Local control and toxicity outcomes following consolidative radiation therapy in patients with high-risk neuroblastoma: a 20-year experience at a single center.

BACKGROUND: Intensive multimodal treatment can improve survival in patients with high-risk neuroblastoma, and consolidative radiation therapy has contributed to local control. We examined the clinical outcomes of patients who underwent consolidative radiation therapy at our institution. METHODS: We retrospectively reviewed the records of patients with high-risk neuroblastoma who underwent consolidative radiation therapy from March 2001 to March 2021 at Asan Medical Center. Patients underwent multimodal treatment including high-dose chemotherapy, surgery, stem cell transplantation, and maintenance therapy. Radiation (median, 21.0 Gy; range, 14-36) was administered to the primary site and surrounding lymph nodes. RESULTS: This study included 37 patients, and the median age at diagnosis was 2.8 years (range, 1.3-10.0). Four patients exhibited local failure, and 5-year free-from locoregional failure rate was 88.7%, with a median followup period of 5.7 years. The 5-year disease-free survival (DFS) and overall survival (OS) rates were 59.1% and 83.6%, respectively. Univariate analysis revealed that patients with neuron-specific enolase levels > 100 ng/mL had significantly worse DFS and OS (P = 0.036, 0.048), and patients with no residual disease before radiation therapy showed superior OS (P = 0.029). Furthermore, patients with 11q deletion or 17q gain exhibited poor DFS and OS, respectively (P = 0.021, 0.011). Six patients experienced grade 1 acute toxicity. Late toxicity was confirmed in children with long-term survival, predominantly hypothyroidism and hypogonadism, typically < grade 3, possibly attributed to combination treatment. Four patients experienced late toxicity ≥ grade 3 with chronic kidney disease, growth hormone abnormality, ileus, premature epiphyseal closure, and secondary tumor, and recovered by hospitalization or surgical treatment. CONCLUSIONS: In patients with high-risk neuroblastoma, consolidative radiotherapy to the primary tumor site resulted in excellent local control and a tolerable safety profile.

p53 stabilisation potentiates [177Lu]Lu-DOTATATE treatment in neuroblastoma xenografts.

PURPOSE: Molecular radiotherapy is a treatment modality that is highly suitable for targeting micrometastases and [177Lu]Lu-DOTATATE is currently being explored as a potential novel treatment option for high-risk neuroblastoma. p53 is a key player in the proapoptotic signalling in response to radiation-induced DNA damage and is therefore a potential target for radiosensitisation. METHODS: This study investigated the use of the p53 stabilising peptide VIP116 and [177Lu]Lu-DOTATATE, either alone or in combination, for treatment of neuroblastoma tumour xenografts in mice. Initially, the uptake of [177Lu]Lu-DOTATATE in the tumours was confirmed, and the efficacy of VIP116 as a monotherapy was evaluated. Subsequently, mice with neuroblastoma tumour xenografts were treated with placebo, VIP116, [177Lu]Lu-DOTATATE or a combination of both agents. RESULTS: The results demonstrated that monotherapy with either VIP116 or [177Lu]Lu-DOTATATE significantly prolonged median survival compared to the placebo group (90 and 96.5 days vs. 50.5 days, respectively). Notably, the combination treatment further improved median survival to over 120 days. Furthermore, the combination group exhibited the highest percentage of complete remission, corresponding to a twofold increase compared to the placebo group. Importantly, none of the treatments induced significant nephrotoxicity. Additionally, the therapies affected various molecular targets involved in critical processes such as apoptosis, hypoxia and angiogenesis. CONCLUSION: In conclusion, the combination of VIP116 and [177Lu]Lu-DOTATATE presents a promising novel treatment approach for neuroblastoma. These findings hold potential to advance research efforts towards a potential cure for this vulnerable patient population.

[131-I-meta-iodo-benzyl-guanidine therapy in childhood neuroblastoma.] / Gyermekkori neuroblastoma kezelésében alkalmazott 131-I-meta-jodo-benzil-guanidin terápia.

Neuroblastoma, representing one-tenth of childhood malignancies, is a clinically and prognostically heterogeneous disease. Survival in cases with poor prognosis has recently been significantly improved by rapidly evolving multimodal therapy. Our 4-year-old patient presented with bitemporal swelling and the diagnostic workup confirmed stage IV neuroblastoma (bone marrow and multiple bone metastases). While the tumor responded well to the initial treatment, it relapsed during post-consolidation therapy. As part of the salvage therapy for this high-risk disease with poor prognosis, 131-I-meta-iodo-benzyl-guanidine treatment was performed for the first time in our country, in a case of pediatric neuroblastoma. Neuroendocrine tissue cells express a norepinephrine transporter capable of uptaking the catecholamine analog meta-iodo-benzyl-guanidine. This mechanism makes it an adequate molecule for the imaging (123-I-meta-iodo-benzyl-guanidine) and target therapy (131-I-meta-iodo-benzyl-guanidine) of neuroendocrine tumors, including neuroblastoma. Treatment with 131-I-meta-iodo-benzyl-guanidine requires specific personnel and infrastructural equipment, particularly in pediatric cases. Careful organization and cooperation between nuclear medicine specialists and collaborating clinicians (pediatric oncologists and adult internists if necessary) are essential. Meta-iodo-benzyl-guanidine therapy, already routinely used abroad, has been considered as part of salvage therapy for recurrent neuroblastoma until now, but ongoing clinical trials suggest that it may become part of the first-line treatment soon. As the indications broaden, it is necessary to make it available for more and more children in our country. Orv Hetil. 2023; 164(39): 1550-1555.

MRI-based inter- and intrafraction motion analysis of the pancreatic tail and spleen as preparation for adaptive MRI-guided radiotherapy in neuroblastoma.

BACKGROUND: In pediatric radiotherapy treatment planning of abdominal tumors, dose constraints to the pancreatic tail/spleen are applied to reduce late toxicity. In this study, an analysis of inter- and intrafraction motion of the pancreatic tail/spleen is performed to estimate the potential benefits of online MRI-guided radiotherapy (MRgRT). MATERIALS AND METHODS: Ten randomly selected neuroblastoma patients (median age: 3.4 years), irradiated with intensity-modulated arc therapy at our department (prescription dose: 21.6/1.8 Gy), were retrospectively evaluated for inter- and intrafraction motion of the pancreatic tail/spleen. Three follow-up MRIs (T2- and T1-weighted ± gadolinium) were rigidly registered to a planning CT (pCT), on the vertebrae around the target volume. The pancreatic tail/spleen were delineated on all MRIs and pCT. Interfraction motion was defined as a center of gravity change between pCT and T2-weighted images in left-right (LR), anterior-posterior (AP) and cranial-caudal (CC) direction. For intrafraction motion analysis, organ position on T1-weighted ± gadolinium was compared to T2-weighted. The clinical radiation plan was used to estimate the dose received by the pancreatic tail/spleen for each position. RESULTS: The median (IQR) interfraction motion was minimal in LR/AP, and largest in CC direction; pancreatic tail 2.5 mm (8.9), and spleen 0.9 mm (3.9). Intrafraction motion was smaller, but showed a similar motion pattern (pancreatic tail, CC: 0.4 mm (1.6); spleen, CC: 0.9 mm (2.8)). The differences of Dmean associated with inter- and intrafraction motions ranged from - 3.5 to 5.8 Gy for the pancreatic tail and - 1.2 to 3.0 Gy for the spleen. In 6 out of 10 patients, movements of the pancreatic tail and spleen were highlighted as potentially clinically significant because of ≥ 1 Gy dose constraint violation. CONCLUSION: Inter- and intrafraction organ motion results into unexpected constrain violations in 60% of a randomly selected neuroblastoma cohort, supporting further prospective exploration of MRgRT.

Phase II study of 131 I-metaiodobenzylguanidine with 5 days of topotecan for refractory or relapsed neuroblastoma: Results of the French study MIITOP.

PURPOSE: We report the results of the French multicentric phase II study MIITOP (NCT00960739), which evaluated tandem infusions of 131 I-metaiodobenzylguanidine (mIBG) and topotecan in children with relapsed/refractory metastatic neuroblastoma (NBL). METHODS: Patients received 131 I-mIBG on day 1, with intravenous topotecan daily on days 1-5. A second activity of 131 I-mIBG was given on day 21 to deliver a whole-body radiation dose of 4 Gy, combined with a second course of topotecan on days 21-25. Peripheral blood stem cells were infused on day 31. RESULTS: Thirty patients were enrolled from November 2008 to June 2015. Median age at diagnosis was 5.5 years (2-20). Twenty-one had very high-risk NBL (VHR-NBL), that is, stage 4 NBL at diagnosis or at relapse, with insufficient response (i.e., less than a partial response of metastases and more than three mIBG spots) after induction chemotherapy; nine had progressive metastatic relapse. Median Curie score at inclusion was 6 (1-26). Median number of prior lines of treatment was 3 (1-7). Objective response rate was 13% (95% confidence interval [CI]: 4-31) for the whole population, 19% for VHR-NBL, and 0% for progressive relapses. Immediate tolerance was good, with nonhematologic toxicity limited to grade-2 nausea/vomiting in eight patients. Two-year event-free survival was 17% (95% CI: 6-32). Among the 16 patients with VHR-NBL who had not received prior myeloablative busulfan-melphalan consolidation, 13 had at least stable disease after MIITOP; 11 subsequently received busulfan-melphalan; four of them were alive (median follow-up: 7 years). CONCLUSION: MIITOP showed acceptable tolerability in this heavily pretreated population and encouraging survival rates in VHR-NBL when followed by busulfan-melphalan.

Gene Expression and Early Radiation Response of Two Distinct Neuroblastoma Cell Lines.

INTRODUCTION: Neuroblastoma is one of the most common childhood cancers with one of the lowest survival rates, accounting for 15% of childhood cancer mortality. Approximately half of children treated for high-risk neuroblastoma will relapse following remission, while another 15% of patients do not respond to initial treatment. External beam radiation is infrequently used for treatment of pediatric cancer such as neuroblastoma, typically reserved for palliative care in patients with aggressive metastatic disease who fail to respond to alternative treatments. Understanding effects of radiation on neuroblastoma cells could improve efficacy of this final means of therapy to decrease tumor burden and stabilize the disease. METHODS: In this study, we found that two microRNAs with opposite functions were expressed in two neuroblastoma cell lines with marked differences in radiosensitivity. Clonogenic assays were used to evaluate the radiation responses for these 2 cell lines, designated SK-N-AS and SK-N-DZ; cells were then irradiated at doses that cause 90% cell killing based on clonogenic assay and their RNA isolated and subjected to microarray analysis. In addition, cells were transfected with pre-miRNA constructs that led to overexpression of microRNAs miR-34a and miR-1228 to determine possible microRNA regulation of radiation response. RESULTS: Statistically significant differences were detected for expression of several thousand genes when the 2 cell lines were compared with each other. In comparison, radiation exposure resulted in only minor gene expression differences of less than 2-fold at the 1 h postirradiation timepoint in both cell lines. Overexpression of miR-34a and miR-1228 in either cell line did not alter this outcome. DISCUSSION: While these two neuroblastoma cell lines are phenotypically diverse and gene expression differences between them are extensive, we observed that the regulation of gene expression in both cell lines is in a stable equilibrium at early timepoints after exposure to ionizing radiation.

Vibrational spectroscopies for biochemical investigation of X-ray exposure effects on SH-SY5Y human neuroblastoma cells.

Neuroblastoma is the most recurring cancer in childhood and adolescence. The SH-SY5Y neuroblastoma cell line is generally adopted for elaborating new therapeutical approaches and/or elaborating strategies for the prevention of central nervous system disturbances. In fact, it represents a valid model system for investigating in vitro the effects on the brain of X-ray exposure using vibrational spectroscopies that can detect early radiation-induced molecular alterations of potential clinical usefulness. In recent years, we dedicated significant efforts in the use of Fourier-transform and Raman microspectroscopy techniques for characterizing such radiation-induced effects on SH-SY5Y cells by examining the contributions from different cell components (DNA, proteins, lipids, and carbohydrates) to the vibrational spectra. In this review, we aim at revising and comparing the main results of our studies to provide a wide outlook of the latest outcomes and a framework for future radiobiology research using vibrational spectroscopies. A short description of our experimental approaches and data analysis procedures is also reported.

Stent-Graft Placement for Radiation-Induced Abdominal Aortic Stenosis after Renal Autotransplantation.

Renovascular hypertension (RVH) is a common cause of secondary hypertension. However, there have been no reports on RVH due to radiation-induced abdominal aorta stenosis after renal autotransplantation. A 27-year-old woman with a history of neuroblastoma treated by radiation therapy and RVH treated with renal autotransplantation presented with hypertension and dyspnea. At age 19, she had experienced hypertensive heart failure due to RVH from radiation-induced left renal artery stenosis and had undergone renal autotransplantation involving the extraction of her left kidney. Her systolic blood pressure (BP) was well-controlled but had increased progressively. She was diagnosed with hypertensive heart failure and admitted to hospital. Although her dyspnea soon subsided after treatment, her BP remained high. Renal artery ultrasound revealed no obvious stenosis. The ankle brachial pressure index (ABI) showed a significant bilateral decrease to 0.71/0.71 (right/left) from 0.94/0.95 eight years before. Magnetic resonance angiography and aortic angiography revealed severe stenosis in the abdominal aorta, and the systolic pressure gradient of intra-aortic blood flow, distal and proximal to a stenotic lesion, was 58 mmHg. These arterial stenoses in the irradiated area were highly suggestive of radiation-induced vasculopathy. She finally underwent an endovascular VIABAHN VBX balloon-expandable stent-graft placement for this radiation-induced abdominal aorta stenosis, which resolved the pressure gradient. After the procedure, her ABI improved to 0.91/0.88 and her BP was well-controlled. This is the first case of successful stent-graft placement for RVH after renal autotransplantation due to radiation-induced abdominal aorta stenosis as a consequence of neuroblastoma.

Haematological and renal toxicity of radiation therapy in neuroblastoma paediatric patients

Purpose The objective of this study was to evaluate the renal and hematologic toxicity in paediatric patients with adrenal high-risk neuroblastoma who have received radiation therapy (RT) as part of radical treatment. Material and methods Pediatric patients diagnosed with high-risk adrenal neuroblastoma who received RT as part of the definitive treatment between January 2004 and May 2020 in a single institution were selected. Complete blood counts (CBC) and creatinine clearance (CrCl) pre-RT and post-RT were compared through the Wilcoxon signed-rank test and correlated with survival analysis by Cox regression. Results Forty-two children with a median age of 3 years at diagnosis and 2.8 years of follow-up were selected. A significant and acute decrease in lymphocytes was found (p = 0.002) 1 month from RT. Patients with a drop higher than 50% of the previous value experimented a significant reduction in overall survival (55 vs 10%; p = 0.031). At the end of the follow-up, a significant increase in all blood counts was observed. With respect to renal function, an acute and significant decrease in CrCl was observed tin patients younger than 4 years who received RT (p = 0.013). However, it was not clinically relevant. Conclusion Our data suggest that acute lymphopenia occurs after RT and could be associated with a poorer prognosis. Other blood counts are reduced after RT and all of them are in physiological range at the end of follow-up. Our cohort presented excellent renal outcomes without any case of chronic renal dysfunction (AU)

Efficacy and Safety of 124I-MIBG Dosimetry-Guided High-Activity 131I-MIBG Therapy of Advanced Pheochromocytoma or Neuroblastoma.

We aim to evaluate the efficacy and safety of 124I-metaiodobenzylguanidine (MIBG) dosimetry-guided high-activity 131I-MIBG therapy of advanced pheochromocytoma or neuroblastoma. Methods: Fourteen patients with advanced pheochromocytoma or neuroblastoma, age 9-69 y, underwent 124I-MIBG PET scans and whole-body retention measurements to assess the whole-body dose as a surrogate of bone marrow toxicity and tumor (absorbed) dose per unit of administered activity. Dosimetry results together with individual patient characteristics were combined to guide a single therapeutic activity to achieve a high tumor dose without exceeding toxicity threshold. Toxicity was assessed for hematologic, hepatic, and renal function. Response was evaluated by RECIST, International Society of Pediatric Oncology Europe Neuroblastoma-like score, change in PET uptake, and quantitative PET parameters (SUVmax, SUVpeak, metabolic tumor volume, total lesion glycolysis), as well as visual decrease in number or in visual intensity of lesions on baseline to follow-up 124I-MIBG PET/CT. Results: The average therapeutic activity was 14 GBq. Eleven of 14 patients (79%) received each more than 10 GBq. One male patient was treated with a single activity of 50 GBq. Three patients were treated with lower activities between 3.5 and 7.0 GBq. Median overall survival was 85 mo (95% CI), and median progression-free survival was 25 mo (95% CI). Four (29%) and 5 (36%) patients demonstrated response (complete response or partial response) by RECIST and functional imaging, respectively. One patient exceeded whole-body dose of 2 Gy and demonstrated grade 3 hematologic toxicity, which resolved spontaneously within 12 mo after the therapy without the need for further treatment. Three patients (21%) demonstrated transient grade 1 renal toxicity. Conclusion: 124I-MIBG dosimetry-guided high-activity 131I-MIBG therapy in patients with advanced pheochromocytoma or neuroblastoma resulted in durable responses with a low rate of manageable adverse events. Efficacy of 124I-MIBG-guided activity escalation should further be assessed in a prospective setting.

Multiple low-dose radiation-induced neuronal cysteine transporter expression and oxidative stress are rescued by N-acetylcysteine in neuronal SH-SY5Y cells.

Recently, several studies have demonstrated that low-dose radiation (LDR) therapy has positively impacts on the treatment of Alzheimer's disease (AD). LDR suppresses the production of pro-neuroinflammation molecules and improves cognitive function in AD. However, it is unclear whether direct exposure to LDR causes beneficial effects and what mechanism is involved in neuronal cells. In this study, we first determined the effect of high-dose radiation (HDR) alone on C6 cells and SH-SY5Y cells. We found that SH-SY5Y cells were more vulnerable than C6 cells to HDR. Moreover, in neuronal SH-SY5Y cells exposed to single or multiple LDR, N-type cells showed decreased cell viability with increasing radiation exposure time and frequency, but S-type cells were unaffected. Multiple LDR increased proapoptotic molecules such as p53, Bax and cleaved caspase-3, and decreased anti-apoptotic molecule (Bcl2). Multiple LDR also generated free radicals in neuronal SH-SY5Y cells. We detected a change in the expression of the neuronal cysteine transporter EAAC1. Pretreatment with N-acetylcysteine (NAC) rescued the increased in EAAC1 expression and the generation of ROS in neuronal SH-SY5Y cells after multiple LDR. Furthermore, we verified whether the increased in EAAC1 expression induces cell defense or cell death promotion signaling. We showed that transient overexpression of EAAC1 reduced the multiple LDR-induced p53 overexpression in neuronal SH-SY5Y cells. Our results indicate that neuronal cells can be injured by increased production of ROS not only by HDR but also by multiple LDR, which suggests that combination treatment with anti-free radical agents such as NAC may be useful in multiple LDR therapy.

Calreticulin Expression Controls Cellular Redox, Stemness, and Radiosensitivity to Function as a Novel Adjuvant for Radiotherapy in Neuroblastoma.

Radiotherapy (RT) is currently only used in children with high-risk neuroblastoma (NB) due to concerns of long-term side effects as well as lack of effective adjuvant. Calreticulin (CALR) has served distinct physiological roles in cancer malignancies; nonetheless, impact of radiation on chaperones and molecular roles they play remains largely unknown. In present study, we systemically analyzed correlation between CALR and NB cells of different malignancies to investigate potential role of CALR in mediating radioresistance of NB. Our data revealed that more malignant NB cells are correlated to lower CALR expression, greater radioresistance, and elevated stemness as indicated by colony- and neurospheroid-forming abilities and vice versa. Of note, manipulating CALR expression in NB cells of varying endogenous CALR expression manifested changes in not only stemness but also radioresistant properties of those NB cells. Further, CALR overexpression resulted in greatly enhanced ROS and led to increased secretion of proinflammatory cytokines. Importantly, growth of NB tumors was significantly hampered by CALR overexpression and was synergistically ablated when RT was also administered. Collectively, our current study unraveled a new notion of utilizing CALR expression in malignant NB to diminish cancer stemness and mitigate radioresistance to achieve favorable therapeutic outcome for NB.

Nurses' Experiences Caring for Children With Neuroblastoma Receiving 131I-Metaiodobenzylguanidine Therapy: A Qualitative Descriptive Study.

Background: Neuroblastoma, the most common extra-cranial solid tumor found in children, carries a high mortality rate due to challenges with metastatic disease at diagnoses and relapse. 131I-Metaiodobenzylguanidine (I-MIBG) therapy provides targeted radiotherapy to treat neuroblastoma, but requires children to be isolated for radiation exposure, with limited access to the healthcare team while hospitalized. There is minimal research outlining the nurses' perspectives on caring for this patient population. Therefore, the aim of this study was to describe the nurses' experiences caring for children receiving 131I-MIBG therapy, focusing on nursing care, challenges, radiation exposure, and preparation. Methods: Ten nurses were recruited using purposeful sampling for this qualitative descriptive study. Semi-structured interview guides and conventional qualitative content analysis guided the data collection and analysis. Results: Nurses overwhelmingly felt isolated from their patients and a decreased sense of connection with the child. Although nurses felt prepared, they had more anxiety with the first patient experience and identified that parent engagement was essential. Overall, nurses shared they had support from written materials outlining the protocols, and members of the multidisciplinary team. More concern for radiation exposure was expressed by nurses of childbearing age and with handling bodily fluids. Discussion: Findings suggest that nurses would benefit from simulation experiences to help prepare for radiation exposure safety, strategies to engage the family in the child's care, and interacting with a child in single-room isolation. Because programs differ around the US, additional research exploring nurses' experiences is warranted to evaluate the best successes in providing 131I-MIBG therapy.

Overcoming inter-observer planning variability in target volume contouring and dose planning for high-risk neuroblastoma - a European multicenter effort of the SIOPEN radiotherapy committee.

BACKGROUND AND PURPOSE: To establish an international quality standard for contouring and planning for high-risk neuroblastoma within the prospective High-Risk Neuroblastoma Study 2 of SIOP-Europe-Neuroblastoma (SIOPEN HR-NBL2), which includes a randomized question on dose escalation for residual disease. MATERIALS AND METHODS: Data on four patients with high-risk neuroblastoma were selected and distributed to the radiotherapy committee of the HR-NBL2 study for independent contouring and planning. Differences in contouring were analyzed using apparent and kappa-corrected agreement. Plans were analyzed regarding the dose-volume histogram metrics. Results were discussed among experts and agreement was obtained. RESULTS: Substantial agreement was found for contouring of the heart (0.64), liver (0.70), left lung (0.74), and right lung (0.74). For contouring of the gastrointestinal tract (0.54), left kidney (0.60), and right kidney (0.59) moderate agreement was obtained. For target volume delineation, agreement for preoperative tumour extent was moderate (0.42), for CTV fair (0.35) and only low (0.06) for residual tumour, respectively. The dose planning strategies appeared to be relatively homogeneous among all experts. CONCLUSION: Considerable variability was found for the delineation of target volumes, particularly the boost volume, whereas the contouring of the organs at risk and the planning strategy were reasonably consistent. In order to obtain reliable results from the randomized HR-NBL2 trial, standardization of target volume delineation based on adequate imaging is crucial.

The radiation response measurement of a single and multiple cell ionization of neuroblastoma cells by infrared laser trap.

Neuroblastoma (NB) is a common type of cancer found mostly in infants and arising from the immature neural crest cells of the sympathetic nervous system. Using laser trapping (LT) technique, the present work contributes to advancing radiotherapy (RT), a leading treatment method for cancer. A single, 2-cells, 3-cells, 4-cells, and 5-cells were trapped using the high-intensity gradient infrared laser at 1064 nm and allowed to become ionized. In this work, a systematic study of Threshold Ionization Energy (TIE) and Threshold Radiation Dose (TRD) versus mass for both single and multi-cell ionization using laser trapping (LT) techniques on NB is presented. The results show that TIE increased as the mass of cells increased, meanwhile TRD decreased with the increase of cell mass. We observed an inverse correlation between TRD and cell mass. We demonstrate how to compute the maximum radiation dosage for cell death using the LT technique. Results show a possible blueprint for computing the TRD in vivo. The use of multiple cell ionization to determine radiation dosage along with better data accuracy concerning the tumor size and density will have profound implications for radiation dosimetry. The diminution in TRD becomes more significant in multiple cell ionization as we see in TRD vs the number of cells entering the trap. This is due to the chain effect generated by radiation and the absorption by water molecules at 1064 nm. This result provides us with better insight into the optimization of the therapeutic ratio.

Modulation of Radiation Biomarkers in a Randomized Phase II Study of 131I-MIBG With or Without Radiation Sensitizers for Relapsed or Refractory Neuroblastoma.

PURPOSE: 131I-metaiodobenzylguanidine (131I-MIBG) has demonstrated efficacy as a single agent in neuroblastoma. Recent trials have focused on 131I-MIBG combination strategies, though little is known about the effect of putative radiosensitizers on biological markers of radiation exposure. METHODS AND MATERIALS: NANT2011-01 evaluated 131I-MIBG therapy alone (arm A) or in combination with vincristine/irinotecan (arm B) or vorinostat (arm C) for patients with relapsed or refractory neuroblastoma. Blood samples were collected before and after 131I-MIBG infusion to determine levels of radiation-associated biomarkers (transcript and protein). The association of biomarker with treatment arm, clinical response, and treatment toxicity was analyzed. RESULTS: The cohort included 99 patients who had at least 1 biomarker available for analysis. Significant modulation in most biomarkers between baseline, 72, and 96 hours following 131I-MIBG was observed. Patients in arm C had the lowest degree of modulation in FLT3 ligand protein. Lower baseline BCL2 transcript levels were associated with higher overall response. Patients with greater increases in FLT3 ligand at 96 hours after 131I-MIBG therapy were significantly more likely to have grade 4 thrombocytopenia. Peripheral blood gene expression of the BCL2 family of apoptotic markers (BCL2L1 and BAX transcripts) was significantly associated with grade 4 hematologic toxicity. RNA sequencing demonstrated little overlap in the top modulated peripheral blood transcripts between randomized arms. CONCLUSIONS: Peripheral blood biomarkers relevant to radiation exposure demonstrate significant modulation after 131I-MIBG and concomitant radiation sensitizers affect extent of modulation. Biomarkers related to hematopoietic damage and apoptosis were associated with hematologic toxicity.

Haematological and renal toxicity of radiation therapy in neuroblastoma paediatric patients.

PURPOSE: The objective of this study was to evaluate the renal and hematologic toxicity in paediatric patients with adrenal high-risk neuroblastoma who have received radiation therapy (RT) as part of radical treatment. MATERIAL AND METHODS: Pediatric patients diagnosed with high-risk adrenal neuroblastoma who received RT as part of the definitive treatment between January 2004 and May 2020 in a single institution were selected. Complete blood counts (CBC) and creatinine clearance (CrCl) pre-RT and post-RT were compared through the Wilcoxon signed-rank test and correlated with survival analysis by Cox regression. RESULTS: Forty-two children with a median age of 3 years at diagnosis and 2.8 years of follow-up were selected. A significant and acute decrease in lymphocytes was found (p = 0.002) 1 month from RT. Patients with a drop higher than 50% of the previous value experimented a significant reduction in overall survival (55 vs 10%; p = 0.031). At the end of the follow-up, a significant increase in all blood counts was observed. With respect to renal function, an acute and significant decrease in CrCl was observed tin patients younger than 4 years who received RT (p = 0.013). However, it was not clinically relevant. CONCLUSION: Our data suggest that acute lymphopenia occurs after RT and could be associated with a poorer prognosis. Other blood counts are reduced after RT and all of them are in physiological range at the end of follow-up. Our cohort presented excellent renal outcomes without any case of chronic renal dysfunction.

Renal function in abdominal neuroblastoma patients undergoing proton radiotherapy.

BACKGROUND: The purpose of this study is to analyze renal function outcomes in abdominal neuroblastoma patients undergoing proton therapy (PT). PROCEDURE: From 2011 to 2019, two single-institution Institutional Review Board-approved protocols prospectively enrolled neuroblastoma patients for data collection. To assess renal function, serum creatinine (Cr), blood urea nitrogen (BUN), and creatinine clearance (CrCl) before proton therapy (pre-PT) were compared with the values at last follow-up. RESULTS: A total of 30 children with abdominal neuroblastoma with median age 3.5 years (range, 0.9-9.1) at time of PT were included in this study. All patients underwent chemotherapy and resection of primary tumor prior to PT. Two patients required radical nephrectomy. Median follow-up after PT was 35 months. Mean dose to ipsilateral and contralateral kidney was 13.9 and 5.4 Gy, respectively. No patients developed hypertension or renal dysfunction during follow-up. There was no statistically significant change in serum BUN (p = .508), CrCl (p = .280), or eGFR (p = .246) between pre-PT and last follow-up. CONCLUSION: At a median follow-up of almost 3 years, renal toxicity was uncommon after PT. Longer follow-up and larger patient cohort data are needed to further assess impact of PT on renal function in this population.

Clinical outcomes of pediatric patients receiving multimodality treatment of second central nervous system relapse of neuroblastoma.

BACKGROUND: In high-risk neuroblastoma, multimodality therapy including craniospinal irradiation (CSI) is effective for central nervous system (CNS) relapse. Management of post-CSI CNS relapse is not clearly defined. PROCEDURE: Pediatric patients with neuroblastoma treated with CSI between 2000 and 2019 were identified. Treatment of initial CNS disease (e.g., CSI, intraventricular compartmental radioimmunotherapy [cRIT] with 131 I-monoclonal antibodies targeting GD2 or B7H3) and management of post-CSI CNS relapse ("second CNS relapse") were characterized. Cox proportional hazards models to evaluate factors associated with third CNS relapse and overall survival (OS) were used. RESULTS: Of 128 patients (65% male, median age 4 years), 19 (15%) received CSI with protons and 115 (90%) had a boost. Most (103, 81%) received cRIT, associated with improved OS (hazard ratio [HR] 0.3, 95% confidence interval [CI]: 0.1-0.5, p < .001). Forty (31%) developed a second CNS relapse, associated with worse OS (1-year OS 32.5%, 95% CI: 19-47; HR 3.8; 95% CI: 2.4-6.0, p < .001), and more likely if the leptomeninges were initially involved (HR 2.5, 95% CI: 1.3-4.9, p = .006). Median time to second CNS relapse was 6.8 months and 51% occurred outside the CSI boost field. Twenty-five (63%) patients underwent reirradiation, most peri-operatively (18, 45%) with focal hypofractionation. Eight (20%) patients with second CNS relapse received cRIT, associated with improved OS (HR 0.1; 95% CI: 0.1-0.4, p < .001). CONCLUSIONS: CNS relapse after CSI for neuroblastoma portends a poor prognosis. Surgery with hypofractionated radiotherapy was the most common treatment. Acknowledging the potential for selection bias, receipt of cRIT both at first and second CNS relapse was associated with improved survival. This finding necessitates further investigation.