7. Treatment of primary metastatic DTC and PDTC - Management of persistence and recurrence of DTC – Thyroid Cancer

Version 1.2 · September 2026 · AWMF 031-056OL
Leitlinienprogramm Onkologie · Deutsche Krebsgesellschaft · Deutsche Krebshilfe · AWMF

Tumor persistence is present if vital tumor is still detectable after initial surgery and adjuvant or curative radioiodine therapy. This can be considered certain if extrathyroidal iodine storage and/or tumor-suspicious lesions are detected using [¹⁸F]FDG-PET/CT with a significantly increased Tg serum concentration. This must be distinguished from recurrence, in which full remission was initially diagnosed after surgery with or without radioiodine therapy.

7.1 Therapy of tumor persistence, recurrence and/or metastases - principles

7.1 · Consensus-based Recommendation 2025

In the relapsed or metastatic situation, the treatment concept shall be determined in an interdisciplinary tumor board: whether and how a remission or improvement or maintenance of quality of life can be achieved by using individual or a combination of treatment modalities.

Consensus: Strong consensus (96%)

The recurrence/persistence situation is too complex to make a general treatment recommendation. This must take into account the patient's general condition, age, treatment preference and ability to undergo treatment. The biology of the primary tumor, the extent of the primary surgical intervention, the location of the metastases, the extent of metastasis and known or suspected iodine avidity must be taken into account. Radioiodine therapy prior to a new operation enables the metastasis/local recurrence to be classified as iodine-avid or iodine-refractory, which is important in terms of prognosis and for any therapies that may be required later.

7.1.1 Locoregional persistence or locoregional recurrence

7.2 · Consensus-based Recommendation 2025

Locoregionally persistent or recurrent DTC, cervical soft tissue infiltrates and persistent or recurrent lymph node metastases should be treated surgically. The individual treatment plan should be recommended in the interdisciplinary tumor board in order to weigh up alternative, concomitant or subsequent treatment options, or monitoring observation for the individual patient.

Consensus: Strong consensus (96%)

The presence of lymph node metastases is an unfavorable predictor: Ricarte-Filho et al. analyzed the recurrence-free survival of patients with lymph node metastases. 246 patients in the period from 1980 to 2002 met the inclusion criteria. The presence of more than 3 lymph node metastases was a predictor of poorer recurrence-free survival. The combined presence of a BRAF mutation together with extranodal tumor spread was a predictor of disease-specific survival [952].

With the increasing use of hybrid imaging (SPECT/CT), small iodine-avid lymph node metastases are seen more frequently after RIT, which would have escaped detection by overlaying the iodine-storing residual thyroid tissue when using the planar technique. Lee et al. reported iodine-avid lymph node metastases in 4/61 patients (7%) in the low-risk group and 31/231 patients (13.4%) in the intermediate-risk group [165].

Ronga et al. reported on the benefit of RIT for the treatment of lymph node metastases: RIT is an effective treatment method for iodine-avid lymph node metastases if they are up to 10 mm in diameter [953][953]. These data confirmed earlier data from Trybek et al. according to which radioiodine was able to achieve a cure in 82.6% of patients (n=57 patients) using radioiodine when lymph node metastases (TxN1M0) were present [954]. Cao et al. also reported successful RIT of iodine-avid lymph node metastases [955]. Small lymph node metastases can thus be eliminated by adjuvant RIT. If small iodine-avid lymph node metastases are still detected after surgery and RIT, the result of the subsequent diagnostic ¹³¹I whole-body scintigraphy can usually be awaited. This measure and measurements of the Tg serum concentration during the course allow a decision to be made on how to proceed.

Ilhan et al. were able to show that small lymph node metastases could be successfully treated with radioiodine (activities used 2.0 - 7.0 GBq). In 65 patients, 67 of 70 lymph node metastases with a volume of less than 0.9 ml were successfully treated with radioiodine, whereas only 6 of 14 lymph node metastases with a volume greater than 0.9 ml were successfully treated. The sensitivity and specificity as well as the positive and negative predictive value for predicting treatment success using this cut-off value were 92% and 73% and 96% and 57% respectively. The results of the short-axis diameter with a cut-off value of less than 1.0 cm yielded values of 90%, 69%, 94% and 56%. The majority, i.e. 88% of ¹³¹I-positive lymph node metastases were thus successfully treated by RIT. Ilhan et al. were thus able to show that small iodine-avid lymph node metastases in particular respond well to radioiodine therapy (tumor volume < 0.9 ml and short-axis diameter < 1 cm). Over a mean follow-up period of 64 months, 56/65 patients (86%) did not have an elevated thyroglobulin level. Volume and short-axis diameter were predictors of treatment success [956].

Wu et al. confirm these data: in their collective of 118 patients with iodine-avid LN metastases and exclusion of distant metastases, radioiodine achieved complete remissions in 33/118 patients (28%) and partial remissions in 62/118 patients (53%). Serial RIT achieved an efficacy of 80.5% (95/118 patients), with up to three RITs with cumulative administration of 3.7-16.7 GBq radioiodine [957]. He et al. also confirm the efficacy of RIT for the treatment of lymph node metastases with a success rate of 88% in 218 patients. The response rate to RIT was 88% (including a cure rate of 20.6% and an improvement rate of 67.4%). Of the total of 406 lymph nodes from 218 patients, 319 lymph nodes (78.6%) were judged to be effectively cured, including 133 (32.8%) lymph nodes that completely disappeared and 186 (45.8%) lymph nodes that shrank. 87 (21.4%) of the 406 lymph nodes showed no obvious morphological changes [958].

If lymph node metastases cannot be successfully treated with RIT, surgery or external radiation may be considered.

Local recurrences of follicular thyroid carcinomas usually manifest as tumor infiltration of the perithyroid soft tissue and less frequently in the form of lymph node metastases. If a resectable soft tissue recurrence is detected in the imaging procedures, this should be extirpated by a systematic compartment-oriented neck dissection. If this has already been performed in a previous procedure, a focused tumor extirpation can also be performed with a sufficient safety margin. If the findings are unclear, the diagnosis can be confirmed preoperatively using an FNAC.

Extensive resection of the trachea and/or esophagus should only be performed in well-differentiated, minimally invasive FTC, taking into account the possibility of distant metastasis, and is only indicated in exceptional cases of grossly invasive FTC.
In terms of possible complications and the oncological radicality to be achieved, recurrent FTC surgery is a very demanding procedure that should only be performed in clinics with the appropriate expertise.
As with all other recurrent thyroid cancer surgery, the procedure should be performed using intraoperative neuromonitoring [959], [960].

7.3 · Consensus-based Recommendation 2025

In a palliative situation, metastases that are threatening and/or impair the quality of life (e.g. skeletal metastases that threaten stability with imminent paraplegic symptoms, metastases with nerve infiltration or vascular erosion, brain metastases) should be treated specifically.

Consensus: Strong consensus (100%)

7.4 · Consensus-based Recommendation 2025

In the case of progressive radioiodine-refractory extensive disease with no other treatment option, the indication for systemic drug therapy shall be examined and discussed with the patient rather than a wait-and-see approach.

Consensus: Strong consensus (100%)

Most patients with a differentiated thyroid carcinoma can be cured by the initial therapy (surgery, possibly with subsequent radioiodine therapy). Figures on the frequency and localization of recurrence as well as the frequency and localization of metastasis already present at the time of diagnosis are heterogeneous. In about 1 - 4% of PTC patients and in about 7 - 28% of FTC patients, distant metastases are already detected initially [961]. Prompt targeted therapy is necessary here. In patients with distant metastases, a delay in RIT of more than 6 months means poorer overall survival, which has already been demonstrated in a follow-up period of only 5-6 years [962].

Shokoohi et al. reported on Canadian data showing that 87% of primary metastatic DTC patients achieve complete remission. However, 136 patients (13%) in their collective had a recurrence, of which 37 patients (3%) had distant metastases, predominantly localized in the lungs (76%) or skeleton (30%) [963].

Carvalho et al. analyzed 4,085 patients in the period from 1996 to 2015. Patients with extrathyroidal infiltration or cervical lymph node metastases or a higher risk of recurrence received radioiodine therapy after surgery. After a median follow-up period of only 58.7 months, 176 patients were found to have a recurrence (4.3%), mostly in lymph nodes. Distant metastases were found in 18 patients (0.4%). The recurrence rate in the low-risk arm was 1.6%, in the intermediate stages 7.4% and 22.7% in the high-risk patients. Distant metastases were found in 18 patients (0.4%) [964].

Goffredo et al. reported 2.2% of DTC patients in the SEER registry (n = 1,291) with metastases at diagnosis; 5-year survival in this metastatic group was 59%, which was significantly worse compared to non-metastatic patients [652].

Data on survival are heterogeneous, with Chow et al. reporting a 10-year survival rate of 85% and a 20-year survival rate of 71% in 164 metastatic patients [965]. Sampson et al. published that the 3-year survival of metastatic FTC patients was 62% worse than that of metastatic PTC patients [966].

Nixon et al. published worse data on long-term survival. Around half of metastatic patients died within the next 5 years if distant metastases were present at the time of diagnosis [967]. Lin et al. also confirm the reduced prognosis of patients with distant metastases: of 70 PTC patients with distant metastases, 70% had died of their disease after a median follow-up period of 10.1 years [968]. Metachronous metastases also have a poor prognosis with a 10-year survival rate of only 57% [969].

According to Li et al., radioiodine treatment is an effective treatment for metastatic patients, with metastatic patients receiving 22 GBq (600 mCi) or more of radioiodine [970].

Generally recognized oncological principles also apply to DTC. The more advanced the disease, the more rapidly it progresses and the more poorly differentiated the tumor, the worse the prognosis. In the case of DTC, however, the special feature is that better differentiation is associated with the preservation of iodine metabolism. The resulting radioiodine therapy can be curative even in the case of extensive metastasis.

The procedure for the individual metastatic localizations will be discussed below. Multiple factors are taken into account when making an individual treatment decision. In addition to the number and location of metastases (tumor burden), tumor dynamics are important. Patient age, co-morbidities, life expectancy and patient wishes play an important role.

The following structured procedure applies to persistent tumor burden or recurrence:

A curative approach uses the treatment options of surgery and/or RIT and/or percutaneous radiotherapy alone or in combination. If metastases are considered inoperable, it must be checked whether a cure can still be achieved with radioiodine therapy, possibly in combination with percutaneous radiotherapy. Otherwise, the curative concept has been exhausted.

If the intention is palliative, surgery/RIT/radiotherapy or a combination may be considered first. If these measures are not indicated or are unsuccessful, controlled waiting or systemic drug therapy may be considered. In addition, redifferentiation therapy (with a low probability of success) can be discussed with the patient; please refer to the relevant chapter.

As long as sufficient iodine storage of the metastases is proven or can be assumed, and if the tumor burden cannot be treated surgically, RIT is usually the treatment of choice. The associated scintigraphy provides information about the radioiodine storage capacity of the metastases and thus also their degree of differentiation. Depending on this result, [¹⁸F]FDG-PET/CT should be planned, especially if the metastases are no longer iodine-avid but de-differentiated.

In the case of localized metastasis, the possibility of resection should be considered as the primary treatment option. The smaller the tumor mass and the higher the degree of differentiation, the better the results of RIT. Especially in the case of lung metastases - including disseminated metastases - RIT can be considered as the sole therapeutic measure. In the case of inoperable tumors and tumors that cannot be completely removed by surgery, radioiodine therapy is carried out if a relevant radioiodine storage is proven or can be assumed.

This approach is supported by a number of retrospective studies reporting on the results of RIT in metastases:
Schlumberger published in 1996 on the benefits of RIT in patients with lung and bone metastases. Patients with a very good response to RIT in the sense of a complete response had a significantly better 15-year overall survival than those who did not (89% versus 8%) [971]. Durante et al. reported on 444 metastatic PTC and FTC patients from 1953 to 1994 with lung (n = 223), bone (n = 115), lung and bone metastases (n = 82), or other metastatic sites. Serial therapies were given at 3-9 month intervals in hypothyroidism for the first two years and then at annual intervals. 43% of patients achieved complete remission on the ¹³¹I whole-body scintigram [972].

Ito et al. (Japan) evaluated 5,969 PTC patients, of whom 71 (1.2%, period 1987 - 2004) had distant metastases at the time of initial diagnosis, predominantly with exclusive lung metastasis (n = 60), or otherwise exclusive bone metastasis (n = 5), lung and bone metastases (n = 5) and 1 pt. with brain metastases. Patients with iodine-avid metastases received one or repeated RIT. 15 patients died at a median follow-up of 7 years and 10 months. The 5- and 10-year survival rates were 78.8 ± 5.2 % and 76.3 ± 5.7 %, respectively [973], [611].

Li et al. analyzed the benefit of RIT in 1,608 patients with distant metastases using the SEER database, including 521 patients (32.4 %) with bone metastases, 90 patients (5.6 %) with brain metastases, 158 patients (9.8 %) with liver metastases, 995 patients (61.9 %) with lung metastases and 50 patients (3.1 %) with other metastases. Distant metastatic patients under 45 years of age who underwent RIT had a 5-year survival rate of 91.7%, while those who underwent percutaneous radiotherapy had a rate of only 45.5%, which was significantly lower than RIT (external beam radiotherapy versus radioiodine therapy), adjusted hazard ratio [HR]: 5.5; 95%CI: 1.672-18.804, p < 0.005). In patients older than 45 years, the 5-year survival rate was 69.1%, compared to 20.0% in patients who underwent EBRT [974].

Overall, metastatic disease often requires an individualized approach that includes a combination of therapeutic options (surgery, radioiodine therapy, radiation, etc.). Shokoohi et al. published their experiences on recurrence therapy and achieved a very good treatment outcome in 67% of patients with multimodal therapy concepts [963]. Different collectives and different treatment concepts also result in variable survival rates. Kim et al. reported on 242 patients with a 5-year survival rate of 85% and a 10-year survival rate of 68% [975].

In addition to the most common metastatic sites (lymph node, lung, skeleton), Madani et al. published on rare metastatic sites [976]. Mihailovic et al. confirm that the radioiodine avidity of metastases or the possibility of treating metastases with radioiodine is associated with a better prognosis than if this is not the case [977]. Patients with metastases in three or more organ systems have a particularly poor survival. Zhang et al. reported on 37/717 patients (5.2%) with metastases in three or more organ systems. The 5-year and 10-year survival was 45.9% and 37.8%, respectively, for patients with distant metastases in three or more organ systems versus 74.5% and 64.9%, respectively, for patients with distant metastases in one or two organ systems.

Radioiodine accumulation in the metastases was the main factor for longer survival [978]. Zunino et al. focused on the occurrence of rare organ metastases and described metastases in 36/3,982 patients (0.9 %), predominantly localized in the CNS. These patients with rare organ metastases often had a poor prognosis: after a median follow-up period of 13 months, 21/36 (58.3 %) patients had died as a result of DTC [979].

7.2 Therapy of tumor persistence, recurrence and/or metastases

7.2.1 Lung metastases

7.5 · Consensus-based Recommendation 2025

Unless the metastases are known to be radioiodine-refractory, RIT should be performed in the case of multilocular or disseminated lung metastases.

Consensus: Strong consensus (96%)

7.6 · Consensus-based Recommendation 2025

Local therapeutic procedures (surgical resection or external radiotherapy) or "watch and wait" can be used for low grade, oligofocal lung metastasis, especially in radioiodine-refractory tumors. An individual treatment plan should be recommended in the interdisciplinary tumor board.

Consensus: Consent (95%)

Sabra et al. presented data on the course of patients with lung metastases who were treated only with TSH-suppressive levothyroxine therapy after thyroidectomy and RIT. The median overall survival of the 199 patients was 10.5 years, the median progression-free survival 3.7 years. At the time of the last follow-up (median 6.9 years after diagnosis of lung metastases), 68% of patients had tumor progression and 46% of patients had died. This collective can be regarded as a reference collective for the spontaneous course of DTC patients with lung metastases [980].

In the case of lung metastasis, a distinction must be made between miliary seeding and multiple single or multiple well-defined metastases [981]. In the former case, it is not possible to determine the size of the metastases or perform a morphological check. The success of radioiodine therapy is good. A cure is possible. When planning the treatment of lung metastases using RIT, the patient's age, the number and distribution pattern of the lung metastases (micro- versus macronodular lung metastases and multilocular-disseminated versus oligofocal tumor burden) and - if preliminary images are available for comparison - the growth dynamics must be taken into account. An increase in the size of lung metastases and the loss of radioiodine accumulation are the cause of different clinical courses and differences in prognosis [982].

Song et al. reported on 256 patients with radioiodine-avid lung metastases (256/372, 68.8 %). Of these patients, 156 patients (156/256, 60.9%) showed a significant decrease in serum thyroglobulin levels after RIT and 138 patients (138/229, 60.3%) showed a morphologic decrease in lung metastases on follow-up CT. Song et al. reported a cure in 62/256 patients (24%) by RIT [983]. Multivariate analysis showed that age, the presence of multiple distant metastases and the size of lung metastases were significant independent variables between the radioiodine-avid and non-radioiodine-avid groups. Patients under 40 years of age, lung metastases up to 1 cm in diameter and possibly also lymph node metastases had a better survival than patients over 40 years of age, lung metastases over 1 cm in diameter and other organ metastases, for example in the skeleton [983]. Yang et al. also reported favorable treatment effects with radioiodine: Of 151 patients with lung metastases, 17 patients achieved a complete response with RIT and 71 patients a partial response. 63 patients had no response. Survival was 72.2% after 5 years, 55.2% after 10 years and 51.3% after 15 years [566].

These data are confirmed by Wang et al. in an evaluation of 20 patients and a meta-analysis. Wang et al. reported a response rate to RIT of 40%, but 58% in the meta-analysis, which had its reasons in the composition of the therapy collectives [984]. In a recent publication, Wang et al. report on the benefits of RIT for the treatment of patients with lung metastases: 83/117 patients (71%) responded to the therapy, documented by a decreasing thyroglobulin level [985]. High cumulative therapy activities were used. Yang et al. report a mean cumulative activity of 19.6 GBq (530 mCi) (range 3.7 - 61 GBq (100 to 1650 mCi)) ¹³¹I. The effectiveness in the group receiving up to 14.8 GBq (400 mCi) cumulative radioiodine was lower (10-year survival rate 38%) than in the group receiving at least 33.3 GBq (900 mCi) (10-year survival rate 80%) [986]. In their meta-analysis, Zang et al. report a pooled effectiveness of RIT for pulmonary metastases of 58% [984].

Kim et al. point to prognostic differences between micrometastasis (lung metastases < 1 cm) and macrometastasis (lung metastases ≥ 1 cm). Macronodular metastases were found in 27/112 patients (24%). These patients had a significantly poorer response to therapy and poorer progression-free survival. Radioiodine avidity had a significant prognostic impact in the group with micronodular lung metastases [987].

Lin et al. reported on lung metastases in FTC patients: 70/272 patients (25.7%) had lung metastases, the 10-year survival rate was 54%. Tumor size and cumulative radioiodine activity had an impact on survival, with a cumulative average of 14.2 ± 1.8 GBq (383 ± 48 mCi) ¹³¹I administered to these patients [988].

Zhu et al. refer to the prognostically unfavorable group of de-differentiated, [¹⁸F]FDG-avid lung metastases [559]. Identifying a prognostically unfavorable group with a short tumor doubling time of less than 1 year can guide the decision to treat with kinase inhibitors [989]. Demarcated lung metastases, on the other hand, can be morphologically monitored and this information can be taken into account when determining the indication for RIT. The younger the patient and the more extensive the lung metastasis, the more generous the indication for RIT. The older the patient and the slower the tumor growth or the Tg doubling time (> 6 - 12 months), the more likely it is that a wait-and-see approach will be chosen [989].

Micronodular, iodine-storing lung metastases (not always visible on CT, often not visible on conventional chest X-ray) can be treated with ¹³¹I at intervals of 6 - 12 months if necessary. The RIT can be repeated as long as there is a relevant ¹³¹I storage. A further RIT is made dependent on the response to the previous RIT. Usually you want to see a (significant) drop in the tumor marker thyroglobulin. There is a treatment corridor with a few high-dose cycles with the longest possible treatment-free intervals versus a higher number of treatment cycles with careful dosing of radioiodine. The former approach is preferable.

The subgroup with micronodular or miliary metastasis has the best prospects of achieving a complete remission. Kim et al. confirmed that complete remissions were found in the group with micronodular metastases [990]. A good response to therapy in micronodular metastases is also reported by Long et al. with a response rate of 95.2 % (20/21 patients) in whom the lung metastases were only visible on iodine imaging but not on CT [991].

If there was initially extensive micronodular lung metastasis, a still measurable Tg level is often present after repeated RIT and decreasing iodine storage of the lung metastases. The indication for a further RIT is then based on the intensity of ¹³¹I storage in the previous ¹³¹I whole-body scintigraphy and the bone marrow reserve (neutrophils, platelets). ¹²⁴I-PET is not very suitable for ruling out disseminated lung metastases; in this situation, a ¹³¹I post-therapy whole-body scintigraphy is superior. The level of therapy activity (standard activity, weight-adapted for children if necessary and the number of RIT depends on the response to previous treatments. When planning repeated radioiodine therapy, possible side effects must be taken into account. If the situation is stable, it may be possible to wait for years and only plan a new RIT if there is clear biochemical or morphological progress. The prognosis is very good, especially in children and adolescents under TSH suppression with levothyroxine [619].

Radiation pneumonitis or radiation fibrosis are rare complications after repeated high-dose ¹³¹I therapies for disseminated lung metastasis. Corticosteroids may also be considered as an adjunctive medication in RIT of disseminated lung metastases to prevent pulmonary fibrosis, but the evidence for this approach is low.

Macronodular, iodine-storing lung metastases should also be treated with ¹³¹I in the event of iodine storage. Treatment activity and the number of RITs depend on the response to previous treatments, disease progression, patient age, metastasis size, the absence/detection of other metastases and the prospects of success of other treatment options. A response to therapy speaks in favor of repeating radioiodine therapy.

In the case of lung metastases without iodine storage, the indication for surgical or ablative procedures should be reviewed. The possibility of atypical, tissue-sparing resection or local therapeutic alternative procedures such as radiofrequency ablation can be used.

In a review (9 studies with 112 children), Pawelczak et al. analyzed the treatment response of lung metastases in children and young adults < 21 years. A complete response was achieved in 47.3% of patients, a partial response in 38.4% and no response in 14.3%. The disease-specific mortality rate was 2.7%. Treatment-associated morbidity was low: only one patient had a secondary malignancy, one of eleven patients examined developed pulmonary fibrosis [463]. Wang et al. also investigated the efficacy of RIT for pulmonary metastases in children: RIT was effective in 55.9% (38 of 68) of patients, disease was stable in 26.5% (18 of 68) and ineffective in 17.6% (12 of 68 children) [992].

7.2.2 Skeletal metastases

7.7 · Consensus-based Recommendation 2025

Radioiodine therapy for the treatment of iodine-avid bone metastases shall only be used in consideration of the number and distribution pattern of the metastases and patient-specific factors. Depending on the extent (e.g. risk of fracture) of the osseous metastases, further therapeutic measures shall be planned.

Consensus: Consent (89%)

Skeletal metastases occur in about 4% of DTC patients and are mainly localized in the spine, pelvis and ribs [993]. Qui et al. reported a lower frequency of 244/67,176 patients (0.36%) of the SEER database with synchronous skeletal metastases, the median survival of these patients was 22 months [994].

Skeletal metastases imply a worse prognosis: at a median follow-up of 11 +/- 9.6 years after diagnosis of DTC, 55% of the 64 patients followed up in this study died [993]. In their review article, Iñiguez-Ariza et al. reported a median survival of 4 years for DTC patients with skeletal metastases [995].

One of the rare localizations of skeletal metastases is the cranial skeleton. Varadarajan et al. reported on 59 patients with metastases in the cranial skeleton based on a review of the published literature. The treatment options are resection, radiotherapy and/or administration of radioiodine [996]. A rare but dramatic complication for the patient is paraplegia due to vertebral fractures of osteolytic metastases [997].

The treatment concept for skeletal metastases must be interdisciplinary. A cure is unlikely. Ramadan et al. specifically investigated the management of metastases in the spine and found a lack of an established treatment concept [998]. There is a spectrum of treatment options that includes surgery, local embolizing procedures, RIT, external radiation and drug therapy options (biphosphonates, VEGF receptor targets, etc.). Patient survival is better if the skeletal metastases can be completely removed or treated with radioiodine [998].

The therapy aims to achieve a high quality of life and avoid pathological fractures. Criteria for selecting a suitable treatment strategy for bone metastases are the risk of pathological fracture (metastases in weight-bearing skeletal segments), the risk of neurological complications (spine), pain symptoms, the storage behavior for ¹³¹I and the radiosensitivity of adjacent organs (percutaneous radiotherapy). Complete surgical resection of isolated bone metastases leads to an improved outcome [998]. Symptomatic bone metastases that cannot be resected or can only be resected incompletely can be treated with a combination of different therapy methods (radioiodine therapy, percutaneous radiotherapy, local interventional therapy, systemic therapy).

Califano et al. reported on 52 DTC patients in a multicenter retrospective evaluation from Argentina, two thirds of whom had multiple skeletal metastases. FTC patients metastasized to the skeleton more frequently (7 - 28%) than PTC patients (1.4 - 7%). The spine is often the site of skeletal metastasis. Skeletal pain was the initial symptom in half of the patients. 42/52 patients were treated with radioiodine, of these 30 patients received a cumulative activity of more than 22.2 GBq (600 mCi ) ¹³¹I. 2- and 5-year survival rates were 64 and 38% respectively. At a median follow-up of 34 months, half of the patients died, a quarter in direct connection with the tumor disease [999].

Small bone metastases without abnormalities on morphological imaging are most likely to be cured with a few radioiodine therapies, especially in young patients [1000], [1001]. In contrast, only a few patients with large and multiple metastases were cured with radioiodine; 5-year survival in these patients was around 60 % [972].

Kondraciuk et al. reported on 74 patients with bone metastases. Those treated with external beam radiotherapy had a better survival: 5-year survival was 59%, median survival 92 months. TERT or BRAF mutations had no unfavorable effect on survival [1002]. Wu et al. report on a retrospective analysis of 77 patients with skeletal metastases, of whom 23/77 patients had received a single therapy and 54/77 multiple therapies; the median survival in the first group was 3.9 years and 7.7 years in the second group. Patients treated with radioiodine within 6 months and those who received radiotherapy had better survival [62].

Mazziotti et al. reported on the Italian MOSCATI study (Metastases Of the Skeleton from CArcinoma of the ThyroId). 131 patients with skeletal metastases were included in this study. Overall mortality was significantly reduced by RIT (HR 0.10; p = 0.02), while drugs interfering with bone metabolism (p = 0.36), external radiotherapy (p = 0.54) and surgical interventions (p = 0.43) had no significant effect on skeletal metastases [1003].

In a recent review, Kato et al. describe the range of treatment options including surgical resection [1004]. Rare localizations such as skeletal metastases of the facial skull may require special surgical interventions [1005], [1006].

Deandreis et al. found no advantages in the comparison of an empirical versus dosimetric approach in the treatment of skeletal metastases using radioiodine [1007].

7.2.3 Brain/CNS metastases

7.8 · Consensus-based Recommendation 2025

When planning the treatment of brain and spinal canal metastases, surgical resection or external radiotherapy shall be considered first. Radioiodine therapy can be used for brain or CNS metastases, but is less effective than the former procedure.

Consensus: Strong consensus (96%)

7.9 · Consensus-based Recommendation 2025

In the case of cerebral or spinal metastases with a risk of compression, glucocorticoids can be administered with the aim of edema prophylaxis or edema reduction.

Consensus: Strong consensus (100%)

Brain metastases are rare. Hong et al. found brain metastases in 25/4,683 DTC patients (0.5%), of these 24 patients had further metastases outside the CNS. 20/24 patients underwent surgery, 4 received radiotherapy and one patient received "best supportive care". The median survival after diagnosis of brain metastases was 27 months [1008]. Osborne et al. reported on 79 DTC patients with brain metastases. The median survival of these patients was only 18 months, which was comparable to the 17.5 months reported in a publication by Wu et al. [1009]. A maximum of 3 brain metastases and surgical resection improved survival [1002]. Even less favorable are the data from Simões-Pereira et al., who reported on 27 patients with brain metastases with a median survival of only 5 months; only the patients who were offered surgery had a slightly better survival [1010]. Wu et al. published 22/2,013 DTC patients with brain metastases (1.1%) from 2000-2020 with a median survival of 17.5 months. Only neurosurgical measures had a favorable impact on survival [1009]. Slutzky-Shraga et al. confirm these statements [1011].

Surgical resection is therefore the primary treatment option for brain metastases, regardless of radioiodine storage. If the CNS metastases are not amenable to a surgical procedure, percutaneous or stereotactic radiotherapy is recommended. If ¹³¹I therapy of iodine-avid CNS metastases is considered, concomitant glucocorticoid administration should be recommended to minimize the potential swelling of metastases or the risk of concomitant peritumoral edema due to TSH stimulation and β-radiation of RIT. RIT is less effective than surgery or external beam radiotherapy for the treatment of brain metastases and is therefore usually a third choice treatment. The benefit of glucocorticoid therapy to reduce pressure symptoms in RIT is not well established, but clinical experience shows that corticosteroids work well for pre-existing symptoms.

Gomes-Lima published on 24 patients with brain metastases. Patients who underwent surgery had a longer median survival time than those who did not undergo surgery (27.3 months versus 6.8 months; P = 0.15). Patients who underwent stereotactic radiosurgery had a longer median survival time than those who did not receive such therapy (52.5 months vs. 6.7 months; P = 0.11). Twelve patients (50%) were treated with tyrosine kinase inhibitors (TKIs), and these had better survival than those who did not receive TKIs (median survival 27.2 months vs. 4.7 months; P , 0.05) [1012].

Although patients with brain metastases have a poorer prognosis, long-term survivors have been reported in individual cases [1013], [1014].

7.3 When is systemic therapy indicated? And which medication should be used?

7.10 · Consensus-based Recommendation 2025

Patients with radioiodine-refractory metastatic DTC that is asymptomatic, stable or minimally progressive, with a low probability of developing rapid progression with clinically significant complications and no indication for local therapy, shall be observed under TSH-suppressive therapy. Regular imaging checks (every 3-12 months) are recommended with evaluation in the interdisciplinary tumor board in the event of clinically significant progression.

Consensus: Strong consensus (100%)

Patients with radioiodine-refractory metastatic DTC often have indolent clinical courses for years without any impairment of their quality of life. Despite the great progress made in the systemic treatment of radioiodine-refractory DTC, it must be borne in mind that complete remissions have only been described in a few individual cases to date and there is insufficient data on the prolongation of overall survival [1015], [24], [60], [1016], [1017]. It also remains unclear on the basis of the current data whether starting treatment earlier improves therapeutic efficacy. This must be carefully weighed up against the high quality of life of patients with advanced radioiodine-refractory DTC, who often have very long stable courses. In view of the sometimes not insignificant side effect profiles of systemic therapy options with a low but clinically relevant mortality risk (1.5-2%) [1018], the motto "less is more" therefore still applies today in line with the current international guidelines [24], [60], [1016], [1017]. The use of molecularly targeted therapies is only indicated if there is significant progression with a high tumor burden, local therapy measures are no longer useful and a Watch & Wait strategy can no longer be justified. The extent of the metastasis, the symptoms caused by the tumor disease, the co-morbidities and the growth dynamics of the radiologically evident lesions are taken into account.

No studies are available to determine adequate intervals for staging examinations as part of the Watch & Wait strategy. Staging intervals of 3-12 months are reasonable, taking into account the tumor burden, growth dynamics and the location of the metastases. Significant progression is assumed according to RECIST criteria if there is an increase of at least 20% in the sum of the longest diameters of the target lesion, if significant new metastatic lesions occur or if tumor-induced symptoms occur. An increase in the tumor marker thyroglobulin alone without morphological progression is not a basis for starting systemic therapy [24].

7.11 · Evidence-based Recommendation 2025

Systemic therapy with the approved multityrosine kinase inhibitors sorafenib, lenvatinib, or cabozantinib (from second-line) shall be considered as part of an evaluation in the interdisciplinary tumor board in patients with radioiodine-refractory DTC/PDTC if metastatic, rapidly progressive (according to RECIST), symptomatic and/or locally immediately threatening disease is present without meaningful local treatment options.

Recommendation grade

A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht

Level of evidence

⊕⊕⊕⊝

Sorafenib: OS [Brose, MS et al. 2014]

⊕⊕⊝⊝

Sorafenib: PFS [Brose, MS et al. 2014]

⊕⊕⊕⊕

Lenvatinib: OS [Schlumberger, M et al. 2015]

⊕⊕⊕⊝

Lenvatinib: PFS [Schlumberger, M et al. 2015]

⊕⊕⊕⊕

Cabozantinib: OS [Brose, MS et al. 2021], [Brose, MS et al. 2022]

⊕⊕⊕⊝

Cabozantinib: OS [Brose, MS et al. 2021], [Brose, MS et al. 2022]

Consensus

Strong consensus (100%)

References

[1019] [1020] [1021] [1022]

There are 3 randomized controlled phase 3 studies on the approved multityrosine kinase inhibitors (MKI) sorafenib (DECISION Trial) [1019], lenvatinib (SELECT Trial) [1020] and the recently approved cabozantinib in second-line therapy (COSMIC-311) [1021]. An update on the latter study has been published [1022].

Based on a randomized, placebo-controlled multicenter phase 3 study (DECISION study) in patients with radioiodine-refractory DTC (sorafenib n=207; placebo n=210), sorafenib was approved in 2014 for the treatment of progressive locally advanced or metastatic radioiodine-refractory DTC. Progression-free survival (PFS) was prolonged to 10.8 months in the treatment arm vs. 5.8 months in the placebo arm, with tumor stabilization in 42% of patients and partial remission in 12.2%; there were no complete remissions. Adverse events were more common in the sorafenib arm (98.6%) than in the placebo arm (87.6%), requiring treatment interruption in 66.2%, dose reduction in 64.3% and treatment discontinuation in 18.8%, with hand-foot syndrome (76.3% vs. 9.6%), diarrhea (68.6% vs. 15.3%), alopecia (67.1% vs. 7.7%) and rash (50.2% vs. 11.5%) reported most frequently [1019].

Lenvatinib was approved as a further oral MKI on the basis of an international, randomized, multicenter phase 3 study (SELECT) for patients with progressive radioiodine-refractory DTC (lenvatinib n=261; placebo n=131) in 2015. It showed a PFS extension of 14.7 months to 18.3 months in the lenvatinib arm versus 3.6 months in the placebo arm, with an objective response rate (ORR) in the lenvatinib group of a remarkable 64.8%, which also included 4 complete remissions. Tumor stabilization was achieved in an additional 23% of patients in the lenvatinib arm. A PFS extension was seen both in treatment-naïve patients (PFS 16.7 months) and in patients who had already received prior therapy with an MKI (PFS 15.1 months), demonstrating the efficacy of lenvatinib in second-line therapy as well. A significant prolongation of OS was not observed for the overall study population, but could be demonstrated for the subgroup of older patients (> 65 years) [1023]. Adverse events occurred in 97.3% of patients in the lenvatinib arm vs. 59.5% of patients in the placebo arm, requiring dose reduction in 67.8%, treatment interruption in 82.4% and treatment discontinuation in 14.2% of patients, with hypertension (67.8% vs. 9.2%), diarrhea (59.4% vs. 8.4%), fatigue syndrome (59% vs. 27.5%), loss of appetite (50.2% vs. 11.5%) and weight loss (46.4% vs. 9.2%) were most frequently reported [1020].

On the basis of convincing data with very good efficacy of cabozantinib in the second- or third-line setting in all histologic DTC subtypes, including poorly differentiated DTC (PDTC), an international multicenter phase 3 study of cabozantinib was conducted in patients with radioiodine-refractory DTC after progression on up to two prior antiangiogenic MKI therapies (COSMIC-311) (cabozantinib n=170; placebo n=88). PFS was 11 months in the treatment arm vs. 1.9 months in the placebo arm (PFS 16.6 months for pretreatment with sorafenib without lenvatinib; PFS 5.8 months for pretreatment with lenvatinib without sorafenib; PFS 7.6 months for pretreatment with sorafenib and lenvatinib). The ORR was 11% for cabozantinib, which included complete remissions (1%), vs. 0% in the placebo arm. Adverse events were more common in the cabozantinib arm (98%) than the placebo arm (85%), requiring dose reduction in 67% and leading to treatment discontinuation in 9%, with diarrhea (62% vs. 3%), hand-foot syndrome (47% vs. 1%) and hypertension (32% vs. 3%) reported most frequently [1021], [1022]. Based on these data, cabozantinib was approved in 2022 for the treatment of adults with locally advanced or metastatic radioiodine-refractory DTC who have experienced progression during or after prior systemic therapy.

None of the studies showed an overall survival benefit with the limitation of the cross-over design. For lenvatinib, a significant prolongation of overall survival was demonstrated in a subgroup analysis for older patients (> 65 y.), who at the same time had significantly more severe side effects (grade ≥3) (89 vs. 67%) and required dose modification more frequently [1023].

In the presence of contraindications or failure of the approved MKI, a number of substances based on efficacy data in phase 2 trials are also available for use in individual treatment trials or optimally - if available - as part of trials, including everolimus [1024], pazopanib [1025], vandetanib [1026], [1027], sunitib [1028], [1029] and axitinib [1030], [1031] (National Comprehensive Cancer Network Guidelines, Thyroid Carcinoma, 2022).

7.12 · Consensus-based Recommendation 2025

In patients with metastatic radioiodine-refractory DTC/PDTC, a molecular genetic analysis of the tumor, including gene fusions, shall be carried out before deciding on the type of systemic therapy so that the use of selective inhibitors can be discussed in the interdisciplinary tumor board.

Consensus: Strong consensus (100%)

Due to the increasing characterization of molecular alterations, at least some of which have been identified as oncogenic drivers, selective inhibitors have also become the focus of interest in radioiodine-refractory DTC in recent years. Based on the current data, a molecular genetic analysis of the tumor is therefore recommended for all patients with radioiodine-refractory progressive DTC so that the use of selective inhibitors can be discussed in an interdisciplinary team. Selective inhibitors are not only used for contraindications to the use of VEGFR-targeted MKI (relative contraindications include, in particular, poor cardiac function, recent myocardial infarction, poorly controlled hypertension, colitis, diverticulitis, ulcer disease, large or poorly healing wounds, intestinal perforations, tumors with invasion of the trachea/esophagus/large vessels, hemoptysis, anticoagulant therapy, very low body weight), but should also be discussed in the interdisciplinary tumor board as alternatives to MKI with a lower side effect rate and convincing effectiveness [1032].

7.13 · Consensus-based Recommendation 2025

In patients with radioiodine-refractory DTC/PDTC who have RET fusion, with metastatic, rapidly progressive (according to RECIST), symptomatic, and/or locally immediately threatening disease without meaningful local treatment options, treatment with a selective RET inhibitor represents an alternative treatment approach with a low side effect rate and high treatment response and should be used.

Consensus: Strong consensus (100%)

DTC can exhibit a number of gene fusions, such as RET, NTRK and ALK fusions, which can be therapeutically targeted with the available selective inhibitors.
The single-arm LIBRETTO-001 phase 1/2 study of the selective RET inhibitor selpercatinib included 22 pre-treated and 12 treatment-naïve patients with RET fusion-positive thyroid carcinomas, which resulted in complete remission in 2 and 4 patients, respectively, and partial remission in 15 and 7 patients, respectively, while the remaining patients showed tumor stabilization (ORR 77% and 92%, respectively). 4 patients achieved complete remission and 15 and 7 patients achieved partial remission, respectively, while the remaining patients showed tumor stabilization (ORR 77% and 92%, respectively) [1033], [1034]. The most common side effects of selpercatinib are dry mouth (39%), hypertension (30%), diarrhea (17%), fatigue (25%), increased liver enzymes (28%).
The long-term course of the patients in the LIBRETTO-001 Phase 1/2 study was published by Wirth [1035]. A total of 66 patients were followed up with regard to the RET fusion-positive tumors. The objective response rate was 85.8% (of non-pretreated patients). The median follow-up time was 24.9 and 30.4 months in the non-pretreated and pretreated groups, respectively. The median progression-free survival was not yet reached in the non-pretreated group. The overall survival rate at median follow-up was 94.4% in the non-pretreated group and 65.5% in the pretreated group. The safety profile was comparable to the initially published LIBRETTO-001 study.
Selpercatinib is now approved for RET fusion-positive thyroid carcinoma in first-line therapy (see bundesanzeiger.de; BAnz AT 10.12.2024 B3).
Similar efficacy was shown in the ARROW phase 2 study of the selective RET inhibitor pralsetinib, for which no approval for thyroid carcinoma is currently being pursued in Europe. The study included 9 patients with RET fusion-positive thyroid carcinoma, of whom 8 patients showed partial remission and one patient showed tumor stabilization. This shows a similar ORR of 89% [1036].

The most common side effects with pralsetinib were increased liver enzymes (34%), constipation (28%), leukopenia (34%), asthenia (26%), neutropenia (34%), anemia (29%). In contrast to the approved MKI therapies, both substances are associated with a relatively mild side effect potential with predominantly grade 1-3 side effects. Due to the documented efficacy and better tolerability, therapy with a selective RET inhibitor is recommended if RET fusions are detected.

7.14 · Evidence-based Recommendation 2025

In patients with radioiodine-refractory DTC/PDTC who have an NTRK fusion, with metastatic, rapidly progressive (according to RECIST), symptomatic, and/or locally immediately threatening disease without meaningful local treatment options, treatment with a selective TRK inhibitor represents an alternative treatment approach with a low side effect rate and high treatment response and should therefore be used.

Recommendation grade

B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht

Level of evidence

⊕⊝⊝⊝

Larotrectinib: OS

⊕⊝⊝⊝

Larotrectinib: PFS

Consensus

Strong consensus (100%)

References

[1037]

NTRK fusion-positive thyroid carcinomas were investigated in basket trials for the TRK inhibitors larotrectinib and entrectinib.
Larotrectinib showed an ORR of 86% in 22 patients with DTC, with 2 complete remissions, 16 partial remissions and 3 stabilizations. In the 13 patients with prior systemic therapies, the ORR was 92%. The PFS rates at 12 and 24 months were 100% and 84%, respectively, and the OS rates at 12, 24, 36 months were 100%, 92% and 79%, respectively. Side effects were predominantly mild (grade 1-2) [1037]. Current data from the basket studies on entrectinib were presented at ESMO 2021, including 13 patients with NTRK fusion-positive thyroid cancer who showed an ORR of 53.85% [1038]. Overall, it is recommended to look for NTRK fusions in radioiodine-refractory DTC, as an effective therapy is available with the selective TRK inhibitors that are tumor-agnostically approved for NTRK fusion-positive solid tumors. Despite the very low confidence in the quality of the evidence, the positive recommendation is made for the life-threatened patient group with NTRK.

7.15 · Consensus-based Recommendation 2025

In patients with radioiodine-refractory DTC/PDTC with metastatic, rapidly progressive (according to RECIST), symptomatic, and/or locally immediately threatening disease without meaningful local treatment options, an individual treatment attempt with a selective ALK inhibitor can be discussed in the interdisciplinary tumor board if ALK fusion is detected.

Consensus: Strong consensus (100%)

In DTC with proven ALK fusion, promising use of ALK inhibitors, such as crizotinib [1039], [1040], [1041], has been shown in individual case reports. To date, there are no systematic clinical studies on ALK inhibitors in ALK fusion-positive thyroid carcinomas, but in individual cases an individualized treatment trial with an ALK inhibitor should be examined.

7.16 · Evidence-based Recommendation 2025

In patients with radioiodine-refractory DTC/PDTC with metastatic, rapidly progressive (according to RECIST), symptomatic, and/or locally immediately threatening disease without meaningful local treatment options, an individual treatment attempt with a selective BRAF inhibitor ± trametinib should be discussed in the interdisciplinary tumor board if a BRAF V600E mutation is detected.

Recommendation grade

B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht

Level of evidence

⊕⊕⊝⊝

⊕⊝⊝⊝

PFS

Consensus

Strong consensus (100%)

References

[1042]

Due to the frequent detection of the BRAF V600E mutation in radioiodine-refractory DTC, the efficacy of selective BRAF inhibitors was investigated both as monotherapy and in combination with MEK inhibitors in advanced, radioiodine-refractory DTC. In a phase 1 study of the BRAF inhibitor dabrafenib, 14 patients with BRAF V600E-positive PTC showed partial remission in 29%, stabilization in 43% and a total tumor volume reduction of at least 10% in 64%. The PFS was 11.3 months [1043]. In a phase 2 study, 53 patients with progressive BRAF V600E-positive DTC were randomized into 2 treatment arms: BRAF inhibitor dabrafenib alone (arm A; n=26) vs. combination dabrafenib with the MEK inhibitor trametinib (arm B; n=27). Partial remission was observed in 9 patients in arm A and in 8 patients in arm B with an objective response rate of 35% and 30% respectively and a PFS of 10.7 months and 15.1 months respectively without statistically significant differences in the two treatment arms. Interestingly, by crossover of patients who showed progression under dabrafenib monotherapy into the dabrafenib + trametinib arm (n=14), tumor stabilization or partial remission was achieved in 12 patients (disease control rate 86%) with an extension of PFS by 7.5 months [1042]. The side effects are relatively moderate overall (predominantly grade1/2), in the dabrafenib arm at 65% (most frequently fever (50%), hyperglycemia (46%), anemia (42%), hand-foot syndrome (42%), nausea (42%), alopecia (42%), chills (42%)), in the dabrafenib/trametinib arm 33% (most frequently fever (59%), nausea (52%), chills (52%), fatigue (52%), hypophosphatemia (41%)).

With low confidence in the quality of evidence, a response of dabrafenib has been shown, but also a superiority of combination therapy with trametinib, which is why the recommendation is made for the life-threatened patient group with a BRAF V600E mutation.

The BRAF inhibitor vemurafenib was investigated in a further Phase 2 study with 2 cohorts: Cohort 1 comprised patients without prior MKI therapy (n=26), Cohort 2 patients who had already been pre-treated with an MKI (n=25). Partial remission was observed in 38.4% of patients in cohort 1, in 27.3% in cohort 2, and stabilization in 57.7% and 63.6% respectively. Most striking was a significantly longer PFS of 18.2 months in cohort 1 vs. 8.9 months in cohort 2. These results indicate that vemurafenib is a very effective therapy for BRAF-positive PTC, especially in first-line therapy. Side effects were predominantly grade 1/2, most commonly rash (73%), fatigue (77%), dysgeusia (54%), creatinine increase (50%), weight loss (54%), joint pain (46%), loss of appetite (52%), nausea (52%), skin papillomas (52%), diarrhea (46%) [1044].

The BRAF inhibitors therefore represent an effective therapy with fewer side effects for BRAF V600E-positive DTC and should be discussed as an alternative to the approved substances in the context of an individualized treatment trial.

Treatment with the selective inhibitors listed above not only shows good antiproliferative efficacy in radioiodine-refractory DTC with corresponding genetic alterations, but can also have a redifferentiating effect with a significant re-induction of radioiodine storage capacity in the tumors, as is known from smaller pilot studies and individual case reports [1045][1046][1047][1048][1049][1050][1051]. It is therefore recommended to check radioiodine storage during ongoing therapy with these selective inhibitors by means of a diagnostic radioiodine scan and to carry out radioiodine therapy if radioiodine storage is sufficient. This so-called redifferentiation therapy should be considered at an early stage, taking into account tumor and radiobiological aspects, if possible in first-line therapy, which requires a detailed explanation with a critical risk-benefit assessment together with the patient, as long as there is no approval for this. Of course, the possibility of study inclusion should always be examined and given preference. In the absence of established protocols, this should be carried out at highly specialized centers.

7.17 · Consensus-based Recommendation 2025

In patients with radioiodine-refractory PDTC with metastatic, rapidly progressive (according to RECIST), symptomatic, and/or locally immediately threatening disease without meaningful local treatment options, an individual treatment attempt with a combination therapy with lenvatinib and pembrolizumab can be discussed at the interdisciplinary tumor board.

Consensus: Strong consensus (100%)

In recent years, immunotherapeutic approaches have also been pursued in advanced, radioiodine-refractory DTC/PDTC, as in ATC. An initial phase 1 basket study of pembrolizumab showed disappointing results for monotherapy with pembrolizumab in 22 enrolled DTC patients with a partial remission of only 9% [1052]. A pilot study (n=8) led by Prof. Dr. Christine Dierks at the University Medical Center Freiburg on pembrolizumab in combination with lenvatinib (6 ATC, 2 PDTC) showed an excellent response in the ATC patients as well as a partial remission in both PDTC patients [1053], [1054]. Internationally, a phase 2 study initiated by the International Thyroid Oncology Group was conducted on this combination therapy in advanced radioiodine-refractory DTC. Cohort 1 (n= 29, combination of lenvatinib and pembrolizumab from the beginning) showed a partial response in 62% and additional tumor stabilization in 35% with a clinical benefit rate of 97% [1055] vs. 88%, which was described for lenvatinib monotherapy in the SELECT trial [1020]. Median progression-free survival was not yet reached, PFS at 12 months was 74%. In cohort 2 (n=25), in which lenvatinib monotherapy was started and pembrolizumab was only added at progression, partial remission was seen in 15% and tumor stabilization in 85% (clinical benefit rate 100%), median PFS was 12.6 months [1056]. This add-on therapy with pembrolizumab at progression under lenvatinib therefore appears to be the more effective approach.

7.18 · Consensus-based Recommendation 2025

Bisphosphonates or denosumab should be considered in patients with diffuse and/or symptomatic bone metastasis, taking into account renal function and monitoring of calcium levels, as well as prior dental evaluation.

Consensus: Strong consensus (100%)

Bone metastasis represents a particular challenge in the management of patients with radioiodine-refractory DTC [1057]. Kinase inhibitor therapy alone is often not sufficient to control bone metastasis, as the efficacy of kinase inhibitors in bone metastases is limited compared to other metastases, such as pulmonary or lymphogenous metastases. In the case of isolated bone metastases, especially symptomatic bone metastases, local therapies, especially radiotherapy, are preferred. In cases of disseminated bone metastasis, the use of bisphosphonates or denosumab is recommended, primarily based on studies in other tumor entities, but also smaller studies in DTC that have shown a delay in the occurrence of skeletal complications [1058], [1059], [1060], [1061].

7.19 · Consensus-based Recommendation 2025

Patients who are eligible for kinase inhibitor therapy shall be informed in detail with individual risk-benefit assessment and information on alternative therapies including best supportive care.

Consensus: Strong consensus (100,0%)

When deciding on systemic therapy, it must be taken into account that there is insufficient data from randomized clinical trials on a number of critical questions in connection with systemic molecularly targeted therapy for radioiodine-refractory DTC, such as the effect of systemic therapy on overall survival and quality of life, optimal patient selection, optimal timing for starting therapy.

Overall, based on the current state of the data, the treatment decision is based on expert opinion and patient preference/philosophy with individual risk-benefit assessment on both sides.

In order to ensure optimal individual treatment planning while exhausting all possible treatment options, including inclusion in controlled clinical trials, these patients should be urgently cared for by an interdisciplinary team of experts at specialized centers.

References

[952] Ricarte-Filho, J, Ganly, I, Rivera, M, Katabi, N, Fu, W, Shaha, A, et.al. Papillary thyroid carcinomas with cervical lymph node metastases can be stratified into clinically relevant prognostic categories using oncogenic BRAF, the number of nodal metastases, and extra-nodal extension., Thyroid, 2012. 22 (6)(6): p. 575-84., https://pubmed.ncbi.nlm.nih.gov/22471242/

[165] Lee, YK, Park, KH, Park, SH, Kim, KJ, Shin, DY, Nam, KH, et.al. Association between diffuse lymphocytic infiltration and papillary thyroid cancer aggressiveness according to the presence of thyroid peroxidase antibody and BRAF, Head Neck, 2018. 40 (10)(10): p. 2271-2279., https://pubmed.ncbi.nlm.nih.gov/29935011/

[953] Ronga, G, Toteda, M, D'Apollo, R, De Cristofaro, F, Filesi, M, Acqualagna, G, et.al. Lymph node metastases from differentiated thyroid carcinoma: does radioiodine still play a role?, Clin Ter, 2012. 163 (5)(5): p. 377-81., https://pubmed.ncbi.nlm.nih.gov/23099964/

[954] Trybek, T, Kowalska, A, Does the presence of regional lymph node metastases have any impact on the complete remission rate in patients with distant metastases of papillary thyroid carcinoma (PTC), treated by radioiodine therapy?, Endokrynol Pol, 2010. 61 (5)(5): p. 443-5., https://pubmed.ncbi.nlm.nih.gov/21049455/

[955] Cao, C. J., Dou, C. Y., Lian, J., Luan, Z. S., Zhou, W., Xie, W., et.al. Clinical outcomes and associated factors of radioiodine-131 treatment in differentiated thyroid cancer with cervical lymph node metastasis, Oncology Letters, 2018. 15(5): p. 8141-8148., https://pubmed.ncbi.nlm.nih.gov/29740497/

[956] Ilhan, H., Mustafa, M., Bartenstein, P., Kuwert, T., Schmidt, D., Rate of elimination of radioiodine-avid lymph node metastases of differentiated thyroid carcinoma by postsurgical radioiodine ablation. A bicentric study, Nuklearmedizin, 2016. 55(6): p. 221-227., https://pubmed.ncbi.nlm.nih.gov/27588323/

[957] Wu, X, Gu, H, Gao, Y, Li, B, Fan, R, Clinical outcomes and prognostic factors of radioiodine ablation therapy for lymph node metastases from papillary thyroid carcinoma., Nucl Med Commun, 2018. 39 (1)(1): p. 22-27., https://pubmed.ncbi.nlm.nih.gov/29135721/

[958] He, Y., Pan, M. Z., Huang, J. M., Xie, P., Zhang, F., Wei, L. G., Iodine-131: An Effective Method for Treating Lymph Node Metastases of Differentiated Thyroid Cancer, Med Sci Monit, 2016. 22: p. 4924-4928., https://pubmed.ncbi.nlm.nih.gov/27974741/

[959] Wojtczak, B, Sutkowski, K, Kaliszewski, K, Barczyński, M, Bolanowski, M, Thyroid reoperation using intraoperative neuromonitoring., Endocrine, 2017. 58 (3)(3): p. 458-466., https://pubmed.ncbi.nlm.nih.gov/29052179/

[960] Sedlmaier, A, Steinmüller, T, Hermanns, M, Nawka, T, Weikert, S, Sedlmaier, B, et.al. Continuous versus intermittent intraoperative neuromonitoring in complex benign thyroid surgery: A retrospective analysis and prospective follow-up., Clin Otolaryngol, 2019. 44 (6)(6): p. 1071-1079., https://pubmed.ncbi.nlm.nih.gov/31565844/

[961] Sabra, M. M., Dominguez, J. M., Grewal, R. K., Larson, S. M., Ghossein, R. A., Tuttle, R. M., et.al. Clinical outcomes and molecular profile of differentiated thyroid cancers with radioiodine-avid distant metastases, J Clin Endocrinol Metab, 2013. 98(5): p. E829-36.

[962] Higashi, T., Nishii, R., Yamada, S., Nakamoto, Y., Ishizu, K., Kawase, S., et.al. Delayed initial radioactive iodine therapy resulted in poor survival in patients with metastatic differentiated thyroid carcinoma: a retrospective statistical analysis of 198 cases, J Nucl Med, 2011. 52(5): p. 683-9., https://pubmed.ncbi.nlm.nih.gov/21498534/

[963] Shokoohi, A., Berthelet, E., Gill, S., Prisman, E., Sexsmith, G., Tran, E., et.al. Treatment for Recurrent Differentiated Thyroid Cancer: A Canadian Population Based Experience, Cureus, 2020. 12(2): p. e7122.

[964] Ywata de Carvalho, A., Kohler, H. F., Gomes, C. C., Vartanian, J. G., Kowalski, L. P., Predictive factors for recurrence of papillary thyroid carcinoma: analysis of 4,085 patients, Acta Otorhinolaryngol Ital, 2021. 41(3): p. 236-242., https://pubmed.ncbi.nlm.nih.gov/34264917/

[652] Goffredo, P., Sosa, J. A., Roman, S. A., Differentiated thyroid cancer presenting with distant metastases: a population analysis over two decades, World Journal of Surgery, 2013. 37(7): p. 1599-605., https://pubmed.ncbi.nlm.nih.gov/23525600/

[965] Cho, S. W., Choi, H. S., Yeom, G. J., Lim, J. A., Moon, J. H., Park, D. J., et.al. Long-term prognosis of differentiated thyroid cancer with lung metastasis in Korea and its prognostic factors, Thyroid, 2014. 24(2): p. 277-86., https://pubmed.ncbi.nlm.nih.gov/23758653/

[966] Sampson, E., Brierley, J. D., Le, L. W., Rotstein, L., Tsang, R. W., Clinical management and outcome of papillary and follicular (differentiated) thyroid cancer presenting with distant metastasis at diagnosis, Cancer, 2007. 110(7): p. 1451-6.

[967] Nixon, I. J., Whitcher, M. M., Palmer, F. L., Tuttle, R. M., Shaha, A. R., Shah, J. P., et.al. The impact of distant metastases at presentation on prognosis in patients with differentiated carcinoma of the thyroid gland, Thyroid, 2012. 22(9): p. 884-9.

[968] Lin, J. D., Hsueh, C., Chao, T. C., Long-Term Follow-Up of the Therapeutic Outcomes for Papillary Thyroid Carcinoma With Distant Metastasis, Medicine, 2015. 94(26): p. e1063., http://ovidsp.ovid.com/ovidweb.cgi?T=JS&CSC=Y&NEWS=N&PAGE=fulltext&D=medc&AN=26131826, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504566/pdf/medi-94-e1063.pdf

[969] Jung, C. K., Lee, S., Bae, J. S., Lim, D. J., Late-onset distant metastases confer poor prognosis in patients with well-differentiated thyroid cancer, Gland Surg, 2020. 9(5): p. 1857-1866.

[970] Lin, J. D., Kuo, S. F., Huang, B. Y., Lin, S. F., Chen, S. T., The efficacy of radioactive iodine for the treatment of well-differentiated thyroid cancer with distant metastasis, Nuclear Medicine Communications, 2018. 39(12): p. 1091-1096., https://pubmed.ncbi.nlm.nih.gov/30180044/

[971] Schlumberger, M., Challeton, C., De Vathaire, F., Travagli, J. P., Gardet, P., Lumbroso, J. D., et.al. Radioactive iodine treatment and external radiotherapy for lung and bone metastases from thyroid carcinoma, J Nucl Med, 1996. 37(4): p. 598-605.

[972] Durante, C., Haddy, N., Baudin, E., Leboulleux, S., Hartl, D., Travagli, J. P., et.al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy, J Clin Endocrinol Metab, 2006. 91(8): p. 2892-9., https://pubmed.ncbi.nlm.nih.gov/16684830/

[973] Ito, Y., Masuoka, H., Fukushima, M., Inoue, H., Kihara, M., Tomoda, C., et.al. Prognosis and prognostic factors of patients with papillary carcinoma showing distant metastasis at surgery (M1 patients) in Japan, Endocr J, 2010. 57(6): p. 523-31., https://pubmed.ncbi.nlm.nih.gov/20379035/

[611] Ito, Y., Miyauchi, A., Ishikawa, H., Hirokawa, M., Kudo, T., Tomoda, C., et.al. Our experience of treatment of cribriform morular variant of papillary thyroid carcinoma; difference in clinicopathological features of FAP-associated and sporadic patients, Endocr J, 2011. 58(8): p. 685-9., https://pubmed.ncbi.nlm.nih.gov/21670544/

[974] Li, C., Wu, Q., Sun, S., Radioactive Iodine Therapy in Patients With Thyroid Carcinoma With Distant Metastases: A SEER-Based Study, Cancer Control, 2020. 27(1): p. 1073274820914661.

[975] Kim, H., Kim, H. I., Kim, S. W., Jung, J., Jeon, M. J., Kim, W. G., et.al. Prognosis of Differentiated Thyroid Carcinoma with Initial Distant Metastasis: A Multicenter Study in Korea, Endocrinol Metab (Seoul), 2018. 33(2): p. 287-295.

[976] Madani, A, Jozaghi, Y, Tabah, R, How, J, Mitmaker, E, Rare metastases of well-differentiated thyroid cancers: a systematic review., Ann Surg Oncol, 2015. 22 (2)(2): p. 460-6., https://pubmed.ncbi.nlm.nih.gov/25192681/

[977] Mihailovic, JM, Stefanovic, LJ, Malesevic, MD, Erak, MD, Tesanovic, DD, Metastatic differentiated thyroid carcinoma: clinical management and outcome of disease in patients with initial and late distant metastases., Nucl Med Commun, 2009. 30 (7)(7): p. 558-64., https://pubmed.ncbi.nlm.nih.gov/19436230/

[978] Zhang, XY, Sun, JW, Qiu, ZL, Wang, Y, Chen, XY, Zhao, JH, et.al. Clinical outcomes and prognostic factors in patients with no less than three distant organ system metastases from differentiated thyroid carcinoma., Endocrine, 2019. 66 (2)(2): p. 254-265., https://pubmed.ncbi.nlm.nih.gov/31317522/

[979] Zunino, A, Pitoia, F, Faure, E, Reyes, A, Sala, M, Sklate, R, et.al. Unusual metastases from differentiated thyroid carcinoma: analysis of 36 cases., Endocrine, 2019. 65 (3)(3): p. 630-636., https://pubmed.ncbi.nlm.nih.gov/31327159/

[980] Sabra, M. M., Ghossein, R., Tuttle, R. M., Time Course and Predictors of Structural Disease Progression in Pulmonary Metastases Arising from Follicular Cell-Derived Thyroid Cancer, Thyroid, 2016. 26(4): p. 518-24.

[981] Ohkuwa, K., Sugino, K., Nagahama, M., Kitagawa, W., Matsuzu, K., Suzuki, A., et.al. Risk stratification in differentiated thyroid cancer with RAI-avid lung metastases, Endocr Connect, 2021. 10(8): p. 825-833.

[982] Casara, D., Rubello, D., Saladini, G., Masarotto, G., Favero, A., Girelli, M. E., et.al. Different features of pulmonary metastases in differentiated thyroid cancer: natural history and multivariate statistical analysis of prognostic variables, J Nucl Med, 1993. 34(10): p. 1626-31., https://pubmed.ncbi.nlm.nih.gov/8410272/

[983] Song, H. J., Qiu, Z. L., Shen, C. T., Wei, W. J., Luo, Q. Y., Pulmonary metastases in differentiated thyroid cancer: efficacy of radioiodine therapy and prognostic factors, European Journal of Endocrinology, 2015. 173(3): p. 399-408., https://pubmed.ncbi.nlm.nih.gov/26104753/

[566] Yang, Z., Flores, J., Katz, S., Nathan, C. A., Mehta, V., Comparison of Survival Outcomes Following Postsurgical Radioactive Iodine Versus External Beam Radiation in Stage IV Differentiated Thyroid Carcinoma, Thyroid, 2017. 27(7): p. 944-952., https://pubmed.ncbi.nlm.nih.gov/28446057/

[984] Zhang, X., Liu, D. S., Luan, Z. S., Zhang, F., Liu, X. H., Zhou, W., et.al. Efficacy of radioiodine therapy for treating 20 patients with pulmonary metastases from differentiated thyroid cancer and a meta-analysis of the current literature, Clinical & Translational Oncology: Official Publication of the Federation of Spanish Oncology Societes & of the National Cancer Institute of Mexico, 2018. 20(7): p. 928-935., https://pubmed.ncbi.nlm.nih.gov/29119458/

[985] Wang, C., Zhang, R., Wang, R., Meng, Z., Zhang, G., Dong, F., et.al. Predictive Value of Thyroglobulin Changes for the Curative Effect of Radioiodine Therapy in Patients With Metastatic Differentiated Thyroid Carcinoma, Front Endocrinol (Lausanne), 2021. 12: p. 667544., https://pubmed.ncbi.nlm.nih.gov/34040584/

[986] Yang, J., Zheng, R., Liang, M., Jia, Y., Lin, L., Geng, J., et.al. Association of the Cumulative Dose of Radioactive Iodine Therapy With Overall Survival in Patients With Differentiated Thyroid Cancer and Pulmonary Metastases, Front Oncol, 2019. 9: p. 558., https://pubmed.ncbi.nlm.nih.gov/31316914/

[987] Kim, M, Kim, WG, Park, S, Kwon, H, Jeon, MJ, Lee, JJ, et.al. Initial Size of Metastatic Lesions Is Best Prognostic Factor in Patients with Metastatic Differentiated Thyroid Carcinoma Confined to the Lung., Thyroid, 2017. 27 (1)(1): p. 49-58., https://pubmed.ncbi.nlm.nih.gov/27750021/

[988] Lin, J. D., Chao, T. C., Hsueh, C., Follicular thyroid carcinomas with lung metastases: a 23-year retrospective study, Endocr J, 2004. 51(2): p. 219-25.

[559] Zhu, G.; Deng, Y.; Pan, L.; Ouyang, W.; Feng, H.; Wu, J.; Chen, P.; Wang, J.; Chen, Y.; Luo, J., Clinical significance of the BRAF V600E mutation in PTC and its effect on radioiodine therapy, Endocrine Connections, 2019. 8: p. 754-763., https://pubmed.ncbi.nlm.nih.gov/31071680/

[989] Sabra, M. M., Sherman, E. J., Tuttle, R. M., Tumor volume doubling time of pulmonary metastases predicts overall survival and can guide the initiation of multikinase inhibitor therapy in patients with metastatic, follicular cell-derived thyroid carcinoma, Cancer, 2017. 123(15): p. 2955-2964.

[990] Kim, D. H., Jung, J. H., Son, S. H., Kim, C. Y., Hong, C. M., Jeong, S. Y., et.al. Difference of clinical and radiological characteristics according to radioiodine avidity in pulmonary metastases of differentiated thyroid cancer, Nucl Med Mol Imaging, 2014. 48(1): p. 55-62.

[991] Long, B., Yang, M., Yang, Z., Yi, H., Li, L., Assessment of radioiodine therapy efficacy for treatment of differentiated thyroid cancer patients with pulmonary metastasis undetected by chest computed tomography, Oncol Lett, 2016. 11(2): p. 965-968.

[619] Reiners, C., Biko, J., Haenscheid, H., Hebestreit, H., Kirinjuk, S., Baranowski, O., et.al. Twenty-five years after Chernobyl: outcome of radioiodine treatment in children and adolescents with very high-risk radiation-induced differentiated thyroid carcinoma, J Clin Endocrinol Metab, 2013. 98(7): p. 3039-48.

[463] Pawelczak, M, David, R, Franklin, B, Kessler, M, Lam, L, Shah, B, Outcomes of children and adolescents with well-differentiated thyroid carcinoma and pulmonary metastases following ¹³¹I treatment: a systematic review., Thyroid, 2010. 20 (10)(10): p. 1095-101., https://pubmed.ncbi.nlm.nih.gov/20860418/

[992] Zhang, XY, Song, HJ, Qiu, ZL, Shen, CT, Chen, XY, Sun, ZK, et.al. Pulmonary metastases in children and adolescents with papillary thyroid cancer in China: prognostic factors and outcomes from treatment with , Endocrine, 2018. 62 (1)(1): p. 149-158., https://pubmed.ncbi.nlm.nih.gov/30022382/

[993] Slook, O, Levy, S, Slutzky-Shraga, I, Tsvetov, G, Robenshtok, E, Shimon, I, et.al. LONG-TERM OUTCOMES AND PROGNOSTIC FACTORS IN PATIENTS WITH DIFFERENTIATED THYROID CARCINOMA AND BONE METASTASES., Endocr Pract, 2019. 25 (5)(5): p. 427-437., https://pubmed.ncbi.nlm.nih.gov/30657361/

[994] Qi, L., Zhang, W., Ren, X., Xu, R., Liu, C., Tu, C., et.al. Incidence and Predictors of Synchronous Bone Metastasis in Newly Diagnosed Differentiated Thyroid Cancer: A Real-World Population-Based Study, Front Surg, 2022. 9: p. 778303.

[995] Iñiguez-Ariza, N. M., Bible, K. C., Clarke, B. L., Bone metastases in thyroid cancer, J Bone Oncol, 2020. 21: p. 100282., https://pubmed.ncbi.nlm.nih.gov/32154098/

[996] Varadarajan, VV, Pace, EK, Patel, V, Sawhney, R, Amdur, RJ, Dziegielewski, PT, Follicular thyroid carcinoma metastasis to the facial skeleton: a systematic review., BMC Cancer, 2017. 17 (1)(1): p. 225., https://pubmed.ncbi.nlm.nih.gov/28351395/

[997] Halnan, K. E., Roberts, P. H., Paraplegia caused by spinal metastasis from thyroid cancer, Br Med J, 1967. 3(5564): p. 534-6., https://pubmed.ncbi.nlm.nih.gov/6038321/

[998] Ramadan, S, Ugas, MA, Berwick, RJ, Notay, M, Cho, H, Jerjes, W, et.al. Spinal metastasis in thyroid cancer., Head Neck Oncol, 2012. 4 (): p. 39., https://pubmed.ncbi.nlm.nih.gov/22730910/

[999] Califano, I, Deutsch, S, Löwenstein, A, Cabezón, C, Pitoia, F, Outcomes of patients with bone metastases from differentiated thyroid cancer., Arch Endocrinol Metab, 2018. 62 (1)(1): p. 14-20., https://pubmed.ncbi.nlm.nih.gov/29694635/

[1000] Petrich, T., Widjaja, A., Musholt, T. J., Hofmann, M., Brunkhorst, T., Ehrenheim, C., et.al. Outcome after radioiodine therapy in 107 patients with differentiated thyroid carcinoma and initial bone metastases: side-effects and influence of age, Eur J Nucl Med, 2001. 28(2): p. 203-8.

[1001] Robenshtok, E., Farooki, A., Grewal, R. K., Tuttle, R. M., Natural history of small radioiodine-avid bone metastases that have no structural correlate on imaging studies, Endocrine, 2014. 47(1): p. 266-72.

[1002] Osborne, J. R., Kondraciuk, J. D., Rice, S. L., Zhou, X., Knezevic, A., Spratt, D. E., et.al. Thyroid Cancer Brain Metastasis: Survival and Genomic Characteristics of a Large Tertiary Care Cohort, Clin Nucl Med, 2019. 44(7): p. 544-549.

[62] Wu, XL, Du, JR, Wang, H, Jin, CX, Sui, GQ, Yang, DY, et.al. Comparison and preliminary discussion of the reasons for the differences in diagnostic performance and unnecessary FNA biopsies between the ACR TIRADS and 2015 ATA guidelines., Endocrine, 2019. 65 (1)(1): p. 121-131., https://pubmed.ncbi.nlm.nih.gov/30830584/

[1003] Mazziotti, G, Formenti, AM, Panarotto, MB, Arvat, E, Chiti, A, Cuocolo, A, et.al. Real-life management and outcome of thyroid carcinoma-related bone metastases: results from a nationwide multicenter experience., Endocrine, 2018. 59 (1)(1): p. 90-101., https://pubmed.ncbi.nlm.nih.gov/29110129/

[1004] Kato, S., Demura, S., Shinmura, K., Yokogawa, N., Shimizu, T., Tsuchiya, H., Current Management of Bone Metastases from Differentiated Thyroid Cancer, Cancers (Basel), 2021. 13(17):

[1005] Shen, J., Wang, S., Zhao, X., Shao, X., Jiang, X., Dai, Y., et.al. Skull metastasis from follicular thyroid carcinoma: report of three cases and review of literature, Int J Clin Exp Pathol, 2015. 8(11): p. 15285-93., https://pubmed.ncbi.nlm.nih.gov/26823882/

[1006] Shimmura, H., Mori, E., Sekine, R., Tei, M., Otori, N., Metastasis of Papillary Thyroid Carcinoma to the Maxillary Sinus: Case Report and Review of the Literature, Case Rep Otolaryngol, 2020. 2020: p. 4056901.

[1007] Deandreis, D, Rubino, C, Tala, H, Leboulleux, S, Terroir, M, Baudin, E, et.al. Comparison of Empiric Versus Whole-Body/-Blood Clearance Dosimetry-Based Approach to Radioactive Iodine Treatment in Patients with Metastases from Differentiated Thyroid Cancer., J Nucl Med, 2017. 58 (5)(5): p. 717-722., https://pubmed.ncbi.nlm.nih.gov/27738010/

[1008] Hong, YW, Lin, JD, Yu, MC, Hsu, CC, Lin, YS, Outcomes and prognostic factors in thyroid cancer patients with cranial metastases: A retrospective cohort study of 4,683 patients., Int J Surg, 2018. 55 (): p. 182-187., https://pubmed.ncbi.nlm.nih.gov/29883619/

[1009] Wu, T., Jiao, Z., Li, Y., Peng, J., Yao, F., Chen, W., et.al. Brain Metastases From Differentiated Thyroid Carcinoma: A Retrospective Study of 22 Patients, Front Endocrinol (Lausanne), 2021. 12: p. 730025., https://pubmed.ncbi.nlm.nih.gov/34603207/

[1010] Simões-Pereira, J., Macedo, D., Bugalho, M. J., Clinical outcomes of a cohort of patients with central nervous system metastases from thyroid cancer, Endocr Connect, 2016. 5(6): p. 82-88.

[1011] Slutzky-Shraga, I., Gorshtein, A., Popovitzer, A., Robenshtok, E., Tsvetov, G., Akirov, A., et.al. Clinical characteristics and disease outcome of patients with non-medullary thyroid cancer and brain metastases, Oncol Lett, 2018. 15(1): p. 672-676.

[1012] Gomes-Lima, C. J., Wu, D., Rao, S. N., Punukollu, S., Hritani, R., Zeymo, A., et.al. Brain Metastases From Differentiated Thyroid Carcinoma: Prevalence, Current Therapies, and Outcomes, J Endocr Soc, 2019. 3(2): p. 359-371., https://pubmed.ncbi.nlm.nih.gov/30706042/

[1013] Guelho, D., Ribeiro, C., Melo, M., Carrilho, F., Long-term survival in a patient with brain metastases of papillary thyroid carcinoma, BMJ Case Rep, 2016. 2016:, https://pubmed.ncbi.nlm.nih.gov/26961557/

[1014] Vrachimis, A, Schmid, KW, Jürgens, H, Schober, O, Weckesser, M, Riemann, B, Cerebral metastases from thyroid carcinoma: complete remission following radioiodine treatment., Dtsch Arztebl Int, 2013. 110 (50)(50): p. 861-6., https://pubmed.ncbi.nlm.nih.gov/24399028/

[1015] Spitzweg, C, Bible, KC, Hofbauer, LC, Morris, JC, Advanced radioiodine-refractory differentiated thyroid cancer: the sodium iodide symporter and other emerging therapeutic targets., Lancet Diabetes Endocrinol, 2014. 2 (10)(10): p. 830-42., https://pubmed.ncbi.nlm.nih.gov/24898835/

[24] Haugen, BR, Alexander, EK, Bible, KC, Doherty, GM, Mandel, SJ, Nikiforov, YE, et.al. 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., Thyroid, 2016. 26 (1)(1): p. 1-133., https://pubmed.ncbi.nlm.nih.gov/26462967/

[60] Perros, P, Boelaert, K, Colley, S, Evans, C, Evans, RM, Gerrard Ba, G, et.al. Guidelines for the management of thyroid cancer., Clin Endocrinol (Oxf), 2014. 81 Suppl 1 (): p. 1-122., https://pubmed.ncbi.nlm.nih.gov/24989897/

[1016] Fugazzola, L, Elisei, R, Fuhrer, D, Jarzab, B, Leboulleux, S, Newbold, K, et.al. 2019 European Thyroid Association Guidelines for the Treatment and Follow-Up of Advanced Radioiodine-Refractory Thyroid Cancer., Eur Thyroid J, 2019. 8 (5)(5): p. 227-245., https://pubmed.ncbi.nlm.nih.gov/31768334/

[1017] Filetti, S, Durante, C, Hartl, DM, Leboulleux, S, Locati, LD, Newbold, K, et.al. ESMO Clinical Practice Guideline update on the use of systemic therapy in advanced thyroid cancer., Ann Oncol, 2022. 33 (7)(7): p. 674-684., https://pubmed.ncbi.nlm.nih.gov/35491008/

[1018] Schutz, FA, Je, Y, Richards, CJ, Choueiri, TK, Meta-analysis of randomized controlled trials for the incidence and risk of treatment-related mortality in patients with cancer treated with vascular endothelial growth factor tyrosine kinase inhibitors., J Clin Oncol, 2012. 30 (8)(8): p. 871-7., https://pubmed.ncbi.nlm.nih.gov/22312105/

[1019] Brose, MS, Nutting, CM, Jarzab, B, Elisei, R, Siena, S, Bastholt, L, et.al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial., Lancet, 2014. 384 (9940)(9940): p. 319-28., https://pubmed.ncbi.nlm.nih.gov/24768112/

[1020] Schlumberger, M, Tahara, M, Wirth, LJ, Robinson, B, Brose, MS, Elisei, R, et.al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer., N Engl J Med, 2015. 372 (7)(7): p. 621-30., https://pubmed.ncbi.nlm.nih.gov/25671254/

[1021] Brose, MS, Robinson, B, Sherman, SI, Krajewska, J, Lin, CC, Vaisman, F, et.al. Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial., Lancet Oncol, 2021. 22 (8)(8): p. 1126-1138., https://pubmed.ncbi.nlm.nih.gov/34237250/

[1022] Brose, MS, Robinson, BG, Sherman, SI, Jarzab, B, Lin, CC, Vaisman, F, et.al. Cabozantinib for previously treated radioiodine-refractory differentiated thyroid cancer: Updated results from the phase 3 COSMIC-311 trial., Cancer, 2022. 128 (24)(24): p. 4203-4212., https://pubmed.ncbi.nlm.nih.gov/36259380/

[1023] Brose, MS, Worden, FP, Newbold, KL, Guo, M, Hurria, A, Effect of Age on the Efficacy and Safety of Lenvatinib in Radioiodine-Refractory Differentiated Thyroid Cancer in the Phase III SELECT Trial., J Clin Oncol, 2017. 35 (23)(23): p. 2692-2699., https://pubmed.ncbi.nlm.nih.gov/28613956/

[1024] Hanna, GJ, Busaidy, NL, Chau, NG, Wirth, LJ, Barletta, JA, Calles, A, et.al. Genomic Correlates of Response to Everolimus in Aggressive Radioiodine-refractory Thyroid Cancer: A Phase II Study., Clin Cancer Res, 2018. 24 (7)(7): p. 1546-1553., https://pubmed.ncbi.nlm.nih.gov/29301825/

[1025] Bible, KC, Suman, VJ, Molina, JR, Smallridge, RC, Maples, WJ, Menefee, ME, et.al. Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study., Lancet Oncol, 2010. 11 (10)(10): p. 962-72., https://pubmed.ncbi.nlm.nih.gov/20851682/

[1026] Leboulleux, S, Bastholt, L, Krause, T, de la Fouchardiere, C, Tennvall, J, Awada, A, et.al. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial., Lancet Oncol, 2012. 13 (9)(9): p. 897-905., https://pubmed.ncbi.nlm.nih.gov/22898678/

[1027] Brose MS, , Fagin JA, , Wirth LJ, , Elisei R, , Sugitani I, , Wu Y, et al., Impact of TSH levels on response to vandetanib in patients with locally advanced or metastatic differentiated thyroid cancer (DTC) who are refractory or unsuitable for radioiodine (RAI) therapy: a phase III study (VERIFY)Thyroid, 2016.

[1028] Carr, LL, Mankoff, DA, Goulart, BH, Eaton, KD, Capell, PT, Kell, EM, et.al. Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation., Clin Cancer Res, 2010. 16 (21)(21): p. 5260-8., https://pubmed.ncbi.nlm.nih.gov/20847059/

[1029] Cohen, E., Needles, B., Cullen, K., Wong, S., III, J., Ivy, S., et.al. Phase 2 study of sunitinib in refractory thyroid cancer, 2008/05/20. 26: p. 6025 - 6025.

[1030] Cohen, EE, Rosen, LS, Vokes, EE, Kies, MS, Forastiere, AA, Worden, FP, et.al. Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study., J Clin Oncol, 2008. 26 (29)(29): p. 4708-13., https://pubmed.ncbi.nlm.nih.gov/18541897/

[1031] Locati, LD, Licitra, L, Agate, L, Ou, SH, Boucher, A, Jarzab, B, et.al. Treatment of advanced thyroid cancer with axitinib: Phase 2 study with pharmacokinetic/pharmacodynamic and quality-of-life assessments., Cancer, 2014. 120 (17)(17): p. 2694-703., https://pubmed.ncbi.nlm.nih.gov/24844950/

[1032] Rao, SN, Cabanillas, ME, Navigating Systemic Therapy in Advanced Thyroid Carcinoma: From Standard of Care to Personalized Therapy and Beyond., J Endocr Soc, 2018. 2 (10)(10): p. 1109-1130., https://pubmed.ncbi.nlm.nih.gov/30250937/

[1033] Sherman, Eric Jeffrey, Wirth, Lori J., Shah, Manisha H., Cabanillas, Maria E., Robinson, Bruce, Laskin, Janessa J., et.al. Selpercatinib efficacy and safety in patients with RET-altered thyroid cancer: A clinical trial update.Wolters Kluwer, Journal of Clinical Oncology, 2021. 39(15_suppl): p. 6073 - 6073., https://doi.org/10.1200/JCO.2021.39.15_suppl.6073

[1034] Wirth, LJ, Sherman, E, Robinson, B, Solomon, B, Kang, H, Lorch, J, et.al. Efficacy of Selpercatinib in , N Engl J Med, 2020. 383 (9)(9): p. 825-835., https://pubmed.ncbi.nlm.nih.gov/32846061/

[1035] Wirth, LJ, Brose, MS, Subbiah, V, Worden, F, Solomon, B, Robinson, B, et.al. Durability of Response With Selpercatinib in Patients With , J Clin Oncol, 2024. 42 (27)(27): p. 3187-3195., https://pubmed.ncbi.nlm.nih.gov/39094065/

[1036] Subbiah, V, Hu, MI, Wirth, LJ, Schuler, M, Mansfield, AS, Curigliano, G, et.al. Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study., Lancet Diabetes Endocrinol, 2021. 9 (8)(8): p. 491-501., https://pubmed.ncbi.nlm.nih.gov/34118198/

[1037] Waguespack, SG, Drilon, A, Lin, JJ, Brose, MS, McDermott, R, Almubarak, M, et.al. Efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma., Eur J Endocrinol, 2022. 186 (6)(6): p. 631-643., https://pubmed.ncbi.nlm.nih.gov/35333737/

[1038] Bazhenova, Lyudmila, Liu, S.V., Lin, J.J., Lu, S., Drilon, Alexander Edward, Chawla, S.P., et.al. 533P Efficacy and safety of entrectinib in patients with locally advanced/metastatic NTRK fusion-positive (NTRK-fp) solid tumours, 2021/09/01. 32: p. S598 - S599.

[1039] Demeure, MJ, Aziz, M, Rosenberg, R, Gurley, SD, Bussey, KJ, Carpten, JD, Whole-genome sequencing of an aggressive BRAF wild-type papillary thyroid cancer identified EML4-ALK translocation as a therapeutic target., World J Surg, 2014. 38 (6)(6): p. 1296-305., https://pubmed.ncbi.nlm.nih.gov/24633422/

[1040] Lee, H, Krishnan, V, Wirth, LJ, Nucera, C, Venturina, M, Sadow, PM, et.al. Case Report of , Thyroid, 2022. 32 (12)(12): p. 1580-1585., https://pubmed.ncbi.nlm.nih.gov/36150036/

[1041] Zhu, L, Ma, S, Xia, B, Remarkable response to alectinib for metastatic papillary thyroid cancer with STRN-ALK fusion: A case report., Front Oncol, 2022. 12 (): p. 1009076., https://pubmed.ncbi.nlm.nih.gov/36439495/

[1042] Busaidy, NL, Konda, B, Wei, L, Wirth, LJ, Devine, C, Daniels, GA, et.al. Dabrafenib Versus Dabrafenib + Trametinib in , Thyroid, 2022. 32 (10)(10): p. 1184-1192., https://pubmed.ncbi.nlm.nih.gov/35658604/

[1043] Falchook, GS, Millward, M, Hong, D, Naing, A, Piha-Paul, S, Waguespack, SG, et.al. BRAF inhibitor dabrafenib in patients with metastatic BRAF-mutant thyroid cancer., Thyroid, 2015. 25 (1)(1): p. 71-7., https://pubmed.ncbi.nlm.nih.gov/25285888/

[1044] Brose, MS, Cabanillas, ME, Cohen, EE, Wirth, LJ, Riehl, T, Yue, H, et.al. Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial., Lancet Oncol, 2016. 17 (9)(9): p. 1272-82., https://pubmed.ncbi.nlm.nih.gov/27460442/

[1045] Lee, YA, Lee, H, Im, SW, Song, YS, Oh, DY, Kang, HJ, et.al. NTRK and RET fusion-directed therapy in pediatric thyroid cancer yields a tumor response and radioiodine uptake., J Clin Invest, 2021. 131 (18)(18):, https://pubmed.ncbi.nlm.nih.gov/34237031/

[1046] Werner, RA, Sayehli, C, Hänscheid, H, Higuchi, T, Serfling, SE, Fassnacht, M, et.al. Successful combination of selpercatinib and radioiodine after pretherapeutic dose estimation in RET-altered thyroid carcinoma., Eur J Nucl Med Mol Imaging, 2023. 50 (6)(6): p. 1833-1834., https://pubmed.ncbi.nlm.nih.gov/36522435/

[1047] Groussin, L, Theodon, H, Bessiene, L, Bricaire, L, Bonnet-Serrano, F, Cochand-Priollet, B, et.al. Redifferentiating Effect of Larotrectinib in , Thyroid, 2022. 32 (5)(5): p. 594-598., https://pubmed.ncbi.nlm.nih.gov/35171708/

[1048] Groussin, L, Bessiene, L, Arrondeau, J, Garinet, S, Cochand-Priollet, B, Lupo, A, et.al. None, Thyroid, 2021. 31 (10)(10): p. 1603-1604., https://pubmed.ncbi.nlm.nih.gov/34405703/

[1049] Rothenberg, SM, McFadden, DG, Palmer, EL, Daniels, GH, Wirth, LJ, Redifferentiation of iodine-refractory BRAF V600E-mutant metastatic papillary thyroid cancer with dabrafenib., Clin Cancer Res, 2015. 21 (5)(5): p. 1028-35., https://pubmed.ncbi.nlm.nih.gov/25549723/

[1050] Dunn, LA, Sherman, EJ, Baxi, SS, Tchekmedyian, V, Grewal, RK, Larson, SM, et.al. Vemurafenib Redifferentiation of BRAF Mutant, RAI-Refractory Thyroid Cancers., J Clin Endocrinol Metab, 2019. 104 (5)(5): p. 1417-1428., https://pubmed.ncbi.nlm.nih.gov/30256977/

[1051] Leboulleux, Sophie, Cao, Christine Do, Zerdoud, Slimane, Attard, Marie, Bournaud, Claire, Benisvy, Danielle, et.al. MERAIODE: A Redifferentiation Phase II Trial With Trametinib and Dabrafenib Followed by Radioactive Iodine Administration for Metastatic Radioactive Iodine Refractory Differentiated Thyroid Cancer Patients With a BRAFV600E Mutation (NCT 03244956), 2021. 5(Supplement_1): p. A876 - A876., https://doi.org/10.1210/jendso/bvab048.1789

[1052] Mehnert J, , Varga A, , Brose M, , Aggarwal R, , Lin C, , Prawira A, et al., Pembrolizumab for advanced paillary and follicular thyroid cancer: preliminary results from the phase 1b KEYNOTE-028 studyJ Clin Oncol, 2016. 33(Suppl 15):

[1053] Dierks C, , Miething C, , Thomusch O, , von Bubnoff N, , Duyster J., Lenvatinib and pembrolizumab as save and effective combination treatment in 8 patients with metastasized anaplastic thyroid cancer (ATC) and poorly differentiated thyroid cancerAnnals of Oncology, 2018. 29 (Suppl_8): p. viii645 - viii8.

[1054] Dierks, C, Seufert, J, Aumann, K, Ruf, J, Klein, C, Kiefer, S, et.al. Combination of Lenvatinib and Pembrolizumab Is an Effective Treatment Option for Anaplastic and Poorly Differentiated Thyroid Carcinoma., Thyroid, 2021. 31 (7)(7): p. 1076-1085., https://pubmed.ncbi.nlm.nih.gov/33509020/

[1055] Haugen, Bryan, French, Jena, Worden, Francis, Konda, Bhavana, Sherman, Eric, Dadu, Ramona, et.al. Lenvatinib plus pembrolizumab combination therapy in patients with radioiodine-refractory (RAIR), progressive differentiated thyroid cancer (DTC): Results of a multicenter phase II international thyroid oncology group trial., 2020/05/20. 38: p. 6512 - 6512.

[1056] Haugen, B., French, J.D., Worden, F., Konda, B., Sherman, E.J., Dadu, R., et.al. 1917P Pembrolizumab salvage add-on therapy in patients with radioiodine-refractory (RAIR), progressive differentiated thyroid cancer (DTC) progressing on lenvatinib: Results of a multicenter phase II International Thyroid Oncology Group Trial, 2020/09/01. 31: p. S1086 - S1087.

[1057] Choksi, P, Papaleontiou, M, Guo, C, Worden, F, Banerjee, M, Haymart, M, Skeletal Complications and Mortality in Thyroid Cancer: A Population-Based Study., J Clin Endocrinol Metab, 2017. 102 (4)(4): p. 1254-1260., https://pubmed.ncbi.nlm.nih.gov/28324052/

[1058] Vitale, G, Fonderico, F, Martignetti, A, Caraglia, M, Ciccarelli, A, Nuzzo, V, et.al. Pamidronate improves the quality of life and induces clinical remission of bone metastases in patients with thyroid cancer., Br J Cancer, 2001. 84 (12)(12): p. 1586-90., https://pubmed.ncbi.nlm.nih.gov/11401309/

[1059] Coleman, R, Woodward, E, Brown, J, Cameron, D, Bell, R, Dodwell, D, et.al. Safety of zoledronic acid and incidence of osteonecrosis of the jaw (ONJ) during adjuvant therapy in a randomised phase III trial (AZURE: BIG 01-04) for women with stage II/III breast cancer., Breast Cancer Res Treat, 2011. 127 (2)(2): p. 429-38., https://pubmed.ncbi.nlm.nih.gov/21394500/

[1060] Wardley, A, Davidson, N, Barrett-Lee, P, Hong, A, Mansi, J, Dodwell, D, et.al. Zoledronic acid significantly improves pain scores and quality of life in breast cancer patients with bone metastases: a randomised, crossover study of community vs hospital bisphosphonate administration., Br J Cancer, 2005. 92 (10)(10): p. 1869-76., https://pubmed.ncbi.nlm.nih.gov/15870721/

[1061] Orita, Y, Sugitani, I, Toda, K, Manabe, J, Fujimoto, Y, Zoledronic acid in the treatment of bone metastases from differentiated thyroid carcinoma., Thyroid, 2011. 21 (1)(1): p. 31-5., https://pubmed.ncbi.nlm.nih.gov/21058881/