RADTHYR: an open-label, single-arm, prospective multicenter phase II trial of Radium-223 for the treatment of bone metastases from radioactive iodine refractory differentiated thyroid cancer

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Abstract

Purpose

This is the first prospective trial evaluating the efficacy of alpha emitter Radium-223 in patients with bone metastases from radioactive iodine (RAI) refractory (RAIR) differentiated thyroid cancer.

Methods

RADTHYR is a multicenter, single-arm prospective Simon two-stage phase II trial (NCT02390934). The primary objective was to establish the efficacy of three administrations of 55 kBq/kg of Radium-223 by ¹⁸F-FDG PET/CT according to PERCIST criteria. Secondary objectives were to establish the efficacy of six administrations of Radium-223 by ¹⁸F-FDG PET/CT, ^99mTc-HMDP bone scan and ¹⁸FNa PET/CT, clinical benefits, changes in serum bone markers, thyroglobulin levels, and safety.

Results

Ten patients were enrolled between July 2015 and December 2017 (4 M; median age 74 years). Prior to Radium-223 administration, patients received a median RAI cumulative activity of 15 GBq (7.4–35.6), external radiation therapy ( n = 9), bone surgery ( n = 8), cimentoplasty ( n = 5), and cryoablation ( n = 2). ¹⁸F-FDG PET/CT showed stable disease (SD) in 4/10 and progressive disease (PD) in 6/10 cases after three administrations and SD in 4/10, PD in 5/10 cases, and 1/10 non-evaluable (NE) case after six administrations. After six injections, ^99mTc-HMDP bone scan showed SD in 9 cases and was NE in 1 case; ¹⁸FNa PET/CT showed SD in 8 cases, partial response (PR) in 1 case, and was NE in 1 case. No significant clinical benefits were reported during the study. A skeletal event occurred in 6 patients (median time without skeletal event of 12.1 months). Seventy-seven adverse events were reported during treatment (7 of grade 3–4). Three patients developed an acute myeloid, a promyelocytic, and a chronic myeloid leukemia after the last Radium-223 administration considered as drug-related.

Conclusion

The trial was stopped after interim analysis for lack of response of bone metastases from RAIR thyroid cancer to Radium-223. Severe hematological toxicity was observed in patients heavily pretreated with RAI and external radiation.

Trial registration number

NCT02390934. Registration date 18.03.2015.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00259-021-05229-y.

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Most cited references 33

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2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer.

Bryan Haugen, Erik Alexander, Keith Bible … (2016)

Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the American Thyroid Association's (ATA's) guidelines for the management of these disorders were revised in 2009, significant scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid nodules and differentiated thyroid cancer.

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From RECIST to PERCIST: Evolving Considerations for PET response criteria in solid tumors.

Richard L. Wahl, Heather Jacene, Yvette Kasamon … (2009)

The purpose of this article is to review the status and limitations of anatomic tumor response metrics including the World Health Organization (WHO) criteria, the Response Evaluation Criteria in Solid Tumors (RECIST), and RECIST 1.1. This article also reviews qualitative and quantitative approaches to metabolic tumor response assessment with (18)F-FDG PET and proposes a draft framework for PET Response Criteria in Solid Tumors (PERCIST), version 1.0. PubMed searches, including searches for the terms RECIST, positron, WHO, FDG, cancer (including specific types), treatment response, region of interest, and derivative references, were performed. Abstracts and articles judged most relevant to the goals of this report were reviewed with emphasis on limitations and strengths of the anatomic and PET approaches to treatment response assessment. On the basis of these data and the authors' experience, draft criteria were formulated for PET tumor response to treatment. Approximately 3,000 potentially relevant references were screened. Anatomic imaging alone using standard WHO, RECIST, and RECIST 1.1 criteria is widely applied but still has limitations in response assessments. For example, despite effective treatment, changes in tumor size can be minimal in tumors such as lymphomas, sarcoma, hepatomas, mesothelioma, and gastrointestinal stromal tumor. CT tumor density, contrast enhancement, or MRI characteristics appear more informative than size but are not yet routinely applied. RECIST criteria may show progression of tumor more slowly than WHO criteria. RECIST 1.1 criteria (assessing a maximum of 5 tumor foci, vs. 10 in RECIST) result in a higher complete response rate than the original RECIST criteria, at least in lymph nodes. Variability appears greater in assessing progression than in assessing response. Qualitative and quantitative approaches to (18)F-FDG PET response assessment have been applied and require a consistent PET methodology to allow quantitative assessments. Statistically significant changes in tumor standardized uptake value (SUV) occur in careful test-retest studies of high-SUV tumors, with a change of 20% in SUV of a region 1 cm or larger in diameter; however, medically relevant beneficial changes are often associated with a 30% or greater decline. The more extensive the therapy, the greater the decline in SUV with most effective treatments. Important components of the proposed PERCIST criteria include assessing normal reference tissue values in a 3-cm-diameter region of interest in the liver, using a consistent PET protocol, using a fixed small region of interest about 1 cm(3) in volume (1.2-cm diameter) in the most active region of metabolically active tumors to minimize statistical variability, assessing tumor size, treating SUV lean measurements in the 1 (up to 5 optional) most metabolically active tumor focus as a continuous variable, requiring a 30% decline in SUV for "response," and deferring to RECIST 1.1 in cases that do not have (18)F-FDG avidity or are technically unsuitable. Criteria to define progression of tumor-absent new lesions are uncertain but are proposed. Anatomic imaging alone using standard WHO, RECIST, and RECIST 1.1 criteria have limitations, particularly in assessing the activity of newer cancer therapies that stabilize disease, whereas (18)F-FDG PET appears particularly valuable in such cases. The proposed PERCIST 1.0 criteria should serve as a starting point for use in clinical trials and in structured quantitative clinical reporting. Undoubtedly, subsequent revisions and enhancements will be required as validation studies are undertaken in varying diseases and treatments.

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Alpha emitter radium-223 and survival in metastatic prostate cancer.

C. Parker, S. Nilsson, D. Heinrich … (2013)

Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition to the best standard of care, in men with castration-resistant prostate cancer and bone metastases. In our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223. At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval [CI], 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events. In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.).

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Author and article information

Contributors

Désirée Deandreis:

ORCID: http://orcid.org/0000-0002-3817-6648

desiree.deandreis@unito.it

Journal

Journal ID (nlm-ta): Eur J Nucl Med Mol Imaging

Journal ID (iso-abbrev): Eur J Nucl Med Mol Imaging

Title: European Journal of Nuclear Medicine and Molecular Imaging

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 1619-7070

ISSN (Electronic): 1619-7089

Publication date (Electronic): 23 February 2021

Publication date PMC-release: 23 February 2021

Publication date (Print): 2021

Volume: 48

Issue: 10

Pages: 3238-3249

Affiliations

[1 ]GRID grid.14925.3b, ISNI 0000 0001 2284 9388, Nuclear Medicine and Endocrine Oncology, , Gustave Roussy and Paris Saclay University, ; 114 Rue Edouard Vaillant, Villejuif, France

[2 ]GRID grid.7605.4, ISNI 0000 0001 2336 6580, Present Address: Department of Medical Sciences, , University of Turin, ; Corso Dogliotti, 14, 10126 Torino, Italy

[3 ]GRID grid.460789.4, ISNI 0000 0004 4910 6535, Department of Biostatistics and Epidemiology, Gustave Roussy, , University Paris-Saclay, ; 114 Rue Edouard Vaillant, Villejuif, France

[4 ]GRID grid.460789.4, ISNI 0000 0004 4910 6535, Oncostat U1018, Inserm, , University Paris-Saclay, ; labeled Ligue Contre le Cancer, 114 Rue Edouard Vaillant, Villejuif, France

[5 ]GRID grid.488470.7, Nuclear Medicine, , Institut Universitaire du Cancer Toulouse Oncopole, ; 1 Avenue Hubert Curien, Toulouse, France

[6 ]GRID grid.413852.9, ISNI 0000 0001 2163 3825, Nuclear Medicine, Hospices Civils de Lyon, , Groupement Hospitalier Est, ; 59 boulevard Pinel, Bron, France

[7 ]GRID grid.413852.9, ISNI 0000 0001 2163 3825, Department of Medical Oncology, Hospices Civils de Lyon, , Groupement Hospitalier Est, ; 59 boulevard Pinel, Bron, France

[8 ]GRID grid.411439.a, ISNI 0000 0001 2150 9058, Thyroid and Endocrine Tumors Unit, , Pitié-Salpêtrière Hospital Sorbonne University, ; 47-83 Boulevard de l’Hôpital, Paris, France

Author information

Désirée Deandreis http://orcid.org/0000-0002-3817-6648

Article

Publisher ID: 5229

DOI: 10.1007/s00259-021-05229-y

PMC ID: 8426251

PubMed ID: 33619600

SO-VID: 681856d7-fa03-4b2f-acd9-8a30548ca891

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 30 October 2020

Date accepted : 1 February 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000801, Bayer HealthCare;

Award ID: NCT02390934

Award Recipient : Sophie Leboulleux

Custom metadata

ScienceOpen disciplines: Radiology & Imaging

Keywords: radium-223,refractory thyroid cancer,bone metastases,alpha emitters,leukemia

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ScienceOpen disciplines: Radiology & Imaging

Keywords: radium-223, refractory thyroid cancer, bone metastases, alpha emitters, leukemia

RADTHYR: an open-label, single-arm, prospective multicenter phase II trial of Radium-223 for the treatment of bone metastases from radioactive iodine refractory differentiated thyroid cancer

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Probing cerebral hemodynamics with BOLD fMRI

Most cited references 33

2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer.

From RECIST to PERCIST: Evolving Considerations for PET response criteria in solid tumors.

Alpha emitter radium-223 and survival in metastatic prostate cancer.

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