A phase IIa trial of molecular radiotherapy with 177-lutetium DOTATATE in children with primary refractory or relapsed high-risk neuroblastoma.

Published on Mar 11, 2020in European Journal of Nuclear Medicine and Molecular Imaging7.081
· DOI :10.1007/S00259-020-04741-X
Jennifer E. Gains9
Estimated H-index: 9
(UCLH: University College London Hospitals NHS Foundation Trust),
Veronica Moroz9
Estimated H-index: 9
(University of Birmingham)
+ 6 AuthorsMark N. Gaze28
Estimated H-index: 28
(UCLH: University College London Hospitals NHS Foundation Trust)
PURPOSE: The objective of this phase IIa, open-label, single-centre, single-arm, two-stage clinical trial was to evaluate the safety and activity of 177-lutetium DOTATATE (LuDO) molecular radiotherapy in neuroblastoma. METHODS: Children with relapsed or refractory metastatic high-risk neuroblastoma were treated with up to four courses of LuDO. The administered activity was 75 to 100 MBq kg(-1) per course, spaced at 8- to 12-week intervals. Outcomes were assessed by the International Neuroblastoma Response Criteria (primary outcome), progression-free survival (PFS), and overall survival (OS). RESULTS: The trial recruited 21 patients; eight received the planned four courses. There was dose-limiting haematologic toxicity in one case, but no other significant haematologic or renal toxicities. None of 14 evaluable patients had an objective response at 1 month after completion of treatment (Wilson 90% CI 0.0, 0.16; and 95% CI is 0.0, 0.22). The trial did not therefore proceed to the second stage. The median PFS was 2.96 months (95% CI 1.71, 7.66), and the median OS was 13.0 months (95% CI 2.99, 21.52). CONCLUSION: In the absence of any objective responses, the use of LuDO as a single agent at the dose schedule used in this study is not recommended for the treatment of neuroblastoma. There are several reasons why this treatment schedule may not have resulted in objective responses, and as other studies do show benefit, the treatment should not be regarded as being of no value. Further trials designed to overcome this schedule's limitations are required. TRIAL REGISTRATION: ISRCTN98918118; URL: https://www.isrctn.com/search?q=98918118.
#1S Arumugam (UCLH: University College London Hospitals NHS Foundation Trust)H-Index: 1
#2NJ Manning-Cork (UCLH: University College London Hospitals NHS Foundation Trust)H-Index: 1
Last. Mark N. Gaze (UCLH: University College London Hospitals NHS Foundation Trust)H-Index: 28
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Abstract Aims External beam radiotherapy is widely used in various ways in the management of neuroblastoma. Despite extensive clinical experience, the precise role of radiotherapy in neuroblastoma remains unclear. The purpose of this systematic review was to survey the published literature to identify, without bias, the evidence for the clinical effectiveness of external beam radiotherapy as part of the initial multimodality treatment of high-risk neuroblastoma. We considered four areas: treatme...
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#1Ruth Ladenstein (Boston Children's Hospital)H-Index: 53
#2Ulrike PötschgerH-Index: 43
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#1Mathias Tesson (Glas.: University of Glasgow)H-Index: 7
#2Richa Vasan (Glas.: University of Glasgow)H-Index: 2
Last. Robert J. Mairs (Glas.: University of Glasgow)H-Index: 27
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Targeted radiotherapy of metastatic neuroblastoma using the somatostatin receptor (SSTR)-targeted octreotide analogue DOTATATE radiolabelled with lutetium-177 (177 Lu-DOTATATE) is a promising strategy. This study evaluates whether its effectiveness may be enhanced by combination with radiosensitising drugs. The growth rate of multicellular tumour spheroids, derived from the neuroblastoma cell lines SK-N-BE(2c), CHLA-15 and CHLA-20, was evaluated following treatment with 177 Lu-DOTATATE, nutlin-3...
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#1Jonathan R. Strosberg (University of Texas MD Anderson Cancer Center)H-Index: 45
#2Edward M. Wolin (University of Texas MD Anderson Cancer Center)H-Index: 28
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#1Jennifer E. Gains (UCLH: University College London Hospitals NHS Foundation Trust)H-Index: 9
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Purpose Neuroblastoma may be treated with molecular radiotherapy, 131I meta-Iodobenzylguanidine and 177Lu Lutetium DOTATATE, directed at distinct molecular targets: Noradrenaline Transporter Molecule (NAT) and Somatostatin Receptor (SSTR2), respectively. This study used immunohistochemistry to evaluate target expression in archival neuroblastoma tissue, to determine whether it might facilitate clinical use of molecular radiotherapy.
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#1Natasha Alexander (U of T: University of Toronto)H-Index: 2
#1Natasha Alexander (U of T: University of Toronto)H-Index: 2
Last. Sylvain Baruchel (U of T: University of Toronto)H-Index: 40
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BACKGROUND: Childhood neuroblastoma is a heterogenous disease with varied clinical presentation and biology requiring different approaches to investigation and management. Metaiodobenzylguanidine (MIBG) is an essential component of metastatic staging for neuroblastoma and has been used as a treatment strategy for relapsed and refractory neuroblastoma. However, as 10% of children with neuroblastoma will have 123I-MIBG non-avid imaging and up to 60% with relapsed and refractory neuroblastoma will ...
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PurposeMore than two decades ago, an international working group established the International Neuroblastoma Response Criteria (INRC) to assess treatment response in children with neuroblastoma. However, this system requires modification to incorporate modern imaging techniques and new methods for quantifying bone marrow disease that were not previously widely available. The National Cancer Institute sponsored a clinical trials planning meeting in 2012 to update and refine response criteria for ...
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#1Ruth Ladenstein (Community College of Rhode Island)H-Index: 53
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Summary Background High-dose chemotherapy with haemopoietic stem-cell rescue improves event-free survival in patients with high-risk neuroblastoma; however, which regimen has the greatest patient benefit has not been established. We aimed to assess event-free survival after high-dose chemotherapy with busulfan and melphalan compared with carboplatin, etoposide, and melphalan. Methods We did an international, randomised, multi-arm, open-label, phase 3 cooperative group clinical trial of patients ...
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#1Val Lewington ('KCL': King's College London)H-Index: 21
#2Bo Lambert (UGent: Ghent University)H-Index: 1
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#2Ghassan El-Haddad (USF: University of South Florida)H-Index: 15
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BackgroundPatients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (177Lu)–Dotatate in patients with advanced, progressive, somatostatin-receptor–positive midgut neuroendocrine tumors. MethodsWe randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive ...
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Cited By6
#1Margarida Simao Rafael (U of T: University of Toronto)
#2Sarah Cohen-Gogo (U of T: University of Toronto)
Last. Daniel A. Morgenstern (U of T: University of Toronto)H-Index: 18
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Theranostics combines diagnosis and targeted therapy, achieved by the use of the same or similar molecules labeled with different radiopharmaceuticals or identical with different dosages. One of the best examples is the use of metaiodobenzylguanidine (MIBG). In the management of neuroblastoma-the most common extracranial solid tumor in children. MIBG has utility not only for diagnosis, risk-stratification, and response monitoring but also for cancer therapy, particularly in the setting of relaps...
#1Jennifer Foster (BCM: Baylor College of Medicine)H-Index: 16
#2Andrew C. Sher (BCM: Baylor College of Medicine)H-Index: 3
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Neuroendocrine tumors (NETs) of the pancreas and midgut are extremely rare in children, and patients presenting with metastatic disease have poor survival. Given this rarity, treatments are extrapolated from guidelines for adults with NET. Recent clinical trials in adults with NETs have shown that the addition of peptide receptor radionuclide therapy (PRRT) with 177 Lu-DOTATATE resulted in a disease control rate of nearly 80%, with minimal side effects. We report our experience using 177 Lu-DOTA...
Neuroblastoma is the most common extracranial solid malignancy in children. At diagnosis, approximately 50% of patients present with metastatic disease. These patients are at high risk for refractory or recurrent disease, which conveys a very poor prognosis. During the past decades, nuclear medicine has been essential for the staging and response assessment of neuroblastoma. Currently, the standard nuclear imaging technique is meta-[123I]iodobenzylguanidine ([123I]mIBG) whole-body scintigraphy, ...
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BACKGROUND A major challenge to the long-term success of neuroblastoma therapy is widespread metastases that survive initial therapy as minimal residual disease (MRD). The SSTR2 receptor is expressed by most neuroblastoma tumors making it an attractive target for molecularly targeted radionuclide therapy. SARTATE consists of octreotate, which targets the SSTR2 receptor, conjugated to MeCOSar, a bifunctional chelator with high affinity for copper. Cu-SARTATE offers the potential to both detect an...
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The common contemporary indications for paediatric molecular radiotherapy (pMRT) are differentiated thyroid cancer and neuroblastoma. It may also have value in neuroendocrine cancers, and it is being investigated in clinical trials for other diseases. pMRT is the prototypical biomarker-driven, precision therapy, with a unique mode of delivery and mechanism of action. It is safe and well tolerated, compared with other treatments. However, its full potential has not yet been achieved, and its wide...
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Neuroblastoma is the most common extra-cranial solid tumor in pediatrics. The objective of this manuscript is to present an image-rich review of the presentation, diagnosis, staging and response assessment in individuals with neuroblastoma with special attention to the role of I-123 mIBG (meta-iodobenzylguanidine). A literature search was performed in the PubMed and Scopus databases to identity articles published between 1980 and March 2020 regarding different aspects of neuroblastoma (presentat...
#1Jennifer E. GainsH-Index: 9
#2Matthew D. Aldridge (UCLH: University College London Hospitals NHS Foundation Trust)H-Index: 5
Last. Mark N. GazeH-Index: 28
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PURPOSE Iodine-131-labelled meta-iodobenzylguanidine (I-mIBG) and lutetium-177-labelled DOTATATE (Lu-DOTATATE) are used for molecular radiotherapy of metastatic neuroblastoma. These are taken up by the noradrenaline transporter (NAT) and the somatostatin receptor subtype 2 (SSTR-2), respectively. Scintigraphy of iodine-123-labelled meta-iodobenzylguanidine (I-mIBG) and gallium-68 DOTATATE (Ga-DOTATATE) PET are used to select patients for therapy. These demonstrate the extent and location of tumo...
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#2April-Louise Smith (UCLH: University College London Hospitals NHS Foundation Trust)H-Index: 1
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Molecular radiotherapy, or targeted radionuclide therapy, uses systemically administered drugs bearing a suitable radioactive isotope, typically a beta emitter. These are delivered via metabolic or other physiological pathways to cancer cells in greater concentrations than to normal tissues. The absorbed radiation dose in tumour deposits causes chromosomal damage and cell death. A partner radiopharmaceutical, most commonly the same vector labelled with a different radioactive atom, with emission...