European Nuclear Medicine Guide
Na[131I]I, Sodium[131I]iodide, sodium iodide (131I) for therapy in association or sub-sequential to target therapy.
Administration: oral or intravenous (i.v.)
Na[124I]I, Sodium[124I]iodide, sodium iodide (124I) for PET/CT based Dosimetry
Administration: intravenous (i.v.)
Na[131I]I, Sodium[131I]iodide or Na[123I]I, Sodium[123I]iodide for SPECT/CT based Dosimetry
Administration: oral or intravenous (i.v.)
Restoration of Iodine-131 uptake in metastatic refractory thyroid cancer through the modulation of intracellular signalling pathways by tyrosine kinase inhibitors.
Sodium[131I]iodide is the milestone for thyroid cancer treatment but in two third of cases patients do not achieve a clinical objective response and become refractory [114,117]. The second line therapy in metastatic patients in case of progressive and high tumour burden disease is based on tyrosine kinase inhibitors administration. In several in-vitro studies, activated intracellular pathways have been demonstrated to induce a reduction/loss of sodium-iodine symporter (NIS) expression or function with subsequent reduction of iodine transportation into thyrocytes and iodine avidity in thyroid cancer lesions. According to pre-clinical data in mice, blockage of this hyperactivated pathways could lead to a re-expression of NIS on the cell membrane. Several compounds (i.e. retinoic acid) have been investigated in the past for redifferentiation approach in patients with distant metastases from thyroid cancer no longer Iodine-131 avid or with faint uptake but none demonstrated a significant effect. The first in human trial, designed at MSKCC on the basis of promising pre-clinical study in BRAF mutated mouse models, showed the potential of target therapy to reinduce a significant Iodine-131 uptake through the inhibition of MAPK cascade in patients treated by selumetinib (MEK inhibitor) before Iodine-131 treatment [118,119]. Eight patients among 20 initially included were finally treated with Iodine-131 and 7 had a confirmed partial radiological response 6 months after treatment. The same group tested vemurafenib in 12 BRAF mutated patients according to a similar design trial and observed partial response to Iodine-131 in 4 patients [120]. A third trial explored a selective BRAF V600 E inhibitor (dabrafenib) that was able to re-induce Iodine-131 uptake in 6/10 patients with 2 partial responses and 4 stable diseases after Iodine-131 treatment [121]. At this moment several pathways have been investigated or are under evaluation in thyroid cancer cells study: MAPK cascade involved in BRAF mutated tumours, the PI3K and the NOTCH signalling pathways but several other targets for redifferentiation approach seem to be promising [122–126].
Further studies in humans have been reported or are ongoing, testing other drugs or different drugs association (NCT03244956) [127–129].
Selumetinib has been tested also in different settings than metastatic patients, in particular in the adjuvant setting of patients at high risk of recurrence (ASTRA Phase III trial, NCT 018443062). Final results are pending.
The correlation between the reinduction of Iodine-131 uptake and the mutational status of the patients (BRAF, RAS, RET/PTC, TERT) is not still clear and should be further investigated.
Absolute contra-indications:
Pregnancy and breast-feeding.
Drug specific contra-indications should be considered for target therapy administration.
The criteria used to select patients in the available studies in humans follow the standard definition of refractory thyroid cancer according to international guidelines [130].
In the metastatic therapeutic setting:
In adjuvant setting:
The subset of patients that really could benefit of this approach is under debate. The emerging opinion is that redifferentiation program won’t be suitable for all patients with metastatic refractory disease and it should be addressed to patients with no iodine 131 avid disease and most likely slowly progressive. Further studies are needed to confirm this hypothesis.
In the MSKCC trials all patients performed a 124I PET/CT after rhTSH administration to evaluate the absence of Iodine-131 uptake and then all patients were treated for 4 weeks with target therapy. A second 124I PET/CT after rhTSH administration was then performed to evaluate the Iodine-131 uptake restoration and to perform lesional Dosimetry. In case of a presumed absorbed dose > 2000 cGy in the metastatic lesions and in case of a calculated MTA maximum tolerated activity < 300 mCi, patients were then treated with a personalized activity Iodine-131 after rhTSH administration [119,120]. The trial by Rotenberg et al proposed a treatment of 6 weeks with dabrafenib and a following empiric Iodine-131 treatment with 5.5 GBq [121]. A multicentre single arm phase II trial ongoing in UK propose Iodine-131 WBS to evaluate the iodine restoration uptake after 4 weeks-treatment with selumetinib and for lesional Dosimetry. An activity of 5.5 GBq after rhTSH is then indicated as treatment scheme [127]. Other retrospective studies report a much longer duration of target therapy before Iodine-131 treatment [131].
There is still no evidence about the correct therapeutic sequence, target therapy dose and duration and Iodine-131 activity to be administered.
Lesional Dosimetry is scheduled in clinical trials to confirm the indication for Iodine-131 treatment in case of a sufficient achieved absorbed dose in the lesions. Further studies’ results will give additional data on the impact of redifferentiation approach on normal organ and lesion dosimetry.
Methods to evaluate Iodine-131 restoration in the cited studies in humans vary from visual analysis or percentage changes in Iodine-131 uptake in case of diagnostic Sodium[131I]iodide [scan or by semiquantitative methods in case of 124I PET/CT. RECIST 1.1 criteria have been usually used to assess morphological response at 3 to 6 months after Iodine-131 treatment according to different trials.
The side effects of this approach are related to classical Iodine-131 treatment, in association to possible side effects specific for target therapy. Even if the duration of target therapy is usually limited some side effects, mostly grade 1-2 side effects, can occur during the first 2-3 weeks of treatment.
Research field.