Multi-modality megatherapy with [131I]metaiodobenzylguanidine, high dose melphalan and total body irradiation with bone marrow rescue: Feasibility study of a new strategy for advanced neuroblastoma

doi:10.1016/0959-8049(94)E0036-4

European Journal of Cancer

Volume 31, Issue 2, 1995, Pages 252-256

https://doi.org/10.1016/0959-8049(94)E0036-4 Get rights and content

Abstract

New therapeutic approaches are needed for advanced neuroblastoma as few patients are currently curable. We describe an innovative strategy combining [¹³¹I]meta-iodobenzylguanidine ([¹³¹I]mIBG) therapy with high dose chemotherapy and total body irradiation. The aim of combining these treatments is to overcome the specific limitations of each when used alone to maximise killing of neuroblastoma cells. Five children received combined therapy with [¹³¹I]mIBG followed by high dose melphalan and fractionated total body irradiation. Autologous bone marrow transplantation was undertaken in 3 patients and allogeneic in 2 patients. One patient received additional localised radiotherapy to residual bulk disease. One patient is alive without relapse 32 months after treatment. 4 patients relapsed after remissions of 9, 10, 14 and 21 months. These results indicate that this combined modality approach is feasible and safe, but further evaluation is necessary to establish whether it has advantages over conventional megatherapy using melphalan alone.

References (14)

T.E. Wheldon et al.
The curability of tumours of differing size by targeted radiotherapy using ¹³¹I or ⁹⁰Y
Radiother Oncol
(1991)
J.A. O'Donoghue
Optimal scheduling of biologically targeted radio-therapy and total body irradiation with bone marrow rescue for the treatment of systemic malignant disease
Int J Radiat Oncol Biol Phys
(1991)
J Pritchard et al.
Is high dose melphalan of value in treatment of advanced neuroblastoma? Preliminary results of a randomised trial by the European Neuroblastoma Study Group
R Ladenstein et al.
Megatherapy and immunotherapy in paediatric solid tumours
P.A. Voûte et al.
Results of treatment with ¹³¹I-metaiodobenzyl-guanidine in patients with neuroblastoma. Future prospects of zetotherapy
L.S. Lashford et al.
Phase I/II study of iodine 131 metaiodobenzylguanidine in chemoresistant neuroblastoma: a United Kingdom Children's Cancer Study Group investigation
J Clin Oncol
(1992)
J.A. O'Donoghue et al.
Implications of the uptake of ¹³¹I-radiolabelled metaiodobenzylguanidine (mIBG) for the targeted radiotherapy of neuroblastoma
Br J Radiol
(1991)

There are more references available in the full text version of this article.

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Timing and chemotherapy association for 131-I-MIBG treatment in high-risk neuroblastoma
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Prognosis of high-risk neuroblastoma is dismal, despite intensive induction chemotherapy, surgery, high-dose chemotherapy, radiotherapy, and maintenance. Patients who do not achieve a complete metastatic response, with clearance of bone marrow and skeletal NB infiltration, after induction have a significantly lower survival rate. Thus, it's necessary to further intensify treatment during this phase. 131-I-metaiodobenzylguanidine (131-I-MIBG) is a radioactive compound highly effective against neuroblastoma, with 32% response rate in relapsed/resistant cases, and only hematological toxicity. 131-I-MIBG was utilized at different doses in single or multiple administrations, before autologous transplant or combined with high-dose chemotherapy. Subsequently, it was added to consolidation in patients with advanced NB after induction, but an independent contribution against neuroblastoma and for myelotoxicity is difficult to determine. Despite results of a 2008 paper demonstrated efficacy and mild hematological toxicity of 131-I-MIBG at diagnosis, no center had included it with intensive chemotherapy in first-line treatment protocols. In our institution, at diagnosis, 131-I-MIBG was included in a 5-chemotherapy drug combination and administered on day-10, at doses up to 18.3 mCi/kg. Almost 87% of objective responses were observed 50 days from start with acceptable hematological toxicity. In this paper, we review the literature data regarding 131-I-MIBG treatment for neuroblastoma, and report on doses and combinations used, tumor responses and toxicity. 131-I-MIBG is very effective against neuroblastoma, in particular if given to patients at diagnosis and in combination with chemotherapy, and it should be included in all induction regimens to improve early responses rates and consequently long-term survival.
MIBG in neuroblastoma diagnosis and treatment
2019, Seminars in Pediatric Surgery
Citation Excerpt :
The variable success of 131I-MIBG as monotherapy in relapsed and refractory disease led to the investigation of combination therapy with various chemotherapy regimens and autologous stem cell rescue. Studies have looked at the combination of Cisplatin,28,29 Cyclophosphamide,30 Topotecan,31 and Melphalan32 with response rates ranging from 27%−80%.28,29,33 Studies have found that combination of chemotherapy regimens and 131I-MIBG are tolerable and side-effect profiles are similar to that of chemotherapy alone, with myelosuppression being the most commonly reported toxicity of combination therapy.5
Neuroblastoma is a heterogenous disease, with solid tumors arising in the adrenal gland or paraspinal regions in young children. Neuroblastoma is unique, with varied presentation and prognosis based on primary location and tumor stage. Tumor behavior and response to treatment ranges from spontaneous regression to disseminated, lethal disease depending on the individual biology of a patient’s tumor. Stratification of the disease has changed, with patients now placed in low, intermediate, and high-risk categories depending on age, stage, and tumor biology. Long-term survival for the high-risk subset of patients with metastatic disease is <40% despite aggressive multimodal therapy. Derived from sympathoadrenal cells of the adrenal medulla and sympathetic nervous system, both malignant neuroblastoma and differentiated tumors have specialized norepinephrine transporter (NET) receptors which are naturally occurring in the sympathetic nervous system throughout the body. Metaiodobenzylguanidine (MIBG) is a norepinephrine analog that undergoes active uptake by NET receptors resulting in accumulation in neuroblastoma as well as tissues normally expressing the NET receptor. When radioiodine labeled, MIBG can be used for both diagnosis and treatment. This article describes the history of MIBG use in neuroblastoma, including its utility as an imaging modality for diagnosis as well as the varied ways in which is it included in the multimodal treatment algorithm.
Improved selectivity of mIBG uptake into neuroblastoma cells in vitro and in vivo by inhibition of organic cation transporter 3 uptake using clinically approved corticosteroids
2016, Nuclear Medicine and Biology
Citation Excerpt :
MIBG (meta-iodobenzylguanidine) is an analog of the catecholamine norepinephrine and can be utilized for imaging and targeted radiotherapy of NT expressing tumors when labeled with radioactive isotopes such as [123I], [124I] or [131I] [1,5]. In contrast to norepinephrine, mIBG is not degraded by mitochondrial monoamine oxidase and remains in the cytoplasm where it is stored in mitochondria [6]. With respect to risk stratification and selection of the most appropriate treatment options, a precise initial staging is highly important [3].
Radiolabeled meta-iodobenzylguanidine (mIBG) is used for imaging and therapy of neuroblastoma as well as pheochromocytoma. However, non-tumorous tissues also incorporate mIBG mainly by organic cation transporters (OCTs). In this study, we tested different clinically approved corticosteroids as potential inhibitors of the OCT3-mediated uptake in vitro and in vivo, to achieve a more selective mIBG tumor uptake.
The in vitro incorporation of [³H]norepinephrine ([³H]NE), [³H]dopamine ([³H]DA) and [¹²³I]mIBG in neuroblastoma cells (SK-N-SH, Kelly, IMR-32) and in HEK-293 cells transfected with human OCT3 was measured with and without supplemental corticosteroids (hydrocortisone, prednisolone, dexamethasone, corticosterone). The in vivo biodistribution of [¹²³I]mIBG in absence and presence of corticosteroids was studied in non-tumor bearing NOD scid gamma mice. Retrospectively, we selected patients with and without corticosteroid treatment prior to [¹²³I]mIBG scintigraphy.
A concentration-dependent inhibitory effect of different corticosteroids on the [³H]NE and [³H]DA uptake via OCT3 was illustrated in vitro. The highest OCT3 inhibition was observed for corticosterone, but clinically used corticosteroids, showed also promising inhibitory effects. In contrast, the uptake in neuroblastoma cells was reduced only moderately. Hydrocortisone or prednisolone had only minor effects on [¹²³I]mIBG uptake of both neuroblastoma cells, but reduced uptake in OCT3 expressing cells significantly. In mice tissues, [¹²³I]mIBG uptake was inhibited by corticosteroids especially in the small intestine and kidney. Finally, in one patient with hydrocortisone treatment performed prior to [¹²³I]mIBG scan, heart and liver uptake was reduced compared to untreated patients.
The OCT3 is widely spread in many organs and responsible for non-targeted uptake of radiolabeled mIBG. In our study, clinically approved corticosteroids inhibited mIBG uptake in OCT3 expressing cells effectively, whereas tracer accumulation in NT (norepinephrine transporter) expressing neuroblastoma cells showed consistency. We conclude, that a single dose of hydrocortisone or prednisolone prior to [¹²³I]mIBG scintigraphy may improve specificity and reduce radiation dose to non-target organs.
Nuclear Medicine
2015, Clinical Radiation Oncology
Nuclear Medicine
2012, Clinical Radiation Oncology: Third Edition
Preclinical assessment of strategies for enhancement of metaiodobenzylguanidine therapy of neuroendocrine tumors
2011, Seminars in Nuclear Medicine
By virtue of its high affinity for the norepinephrine transporter (NET), [¹³¹I]metaiodobenzylguanidine ([¹³¹I]MIBG) has been used for the therapy of tumors of neuroectodermal origin for more than 25 years. Although not yet universally adopted, [¹³¹I]MIBG targeted radiotherapy remains a highly promising means of management of neuroblastoma, pheochromocytoma, and carcinoids. Appreciation of the mode of conveyance of [¹³¹I]MIBG into malignant cells and of factors that influence the activity of the uptake mechanism has indicated a variety of means of increasing the effectiveness of this type of treatment. Studies in model systems revealed that radiolabeling of MIBG to high specific activity reduced the amount of cold competitor, thereby increasing tumor dose and minimizing pressor effects. Increased radiotoxicity to targeted tumors might also be achieved by the use of the α-particle emitter [²¹¹At]astatine rather than ¹³¹I as radiolabel. Recently it has been demonstrated that potent cytotoxic bystander effects were induced by [¹³¹I]MIBG, [¹²³I]MIBG, and [²¹¹At]meta-astatobenzylguanidine. Discovery of the structure of bystander factors could increase the therapeutic ratio achievable by MIBG targeted radiotherapy. [¹³¹I]MIBG combined with topotecan produced supra-additive cytotoxicity in vitro and tumor growth delay in vivo. The enhanced antitumor effect was consistent with a failure to repair DNA damage. Initial findings suggest that further enhancement of efficacy might be achieved by triple combination therapy with drugs that disrupt alternative tumor-specific pathways and synergize not only with [¹³¹I]MIBG abut also with topotecan. With these ploys, it is expected that advances will be made toward the optimization of [¹³¹I]MIBG therapy of neuroectodermal tumors.

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PaperMulti-modality megatherapy with [131I]metaiodobenzylguanidine, high dose melphalan and total body irradiation with bone marrow rescue: Feasibility study of a new strategy for advanced neuroblastoma

Abstract

Radiother Oncol

Int J Radiat Oncol Biol Phys

Is high dose melphalan of value in treatment of advanced neuroblastoma? Preliminary results of a randomised trial by the European Neuroblastoma Study Group

Megatherapy and immunotherapy in paediatric solid tumours

Results of treatment with 131I-metaiodobenzyl-guanidine in patients with neuroblastoma. Future prospects of zetotherapy

Phase I/II study of iodine 131 metaiodobenzylguanidine in chemoresistant neuroblastoma: a United Kingdom Children's Cancer Study Group investigation

J Clin Oncol

Implications of the uptake of 131I-radiolabelled metaiodobenzylguanidine (mIBG) for the targeted radiotherapy of neuroblastoma

Br J Radiol

Paper
Multi-modality megatherapy with [¹³¹I]metaiodobenzylguanidine, high dose melphalan and total body irradiation with bone marrow rescue: Feasibility study of a new strategy for advanced neuroblastoma

Results of treatment with ¹³¹I-metaiodobenzyl-guanidine in patients with neuroblastoma. Future prospects of zetotherapy

Implications of the uptake of ¹³¹I-radiolabelled metaiodobenzylguanidine (mIBG) for the targeted radiotherapy of neuroblastoma