Current Clinical Trials in Neuroblastoma
Current Clinical Trials in Neuroblastoma
Neuroblastoma is a pediatric malignant tumor of the postganglionic sympathetic nervous system that usually develops in the adrenal gland or in nonadrenal abdominal or thoracic sites. It is the most common malignancy in infants and the most common extracranial solid tumor of childhood, with approximately 650 cases diagnosed annually in the United States. The dramatic age-related survival differences among neuroblastoma patients with a similar tumor stage emphasize the heterogeneity of neuroblastoma pathobiology. Early research efforts to understand the pathobiology of neuroblastoma[3-5] and the significant progress made in neuroblastoma molecular biology have informed the clinical treatment of neuroblastoma.
The adoption of the International Neuroblastoma Staging System (INSS) and International Neuroblastoma Response Criteria (INRC) for the diagnosis, staging, and response to treatment of neuroblastoma has facilitated the incorporation of tumor biological characteristics (favorable and unfavorable) into the development of low-, intermediate-, and high-risk treatment stratification for neuroblastoma clinical trials designed by the Children’s Oncology Group (COG). Newly diagnosed patients are stratified by age (less than or greater than 365 days old) and the tumor’s INSS stage, but tumor tissue analysis is central to determining a patient’s treatment risk stratification (see Table 1). Tumor histology is evaluated using the Shimada histologic classification of favorable or unfavorable biology; molecular biological characteristics of N-myc amplification and DNA ploidy are established prior to treatment selection.
Children with localized neuroblastoma and a favorable tumor biology can usually be cured with surgery alone; chemotherapy and radiotherapy are employed only for progressive or recurrent disease, or for patients diagnosed with spinal cord compression. Although stage 2 patients with incomplete tumor excision or positive ipsilateral lymph nodes have a higher likelihood of local recurrence, the majority of these patients can be salvaged with repeat surgery alone, with an ultimate survival rate of 98%.
In the current Pediatric Oncology Group (POG) legacy study, P9641, for low-risk neuroblastoma, all stage 1 and select stage 2 patients undergo surgery(s) to remove as much of the primary tumor and involved lymph nodes as can be safely resected. Patients whose disease has been greater than 50% resected are systematically observed. If less than 50% of the tumor has been resected or the residual tumor threatens vital organs, then four cycles of outpatient chemotherapy including carboplatin (Paraplatin), etoposide, cyclophosphamide (Cytoxan, Neosar), and doxorubicin are given. Regression of residual disease, without the use of chemotherapy, is expected to occur in the majority of patients whose tumors are incompletely resected at diagnosis. If progressive or recurrent disease is observed in any patient, reoperation is attempted. If low-risk disease is again completely resected, the patient is systematically observed; otherwise, four courses of chemotherapy are administered.
Children with advanced regional neuroblastoma represent a biologically heterogeneous group of patients. Clinical trials have shown that stage 3 infants with nonamplified N-myc and older children with nonamplified N-myc and a favorable histopathology treated with low-intensity combination chemotherapy, eventual gross total tumor resection, and/or local radiotherapy can achieve an excellent outcome (4-year event-free survival of 100%). Selected infants with disseminated neuroblastoma (stage 4 with favorable biology) are treated with less intensive adjuvant chemotherapy, while stage 4S patients can be treated with supportive care or low-dose cytotoxic therapy if symptomatic[13,14] and have an excellent outcome.
For infants and children with intermediate-risk neuroblastoma, COG protocol A3961 recommends surgery to remove as much of the primary tumor and involved lymph nodes as can be safely resected with minimum morbidity. Patients then receive four cycles of chemotherapy, as in P9641 if the tumor is of favorable biology, and eight cycles of chemotherapy if the tumor is of unfavorable biology.
A randomized study has demonstrated that high-dose chemotherapy and radiotherapy followed by transplantation of autologous bone marrow is superior to conventional chemotherapy as consolidation therapy in children with high-risk neuroblastoma with a 34% vs 22% 3-year event-free survival, respectively. The addition of 6 months of maintenance therapy using 2-week cycles of the differentiation agent 13-cis-retinoic acid (13-cis-RA) was of benefit in both the autologous bone marrow transplant and conventional chemotherapy treatment groups with a 3-year event-free survival of 46% for those receiving 13-cis-RA vs 29% for those assigned no further therapy.
Investigations have been under way to incorporate immunotherapy as treatment of minimal residual disease in children with high-risk neuroblastoma after induction and consolidation therapy. Antibodies targeting the GD2 glycoside, commonly expressed on neuroblastoma cells, can be safely administered to children[16,17] in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), and there is evidence that such treatment can clear residual neuroblastoma from the bone marrow.
Among high-risk patients, the current COG phase III study, A3973, is designed to determine the event-free survival and toxicity of a myeloablative consolidation with infusion of autologous purged peripheral blood stem cells (PBSC) vs unpurged PBSC followed by local radiotherapy. A dose-intensive induction therapy using six cycles of cyclophosphamide, doxorubicin, and vincristine alternating with cisplatin (Platinol) and etoposide is being utilized. After completion of CEM chemotherapy (high-dose carboplatin, etoposide, and melphalan [Alkeran]) and stem cell transplant, A3973 patients will be offered enrollment in ANBL0032. The ANBL0032 maintenance therapy study will evaluate whether 13-cis-RA with the addition of five courses of the anti-GD2 monoclonal antibody Ch14.18 plus GM-CSF/interleukin-2 treatment improves event-free and overall survival as compared to 13-cis-RA alone. Patients in A3971 who refuse or are unable to receive myeloablative therapy will receive maintenance therapy with topotecan (Hycamtin) and cyclophosphamide.
Additionally, a limited-institution COG pilot study, ANBL00P1, for high-risk patients is under way to assess the feasibility of tandem high-dose chemotherapy with autologous stem cell rescue as a means of increasing dose-intensive therapy. After completion of induction chemotherapy and collection of peripheral blood stem cells with CD34+ selection, patients will proceed to tandem high-dose intensification using thiotepa (Thioplex) and cyclophosphamide as the first conditioning regimen, and CEM as the second conditioning regimen. Appropriate local radiation therapy will follow completion of the tandem transplants.