MIBG Therapy Research Articles

Quantification and dosimetry of small volumes including associated uncertainty estimation

BackgroundAccurate quantification of radioactivity in a source of interest relies on accurate registration between SPECT and anatomical images, and appropriate correction of partial volume effects (PVEs). For small volumes, exact registration between the two imaging modalities and recovery factors used to correct for PVE are unreliable. There is currently no guidance relating to quantification or the associated uncertainty estimation for small volumes.Material and methodsA method for quantification of small sources of interest is proposed, which uses multiple oversized volumes of interest. The method was applied to three Na[131I]I activity distributions where a Na[131I]I capsule was situated within a cylindrical phantom containing either zero background, uniform background or non-uniform background and to a scenario with small lesions placed in an anthropomorphic phantom. The Na[131I]I capsule and lesions were quantified using the proposed method and compared with measurements made using two alternative quantification methods. The proposed method was also applied to assess the absorbed dose delivered to a bone metastasis following [131I]mIBG therapy for neuroblastoma including the associated uncertainty estimation.ResultsThe method is accurate across a range of activities and in varied radioactivity distributions. Median percentage errors using the proposed method in no background, uniform backgrounds and non-uniform backgrounds were − 0.4%, − 0.3% and 1.7% with median associated uncertainties of 1.4%, 1.4% and 1.6%, respectively. The technique is more accurate and robust when compared to currently available alternative methods.ConclusionsThe proposed method provides a reliable and accurate method for quantification of sources of interest, which are less than three times the spatial resolution of the imaging system. The method may be of use in absorbed dose calculation in cases of bone metastasis, lung metastasis or thyroid remnants.

Clinical and biologic predictors of response to MIBG therapy: A report from the new approaches to neuroblastoma therapy (NANT) consortium.

e22003 Background: 131I-metaiodobenzylguanidine (MIBG) remains one of the most active agents for neuroblastoma. The clinical and biologic predictors of response to MIBG therapy have not been systematically characterized in a recent era trial. Methods: Patients 1-30 years were enrolled on the randomized phase 2 trial of MIBG vs. MIBG/vincristine/irinotecan vs. MIBG/vorinostat for relapsed/refractory neuroblastoma (NANT2011-01, NCT02035137) between 2014-2019. Data were compared between those who had an objective response (partial response or better using NANT response criteria) to MIBG after the first cycle and those who did not according to clinical features (age at study enrollment; sex; response to prior therapy; prior receipt of MIBG therapy; bone marrow involvement at study enrollment; and measurable disease status at study enrollment) and MYCN status. Univariate analyses were performed using odds ratio and Fisher exact tests. Multivariate logistic regression analysis was used to identify predictors of response to MIBG therapy while controlling for key confounders. Results: 105 response-evaluable patients were included in the analytic cohort. Across the 3 study arms, 20% (21/105) had an objective response to the treatment. Only measurable disease status was statistically significantly associated with response to therapy, with higher rates of response among patients without measurable disease at study enrollment (30% vs. 13%, p = 0.049). Response to prior therapy, sex, MYCN status, and measurable disease status showed univariate odds ratios of 2 or greater (Table). Only measurable disease status remained statistically significant in the multivariate analysis (p = 0.043, Table). Conclusions: Patients without measurable disease have a higher rate of objective responses to MIBG therapy. Understanding these differences based upon predictors of response may help to inform stratification methods for future MIBG clinical trials.[Table: see text]

I-131 metaiodobenzylguanidine therapy is a significant treatment option for pheochromocytoma and paraganglioma.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours of chromaffin cells. Several modalities are currently available to treat patients with PPGL. These treatment modalities include surgery, chemotherapy, molecular targeted therapy and radiopharmaceuticals. I-131 metaiodobenzylguanidine (mIBG), a classic radiopharmaceutical, can be taken up through specific receptors and sited into many, but not all, PPGL cells. Many studies have investigated the efficacy and toxicity of I-131 mIBG therapy. These studies reported significant results in terms of objective, hormonal and symptomatic responses as well as tolerable toxicities in patients. This article reviews the reported experiences of patients who underwent I-131 mIBG therapy for PPGL with a focus on functions and deficiencies of the therapy.

Phase I study of 131I-MIBG with dinutuximab for patients with relapsed or refractory neuroblastoma: A report from the new approaches to neuroblastoma therapy (NANT) consortium.

10038 Background: 131I-metaiodobenzylguanidine (MIBG) is one of the most active salvage therapies for patients with relapsed or refractory (R/R) high-risk neuroblastoma (HRNB). Preclinical neuroblastoma studies show cooperative effects when radiation is combined with anti-GD2 monoclonal antibody (mAb). We hypothesized that MIBG would synergize with the anti-GD2 mAb dinutuximab to provide improved anti-tumor responses. The primary aims of Part A of this study were to determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) of MIBG administered with dinutuximab in children with R/R HRNB and to define and describe the toxicities. Methods: Patients 1-29 years of age with R/R HRNB who had MIBG uptake in ≥ 1 site were eligible. Prior anti-GD2 mAb therapy was allowed provided it was not administered with MIBG and not permanently discontinued due to toxicity. One prior MIBG therapy was allowed. MIBG was administered on day 1 at one of three dose levels (DLs): 12, 15, and 18 mCi/kg (DL1-DL3, respectively) with an expansion cohort at the RP2D. Doses were escalated using a rolling six design starting at DL1. The primary endpoint was dose-limiting toxicity (DLT) during course 1. Dinutuximab (17.5 mg/m2/dose) was administered intravenously on days 8-11 and 29-32 and GM-CSF (250 mcg/m2/dose) subcutaneously on days 8-17 and 29-38. Autologous peripheral blood stem cells were infused to all patients on day 15 (+/- 2 days). A maximum of 2 courses per patient were allowed. Response rate was defined as the proportion of patients with a complete or partial response. Results: Thirty-one patients were enrolled. Fourteen were evaluable for dose escalation (4 on DL1, 4 on DL2, and 6 on DL3); 5 evaluable patients were treated in the DL3 expansion. The median age was 7.4 years (range: 3.1 – 22.0) and 20 (65%) were male. Twenty-seven (87%) patients had previously received a median of 8.5 cycles of chemoimmunotherapy (range: 2 – 21). Eight patients previously progressed while receiving anti-GD2 mAb including 7 in DL3. Five (16%) patients had previously received MIBG. No patient at any dose level experienced DLT. Common grade 3/4 treatment-related toxicities were expected hematologic toxicities attributable to MIBG and non-hematologic toxicities attributable to dinutuximab or GM-CSF. Among 26 response-evaluable patients, the centrally-confirmed response rate was 31% across all dose levels: 2/6 (33%) in DL1, 3/5 (60%) in DL2, and 3/15 (20%) in DL3. There were 3 minor responses, 1 in DL2 and 2 in DL3. Conclusions: The RP2D of MIBG in combination with standard doses of dinutuximab and GM-CSF is 18 mCi/kg. This radioimmunotherapy regimen is well-tolerated without additive toxicity. Preliminary efficacy data are encouraging in this heavily pre-treated patient population. A phase 2 trial of this regimen is planned in patients with R/R HRNB. Clinical trial information: NCT03332667.

Addition of chemo-immunotherapy to standard induction chemotherapy for high-risk neuroblastoma.

e22009 Background: The outcome of high risk neuroblastoma (HR-NBL) remains poor despite the use of multimodality approach. Improved end-induction response (EOI-R) after standard induction chemotherapy (SIC) is associated with longer survival1. Post-induction curie score (CS) > 2 is associated with inferior outcome2. The combination of chemo immunotherapy (CIT) with irinotecan/temodar/dinutuximab/GMCSF (ITDG) demonstrated an objective response of 53% in patients with relapsed/refractory disease3, however, the specific impact of the addition of CIT in improving EOI-R permitting continuation of therapy with surgery, ASCT, radiotherapy, and consolidative immunotherapy has not been systematically evaluated. Here we present the outcome of 8 patients who received SIC followed by CIT that achieved a CS < 2 prior to ASCT and were able to complete multimodality therapy. Methods: Single-site retrospective review of HR-NBL patients that failed to achieve adequate EOI-R after SIC during 2016 – 2021. Results: 21 patients with HR-NBL treated with SIC were identified. 8/21 patients (38%) failed to achieve adequate EOI-R: 3 patients were deemed to have partial response (PR), and unresectable tumors after 5 cycles SIC, 3 patients achieved complete remission (CR) of primary tumor but had CS > 2 at the EOI, 1 patient had stable disease (SD) with CS > 2 after 4 cycles of SIC, and 1 patient progressive disease (PD), and CS > 2 after 3 cycles of SIC. All patients received CIT with ITDG (2 – 6 cycles). The 3 patients with unresectable tumors, and 2 patients with CS > 2 achieved adequate response with CS < 2 after 2-4 CIT cycles. They were able to undergo resection and achieve CR. The patient with PD achieved CR of primary tumor after 2 ITDG-cycles allowing surgical resection, and ultimately achieved a CS = 0 after 4 additional ITDG-cycles. The patient with SD received 6 ITDG-cycles but remain SD with CS = 24 and went on to receive MIBG therapy. 5/8 patients were able to proceed with ASCT, radiation and, post consolidative immunotherapy. One patient did not receive ASCT due to surgery-related acute kidney injury but completed radiation and consolidative immunotherapy. Post CIT progression free survival (PFS) ranges from 4 – 56 months. Three patients are free of disease at 17, 38 and 36 months after completing post consolidation immunotherapy, 3 patients completed post consolidation immunotherapy and 1 has received 2 cycles. Conclusions: This short retrospective observational analysis demonstrate that the addition of CIT with ITDG in children with HR-NBL with less than PR, SD and/or PD after SIC is feasible, aids in achieving end-induction goals of CR and CS < 2, and permits many patients to complete consolidative ASCT, radiation, and post-consolidation immunotherapy. While the COG is planning to evaluate addition of ITDG in induction therapy, patients currently being treated off study may benefit from the addition of ITDG after SIC to improve EOI-R.

Embracing Inpatient Radiopharmaceutical Therapies in Radiation Oncology: An Example With Commissioning Pediatric I-131 MIBG Therapy

<h3>Purpose/Objective(s)</h3> Radiopharmaceutical therapy is rapidly expanding in radiation oncology and nuclear medicine. Iodine-131 metaiodobenzylguanidine (I-131 MIBG) is an inpatient therapy involving long infusion times and special consideration for radiation exposure and contamination control. In this study, we outline our process for commissioning pediatric I-131 MIBG therapy with a multidisciplinary team and perform a failure modes and effects analysis to assess the robustness of our procedures. <h3>Materials/Methods</h3> To commission pediatric I-131 MIBG therapy, we (1) created a multidisciplinary team with the appropriate skills, (2) located a space that met the needs of this intensive inpatient therapy, and (3) developed procedures that maximized safety. We identified failure modes (FM) from room design to patient/room release and scored them (1-10) according to their risk for occurrence (O), severity (S), and lack of detectability (D), per AAPM Task Group 100. The risk-priority number (RPN) is the product of these scores and identifies the FMs with the greatest risk. <h3>Results</h3> Our multidisciplinary team includes an authorized user (radiation oncologist/nuclear medicine physician), pediatric oncologists, radiation therapists, nurses, therapy medical physicists, and radiation safety staff. The space has a dedicated restroom and shower with appropriate plumbing, shielding built into the patient room/restroom construction, appropriate ventilation/filtration, and enough space for the patient, the infusion team (3-5), equipment, and mobile shields. The procedures meet regulatory and institutional safety standards and allow for appropriate radiation exposure and contamination control. 149 FMs were identified. The FMs with the greatest RPN were related to training deficiencies: (1) training of staff was inadequate (O = 5, S = 8, D = 4, RPN = 160), (2) caregivers did not understand radiation safety training (O = 5, S = 7, D = 4, RPN = 140), and (3) saline bag line and other dose lines (if multiple vials) were not clamped properly during dose infusion (O = 4, S = 8, D = 4, RPN = 128). 36/149 (24%) FMs had a high severity (S≥7). Of those, 11 (7% of all FMs) had a moderate risk of occurrence or going undetected (O or D > 3 but < 7) and none had a high risk of occurrence or going undetected (O or D ≥7). The remaining 25 high severity FMs were associated with commissioning, training, and room design/construction (14/25); drug ordering and patient preparation (7/25); and dose infusion (4/25). We attribute these FMs' relatively low risk of occurrence or going undetected to extensive checklists and redundant procedures. <h3>Conclusion</h3> Pediatric I-131 MIBG therapy is a complex treatment that requires careful consideration during commissioning. With a properly trained multidisciplinary team, robust procedures and checklists, and appropriate resources, it can be implemented safely and effectively.

A safety and feasibility trial of 131 I-MIBG in newly diagnosed high-risk neuroblastoma: A Children's Oncology Group study.

131 I-meta-iodobenzylguanidine (131 I-MIBG) is effective in relapsed neuroblastoma. The Children's Oncology Group (COG) conducted a pilot study (NCT01175356) to assess tolerability and feasibility of induction chemotherapy followed by 131 I- MIBG therapy and myeloablative busulfan/melphalan (Bu/Mel) in patients with newly diagnosed high-risk neuroblastoma. Patients with MIBG-avid high-risk neuroblastoma were eligible. After the first two patients to receive protocol therapy developed severe sinusoidal obstruction syndrome (SOS), the trial was re-designed to include an 131 I-MIBG dose escalation (12, 15, and 18 mCi/kg), with a required 10-week gap before Bu/Mel administration. Patients who completed induction chemotherapy were evaluable for assessment of 131 I-MIBG feasibility; those who completed 131 I-MIBG therapy were evaluable for assessment of 131 I-MIBG + Bu/Mel feasibility. Fifty-nine of 68 patients (86.8%) who completed induction chemotherapy received 131 I-MIBG. Thirty-seven of 45 patients (82.2%) evaluable for 131 I-MIBG + Bu/Mel received this combination. Among those who received 131 I-MIBG after revision of the study design, one patient per dose level developed severe SOS. Rates of moderate to severe SOS at 12, 15, and 18 mCi/kg were 33.3%, 23.5%, and 25.0%, respectively. There was one toxic death. The 131 I-MIBG and 131 I-MIBG+Bu/Mel feasibility rates at the 15 mCi/kg dose level designated for further study were 96.7% (95% CI: 83.3%-99.4%) and 81.0% (95% CI: 60.0%-92.3%). This pilot trial demonstrated feasibility and tolerability of administering 131 I-MIBG followed by myeloablative therapy with Bu/Mel to newly diagnosed children with high-risk neuroblastoma in a cooperative group setting, laying the groundwork for a cooperative randomized trial (NCT03126916) testing the addition of 131 I-MIBG during induction therapy.

Changes in ctDNA levels after MIBG therapy in patients with relapsed or refractory neuroblastoma.

10012 Background: Circulating tumor DNA (ctDNA) is detectable in children with neuroblastoma. Less is known about how levels change during treatment and the implications of these changes. We evaluated ctDNA pre- and post- 131I-metaiodobenzylguanidine (MIBG) therapy. Methods: We utilized plasma samples from NANT11-01 (NCT02035137), a multi-center, open label, randomized phase II clinical trial evaluating MIBG with or without radiation sensitizers for patients with relapsed or refractory neuroblastoma. Plasma was collected at Baseline prior to MIBG, 72 hours (Hr72), 96 hours (Hr96), 15 days after MIBG (D15), and prior to a second course among patients without progression who received a second course (C2). Samples were analyzed for percent ctDNA levels using ultra-low passage whole genome sequencing. We evaluated associations between ctDNA findings with baseline disease measures of percent involvement in bone marrow, Curie score, and RECIST disease sum of diameters as well as overall response by NANT Response Criteria v1.2 (complete response or partial response coded as responders). Results: Eighty-four patients had a baseline sample and were included in this analysis. Of the 37 patients (44%) with detectable ctDNA at baseline, the median ctDNA level was 32% (range 3.9-91%). Baseline ctDNA levels showed a significant positive correlation with percent involvement in bone marrow (r=0.37; p=0.0004) and Curie score (r=0.26; p = 0.018), but not RECIST sum of diameters for soft tissue sites (r=0.065; p=0.56). Following therapy, the proportions of patients with detectable ctDNA were: Hr72 47% (34/73; median level 28%); Hr96 50% (26/52; median 28%); D15 33% (7/21; median 4%); and C2 14% (3/21; median 50%). Rate of ctDNA detection was similar between responders and non-responders at baseline, Hr72, and Hr96, but lower among responders at D15 and C2 (Table). Among the 21 patients with C2 data, ctDNA levels were either undetectable (n=18) or lower than Cycle 1 Baseline (n=3). Among patients with detectable baseline ctDNA, the median relative ctDNA level at Hr72 (Hr72 ctDNA/baseline ctDNA) for non-responders was 0.87 (n=24) vs. 1.16 for responders (n=7). In contrast, the median relative ctDNA level at C2 for non-responders was 0.56 (n=4) vs. 0 for responders (n=4). Conclusions: ctDNA is detectable in a substantial proportion of patients with relapsed / refractory neuroblastoma, with levels correlated with conventional measures of disease burden. Following MIBG therapy, early timepoints (Hr72 and Hr96) are less informative, whereas ctDNA becomes undetectable at D15 and C2 more commonly in patients with clinical response.[Table: see text]

Factors Modifying Outcome After MIBG Therapy in Children With Neuroblastoma-A National Retrospective Study.

BackgroundNeuroblastoma is the most common pediatric extracranial tumor with varied prognoses, but the survival of treated refractory or relapsing patients remains poor.ObjectiveThis analysis presents the outcomes of children with neuroblastoma undergoing MIBG therapy in Poland in 2006-2019.Study DesignA retrospective cohort of 55 patients with refractory or relapsed neuroblastoma treated with I-131 MIBG in Poland in 2006-2019 was analyzed. The endpoints were overall survival (OS), event-free survival (EFS), cumulative incidence (CI) of second cancers and CI of hypothyroidism. Survival curves were estimated using the Kaplan-Meier method and compared between the cohorts by the log-rank test. Cox modeling was adopted to estimate hazard ratios for OS and EFS, considering factors with P < 0.2.ResultsFifty-five patients with a median age of 78.4 months (range 18-193) with neuroblastoma underwent one or more (4 patients) courses of MIBG I-131 therapy. Fifteen patients were not administered chemotherapy, 3 children received standard-dose chemotherapy, and 37 patients were administered high-dose chemotherapy (HDCT) (busulfan-melphalan in 24 and treosulfan-based in 12 patients). Forty-six patients underwent stem cell transplantation, with autologous (35 patients), haploidentical (6), allogeneic (4), and syngeneic grafts (1). The median time from first MIBG therapy to SCT was 22 days. Children with relapsing tumors had inferior OS compared to those with primary resistant disease (21.2% vs 58.7%, p=0.0045). Survival was better in patients without MYCN gene amplification. MIBG therapy was never curative, except in patients further treated with HDCT with stem cell rescue irrespective of the donor type. 31 patients were referred for immune therapy after MIBG therapy, and the 5-year OS in this group was superior to the untreated children (55.2% vs 32.7%, p=0.003), but the difference in the 5-year EFS was not significant (25.6% vs 32.9%, p=ns). In 3 patients, a second malignancy was diagnosed. In 19.6% of treated children, hypothyroidism was diagnosed within 5 years after MIBG therapy.ConclusionMIBG therapy can be incorporated into the therapeutic strategy of relapsed or resistant neuroblastoma patients as preconditioning with HDCT rather than stand-alone therapy. Follow-up is required due to the incidence of thyroid failure and risk of second cancers.

Attenuation of Gamma Radiation Using ClearView Radiation ShieldingTM in Nuclear Power Plants, Hospitals and Radiopharmacies

Radiation protection materials, such as lead (Pb), water, concrete, steel, and aluminum, have been successfully used for decades. Although they are effective shields, these materials do have limitations. For example, lead is heavy and toxic, and water and concrete must be thick to provide significant shielding, all of which renders these materials prohibitive for certain applications. For example, the half-value layer for water to shield against Co is 30.48 cm (12"), which makes it an extremely bulky material. The development of ClearView Radiation Shielding addresses some of the limitations that are faced by traditional radiation protection shields. The product is a transparent liquid gamma radiation shield that can be fabricated in custom sizes and thicknesses. Here, we describe applications of ClearView Radiation Shielding in nuclear plants and hospitals. ClearView Radiation Shielding is used to shield nuclear power plant workers from Co in critical path and high dose in refueling outages to observe automated operations inside the containment, and operations such as cylindrical frisking stations and benchtop sampling. ClearView Radiation Shielding is designed as rolling shields and radionuclide containments in hospitals to protect staff and families during unsealed radionuclide treatment such as MIBG and Lutetium therapies. For successful implementation in hospitals, the product was tested against various radioisotopes, also described in this work. Operational uses of ClearView Radiation Shielding in commercial nuclear and medical industries allows staff working in radioactive environments visibility, better communication and similar levels of radiation protection compared with traditional shielding materials. The product helps improve workflows and reduced total dose received by workers. Additionally, attenuation measurements using ClearView Radiation Shielding against multiple isotopes was performed. With 1.25 cm (0.5") ClearView Radiation Shielding thickness, the shield attenuated 1) 65% of the effective dose from I, 2) 35.15% of the effective dose from Cs, and 3) 22.5% of the effective dose from Co. Isotopes in the range of 35 keV to 1899 keV. 3.81 were attenuated greater than 90% with a ClearView Radiation Shielding shield thickness of 7.62 cm (3"). The half-value layer for Co with a ClearView Radiation Shielding thickness of 3.81 cm (1.5") attenuated the effective dose of F gammas by 85.59%. With a density of 2.3 g cm, ClearView Radiation Shielding was measured to be half the weight of lead for equal shielding. ClearView Radiation Shielding is transparent, lightweight, and an alternative material to conventional radiation shields to reduce radiation exposure.

MIBG Therapy for Neuroblastoma: Precision Achieved With Dosimetry, and Concern for False Responders.

Neuroblastoma causes 15% of cancer mortality in children. High risk neuroblastoma has poor prognosis, with high relapse rate and mortality despite multimodal treatment. 123-I-meta-iodo-benzyl-guanidine (mIBG) scintigraphy is one of the current standard diagnostic procedures in neuroblastoma. mIBG can also be used therapeutically, labeled with 131-I, as a radiopharmaceutical agent, delivering targeted radiotherapy to tumoral sites. But published data of this strategy show heterogeneous results. One concern is that in most reports the infused activity is only based in body-weight, which could lead to infra or over-treatment, depending on inter-patient variability in radiation absorption. Activity adjustment by whole-body dosimetry can be used to homogeneize the treatment. Also, mIBG avid tumors may lose avidness along the treatment. As mIBG is used both for treatment and response evaluation, this could result in undetected progressions in patients with apparent complete response. We present a retrospective single-center review of neuroblastoma patients who received therapeutic 131-I-mIBG, focusing on cases with dosimetry-adjusted activity. Dosimetry allowed for a more precise delivery of radiation, reducing 81.1% of deviation from absorption target of 4 Gray (Gy), from 23.4% (±0.936 Gy) to 4.4% (± 0.176 Gy). Patients who showed partial or complete response had better and longer survival. Relapse/progression in non-responders was an early event (within 3 months from treatment). We also present one case of progression with apparent complete response due to loss of mIBG avidness, detected in our series.

Modulation of radiation biomarkers in a randomized phase II study of 131I-MIBG with or without radiation sensitizers for resistant/relapsed neuroblastoma.

e22514 Background: 131I-metaiodobenzylguanidine (MIBG), a radiopharmaceutical agent, has demonstrated efficacy as a single agent for patients with neuroblastoma. Recently, trials have focused on MIBG combination strategies, though little is known about impact of combination agents on markers of radiation exposure. Methods: NANT11-01 (NCT02035137) was a multicenter, open label, randomized phase II clinical trial that evaluated MIBG therapy alone (Arm A) or in combination with vincristine/irinotecan (Arm B) or vorinostat (Arm C) for patients with resistant/relapsed neuroblastoma. We collected blood samples at baseline and 72 hours after MIBG infusion and determined plasma flt3 ligand, serum amylase, gamma-H2AX levels, and gene expression for key transcripts. We plotted relative change from baseline and evaluated association of marker modulation by treatment arm and clinical response using NANT response criteria. Results: The cohort included 65 patients who had at least one biomarker available for analysis (19 Arm A; 24 Arm B; 22 Arm C). Across all arms, plasma flt3 ligand and serum amylase were significantly positively modulated while BCLXL/BCL2L1 and BCL2 gene expression demonstrated significant negative modulation by 72 hours after MIBG infusion compared to baseline (p &lt; 0.001 for all markers). For patients randomized to Arm B, we observed significantly greater positive modulation of Flt3 ligand (geometric mean fold change 4.21 for Arm B vs. 2.22 and 2.08 for Arms A and C, respectively; p &lt; 0.001) and significantly greater negative modulation of BCLXL/BCL2L1 (geometric mean fold change 0.11 for Arm B vs. 0.55 and 0.43 for Arms A and C, respectively; p &lt; 0.001). There were no statistically significant associations of differential modulation of a specific biomarker with higher likelihood of response (partial response or better), though there was a trend to suggest that responders had greater gamma-H2AX modulation (p = 0.053). Conclusions: Peripheral blood biomarkers relevant to radiation exposure demonstrate significant modulation after MIBG treatment, with differential modulation when chemotherapy is combined with MIBG. Analysis of additional markers and additional samples is ongoing. Clinical trial information: NCT02035137.

SDHx-related pheochromocytoma/paraganglioma - genetic, clinical, and treatment outcomes in a series of 30 patients from a single center.

Germline mutations in the four genes that encode the succinate dehydrogenase complex (SDHx) are a risk factor for developing pheochromocytomas and/or paragangliomas. The precise genotype-phenotype correlations are still uncertain and the most common SDHx genetic defects in the Portuguese population are poorly described. The objectives of our study were to characterize the genetic alterations, clinical features, and treatment outcomes of a cohort of SDHx-related pheochromocytomas and/or paragangliomas patients. Single center, retrospective analysis based on the presence of a SDHx mutation in cases diagnosed from 1986 until October 2016. Thirty cases were included. The mean age at diagnosis was 36.8 years (±15.4 years) and 53.3% were females. Remission was observed in 33.3% and stable disease (including partial responses) in 53.0%. SDHC and SDHD patients were prone to develop single and multiple head and neck paragangliomas, respectively. SDHB patients carried an increased risk of malignancy. Deletions in SDHB exon-1 and in SDHD exon-4 were the most common genetic findings. SDHB patients and head and neck paragangliomas had the worse prognosis, the former related to malignancy, and the latter to cranial nerve deficits, unresectable disease, and multimodality interventions. Peptide receptor radionuclide therapy and radioactive iodine MIBG therapy proved to be ineffective. Radiotherapy represented a good alternative in unresectable head and neck paragangliomas and in bone metastases. This single center study is the most complete Portuguese cohort in the literature and helps to understand the behavior of tumors based on their genotype and anatomical location.

Assessment of the dicentric chromosome assay as a biodosimetry tool for more personalized medicine in a case of a high risk neuroblastoma 131I-mIBG treatment

Purpose: The aims of this study were to estimate the whole - body absorbed - dose with the Dicentric Chromosome Assay (DCA) (biodosimetry) for 131I - metaiodobenzylguanidine (131I - mIBG) therapy for high - risk neuroblastoma, and to obtain an initial correlation with the physical dosimetry calculated as described by the Medical Internal Radiation Dosimetry formalism (MIRD). Together both objectives will aid the optimization of personalized targeted radionuclide therapies.Material and methods: A 12 year-old child with relapsed high-risk neuroblastoma was treated with 131I-mIBG: a first administration with activity <444 MBq/kg was used as a tracer in order to calculate the activity needed in a second administration to achieve a whole body prescribed dose of ∼4 Gy. Blood samples were obtained before and seven days after each administration to analyze the frequency of dicentrics. Moreover, consequent estimations of retained activity were done every few hours from equivalent dose rate measurements at a fixed position, two meters away from the patient, in order to apply the MIRD procedure. Blood samples were also drawn every 2- to -3 days to assess bone marrow toxicity.Results: For a total activity of 22,867 MBq administered over two phases, both biological and physical dosimetries were performed. The former estimated a whole-body cumulated dose of 3.53 (2.58–4.41) Gy and the latter a total whole-body absorbed dose of 2.32 ± 0.48 Gy. The patient developed thrombocytopenia grade 3 after both infusions and neutropenia grade 3 and grade 4 (based on CTCAE 4.0) during respective phases.Conclusion: The results indicate a possible correlation between biodosimetry and standard physical dosimetry in 131I-mIBG treatment for high-risk neuroblastoma. A larger cohort and refinement of the DCA for internal irradiation are needed to define the role of biodosimetry in clinical situations.

Radiation Safety Aspects of Iodine-131 metaiodobenzylguanidine (131I mIBG) Therapy Program Startup.

As a medical center without a pre-existing radiopharmaceutical therapy program, it was a daunting endeavor to implement a I metaiodobenzylguanidine (mIBG) high-dose treatment regimen. It took several years of planning with hospital administration, vendors, and Texas Department of Health Radiological Control regulators to establish a viable program. Effective communication between physicians, nursing, nuclear medicine, environmental services, maintenance, and other support staff is essential and paramount for the successful execution and continued sustainability of the mIBG therapy program. Besides providing an effective treatment for patients, an additional goal for the program is to keep radiation exposure As Low As Reasonably Achievable (ALARA) for staff and patient caregivers. As such, start-up presented many training, logistical, and radiation safety challenges. The location of the isolation room and shielding specifications were designed to keep radiation exposure to public access areas to less than 2 microsieverts per hour. Before the first patient was treated the policies and procedures for training, radiation safety, product quality control, and infusion process needed to be developed, tested, and approved by various committees. Furthermore, a similar process was required for developing room set-up, post therapy cleanup, and waste storage procedures. Throughout the maturation process of the program, the departments involved have found that our safety culture has continually improved by the re-enforcement of knowledge and lessons learned, as both the ancillary and treatment staff grew more confident in each other's ability during more patient treatments are performed. This article describes the process and lessons learned during the time leading up to the startup and early years of the mIBG therapy program.

131-I MIBG therapy of malignant pheochromocytoma and paraganglioma tumours - a single-centre study.

Pheochromocytomas and paragangliomas are rare tumors deriving from chromaffin cells of adrenal medulla or paraganglia. They are usually benign but 10-35% of them present malignant behavior. The aim of the study was to evaluate the efficacy and safety of 131-I MIBG therapy in malignant pheochromocytoma /paraganglioma patients (MPPGL). 18 patients (7 women and 11 men) were included in this study. Between 2002 and 2016 they underwent 131-I MIBG therapy because of MPPGL and their medical data were analyzed retrospectively. Clinical indications for the treatment included progressive disease or massive tissue involvement independently from disease progression. Tumor response for the first time was assessed 3 months after the last treatment according to Response Evaluation Criteria in Solid Tumors criteria and by 131-I MIBG scans. The mean single dose used was 7.25 GBq (196 mCi) and mean cumulative dose 33.08 GBq ( 894 mCi). In 2 (11%) patients complete tumor response was achieved. In 1 (6%) patient partial response was obtained. In 13 (72%) patients stable disease was observed. In 2 (11%) patients progression was diagnosed three months after treatment discontinuation. In the whole studied group the progression free survival time was 85 months and overall 5-year survival was 87%. Radionuclide treatment with use of 131-I MIBG may be effective form of palliative treatment for patients with inoperative neoplasm spread, progressive disease or patients requiring alleviation of symptoms. < p > < /p >.

Lymphnode tuberculosis in a 4-year-old boy with relapsed ganglioneuroblastoma: a case report

BackgroundMycobacterium tuberculosis (M. tuberculosis) disease is a generally well-known problem among immunocompromised adults and children. In pediatric oncology, only few cases of M. tuberculosis disease are reported so far.Case presentationWe report a case of concomitant lymphnode tuberculosis in a 4-year-old German boy with relapsed ganglioneuroblastoma. 18 months after the initial diagnosis, relapse with new paravertebral lesions and new lesions in the left lower lobe of the lung and in the perihilar lymphnodes suspicious of metastases of the ganglioneuroblastoma were detected. While relapse in the tumor was confirmed, unexpectedly, pathologic examination revealed morphological diagnosis of lymphnode tuberculosis. The boy was of German background without previous history of tuberculosis exposure. Both, antituberculostatic and relapse treatment were immediately initiated. Three months on, MRI revealed regressive findings in the lung and lymphnodes and partial response in the tumor. The patient underwent second MiBG therapy and haploidentical stem cell transplantation.ConclusionThe diagnosis of lymphnode tuberculosis in a 4-year-old German boy with relapsed ganglioneuroblastoma was only made by chance, but most likely saved his life. Pediatric oncologist should be aware of tuberculosis as the incidence might increase over time and the timely diagnosis of a potentially preventable M. tuberculosis disease is irreplaceable. Further studies are needed to explore the incidence of M. tuberculosis infections and the value of IGRA, testing for latent tuberculosis infection prior to chemotherapy in children with underlying malignancies.

Abstract 688: Meta-[211At]astatobenzylguanidine ([211At]MABG) is a potent alpha particle emitting systemic targeted radiotherapeutic in preclinical models of neuroblastoma

Abstract BACKGROUND The alpha particle emitting radiotherapeutic [211At]MABG theoretically has superior radiobiological properties for anti-tumor efficacy compared to the currently used agent ([131I]MIBG). Specifically, [131I]MIBG does not target microscopic deposits due to the long path length of the beta particles, while alpha particles have both a short path length and higher linear energy transfer to induce clustered double strand breaks. Here we sought to define the anti-tumor activity of [211At]MABG in preclinical models of human neuroblastoma (NB). METHODS 211At was synthesized using a bismuth target via the 209Bi(α,2n)211At reaction and used for solid-phase radiosynthesis of [211At]MABG (Ultratrace, Progenics, NY). We determined NET (SLC6A2) mRNA and protein expression in 35 NB cell lines and created isogenic pairs by overexpression of NET in 5 NB cell models. We performed uptake, cytotoxicity and biodistribution studies using these models with [131I]MIBG and [211At]MABG and extrapolated human dosimetry. Additionally, dose escalation studies with [211At]MABG (n=10 at each dose, range 10-100 uCi) were performed to determine toxicity in SCID mice. Therapeutic in vivo trials were conducted with NET transfected xenografts and patient derived xenograft (PDX) models injected intravenously with escalating doses of [211At]MABG, [131I]MIBG or vehicle (n=10 respectively). RESULTS We now routinely synthesize [211At]MABG with a radiochemical yield of 50-70% and radiochemical purity &amp;gt;99%. NET-overexpressing cell lines showed 4-10 fold higher uptake of NET ligands than parental isogenic lines, and tumor-specific [211At]MABG uptake (tumor-muscle ratios of 7.37). Estimated dosimetry confirmed the potential to deliver therapeutic doses to tumors. Intravenous [211At]MABG was well tolerated in murine models at doses of 10 and 25 µCi except for transient thrombocytopenia (nadir at 6 weeks; p=0.001 and p=0.0005 respectively) while doses higher than 50 uCi caused significant weight loss. [211At]MABG was a potent cytotoxic agent in vitro (EC50’s ranged from 0.0006-0.1 uCi/ml compared to 0.25-46 uCi/ml with [131I]MIBG). Single dose therapeutic trials showed significant regression of established NET overexpressing SKNSH xenograft and COG-N-453x PDX models (p&amp;lt;0.0001) sustained for a median of 14.5 days, comparable to single dose [131I]MIBG therapy and prolonged survival was noted in mice receiving [211At]MABG. CONCLUSIONS The biodistribution and uptake of [211At]MABG is similar to [131I]MIBG and there was no unanticipated toxicity. [211At]MABG is more potent than [131I]MIBG in vitro and the two agents showed similar activity in bulky xenograft models, remarkable due to the several log difference in half-life (7.2 hours for [211At]MABG, 8.04 days for [131I]MIBG). Additional studies exploring fractionated dosing of [211At]MABG are ongoing and will be reported. Citation Format: Vandana Batra, Jimmy Elias, Mehran Makvandi, Matthew Tsang, Pietro Ranieri, Catherine Hou, Yimei Li, Daniel A. Pryma, John M. Maris. Meta-[211At]astatobenzylguanidine ([211At]MABG) is a potent alpha particle emitting systemic targeted radiotherapeutic in preclinical models of neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 688. doi:10.1158/1538-7445.AM2017-688

Anatomic Patterns of Relapse and Progression Following Treatment With 131I-MIBG in Metastatic Neuroblastoma

Neuroblastoma is the most common pediatric extracranial solid tumor. Patients with MIBG-avid relapsed or refractory neuroblastoma after up front therapy may exhibit significant, but often transient, responses to salvage treatment with 131I-MIBG. It is not known whether disease progression following 131I-MIBG treatment occurs in previously involved versus new anatomic sites of disease. Understanding this pattern of relapse may inform the use of consolidative external beam radiation therapy following 131I-MIBG administration. Patients with relapsed or refractory metastatic MIBG-avid neuroblastoma or ganglioneuroblastoma who received single-agent 131I-MIBG on phase 2 and compassionate access protocols at a single-institution were included if they had 1) stable or responding disease 6-8 weeks following 131I-MIBG infusion, but subsequently experienced disease progression and 2) had serial diagnostic MIBG scans available from protocol enrollment through first progression. Scans were reviewed to establish anatomic locations and temporal evolution of MIBG-avid disease. Progression was defined as development of MIBG-avid disease in a previously uninvolved anatomic location, or as recurrence of MIBG avidity in a previously involved site that had fully cleared following MIBG treatment. A total of 142 MIBG-avid metastatic sites were identified immediately prior to MIBG therapy in a cohort of 15 patients (seven male, eight female). Median age at first 131I-MIBG treatment was 9.6 years (range, 4.3-51.2). Following first 131I-MIBG infusion, and prior to disease progression, five patients received additional 131I-MIBG treatments, but none received external beam radiation therapy. Median time to progression after first 131I-MIBG treatment was 0.6 years (range, 0.2-2.5). At first progression, a total of 140 MIBG-avid sites were identified, of which 103 (74%) overlapped with pretreatment disease sites, while 37 (26%) represented anatomically new disease areas. Nine of 15 patients had one or more new MIBG avid site at first progression. Of the 103 involved sites at progression that overlapped with pretreatment disease, 19 represented relapsed sites that had cleared following MIBG therapy, 19 were persistent but increasingly MIBG-avid, and 65 were stably persistent. Previously involved anatomic disease sites predominate at disease progression following 131I-MIBG treatment; nevertheless, the majority of patients progressed in at least one new anatomic disease site. This observation suggests that consolidative focal therapies targeting residual disease sites may be of limited benefit in preventing systemic disease progression following 131I-MIBG treatment of relapsed or refractory neuroblastoma.

RADIONUCLIDE IMAGING AND THERAPY OF NEUROENDOCRINE TUMOURS

The incidence and prevalence of neuroendocrine tumours (NETs) are on the rise. Although NETs are a heterogeneous group of tumours, they have some similar properties, for example, that they can concentrate neuroamines and tend to have a high degree of somatostatin receptor (SSR) expression. These mechanisms can be exploited and this article discusses the important role of radionculide imaging and radionculide therapy in the management of NETs based on these mechanisms. This article reviews the current literature and discusses the role of radionuclide imaging in NETs both in terms of SSR imaging and neuroamine (metaiodobenzylguanidine [MIBG]) imaging. We discuss state-of- the-art 68Ga-radiopeptide imaging and indications for it use. We also discuss the role of 18F-FDG and other tracers in the management of NETs. The second half of the article focuses on radiotargeted treatment of NETs, discussing I-131 MIBG therapy and focussing on the emergence of peptide receptor radionuclide therapy. We discuss the clinical results, toxicities and patient selection for PRRT. Key words: DOTA octreotide, DOTATATE, Ga-68, Lu-177, metaiodobenzylguanidine, neuroendocrine tumours, peptide receptor radionuclide therapy, Y-90