chemotherapy may consist of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide, or cyclophosphamide and topotecan. The cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen as used in prior COG trials (COG-P9641 and COG-A3961).
Older children with local recurrence with either unfavorable International Neuroblastoma Pathology Classification at diagnosis or MYCN gene amplification have a poor prognosis and may be treated with surgery, aggressive combination chemotherapy, or offered entry into a clinical trial.
Evidence (surgery and chemotherapy):
- A COG study of treatment of low-risk patients with stage 1, 2A, 2B, and 4S neuroblastoma enrolled 915 patients, 800 of whom were asymptomatic and were treated with surgery alone followed by observation. The others received chemotherapy with or without surgery.
- About 10% of patients developed progressive or recurrent tumor. Most recurrences were treated on study with surgery alone or moderate chemotherapy with or without surgery, and most were salvaged as demonstrated by the EFS (89%) and OS (97%) rates at 5 years.
Treatment options for metastatic recurrent neuroblastoma initially classified as low risk include the following:
- Observation (if metastatic disease is in a 4S pattern in an infant).
Metastatic recurrent or progressive neuroblastoma in an infant initially categorized as low risk and younger than 1 year at recurrence may be treated according to tumor biology as defined in the prior COG trials (COG-P9641 and COG-A3961):
- If the biology is completely favorable, metastasis is in a 4S pattern, and the recurrence or progression is within 3 months of diagnosis, the patient is observed systematically.
- If the metastatic progression or recurrence occurs more than 3 months after diagnosis or not in a 4S pattern, then the primary tumor is resected if possible and chemotherapy is given.
Chemotherapy may consist of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen, as used in prior COG trials (COG-P9641 and COG-A3961).
Any child initially categorized as low risk who is older than 1 year at the time of metastatic recurrent or progressive disease and whose recurrence is not in the stage 4S pattern usually has a poor prognosis and should be considered for high-risk therapy.
- Treatment may consist of an aggressive regimen of combination chemotherapy.
Recurrent Neuroblastoma in Patients Initially Classified as Intermediate Risk
The treatment options for locoregional and metastatic recurrence in patients with intermediate-risk neuroblastoma are derived from the results of the COG-A3961 trial. Among 479 patients with intermediate-risk neuroblastoma treated on the COG-A3961 clinical trial, 42 patients developed disease progression. The rate was 10% of those with favorable biology and 17% of those with unfavorable biology. Thirty patients had locoregional recurrence, 11 had metastatic recurrence, and one had both types of recurrent disease. Six of the 42 patients died of disease, while 36 patients were salvaged. Thus, most patients with intermediate-risk neuroblastoma and disease progression may be salvaged.
Treatment options for locoregional recurrent neuroblastoma initially classified as intermediate risk include the following:
- Surgery (complete resection).
- Surgery (incomplete resection) followed by chemotherapy.
The current standard of care is based on the experience from the COG Intermediate-Risk treatment plan (COG-A3961). Locoregional recurrence of neuroblastoma with favorable biology that occurs more than 3 months after completion of chemotherapy may be treated surgically. If resection is less than near total, then additional chemotherapy may be given. Chemotherapy may consist of moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide. The cumulative dose of each agent is kept low to minimize permanent injury from the chemotherapy regimen, as used in a prior COG trial (COG-A3961).
Treatment options for metastatic recurrent neuroblastoma initially classified as intermediate risk include the following:
- High-risk therapy.
Patients with metastatic recurrent neuroblastoma are treated like patients with newly diagnosed high-risk neuroblastoma. (Refer to the Treatment Options for High-Risk Neuroblastoma section of this summary for more information.)
Recurrent Neuroblastoma in Patients Initially Classified as High Risk
Any recurrence in patients initially classified as high risk signifies a very poor prognosis. Clinical trials may be considered. Palliative care should be considered as part of the patient's treatment plan.
Treatment options for recurrent or refractory neuroblastoma in patients initially classified as high risk include the following:
- Topotecan in combination with cyclophosphamide or etoposide.
- Temozolomide with irinotecan.
- Iodine 131-mIBG (131I-mIBG) alone, in combination with other therapy, or followed by stem cell rescue.
- Second autologous stem cell transplantation (SCT) after retrieval chemotherapy. (Refer to the Autologous Hematopoietic Cell Transplantation section in the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation.)
It is not known whether one therapeutic approach is superior to another.
- Topotecan in combination with cyclophosphamide or etoposide has been used in patients with recurrent disease who did not receive topotecan initially.[12,13]; [Level of evidence: 1A]
- The combination of irinotecan and temozolomide had a 15% response rate in one study.[Level of evidence: 2A]
- High-dose carboplatin, irinotecan, and/or temozolomide has been used in patients resistant or refractory to regimens containing topotecan.
- A retrospective study reported on 74 patients who received 92 cycles of ifosfamide, carboplatin, and etoposide, included 37 patients who received peripheral blood stem cell rescue following response to this drug combination.
- Disease regressions (major and minor responses) were achieved by 14 of 17 patients (82%) with a new relapse, 13 of 26 patients (50%) with refractory neuroblastoma, and 12 of 34 patients (35%) who were treated for progressive disease during chemotherapy (P = .005).
- Grade 3 toxicities were rare.
Evidence (second autologous SCT following retrieval chemotherapy):
- Second autologous stem cell transplantation (SCT) after retrieval chemotherapy may be considered, particularly in the setting of a clinical trial. (Refer to the Autologous Hematopoietic Cell Transplantation section in the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation.)
- Data from three consecutive German high-risk neuroblastoma trials described 253 children relapsing after intensive chemotherapy with autologous SCT who had a 5-year OS rate of less than 10%. Only 23 of the 253 patients eventually proceeded to a second autologous SCT following retrieval chemotherapy.[Level of evidence: 3iiiA]
- Among these patients, the 3-year OS rate was 43%, but the 5-year OS rate was less than 20%.
- This shows that intensive second-line therapy is feasible, although even with intensive therapy and second autologous SCT, only a small minority of relapsed high-risk neuroblastoma patients may benefit.
Allogeneic transplantation has a historically low success rate in recurrent or progressive neuroblastoma. In a retrospective registry study, allogeneic SCT after a previous autologous SCT appeared to offer minimal benefit. Disease recurrence remains the most common cause of treatment failure.
Recurrent Neuroblastoma in the Central Nervous System
Central nervous system (CNS) involvement, although rare at initial presentation, may occur in 5% to 10% of patients with recurrent neuroblastoma. Because upfront treatment for newly diagnosed patients does not adequately treat the CNS, the CNS has emerged as a sanctuary site leading to relapse.[25,26] CNS relapses are almost always fatal, with a median time to death of 6 months.
Treatment options for recurrent neuroblastoma in the CNS include the following:
- Surgery and radiation therapy.
- Novel therapeutic approaches.
Current treatment approaches generally include eradicating bulky and microscopic residual disease in the CNS and minimal residual systemic disease that may herald further relapses. Neurosurgical interventions serve to decrease edema, control hemorrhage, and remove bulky tumor before starting therapy. Compartmental radioimmunotherapy using intrathecal radioiodinated monoclonal antibodies has been tested in patients with recurrent metastatic CNS neuroblastoma after surgery, craniospinal radiation therapy, and chemotherapy.
Treatment Options Under Clinical Evaluation for Recurrent or Refractory Neuroblastoma
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-ANBL1221 (NCI-2012-03125; NCT01767194) (A Phase II Randomized Trial of Irinotecan/Temozolomide with Temsirolimus or Chimeric 14.18 Antibody [ch14.18] in Children with Refractory, Relapsed, or Progressive Neuroblastoma): This Pick the Winner phase II study is designed to compare the response rates and progression-free survival for patients with refractory, relapsed, or progressive neuroblastoma receiving temsirolimus or ch14.18 in combination with irinotecan and temozolomide. Patients more than 365 days of age who have progressed from INSS stage 1, 2, or 4S and have received no chemotherapy or only one cycle of chemotherapy are eligible for this trial. (Refer to the featured clinical trial, Monoclonal Antibody Therapy for Relapsed or Treatment-Resistant Neuroblastoma, for more information.)
- NANT N2011-04 (NCI-2012-02011; NCT01711554) (Lenalidomide and Monoclonal Antibody With or Without Isotretinoin in Treating Younger Patients With Refractory or Recurrent Neuroblastoma): This study is to determine the maximum tolerated dose and/or recommended phase II dose of lenalidomide in combination with fixed doses of ch14.18 given intravenously for 4 days (days 8–11) and isotretinoin given twice each day orally for 14 days (days 15–28) and repeated every 28 days to children with refractory or recurrent neuroblastoma. (Refer to the featured clinical trial, Monoclonal Antibody Therapy for Relapsed or Treatment-Resistant Neuroblastoma, for more information.)
- NCT00911560 (Bivalent Vaccine With Escalating Doses of the Immunological Adjuvant OPT-821, in Combination With Oral Beta-Glucan for High-Risk Neuroblastoma): The purpose of this study is to test the safety of a vaccine against neuroblastoma and its effect on cancer.
- Studies with the ALK inhibitor crizotinib include the following: COG-ADVL0912 (NCT00939770), a phase I and II study of PF-02341066, an oral small molecule inhibitor of anaplastic lymphoma kinase (ALK) and C-met, in children with relapsed/refractory solid tumors and anaplastic large cell lymphoma; and ADVL1212 (NCT01606878), a phase I study of crizotinib in combination with conventional chemotherapy for relapsed or refractory solid tumors or anaplastic large cell lymphoma.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent 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.
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- 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]
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