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