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

Désirée Deandreis,Laurence Leenhardt,Claire Bournaud,Sophie Leboulleux,Isabelle Borget,Aline Maillard,Lavinia Vija,Slimane Zerdoud,Christophe Sajous,Marie Terroir,Martin Schlumberger

doi:10.1007/s00259-021-05229-y

Abstract

PurposeThis 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.MethodsRADTHYR 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.ResultsTen 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.ConclusionThe 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 numberNCT02390934. Registration date 18.03.2015.

Highlights

Distant metastases occur in 4 to 10% of patients with differentiated thyroid cancer (DTC) [1]
The secondary objectives were to (1) evaluate the efficacy of six monthly administrations of Radium-223 by 18F-FDG PET/CT according to PET Response Criteria In Solid Tumor (PERCIST) criteria; (2) evaluate monthly the clinical benefits during treatment; (3) evaluate the time to occurrence of skeletal events; (4) evaluate the response on 99mTc-hydroxymethylene diphosphonate (HMDP) bone scan and on sodium-fluoride (18FNa) PET/CT after three and six monthly administrations of Radium-223; (5) describe monthly changes in serum alkaline phosphatase (ALP), bone-ALP, and thyroglobulin (Tg) during Radium-223 administration; and 6) assess the safety of Radium-223 according to NCI CTCAE version 4
We present the results of the statistical analyses performed on the whole study population

Summary

Introduction

Distant metastases occur in 4 to 10% of patients with differentiated thyroid cancer (DTC) [1]. Bone lesions are present in 20–40 % of patients with distant metastases; they can be synchronous or metachronous to primary thyroid tumor diagnosis and are the most challenging metastases to treat [4]. Bone lesions are often large with soft tissue infiltration, poor response to RAI, or progressive loss of RAI uptake with subsequent worst prognosis especially when present since the beginning of the clinical history [4, 6]. Local treatments such as surgery, external beam radiation, thermoablation, and cement injection may prevent skeletal-related events as well as bone resorption inhibitors such as denosumab or bisphosphonates [7–9]. The rapid occurrence of bone events remains frequent, occurring in one third of patients with bone metastases, highlighting the need for specific bone treatments [10]

Methods

Results

Conclusion