Dr. Julie R. Park
Julie R. Park, MD, of Seattle Children’s Hospital and the University of Washington School of Medicine, presented the study results on behalf of the Children’s Oncology Group (COG). She noted that the improved probability of EFS was seen in patients who survived induction therapy without disease progression or severe induction-related toxicity.
Neuroblastoma is the most common extracranial tumor of childhood. Using clinical and biologic prognostic factors in children with neuroblastoma, Dr. Park said, “we can identify a cohort of patients with high-risk neuroblastoma who have a dismal outcome. They account for greater than 50% of all children diagnosed with neuroblastoma, and greater than 10% of all childhood cancer mortality.” Despite aggressive multiagent therapy, fewer than 50% of patients survive.
Describing the rationale for the study, Dr. Park said that previous studies have shown that intensification of consolidation treatment with the addition of single ASCT resulted in improved EFS. The investigators hypothesized that further intensification with tandem ASCT might result in further improvements. Previous experience showed that peripheral blood stem cells (PBSCs) can be collected in children with neuroblastoma, and pilot studies found that tandem ASCT demonstrated tolerable toxicity and suggested efficacy.
Patients in the study underwent six cycles of chemotherapy, beginning with two cycles of cyclophosphamide and topotecan. At that time, PBSCs were harvested, and induction continued with alternating cycles of cisplatin/etoposide and cyclophosphamide/vincristine/doxorubicin, plus surgery. Patients were then randomly assigned to single ASCT with carboplatin/etoposide/melphalan or to tandem ASCT with cyclophosphamide/thiotepa followed by modified carboplatin/etoposide/melphalan. All patients received radiotherapy at the primary tumor site. Patients with non-MYCN–amplified stage 3 or stage 4 tumors were nonrandomly assigned to receive the single ASCT regimen.
Approximately 70% of eligible patients who completed induction and consolidation entered a second clinical trial that evaluated postconsolidation immunotherapy with isotretinoin alone compared with isotretinoin plus dinutuximab and cytokines.
Of 655 patients enrolled, 355 were randomly assigned, with 179 receiving single ASCT and 176 receiving tandem ASCT; 27 patients were nonrandomly assigned to single ASCT.
At 3 years after randomization, tandem ASCT improved EFS, the primary endpoint of the study, but not overall survival (OS; Dr. Park noted that the trial was not powered to detect a difference in OS). Three-year EFS was 61.4 ± 3.7% in patients receiving tandem ASCT and 48.4 ± 3.8% in those receiving single ASCT (p = 0.0081). Three-year OS was 74.0 ± 3.4% for tandem ASCT and 69.1 ± 3.5% for single ASCT (p = 0.1850).
Regarding safety, rates of the most common severe (grade 3 or higher) nonhematologic toxicities were similar between the treatment arms, including infections (p = 0.9169), mucosal-related (p = 0.3672), and hepatic or sinusoidal obstructive disorder (p = 0.9002). Toxic deaths occurred in seven patients (4.1%) in the single ASCT arm and two patients (1.2%; p = 0.1746) in the tandem ASCT arm.
The benefit of tandem ASCT was preserved in patients who went on to receive immunotherapy, Dr. Park reported. In these patients, 3-year EFS after enrollment onto the immunotherapy trial was 73.7 ± 4.2% with tandem ASCT (120 patients) and 56.0 ± 4.4% with single ASCT (126 patients; p = 0.0033), and 3-year OS was 83.7 ± 3.5% with tandem ASCT and 74.4 ± 3.9% with single ASCT (p = 0.0322).
Dr. Dominique Valteau-Couanet
Dr. Valteau-Couanet, president of the International Society for Paediatric Oncology Europe Neuroblastoma (SIOPEN), said close collaboration between COG and SIOPEN will enable investigators in coming years to design complementary studies to define the most effective risk-tailored intensified strategies for neuroblastoma.
Deborah Schrag, MD, MPH, of the Dana-Farber Cancer Institute and Harvard Medical School, discussed value considerations of the study using a value framework developed by ASCO. The ASCO Value Framework uses a scoring algorithm based on clinical benefit, durable benefit, and other parameters.
“The health system value of tandem transplant for pediatric neuroblastoma is likely to be very high,” she said. The ASCO framework would assign a high value because the treatment has the potential to increase cure rates for young children with a reasonable cost in a disease with a relatively low incidence (less than 10,000 cases per year globally). Health systems in high-income countries should and will adopt this therapy, she said, and those in middle-income countries will also seek to adopt it, although access to care may be an issue.