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Feasibility of Administering High-Dose (131) I-MIBG Therapy to Children with High-Risk Neuroblastoma Without Lead-Lined Rooms.

ABSTRACT: Although (131) I-metaiodobenzylguanidine ((131) I-MIBG) therapy is increasingly used for children with high-risk neuroblastoma, a paucity of lead-lined rooms limits its wider use. We implemented radiation safety procedures to comply with New York City Department of Health and Mental Hygiene regulations for therapeutic radioisotopes and administered (131) I-MIBG using rolling lead shields.Patients received 0.67 GBq (18 mCi)/kg/dose (131) I-MIBG on an IRB-approved protocol (NCT00107289). Radiation safety procedures included private room with installation of rolling lead shields to maintain area dose rates ?0.02 mSv/hr outside the room, patient isolation until dose rate <0.07 mSv/hr at 1 m, and retention of a urinary catheter with collection of urine in lead boxes. Parents were permitted in the patient's room behind lead shields, trained in radiation safety principles, and given real-time radiation monitors.Records on 16 (131) I-MIBG infusions among 10 patients (age 2-11 years) were reviewed. Mean ± standard deviation (131) I-MIBG administered was 17.67 ± 11.14 (range: 6.11-40.59) GBq. Mean maximum dose rates outside treatment rooms were 0.013 ± 0.008 mSv/hr. Median time-to-discharge was 3 days post-(131) I-MIBG. Exposure of medical staff and parents was below regulatory limits. Cumulative whole-body dose received by the physician, nurse, and radiation safety officer during treatment was 0.098 ± 0.058, 0.056 ± 0.045, 0.055 ± 0.050 mSv, respectively. Cumulative exposure to parents was 0.978 ± 0.579 mSv. Estimated annual radiation exposure for inpatient nurses was 0.096 ± 0.034 mSv/nurse. Thyroid bioassay scans on all medical personnel showed less than detectable activity. Contamination surveys were <200 dpm/100 cm(2) .The use of rolling lead shields and implementation of specific radiation safety procedures allows administration of high-dose (131) I-MIBG and may broaden its use without dedicated lead-lined rooms.

SUBMITTER: Chu BP

PROVIDER: S-EPMC4801722 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Feasibility of Administering High-Dose (131) I-MIBG Therapy to Children with High-Risk Neuroblastoma Without Lead-Lined Rooms.

Chu Bae P BP Horan Christopher C Basu Ellen E Dauer Lawrence L Williamson Matthew M Carrasquillo Jorge A JA Pandit-Taskar Neeta N Modak Shakeel S

Pediatric blood & cancer 20160115 5

<h4>Background</h4>Although (131) I-metaiodobenzylguanidine ((131) I-MIBG) therapy is increasingly used for children with high-risk neuroblastoma, a paucity of lead-lined rooms limits its wider use. We implemented radiation safety procedures to comply with New York City Department of Health and Mental Hygiene regulations for therapeutic radioisotopes and administered (131) I-MIBG using rolling lead shields.<h4>Procedure</h4>Patients received 0.67 GBq (18 mCi)/kg/dose (131) I-MIBG on an IRB-appro ...[more]

PMID: 26773712

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Project description:Calculating internal dose from therapeutic radionuclides currently relies on estimates made from multiple radiation exposure measurements, converted to absorbed dose in specific organs using the Medical Internal Radiation Dose (MIRD) schema. As an alternative biodosimetric approach, we utilized gene expression analysis of whole blood from patients receiving targeted radiotherapy. Collected blood from patients with relapsed or refractory neuroblastoma who received (131)I-labeled metaiodobenzylguanidine ((131)I-mIBG) at the University of California San Francisco (UCSF) was used to compare calculated internal dose with the modulation of chosen gene expression. A total of 40 patients, median age 9 years, had blood drawn at baseline, 72 and 96 h after (131)I-mIBG infusion. Whole-body absorbed dose was calculated for each patient based on the cumulated activity determined from injected mIBG activity and patient-specific time-activity curves combined with (131)I whole-body S factors. We then assessed transcripts that were the most significant for describing the mixed therapeutic treatments over time using real-time polymerase chain reaction (RT-PCR). Modulation was evaluated statistically using multiple regression analysis for data at 0, 72 and 96 h. A total of 10 genes were analyzed across 40 patients: CDKN1A; FDXR; GADD45A; BCLXL; STAT5B; BAX; BCL2; DDB2; XPC; and MDM2. Six genes were significantly modulated upon exposure to (131)I-mIBG at 72 h, as well as at 96 h. Four genes varied significantly with absorbed dose when controlling for time. A gene expression biodosimetry model was developed to predict absorbed dose based on modulation of gene transcripts within whole blood. Three transcripts explained over 98% of the variance in the modulation of gene expression over the 96 h (CDKN1A, BAX and DDB2). To our knowledge, this is a novel study, which uses whole blood collected from patients treated with a radiopharmaceutical, to characterize biomarkers that may be useful for biodosimetry. Our data indicate that transcripts, which have been previously identified as biomarkers of external exposures in ex vivo whole blood and in vivo radiotherapy patients, are also good early indicators of internal exposure. However, for internal sources of radiation, the biokinetics and physical decay of the radionuclide strongly influence the gene expression.

Project description:BackgroundThe therapeutic use of [131I]meta-iodobenzylguanidine ([131I]MIBG) is often accompanied by hematological toxicity, mainly consisting of persistent and severe thrombocytopenia. While MIBG accumulates in neuroblastoma cells via selective uptake by the norepinephrine transporter (NET), the serotonin transporter (SERT) is responsible for cellular uptake of MIBG in platelets. In this study, we have investigated whether pharmacological intervention with selective serotonin reuptake inhibitors (SSRIs) may prevent radiotoxic MIBG uptake in platelets without affecting neuroblastoma tumor uptake.MethodsTo determine the transport kinetics of SERT for [125I]MIBG, HEK293 cells were transfected with SERT and uptake assays were conducted. Next, a panel of seven SSRIs was tested in vitro for their inhibitory potency on the uptake of [125I]MIBG in isolated human platelets and in cultured neuroblastoma cells. We investigated in vivo the efficacy of the four best performing SSRIs on the accumulation of [125I]MIBG in nude mice bearing subcutaneous neuroblastoma xenografts. In ex vivo experiments, the diluted plasma of mice treated with SSRIs was added to isolated human platelets to assess the effect on [125I]MIBG uptake.ResultsSERT performed as a low-affinity transporter of [125I]MIBG in comparison with NET (Km = 9.7??M and 0.49??M, respectively). Paroxetine was the most potent uptake inhibitor of both serotonin (IC50 = 0.6?nM) and MIBG (IC50 = 0.2?nM) in platelets. Citalopram was the most selective SERT inhibitor of [125I]MIBG uptake, with high SERT affinity in platelets (IC50 = 7.8?nM) and low NET affinity in neuroblastoma cells (IC50 = 11.940?nM). The in vivo tested SSRIs (citalopram, fluvoxamine, sertraline, and paroxetine) had no effect on [125I]MIBG uptake levels in neuroblastoma xenografts. In contrast, treatment with desipramine, a NET selective inhibitor, resulted in profoundly decreased xenograft [125I]MIBG levels (p < 0.0001). In ex vivo [125I]MIBG uptake experiments, 100- and 34-fold diluted murine plasma of mice treated with citalopram added to isolated human platelets led to a decrease in MIBG uptake of 54-76%, respectively.ConclusionOur study demonstrates for the first time that SSRIs selectively inhibit MIBG uptake in platelets without affecting MIBG accumulation in an in vivo neuroblastoma model. The concomitant application of citalopram during [131I]MIBG therapy seems a promising strategy to prevent thrombocytopenia in neuroblastoma patients.

Project description:Abstract Introduction: Iobenguane scan positive cancers including pheochromocytoma/paraganglioma (PPGL), neuroblastoma, and gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are heterogeneous tumors that arise from neuroendocrine cells. Recently, high-specific-activity I-131 meta-iodobenzylguanidine (HSA I-131 MIBG, AZEDRA®) was approved in the US for treatment of adult and pediatric patients 12 years and older with iobenguane scan positive, unresectable, locally advanced or metastatic PPGL. We present a pooled analysis of all available clinical trials to further assess the safety profile of HSA I-131 MIBG. Methods: 118 patients from four HSA I-131 MIBG clinical trials (NCT00339131; NCT00458952; NCT00874614; NCT00659984) were included in a pooled analysis for safety assessments. Adverse events (AEs), laboratory tests, number and quantity of HSA I-131 MIBG doses, hypertensive events, blood pressure (BP), heart rate, ECG, and AEs of special interest (AESI) were analyzed using descriptive statistics. Results: Gastrointestinal (GI) toxicities, especially nausea and vomiting, were the most common AEs associated with HSA I-131 MIBG. GI toxicities were not reported after dosimetry doses. GI, blood and lymphatic system, and vascular disorders were higher in PPGL than in neuroblastoma after therapeutic dose 1 when compared to therapeutic dose 2. The incidence of potentially clinically significant changes in BP was similar following dosimetric and therapeutic doses and are consistent with the underlying hypertension associated with PPGL. No spike in systolic and diastolic BP was observed within the first 4 hours of HSA I-131 MIBG administration, and there were no acute hypertensive crises following dosing. A possibly drug-related mild increase in BP within 48 hours of therapeutic dosing was observed in 1 subject with PPGL. Variations in heart rate (>20 beats/min) were higher after therapeutic dose 1 than after other doses. No clinically significant trends were seen in mean ECG results or mean changes from baseline. All patients received at least one concomitant medication. About 40% of patients received β-blockers, 39% α-blockers, and about 27% other peripheral vasodilators. 87.3% of patients reported an AESI, defined as AEs that are related to the acute and/or chronic effects of radiation toxicity seen any time post dosing. The most common AESIs were nausea (66.1%), thrombocytopenia (50.0%), fatigue (50.0%), neutropenia (42.4%), and diarrhea (22.9%). The incidence of most AESIs were similar after each therapeutic dose. Conclusions: HSA I-131 MIBG demonstrated a favorable safety profile in iobenguane scan positive cancers. AEs followed an expected pattern comparable to other radioactive therapeutic agents. Most cardiovascular events, including hypertensive events mostly commonly observed in PPGL, were not considered related to HSA I-131 MIBG.

Dataset Information

Feasibility of Administering High-Dose (131) I-MIBG Therapy to Children with High-Risk Neuroblastoma Without Lead-Lined Rooms.

Publications

Feasibility of Administering High-Dose (131) I-MIBG Therapy to Children with High-Risk Neuroblastoma Without Lead-Lined Rooms.

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