Bevacizumab, Irinotecan, or Topotecan Added to Temozolomide for Children With Relapsed and Refractory Neuroblastoma: Results of the ITCC-SIOPEN BEACON-Neuroblastoma Trial.

PURPOSE: Outcomes for children with relapsed and refractory high-risk neuroblastoma (RR-HRNB) remain dismal. The BEACON Neuroblastoma trial (EudraCT 2012-000072-42) evaluated three backbone chemotherapy regimens and the addition of the antiangiogenic agent bevacizumab (B). MATERIALS AND METHODS: Patients age 1-21 years with RR-HRNB with adequate organ function and performance status were randomly assigned in a 3 × 2 factorial design to temozolomide (T), irinotecan-temozolomide (IT), or topotecan-temozolomide (TTo) with or without B. The primary end point was best overall response (complete or partial) rate (ORR) during the first six courses, by RECIST or International Neuroblastoma Response Criteria for patients with measurable or evaluable disease, respectively. Safety, progression-free survival (PFS), and overall survival (OS) time were secondary end points. RESULTS: One hundred sixty patients with RR-HRNB were included. For B random assignment (n = 160), the ORR was 26% (95% CI, 17 to 37) with B and 18% (95% CI, 10 to 28) without B (risk ratio [RR], 1.52 [95% CI, 0.83 to 2.77]; P = .17). Adjusted hazard ratio for PFS and OS were 0.89 (95% CI, 0.63 to 1.27) and 1.01 (95% CI, 0.70 to 1.45), respectively. For irinotecan ([I]; n = 121) and topotecan (n = 60) random assignments, RRs for ORR were 0.94 and 1.22, respectively. A potential interaction between I and B was identified. For patients in the bevacizumab-irinotecan-temozolomide (BIT) arm, the ORR was 23% (95% CI, 10 to 42), and the 1-year PFS estimate was 0.67 (95% CI, 0.47 to 0.80). CONCLUSION: The addition of B met protocol-defined success criteria for ORR and appeared to improve PFS. Within this phase II trial, BIT showed signals of antitumor activity with acceptable tolerability. Future trials will confirm these results in the chemoimmunotherapy era.

Novel therapeutic approaches for pediatric diencephalic tumors: improving functional outcomes.

Pediatric diencephalic tumors represent a histopathologically and molecularly diverse group of neoplasms arising in the central part of the brain and involving eloquent structures, including the hypothalamic-pituitary axis (HPA), optic pathway, thalamus, and pineal gland. Presenting symptoms can include significant neurological, endocrine, or visual manifestations which may be exacerbated by injudicious intervention. Upfront multidisciplinary assessment and coordinated management is crucial from the outset to ensure best short- and long-term functional outcomes. In this review we discuss the clinical and pathological features of the neoplastic entities arising in this location, and their management. We emphasize a clear move towards 'function preserving' diagnostic and therapeutic approaches with novel toxicity-sparing strategies, including targeted therapies.

Access to early-phase clinical trials for children with relapsed and refractory neuroblastoma: A multicentre international study.

OBJECTIVES: Neuroblastoma is the most common extracranial tumour in children, and prognosis for refractory and relapsed disease is still poor. Early-phase clinical trials play a pivotal role in the development of novel drugs. Ensuring adequate recruitment is crucial. The primary aim was to determine the rate of participation trials for children with refractory/relapsed neuroblastoma in two of the largest drug development European institutions. METHODS: Data from patients diagnosed with refractory/relapsed neuroblastoma between January 2012 and December 2018 at the two institutions were collected and analysed. RESULTS: Overall, 48 patients were included. A total of 31 (65%) refractory/relapsed cases were enrolled in early-phase trials. The main reasons for not participating in clinical trials included not fulfilling eligibility criteria prior to consent (12/17, 70%) and screening failure (2/17, 12%). Median time on trial was 4.3 months (range 0.6-13.4). Most common cause for trial discontinuation was disease progression (67.7%). Median overall survival was longer in refractory (28 months, 95% CI: 20.9-40.2) than in relapsed patients (14 months, 95% CI: 8.1-20.1) (p = .034). CONCLUSIONS: Although two thirds of children with refractory/relapsed neuroblastoma were enrolled in early-phase trials, recruitment rates can still be improved. The main cause for not participating on trials was not fulfilling eligibility criteria prior to consent, mainly due to performance status and short life expectancy. This study highlights the hurdles to access to innovative therapies for children with relapsed/refractory neuroblastomas, and identifies key areas of development to improve recruitment to early-phase trials.

Outcome of SIOP patients with low- or intermediate-risk Wilms tumour relapsing after initial vincristine and actinomycin-D therapy only - the SIOP 93-01 and 2001 protocols.

PURPOSE: Society of International Pediatric Oncology - Renal Tumor Study Group (SIOP-RTSG) treatment recommendations for relapsed Wilms tumour (WT) are stratified by the intensity of first-line treatment. To explore the evidence for the treatment of patients relapsing after vincristine and actinomycin-D (VA) treatment for primary WT, we retrospectively evaluated rescue treatment and survival of this patient group. PATIENTS AND METHODS: We included 109 patients with relapse after VA therapy (no radiotherapy) for stage I-II primary low- or intermediate-risk WT from the SIOP 93-01 and SIOP 2001 studies. Univariate Cox regression analysis was performed to study the effect of relapse treatment intensity on event-free survival (EFS) and overall survival (OS). Relapse treatment intensity was classified into vincristine, actinomycin-D, and either doxorubicin or epirubicin (VAD), and more intensive therapies (ifosfamide/carboplatin/etoposide [ICE]/≥ 4 drugs/high-dose chemotherapy with haematopoietic stem cell transplantation [HD HSCT]). RESULTS: Relapse treatment regimens included either VAD, or cyclophosphamide/carboplatin/etoposide/doxorubicin (CyCED), or ICE backbones. Radiotherapy was administered in 62 patients and HD HSCT in 15 patients. Overall, 5-year EFS and OS after relapse were 72.3% (95% confidence interval [CI]: 64.0-81.6%) and 79.3% (95% CI: 71.5-88.0%), respectively. Patients treated with VAD did not fare worse when compared with patients treated with more intensive therapies (hazard ratio EFS: 0.611 [95% CI: 0.228-1.638] [p-value = 0.327] and hazard ratio OS: 0.438 [95% CI: 0.126-1.700] [p-value = 0.193]). CONCLUSION: Patients with relapsed WT after initial VA-only treatment showed no inferior EFS and OS when treated with VAD regimens compared with more intensive rescue regimens. A subset of patients relapsing after VA may benefit from less intensive rescue treatment than ICE/CyCED-based regimens and deserve to be pinpointed by identifying additional (molecular) prognostic factors in future studies.

Circulating tumour DNA sequencing to determine therapeutic response and identify tumour heterogeneity in patients with paediatric solid tumours.

OBJECTIVE: Clinical diagnostic sequencing of circulating tumour DNA (ctDNA) is well advanced for adult patients, but application to paediatric cancer patients lags behind. METHODS: To address this, we have developed a clinically relevant (67 gene) NGS capture panel and accompanying workflow that enables sensitive and reliable detection of low-frequency genetic variants in cell-free DNA (cfDNA) from children with solid tumours. We combined gene panel sequencing with low pass whole-genome sequencing of the same library to inform on genome-wide copy number changes in the blood. RESULTS: Analytical validity was evaluated using control materials, and the method was found to be highly sensitive (0.96 for SNVs and 0.97 for INDEL), specific (0.82 for SNVs and 0.978 for INDEL), repeatable (>0.93 [95% CI: 0.89-0.95]) and reproducible (>0.87 [95% CI: 0.87-0.95]). Potential for clinical application was demonstrated in 39 childhood cancer patients with a spectrum of solid tumours in which the single nucleotide variants expected from tumour sequencing were detected in cfDNA in 94.4% (17/18) of cases with active extracranial disease. In 13 patients, where serial samples were available, we show a close correlation between events detected in cfDNA and treatment response, demonstrate that cfDNA analysis could be a useful tool to monitor disease progression, and show cfDNA sequencing has the potential to identify targetable variants that were not detected in tumour samples. CONCLUSIONS: This is the first pan-cancer DNA sequencing panel that we know to be optimised for cfDNA in children for blood-based molecular diagnostics in paediatric solid tumours.

High grade gliomas in young children: The South Thames Neuro-Oncology unit experience and recent advances in molecular biology and targeted therapies.

High grade gliomas (HGG) have a dismal prognosis with survival rates of 15-35%. Approximately 10-12% of pediatric HGG occur in young children and their molecular biology and clinical outcomes differ from those arising at older ages. We report on four children aged <5 years newly diagnosed with non-brainstem HGG between 2011 and 2018 who were treated with surgery and BBSFOP chemotherapy. Two died of tumor progression. The other two are still alive without radiotherapy at 3.8 and 3.9 years from diagnosis: one of whom remains disease-free off treatment; and the other one, whose tumor harbored a KCTD16:NTRK2 fusion, went on to receive larotrectinib. Additionally we review the general management, outcomes and latest updates in molecular biology and targeted therapies for young children with HGG. Infant gliomas can be stratified in molecular subgroups with clinically actionable oncogenic drivers. Chemotherapy-based strategies can avoid or delay the need for radiotherapy in young children with HGG. Harnessing the potential of NTRK, ALK, ROS1 and MET inhibitors offers the opportunity to optimize the therapeutic armamentarium to improve current outcomes for these children.

Defibrotide treatment but not prophylaxis is useful in hepatic sinusoidal obstruction syndrome in children undergoing autologous stem cell transplant following high-dose chemotherapy: A single-center experience from the Royal Marsden Hospital, UK.

BACKGROUND: Hepatic sinusoidal obstruction syndrome (SOS) is a serious complication of autologous stem cell transplant (ASCT) in children with historically high mortality rates. Defibrotide has shown proven benefit in its treatment and may have a modest role in prevention. We report our experience with SOS in children undergoing autologous transplant. METHODS: Case records of 82 consecutive patients undergoing ASCT following high-dose chemotherapy between 2010 and 2017 were reviewed. Defibrotide was used for treatment of all with SOS and prophylactically in patients receiving busulfan-based conditioning until 2014. RESULTS: Fourteen of the 82 children (17%) were diagnosed with SOS. The incidence was higher in those receiving busulfan-based conditioning (13/42 vs 1/40, P = 0.008). Mean (±SD) time to diagnosis of SOS was 19 (±5.6) days following stem cell rescue. Bilirubin levels and ultrasound were normal in 7/14 and 3/14 patients. Coagulopathy was noted in 10/14; one child developed multiorgan involvement. Nine children had mild SOS, whereas two and three had moderate and severe SOS, respectively. Intensive care was required for four of five non-mild cases. Patients with SOS had significantly delayed platelet recovery, higher transfusion requirement, and longer hospital stay. Unavailability of defibrotide prophylaxis for 17/42 receiving busulfan did not change the incidence of SOS (7/25 with defibrotide vs 6 /17 without defibrotide, P = 0.74). There was no significant difference in the severity of SOS between these groups. CONCLUSION: Hepatic SOS was more commonly seen in children receiving busulfan-based conditioning. Stopping the use of prophylactic defibrotide did not increase incidence or severity of SOS. Overall outcome was excellent with supportive care and timely treatment with defibrotide.

Surgical tracheostomy in children with malignancy receiving intensive chemotherapy: A case series and review of literature.

We retrospectively reviewed a paediatric intensive care unit database that supports a tertiary oncology service to explore safety and outcome of tracheostomy in oncology patients over a 12-year period and reviewed literature. A total of 895 patients were admitted with a haematological or a solid tumour malignancy of which 222 were ventilated. Six of 222 (2.7%) ventilated children were tracheostomised. Four of six children tracheostomised for ventilatory support received intensive chemotherapy complicated by neutropenia and thrombocytopenia. There was no significant tracheostomy-related complication. Tracheostomy improved patient comfort, reduced sedative requirement, and may have helped recovery. Tracheostomy should be considered early in selected children with haemato-oncological diagnoses requiring prolonged ventilation.

A tailored molecular profiling programme for children with cancer to identify clinically actionable genetic alterations.

BACKGROUND: For children with cancer, the clinical integration of precision medicine to enable predictive biomarker-based therapeutic stratification is urgently needed. METHODS: We have developed a hybrid-capture next-generation sequencing (NGS) panel, specifically designed to detect genetic alterations in paediatric solid tumours, which gives reliable results from as little as 50 ng of DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissue. In this study, we offered an NGS panel, with clinical reporting via a molecular tumour board for children with solid tumours. Furthermore, for a cohort of 12 patients, we used a circulating tumour DNA (ctDNA)-specific panel to sequence ctDNA from matched plasma samples and compared plasma and tumour findings. RESULTS: A total of 255 samples were submitted from 223 patients for the NGS panel. Using FFPE tissue, 82% of all submitted samples passed quality control for clinical reporting. At least one genetic alteration was detected in 70% of sequenced samples. The overall detection rate of clinically actionable alterations, defined by modified OncoKB criteria, for all sequenced samples was 51%. A total of 8 patients were sequenced at different stages of treatment. In 6 of these, there were differences in the genetic alterations detected between time points. Sequencing of matched ctDNA in a cohort of extracranial paediatric solid tumours also identified a high detection rate of somatic alterations in plasma. CONCLUSION: We demonstrate that tailored clinical molecular profiling of both tumour DNA and plasma-derived ctDNA is feasible for children with solid tumours. Furthermore, we show that a targeted NGS panel-based approach can identify actionable genetic alterations in a high proportion of patients.

Managing peritoneal involvement in children and young people with rhabdomyosarcoma: A single-center experience from the United Kingdom.

We describe our experience in managing nine children and adolescents with rhabdomyosarcoma (RMS) and peritoneal involvement. The radiological pattern of peritoneal involvement was diverse from only ascites to solid peritoneal mass/omental caking. Treatment included systemic chemotherapy in all, surgery in three, and radiotherapy in eight. Two patients with presumed nonmalignant ascites, no solid peritoneal metastasis, nonalveolar histology, near-complete resection of residual disease, and radiotherapy survived long term. One patient has just completed treatment, and the remaining six relapsed/progressed at the time of reporting. Five of six patients died after a median of 5 (3-7) months from relapse despite second-line chemotherapy.

Post-radiotherapy apparent diffusion coefficient (ADC) in children and young adults with high-grade gliomas and diffuse intrinsic pontine gliomas.

Objectives: Diffusion-weighted magnetic resonance imaging (DW-MRI) offers potential to monitor response and predict survival in high-grade gliomas (HGG) and diffuse intrinsic pontine gliomas (DIPG). We hypothesized that post-radiotherapy DW-MRI may provide prognostic imaging biomarkers in children and young adults with these tumors. Methods: Patients aged ≤21 years diagnosed between 2005 and 2012 were eligible. The tumor median apparent diffusion coefficient (ADC) and its 5th percentile (C5-ADC) were determined at the first post-radiotherapy scan and at the time of radiological progression. DW-MRI parameters were correlated with survival endpoints, temozolomide use and pseudoprogression, when it occurred. Results: Out of 40 patients (20 HGG, 20 DIPG), 23 had evaluable DW-MRI post-radiotherapy and 25 at radiological progression. There were 6 episodes of pseudoprogression. Hazard ratios (95%CI) for progression-free survival were 0.998 (0.993-1.003) for median ADC and 1.003 (0.996-1.010) for C5-ADC. Hazard ratios (95%CI) for overall survival were 1.0009 (0.996-1.006) for median ADC and 0.998 (0.992-1.004) for C5-ADC. Post-radiotherapy median and C5-ADC values were not significantly different between patients treated with radiotherapy alone versus radiotherapy/temozolomide. The median and C5-ADC values were not significantly different at the time of pseudoprogression compared to those at tumor progression. Conclusions: Post-radiotherapy median ADC and C5-ADC were not prognostic, nor able to differentiate radiosensitization with temozolomide or occurrence of pseudoprogression in this cohort of HGG and DIPG patients. Further exploration of alternative DW parameters, study timepoints or data modeling may contribute to the development of prognostic/predictive imaging biomarkers for children and young adults with HGG or DIPG.

MRI Imaging of the Hemodynamic Vasculature of Neuroblastoma Predicts Response to Antiangiogenic Treatment.

Childhood neuroblastoma is a hypervascular tumor of neural origin, for which antiangiogenic drugs are currently being evaluated; however, predictive biomarkers of treatment response, crucial for successful delivery of precision therapeutics, are lacking. We describe an MRI-pathologic cross-correlative approach using intrinsic susceptibility (IS) and susceptibility contrast (SC) MRI to noninvasively map the vascular phenotype in neuroblastoma Th-MYCN transgenic mice treated with the vascular endothelial growth factor receptor inhibitor cediranib. We showed that the transverse MRI relaxation rate R 2* (second-1) and fractional blood volume (fBV, %) were sensitive imaging biomarkers of hemorrhage and vascular density, respectively, and were also predictive biomarkers of response to cediranib. Comparison with MRI and pathology from patients with MYCN-amplified neuroblastoma confirmed the high degree to which the Th-MYCN model vascular phenotype recapitulated that of the clinical phenotype, thereby supporting further evaluation of IS- and SC-MRI in the clinic. This study reinforces the potential role of functional MRI in delivering precision medicine to children with neuroblastoma. SIGNIFICANCE: This study shows that functional MRI predicts response to vascular-targeted therapy in a genetically engineered murine model of neuroblastoma.

Long-term analysis of children with metastatic neuroblastoma treated in the ENSG5 randomised clinical trial.

BACKGROUND: The European Neuroblastoma Study Group 5 (ENSG5) trial showed that time-intensive "rapid" induction chemotherapy (COJEC) was superior to "standard" 3-weekly chemotherapy for children with high-risk metastatic neuroblastoma. Long-term outcomes of the ENSG5 trial were analysed. PROCEDURE: Patients with metastatic neuroblastoma aged ≥12 months were randomly assigned to "standard" or "rapid" induction, receiving the same chemotherapy drugs and doses. Event-free survival (EFS) and overall survival (OS) were analysed and prognostic factors evaluated. Amongst patients surviving >5 years, a population of children with persistent metastatic disease after the end of treatment was identified and described. RESULTS: Ten-year EFS was 18.2% (95% confidence interval: 12.2-25.2) for the "standard" arm and 26.8% (19.5-34.7) for the "rapid" arm (hazard ratio [HR] 0.85, P = 0.28). Ten-year OS for the "standard" arm was 19.7% (13.4-26.8) and 28.3% (20.8-36.2) for the "rapid arm" (HR 0.83, P = 0.19). There was a trend for worse EFS and OS for patients having MYCN amplification (HR 1.37 and 1.40, respectively) and those with partial and mixed response to induction (HR 1.69 and 1.75 for EFS and 1.66 and 2.00 for OS, respectively). Among 69 patients who survived >5 years, six had persistent metastatic disease after the end of treatment. CONCLUSION: The benefit of the "rapid" induction regimen seems to be maintained in the long term, although the small number of survivors could justify the lack of statistical significance. MYCN amplification and poor metastatic response to induction could be associated with worse outcomes. A small group of patients with persistent metastatic disease that survived long term has been described.

Functional diversity and cooperativity between subclonal populations of pediatric glioblastoma and diffuse intrinsic pontine glioma cells.

The failure to develop effective therapies for pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively assess the extent to which this was present in these tumors through subclonal genomic analyses and to determine whether distinct tumor subpopulations may interact to promote tumorigenesis by generating subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced tumors revealed multiple tumor subclones, spatially and temporally coexisting in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations that we propose cooperate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B (SUV420H1), present in <1% of cells, abrogate DNA repair and confer increased invasion and migration on neighboring cells, in vitro and in vivo, through chemokine signaling and modulation of integrins. These data indicate that even rare tumor subpopulations may exert profound effects on tumorigenesis as a whole and may represent a new avenue for therapeutic development. Unraveling the mechanisms of subclonal diversity and communication in pGBM and DIPG will be an important step toward overcoming barriers to effective treatments.

Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma.

We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification.

Pseudoprogression in children, adolescents and young adults with non-brainstem high grade glioma and diffuse intrinsic pontine glioma.

Pseudoprogression (PsP) is a treatment-related phenomenon which hinders response interpretation. Its prevalence and clinical impact have not been evaluated in children/adolescents. We assessed the characteristics, risk factors and prognosis of PsP in children/adolescents and young-adults diagnosed with non-brainstem high grade gliomas (HGG) and diffuse intrinsic pontine gliomas (DIPG). Patients aged 1-21 years diagnosed with HGG or DIPG between 1995 and 2012 who had completed radiotherapy were eligible. PsP was assessed according to study-specific criteria and correlated with first-line treatment, molecular biomarkers and survival. Ninety-one patients (47 HGG, 44 DIPG) were evaluable. Median age: 10 years (range, 2-20). Eleven episodes of PsP were observed in 10 patients (4 HGG, 6 DIPG). Rates of PsP: 8.5 % (HGG); 13.6 % (DIPG). Two episodes of PsP were based on clinical findings alone; nine episodes had concurrent radiological changes: increased size of lesions (n = 5), new focal enhancement (n = 4). Temozolomide, MGMT methylation or H3F3A mutations were not found to be associated with increased occurrence of PsP. For HGG, 1-year progression-free survival (PFS) was 41.9 % no-PsP versus 100 % PsP (p = 0.041); differences in 1-year overall survival (OS) were not significant. For DIPG, differences in 1-year PFS and OS were not statistically significant. Hazard ratio (95 %CI) of PsP for OS was 0.551 (0.168-1.803; p = 0.325) in HGG; and 0.308 (0.107-0.882; p = 0.028) in DIPG. PsP occurred in both pediatric HGG and DIPG patients at a comparable rate to adult HGG. PsP was associated with improved 1-yr PFS in HGG patients. PsP had a protective effect upon OS in DIPG patients.

Craniospinal irradiation with concomitant and adjuvant temozolomide--a feasibility assessment of toxicity in patients with glioblastoma with a PNET component.

There is no standard treatment for glioblastoma with elements of PNET (GBM-PNET). Conventional treatment for glioblastoma is surgery followed by focal radiotherapy with concurrent temozolomide. Given the increased propensity for neuroaxial metastases seen with GBM-PNETs, craniospinal irradiation (CSI) with temozolomide (TMZ) could be a feasible treatment option but little is known regarding its toxicity. The clinical records of all patients treated at two UK neuro-oncology centres with concurrent CSI and TMZ were examined for details of surgery, radiotherapy, chemotherapy and toxicities related to the CSI-TMZ component of their treatment. Eight patients were treated with CSI-TMZ, the majority (6/8) for GBM-PNET. All patients completed radiotherapy to the craniospinal axis 35-40 Gy in 20-24 daily fractions with a focal boost to the tumour of 14-23.4 Gy in 8-13 daily fractions. Concurrent TMZ was administered at 75 mg/m(2) for seven of the cohort, with the other patient receiving 50 mg/m(2). The most commonly observed non-haematological toxicities were nausea and vomiting, with all patients experiencing at least grade 2 symptoms of either or both. All patients had at least grade 3 lymphopaenia. Two patients experience grade 4 neutropaenia and grade 3 thrombocytopaenia. Three of the eight patients required omission of TMZ for part of their chemoradiotherapy and 3/8 required hospital admission at some point during chemoradiotherapy. The addition of TMZ to CSI did not interrupt radiotherapy. Principal toxicities were neutropaenia, lymphopaenia, thrombocytopaenia, nausea and vomiting. Treatment with CSI-TMZ merits further investigation and may be suitable for patients with tumours at high-risk of metastatic spread throughout the CNS who have TMZ-sensitive pathologies.

Individualized 131I-mIBG therapy in the management of refractory and relapsed neuroblastoma.

OBJECTIVE: Iodine-131-labelled meta-iodobenzylguanidine (I-mIBG) therapy is an established treatment modality for relapsed/refractory neuroblastoma, most frequently administered according to fixed or weight-based criteria. We evaluate response and toxicity following a dosimetry-based, individualized approach. MATERIALS AND METHODS: A review of 44 treatments in 25 patients treated with I-mIBG therapy was performed. Patients received I-mIBG therapy following relapse (n=9), in refractory disease (n=12), or with surgically unresectable disease despite conventional treatment (n=4). Treatment schedule (including mIBG dose and number of administrations) was individualized according to the clinical status of the patient and dosimetry data from either a tracer study or previous administrations. Three-dimensional tumour dosimetry was also performed for eight patients. RESULTS: The mean administered activity was 11089±7222 MBq and the mean whole-body dose for a single administration was 1.79±0.57 Gy. Tumour-absorbed doses varied considerably (3.70±3.37 mGy/MBq). CTCAE grade 3/4 neutropenia was documented following 82% treatments and grade 3/4 thrombocytopenia following 71% treatments. Further acute toxicity was found in 49% of patients. All acute toxicities resolved with appropriate therapy. The overall response rate was 58% (complete or partial response), with a further 29% of patients having stable disease. CONCLUSION: A highly personalized approach combining patient-specific dosimetry and clinical judgement enables delivery of high activities that can be tolerated by patients, particularly with stem cell support. We report excellent response rates and acceptable toxicity following individualized I-mIBG therapy.

Additional Therapies to Improve Metastatic Response to Induction Therapy in Children With High-risk Neuroblastoma.

Children with high-risk neuroblastoma who fail to achieve adequate metastatic response after induction chemotherapy have dismal outcome and new therapeutic strategies are needed. However, timing of introduction of novel agents still remains under discussion. Given an increase in number of phase I-II studies of molecularly targeted drugs in neuroblastoma, it is crucial to determine, as early as possible, which patients may be suitable candidates for new therapeutic strategies. This single-center retrospective analysis of patients with high-risk neuroblastoma showed that the addition of conventional chemotherapy improved the quality of metastatic response only for the group of patients with partial response. It is therefore proposed to develop stratification criteria for those patients very unlikely to benefit from a plethora of additional lines of treatment, but might benefit from introduction of novel agents.