4. Discussion
Myeloablative chemotherapy followed by ASCT, and immunotherapy with
dinutuximab are established modalities in the current treatment for
HR-NB.2 The role of sequential transplants is being
investigated. A recent Children’s Oncology Group trial demonstrated a
3-year EFS of 61.6% with tandem transplants, including thiotepa
followed by dose reduced carboplatin, etoposide, and
melphalan.1 The strategy of treating patients without
ASCT has been reported in a single-center trial by Kushner et
al.17 While an impressive 5-year EFS of 51% was
observed without ASCT, the protocol included anti-GD2 antibody besides
multiagent intensive chemotherapy.17
The majority of children with HR-NB reside in LMIC, where ASCT, as well
as dinutuximab, are unavailable to most. In centers where facilities for
ASCT are available, expense and waiting period, along with diverse
resource allocation, may render it difficult to offer ASCT to every
patient with HR-NB. Turkish Pediatric Oncology Group reported a median
waiting period of 8 months (range: 5-16) for proceeding to ASCT from
diagnosis.8 ASCT was administered to merely 17% of
patients in the study from Turkey.8 Further, the time
lag resulted in disease progression in 9%. Among 295 patients with
HR-NB in the National data from South Africa, merely 11 (3.7%) received
ASCT due to limited availability and dependence on private
insurance.18 Similarly, 8.8% of patients with stage 4
neuroblastoma were consolidated with ASCT in a single-center report from
New Delhi, India.19 Selected reports on the survival
of HR-NB without ASCT and dinutuximab are summarized in Table 3. The
survival is wide-ranging, with the majority of data indicating an EFS
below 20%.
Alternative strategies to consolidation with ASCT have been explored in
settings with limited resources. The Pediatric Oncology in Developing
Countries committee of the International Society of Pediatric Oncology
(SIOP-PODC) has published guidelines for the management of neuroblastoma
in LMIC.10 Multiple chemotherapy options in place of
ASCT are suggested with curative intent. The options include, a) 4
cycles of modified Pediatric Oncology Group (POG) 9341 regimen,
consisting of etoposide, ifosfamide, cisplatin, carboplatin, vincristine
and doxorubicin in varying combinations, b) 2 cycles each of
cyclophosphamide, doxorubicin, vincristine (CAdO) and carboplatin,
etoposide (CE) regimens, or c) 6-cycles of cyclophosphamide and
topotecan.10 The continuation of 4-cycles of POG 9341
has an expected EFS of 20%.3,10 Oral cyclophosphamide
has been used for maintenance therapy as well. It is administered for 4
cycles, 8 days each at 150 mg/m2 per day, with a
3-year EFS of 31%.29
Topotecan has been utilized in the treatment of HR-NB in several trials.
In the HR-NBL1/SIOPEN trial, 2-cycles of TVD were administered to
patients who had an inadequate response to induction chemotherapy,
preventing progression to ASCT. The administration of TVD enabled 36%
additional patients to achieve a PR status, mandated for
ASCT.30 However, the EFS was reduced to 24% in
comparison to 42% in patients who did not require TVD (P-value
0.0036).2 Administration of TVD is no longer
recommended in the CCLG guidelines for patients who fail to achieve
metastatic clearance due to a lack of evidence showing improvement in
survival.2, 31
Topotecan has been administered infrequently in newly diagnosed HR-NB.
In a pilot study by COG, pharmacokinetically guided doses of topotecan
were administered along with cyclophosphamide. An induction response
rate of 84% was observed.32 A similar combination was
used in a multicentric trial in Thailand, with 82% of patients
attaining remission.33 A phase II investigational
window study by POG noted an objective response (complete, partial or
mixed) with 2-cycles of single-agent topotecan.34
Lacking access to ASCT in the selected cases of HR-NB, we choose to
administer 4-cycles of TVD as consolidation instead. Multiple cycles,
ranging from 1-9 of TVD, were administered in phase II multicentric
Italian study in children with relapsed or refractory
neuroblastoma.35 Progression-free survival was
observed in 15 (60%) children at a median of 9
months.35 We observed mortality of 3.5% and 5%
during induction and consolidation, respectively. Mortality of 4.1% was
reported with rapid COJEC in 130 children by European Neuroblastoma
Study Group and the Children’s Cancer and Leukaemia Group in
2008.36 As per SIOP-PODC, a toxic death rate exceeding
5% for induction and 10% for consolidation should prompt an assessment
and reduction of treatment intensity if supportive care cannot be
augmented.10 HR-NBL1/SIOPEN trial did not report toxic
deaths during rapid COJEC as well as with 2-cycles of
TVD.30 Morbidity with TVD was predominantly
hematological with grade 3 or 4 neutropenia in 84%
patients.30 Admission for the administration of
antibiotics was recorded in 34.1% cycles.30 Admission
for antibiotics was observed in 46% cycles of TVD in our study. We
consider toxicity from rapid COJEC and TVD in our setting to be
acceptable.
For ASCT to be widely available to patients with HR-NB in LMIC, we
incorporated several low-cost adaptations, reported
earlier.7 The strategy now enables us to offer ASCT
universally to all patients with HR-NB in our center. The 3-year OS of
patients with HR-NB with ASCT was 41% in our center. The OS with ASCT
exceeds the OS of 29.3% observed without ASCT in the current study,
though the difference is not significant (P-value 0.46). The efficacy of
ASCT for HR-NB cannot be suitably commented on the comparison of the two
studies, due to the limited size of cohorts. The limitations of the
study are a retrospective design with a limited number of patients from
a single-center.
In conclusion, 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 will
aid stakeholders in LMIC for making informed decisions while considering
the options of treatment for HR-NB if access to ACST and dinutuximab is
lacking.