The prognosis of high-risk neuroblastoma (NB) continues to be poor. The early development of resistance often leads to disease recurrence. In the present study, an innovative induction regimen, including an intensive initial radio-chemotherapy sequence based on the use of iodine-131-metaiodobenzylguanidine (131-I-MIBG), was investigated. The duration of the regimen lasted only one month. Fifteen newly diagnosed patients aged >18 months with high-risk NB were treated with cisplatin, etoposide, cyclophosphamide, and vincristine, followed on day 10 by 131-I-MIBG (dose: 12−18.3 mCi/kg). Cisplatin and vincristine were administered on day 20 and 21 followed by the re-administration of vincristine, cyclophosphamide, and doxorubicin on day 29 and 30. Non-hematologic toxicity was not observed. Moderate hematologic toxicity was present probably attributable to chemotherapy. The evaluation of response was performed approximately 50 days after the initiation of treatment, yielding four complete responses, eight very good partial responses, one partial response, and two non-responses. Importantly, a complete metastatic response was achieved in 87% of patients. The present pilot study, which includes 131-I-MIBG, allows for a highly effective continuous exposure of tumor cells to both chemotherapy and radiotherapy. Furthermore, early high-dose chemotherapy followed by stem cell rescue may achieve high levels of tumor cell clearance and improve the prognosis of high-risk NB.

OBJECTIVE: Paediatric high-risk neuroblastoma has poor prognosis despite modern multimodality therapy. This phase I/II study aimed to determine the safety, dose-limiting toxicity (DLT), and efficacy of high-dose 131I-meta-iodobenzylguanidine (131I-mIBG) therapy combined with single high-dose chemotherapy (HDC) and haematopoietic stem cell transplantation (HSCT) in high-risk neuroblastoma in Japan.
METHODS: Patients received 666 MBq/kg of 131I-mIBG and single HDC and HSCT from autologous or allogeneic stem cell sources. The primary endpoint was DLT defined as adverse events associated with 131I-mIBG treatment posing a significant obstacle to subsequent HDC. The secondary endpoints were adverse events/reactions, haematopoietic stem cell engraftment and responses according to the Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1) and 123I-mIBG scintigraphy. Response was evaluated after engraftment.
RESULTS: We enrolled eight patients with high-risk neuroblastoma (six females; six newly diagnosed and two relapsed high-risk neuroblastoma; median age, 4 years; range, 1-10 years). Although all patients had adverse events/reactions after high-dose 131I-mIBG therapy, we found no DLT. Adverse events and reactions were observed in 100% and 25% patients during single HDC and 100% and 12.5% patients during HSCT, respectively. No Grade 4 complications except myelosuppression occurred during single HDC and HSCT. The response rate according to RECIST 1.1 was observed in 87.5% (7/8) in stable disease and 12.5% (1/8) were not evaluated. Scintigraphic response occurred in 62.5% (5/8) and 37.5% (3/8) patients in complete response and stable disease, respectively.
CONCLUSIONS: 131I-mIBG therapy with 666 MBq/kg followed by single HDC and autologous or allogeneic SCT is safe and efficacious in patients with high-risk neuroblastoma and has no DLT.
BACKGROUND: jRCTs041180030.
UNASSIGNED: Feasibility of high-dose iodine-131-meta-iodobenzylguanidine therapy for high-risk neuroblastoma preceding myeloablative chemotherapy and haematopoietic stem cell transplantation (High-dose iodine-131-meta-iodobenzylguanidine therapy for high-risk neuroblastoma). URL OF REGISTRY: https://jrct.niph.go.jp/en-latest-detail/jRCTs041180030 .
UNASSIGNED: 12/01/2018.

Purpose: Neuroblastoma is the most common extracranial solid tumor in children, and most patients are at high risk when they are initially diagnosed. The roles of surgery and induction chemotherapy in patients with high-risk neuroblastoma have been a subject of much controversy and debate. The objective of the current study was to assess the roles of surgery in high-risk neuroblastoma. Method: The review protocol was prospectively registered (PROSPEROID: CRD42021253961). The PubMed, Embase, Cochrane, and CNKI databases were searched from inception to January 2020 with no restrictions on language or publication date. Clinical studies comparing the outcomes of different surgical ranges for the treatment of high-risk neuroblastoma were analyzed. The Mantel-Haenszel method and a random effects model was utilized to calculate the hazard ratio (95% CI). Results: Fourteen studies that assessed 1,915 subjects met the full inclusion criteria. Compared with the gross tumor resection (GTR) group, complete tumor resection (CTR) did not significantly improve the 5-year EFS [p = 1.0; HR = 0.95 (95% CI, 0.87-1.05); I 2 = 0%], and the 5-year OS [p = 0.76; HR = 1.08 (95% CI, 0.80-1.46); I 2 = 0%] of patients. GTR or CTR resection had significantly better 5-year OS [p = 0.45; HR = 0.56 (95% CI, 0.43-0.72); I 2 = 0%] and 5-year EFS [p = 0.15; HR = 0.80 (95% CI, 0.71-0.90); I 2 = 31%] than subtotal tumor resection (STR) or biopsy only; however, both CTR or GTR showed a trend for more intra and post-operative complications compared with the STR or biopsy only [p = 0.37; OR = 1.54 (95% CI, 1.08-2.20); I 2 = 0%]. The EFS of the patients who underwent GTR or CTR at the time of diagnosis and after induction chemotherapy were similar [p = 0.24; HR = 1.53 (95% CI, 0.84-2.77); I 2 = 29%]. Conclusion: For patients with high-risk neuroblastoma, complete tumor resection and gross tumor resection of the primary tumor were related to improved survival, with very limited effects on reducing intraoperative and postoperative complications. It is necessary to design strong chemotherapy regimens to improve the survival rate of advanced patients. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, PROSPEROID [CRD42021253961].

Standard supportive care during induction therapy for high-risk neuroblastoma (HR-NBL) includes primary prophylactic granulocyte colony-stimulating factor (G-CSF) aimed at limiting duration of neutropenia, reducing infection risk, and minimizing treatment delays. Preclinical models suggest that G-CSF promotes maintenance of neuroblastoma cancer stem cells and may reduce the efficacy of chemotherapy. This study\'s objective was to determine the safety and feasibility of administering induction chemotherapy without routine use of prophylactic G-CSF.
Children with newly diagnosed HR-NBL received six-cycle induction chemotherapy regimen without prophylactic G-CSF in four cycles. G-CSF was administered for stem cell mobilization after cycle 3 and granulocyte-monocyte colony-stimulating factor after cycle 5 prior to surgical resection of primary disease. The primary outcome measure was the incidence of grade 3 or higher infection. We hypothesized that the per patient infection rate would be comparable to our institutional baseline rate of 58% in patients with HR-NBL receiving induction chemotherapy with prophylactic growth factor support. The trial used an A\'Hern single-stage design.
Twelve patients with HR-NBL received 58 cycles of chemotherapy on study. Three patients completed the entire six-cycle regimen with no infections. Nine patients experienced grade 3 infections (bacteremia four, urinary tract infection two, skin/soft tissue infection three). No patients experienced grade 4 infections or required intensive care treatment for infection.
A greater than expected number of serious bacterial infections were observed during administration of induction chemotherapy for HR-NBL without primary prophylactic G-CSF. These results support continued prophylactic administration growth factor during induction chemotherapy.

Patients with high-risk neuroblastoma (HR NBL) treated with myeloablative regimens are reported to be at risk for cardiovascular morbidity, and this risk may be increased by impaired renal function.
Long-term renal function was assessed in a national cohort of 18 (age 22.4 ± 4.9 years) HR NBL survivors by plasma creatinine (P-Cr), urea, and cystatin C (P-Cys C) concentrations, urine albumin/creatinine ratio (ACR), and estimated glomerular filtration rate (eGFR). Ambulatory blood pressure was monitored, and common carotid intima-media thickness (CIMT) and left ventricular mass index (LVMI) were evaluated.
No significant difference in P-Cr, P-Cys C, or eGFR was found between the NBL survivors and the age- and sex-matched 20 controls. P-Cys C-based eGFR (eGFRcysc) was significantly lower than the P-Cr-based eGFRcr (97 ± 17 mL/min/1.73 m2 vs 111 ± 19 mL/min/1.73 m2 , P < 0.001) among the NBL survivors. The eGFRcysc was below normal in 28%, and ACR was above normal in 22% of the NBL survivors. Abnormal blood pressure was found in 56% of the survivors, and an additional 17% were normotensive at daytime but had significant nocturnal hypertension. Both ACR and P-Cys C were associated with nighttime diastolic hypertension.
Long-term survivors of childhood HR NBL showed signs of only mild renal dysfunction associated with diastolic hypertension. Elevated ACR and P-Cys C were the most sensitive indicators of glomerular renal dysfunction and hypertension in this patient cohort.

Neuroblastoma is a sympathetic nervous system tumor, primarily presenting in children under 6 years of age. The long-term prognosis for patients with high-risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapy. This report provides an update to a phase II trial evaluating DFMO as maintenance therapy in HRNB. Event-free survival (EFS) and overall survival (OS) of 81 subjects with HRNB treated with standard COG induction, consolidation and immunotherapy followed by 2 years of DFMO on the NMTRC003/003b Phase II trial were compared to a historical cohort of 76 HRNB patients treated at Beat Childhood Cancer Research Consortium (BCC) hospitals who were disease-free after completion of standard upfront therapy and did not receive DFMO. The 2- and 5-year EFS were 86.4% [95% confidence interval (CI) 79.3%-94.2%] and 85.2% [77.8%-93.3%] for the NMTRC003/003b subset vs 78.3% [69.5%-88.3%] and 65.6% [55.5%-77.5%] for the historical control group. The 2- and 5-year OS were 98.8% [96.4-100%] and 95.1% [90.5%-99.9%] vs 94.4% [89.3%-99.9%] and 81.6% [73.0%-91.2%], respectively. DFMO maintenance for HRNB after completion of standard of care therapy was associated with improved EFS and OS relative to historical controls treated at the same institutions. These results support additional investigations into the potential role of DFMO in preventing relapse in HRNB.

Long-term survival of high-risk neuroblastoma patients is still below 50% despite intensive multimodal treatment. This trial aimed to address whether the addition of two topotecan-containing chemotherapy courses compared to standard induction therapy improves event-free survival (EFS) of these patients.
An open-label, multicenter, prospective randomized controlled trial was carried out at 58 hospitals in Germany and Switzerland. Patients aged 1-21 years with stage 4 neuroblastoma and patients aged 6 months to 21 years with MYCN-amplified tumors were eligible. The primary endpoint was EFS. Patients were randomly assigned to standard induction therapy with six chemotherapy courses or to experimental induction chemotherapy starting with two additional courses of topotecan, cyclophosphamide, and etoposide followed by standard induction chemotherapy (eight courses in total). After induction chemotherapy, all patients received high-dose chemotherapy with autologous hematopoietic stem cell rescue and isotretinoin for consolidation. Radiotherapy was applied to patients with active tumors at the end of induction chemotherapy.
Of 536 patients enrolled in the trial, 422 were randomly assigned to the control arm (n = 211) and the experimental arm (n = 211); the median follow-up time was 3.32 years (interquartile range 1.65-5.92). At data lock, the 3-year EFS of experimental and control patients was 34% and 32% [95% confidence Interval (CI) 28% to 40% and 26% to 38%; P = 0.258], respectively. Similarly, the 3-year overall survival of the patients did not differ [54% and 48% (95% CI 46% to 62% and 40% to 56%), respectively; P = 0.558]. The response to induction chemotherapy was not different between the arms. The median number of non-fatal toxicities per patient was higher in the experimental group while the median number of toxicities per chemotherapy course was not different.
While the burden for the patients was increased by prolonging the induction chemotherapy and the toxicity, the addition of two topotecan-containing chemotherapy courses did not improve the EFS of high-risk neuroblastoma patients and thus cannot be recommended. CLINICAL TRIALS.
NCT number 03042429.