Abstract
Background:  The majority of patients with high-risk neuroblastoma (HR-NB) in low- and middle-income countries (LMIC) do not have access to autologous stem cell transplant (ASCT) and dinutuximab. Consolidation with non-myeloablative chemotherapy is not well-defined, and the outcomes are variable. We report a single-center outcome of patients with HR-NB, treated with non-myeloablative consolidation. A tabulated compilation of similar reports is included.
Procedure: A retrospective chart review of patients with HR-NB was performed from January 2009 till June 2016. Patients were treated on the backbone of HR-NBL1/SIOPEN protocol. Treatment included induction with rapid-COJEC, surgery, consolidation, radiotherapy to the primary tumor, and differentiation therapy with isotretinoin. Consolidation included 4 cycles of topotecan, vincristine, and doxorubicin (TVD) instead of ASCT. Infusion of vincristine and doxorubicin were modified for ease and to enable administration in daycare.
Results:  Over 7-½ years, 28 patients with HR-NB were treated. Two (7%) patients had therapy-related mortality. A relapse or disease progression occurred in 11 (39%) patients at a median duration of 17 months (IQR: 5, 18). Treatment abandonment was observed in 4 (14%) patients. The 4-year event-free survival was 29.3%. The median follow up of disease-free patients is 49 months (IQR: 45, 79). Patients with relapse were not treated further.
Conclusions:  A 4-year EFS of 29.3% was observed when 4-cycles of TVD were administered instead of ASCT in patients with HR-NB. The study and the review will aid stakeholders in LMIC for decision-making while considering the options of treatment for HR-NB if access to ACST and dinutuximab is lacking.
Introduction
High-risk neuroblastoma (HR-NB) is a challenging disease to treat. The state of the art treatment of HR-NB includes induction chemotherapy, surgery, consolidation with autologous stem cell transplantation (ASCT), radiotherapy, immunotherapy with dinutuximab, and differentiation therapy with isotretinoin. The role of tandem ASCT is being explored.1 The survival rates in trials from high-income countries (HIC) are between 40-60%.2-4
There is limited data on the outcome of HR-NB from low-middle income countries (LMIC), likely reflecting a publication bias of the disease with an unfavorable outcome. The typical challenges in LMIC include suboptimal supportive care, finances, availability of beds, undernutrition, and treatment abandonment.5 The aid from non-government organizations is frequently directed to cancers with a favorable outcome. Expertise and facility for high-dose chemotherapy with ASCT rescue is available in limited centers in LMIC.6-9 Dinutuximab is not available in the majority of LMIC, including India. A diagnosis of HR-NB is grueling for the pediatric oncology team, the patient, and the family alike. Amid the arduous situation, the treating physician is faced with the question if attempting a cure of HR-NB without ASCT and dinutuximab is worthwhile.
In the absence of ASCT, therapy may be consolidated with non-myeloablative chemotherapy. Limited standardized protocols for effective chemotherapy consolidation are reported.10The survival of HR-NB with ASCT and low-cost adaptations for performing ASCT have been published from our center recently.7Along the road to developing ASCT services, several patients in our center were unable to opt for ASCT, due to the constraints listed earlier. They were treated with HR-NBL1/SIOPEN protocol without ASCT. Consolidation with ASCT was replaced with 4 cycles of topotecan, vincristine, and doxorubicin (TVD). The outcome of patients with HR-NB treated without ACST and dinutuximab is reported in this manuscript.
Methods
A retrospective chart review of patients with HR-NB was performed from January 2009 till June 2016 (7½-years). Approval was obtained from the institute’s ethics committee. High-risk disease was defined as, a) stage 4 disease in children older than 18-months, b) stage 4 disease, age 12-18 months, with unfavorable histology, or, c) any age, stage 3 or 4 disease, MYCN amplified.10 Any patient with stage 3 disease in whom MYCN amplification was not available was excluded from the analysis due to uncertainty in risk categorization.
Imaging consisted of either computed tomography or magnetic resonance imaging of the primary site. The diagnosis was by fine-needle aspiration cytology or biopsy of the primary tumor.11 Bilateral bone marrow aspirate and trephine were performed in all. Technetium-99m bone scintigraphy was done until April 2012. Subsequently, a positron emission tomography scan was performed to stage the disease. Weight for age was derived from WHO Anthro software v3.2.2 and Anthro plus software v1.0.4 for patients below 5-years, and 5-10 years, respectively.12,13 A value between - 2 and - 3 Z score was classified as moderate, and below - 3 Z score as severe under-weight.14