European Nuclear Medicine Guide
Radiopharmaceutical:
Na[131I]I, Sodium[131I]iodide, sodium iodide (131I) for therapy in association with 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-thirds of cases patients do not show a clinically objective response and become refractory [29,30]. The second-line therapy in metastatic patients with progressive disease and high tumour exposure is based on administration of tyrosine kinase inhibitors. 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 these 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 a re-differentiation approach in patients with distant metastases from thyroid cancer that are 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 a promising pre-clinical study in BRAF-mutated mouse models, showed the potential of target therapy to re-induce a significant iodine-131 uptake through the inhibition of MAPK cascade in patients treated with selumetinib (MEK inhibitor) before iodine-131 treatment [31,32]. Eight patients among the 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 in a similarly designed trial and observed a partial response to iodine-131 in 4 patients [33]. 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 [34]. More recently, the association of selective drugs for BRAF-mutated tumours (dabrafenib and trametinib) showed very good results, with re-differentiation induced in 90% of the patients treated and prolonged partial responses [35]. Other association strategies need to be validated [36–38], several other pathways are under evaluation (the PI3K and the NOTCH signalling pathways), and several other targets (NTRAK or RET mutation) for the re-differentiation approach seem to be promising [39–43]. The correlation between the re-induction of iodine-131 uptake and the mutational status of the patients (BRAF, RAS, RET/PTC, TERT) seems increasingly important for a personalised approach.
Finally, selumetinib has also been tested in different settings other than metastatic patients, in particular in the adjuvant setting in patients at high risk of recurrence. In the ASTRA Phase III trial, NCT 018443062 [44], patients with DTC at high risk of primary treatment failure were randomly assigned 2:1 to selumetinib 75 mg orally twice daily or placebo for approximately 5 weeks, followed by radioactive iodine. No statistically significant difference in CR rate was observed between the two arms 18 months after RAI (selumetinib n = 62 [40%]; placebo n = 30 [38%]; odds ratio 1.07 [95% CI, 0.61 to 1.87]; P = .8205).
Absolute contraindications:
Pregnancy and breastfeeding.
Drug-specific contraindications 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 [45].
In the metastatic therapeutic setting:
Differentiated thyroid cancer (well and/or poorly differentiated).
At least one metastatic lesion not iodine-131 avid on diagnostic iodine-131 whole- body scan.
Iodine-131 avid lesion stable or progressive within 12–14 months according to RECIST 1.1 criteria despite previous iodine-131 treatments.
Mainly 2-[18F[FDG avid lesions at PET/CT.
The subset of patients that really could benefit from this approach is under debate. The emerging opinion is that the re-differentiation programme will not be suitable for all patients with metastatic refractory disease, and that it should be targeted at patients with disease that is not iodine-131 avid 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 the event of a presumed absorbed dose > 2000 cGy in the metastatic lesions and a calculated maximum tolerated activity (MTA) <21 GBq, patients were then treated with a personalised activity of iodine-131 after rhTSH administration [32,33]. The trial by Rotenberg et al proposed a 6-week treatment with dabrafenib and a subsequent empirical iodine-131 treatment with 5.5 GBq [34]. A multicentre single-arm phase II trial ongoing in the UK proposes iodine-131 WBS to evaluate the restoration of iodine uptake after 4 weeks of treatment with selumetinib and for lesional dosimetry, as well as MERAIODE trial with dabrafenib+trametinib. An activity of 5.5 GBq after rhTSH is then mostly indicated as a treatment scheme [36]. Other retrospective studies report a much longer duration of target therapy before iodine-131 treatment [46].
There is still no evidence about the correct therapeutic sequence, target therapy dose and duration, or iodine-131 activity to be administered.
Lesional dosimetry is scheduled in clinical trials to confirm the indication for iodine-131 treatment in the event of a sufficient achieved absorbed dose in the lesions. The results of further studies will supply additional data on the impact of the re-differentiation approach on normal organ and lesion dosimetry (absorbed radiation dose delivered specifically to individual lesions or tumours).
Methods to evaluate iodine-131 restoration in the cited studies in humans vary from visual analysis or percentage changes in iodine-131 uptake in the case of diagnostic sodium[131I] iodide scan to semi-quantitative methods in the case of 124I PET/CT. RECIST 1.1 criteria have usually been 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 those of classical iodine-131 treatment, in association with possible side effects specific to the target therapy. Even though the duration of target therapy is usually limited, some side effects, mostly of grade 1–2, can occur during the first 2–3 weeks of treatment.
Research field.