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.