Clinical characteristics, treatment, and long-term outcome of patients with brain metastases from thyroid cancer

Brain metastases (BM) in patients with thyroid cancer (TC) are rare with an incidence of 1% for papillary and follicular, 3% for medullary and up to 10% for anaplastic TC (PTC, FTC, MTC and ATC). Little is known about the characteristics and management of BM from TC. Thus, we retrospectively analyzed patients with histologically verified TC and radiologically verified BM identified from the Vienna Brain Metastasis Registry. A total of 20/6074 patients included in the database since 1986 had BM from TC and 13/20 were female. Ten patients had FTC, 8 PTC, one MTC and one ATC. The median age at diagnosis of BM was 68 years. All but one had symptomatic BM and 13/20 patients had a singular BM. Synchronous BM at primary diagnosis were found in 6 patients, while the median time to BM diagnosis was 13 years for PTC (range 1.9–24), 4 years for FTC (range 2.1–41) and 22 years for the MTC patient. The overall survival from diagnosis of BM was 13 months for PTC (range 1.8–57), 26 months for FTC (range 3.9–188), 12 years for the MTC and 3 months for the ATC patient. In conclusion, development of BM from TC is exceedingly rare and the most common presentation is a symptomatic single lesion. While BM generally constitute a poor prognostic factor, individual patients experience long-term survival following local therapy.


Introduction
Thyroid cancer (TC) is a rare type of cancer with an incidence of 8/100.000 people in Austria per year affecting mostly women with a female/male ration of 2:1 [1]. Clinical

Baseline characteristics at primary diagnosis
The Vienna Brain Metastasis Registry consisted of 6074 patients at the cut-off date, December 31st, 2021. In total, 20 (0.3%) patients had a histologically verified diagnosis of TC and radiologically verified BM and were thus included in this analysis, see

Patient selection
The current analysis is a retrospective review of patients with a histologically verified diagnosis of TC and documented BM treated at the Medical University of Vienna between 1986 and 2020. Patients with TC and BM were identified from the Vienna Brain Metastasis Registry, a database established at the Division of Oncology, Medical University of Vienna, including patients with cerebral metastases since 1986 [28]. General clinical data as well as BM-specific data were retrospectively extracted from routine medical records and anonymized for further analysis. This investigation has been approved by the local ethical board of the Medical University of Vienna (EK No 1692/2022).

Baseline characteristics
Baseline characteristics and the clinical course of patients were retrieved from electronic medical records including sex, age, Eastern Cooperative Oncology Group performance status (ECOG-PS) at diagnosis of TC and BM, histological subtype, staging at primary diagnosis, time to development of distant metastases and BM, progression and OS. Distant metastases were defined as extracranial metastases other than BM. The histological subtype was documented and included PTC, FTC, MTC and ATC. Furthermore, treatment modalities and response to therapies (surgical resection, number and cumulative dose of RAI therapies, systemic radio-/chemo-/targeted therapies), the clinical course and survival outcomes were assessed, i.e., progression-free survival (PFS), OS and cause of death, if applicable.

BM specific characteristics
The diagnosis of BM was established with computed tomography, magnetic resonance imaging, whole-body I-131 scan or 18 F-FDG-positron emission computed tomography. In addition, histological assessment was performed in patients undergoing resection of BM. Documented treatment options included surgical intervention, stereotactic radiosurgery (SRS), whole-brain radiation therapy (WBRT), external beam radiation therapy (EBRT) or best supportive care (BSC). For this analysis, we have documented and grouped symptoms caused by BM as follows: (1) neurological deficits: including aphasia, sensorimotor dysfunctions, vertigo, impaired vision and cognitive impairment; (2) increased intracranial pressure: emesis and headache and (3) epileptic seizures including focal and generalized seizures. We have furthermore assessed the number, size (in cm) and localization of intracranial lesions. The number of BM were lesion located in a vertebral body, rib, scapula, tibia, femur, or pelvis and two patients with disseminated bone metastases. For more details regarding baseline patient characteristics, see Table 1.
In addition to the 8 patients with extracranial distant metastases at initial diagnosis, 12 patients developed distant metastases during course of disease. The median time to development of distant metastases from initial diagnosis of TC was 8.7 years for DTC with a wide range between 1.5 and 42 years (both patients had FTC). Patients with FTC developed distant metastases earlier compared to patients with PTC (1.8 vs. 9.5 years, respectively, p = 0.57). 6 patients with FTC and 5 patients with PTC had localized disease at primary diagnosis. The patient with MTC developed distant metastases 19 years after initial diagnosis and the patient with ATC presented with distant metastases at primary diagnosis. As expected, at diagnosis of BM, distant metastases were predominately located in the lung and bones among 19/20 patients (95%) and one patient had distant metastases in the lung, bones and adrenal glands.

Clinical characteristics at BM diagnosis
In total, 6/20 patients had BM at TC diagnosis. Of those, two patients had PTC, three had FTC and one had ATC. No patient presented with BM as the only metastatic site, as all patients also had synchronous distant metastases in the lung and bones. The median time from TC diagnosis to BM was 8.5 years for 13 DTC patients (range 0.7-41.2 years). Patients with FTC (n = 6) developed BM earlier compared to patients with PTC (n = 5) with 4 vs. 13 years, respectively between FTC and PTC (54 vs. 56 years, respectively). The two patients presenting with MTC and ATC were 50 and 66 years, respectively. ECOG-PS at initial diagnosis was good in all patients, with 12 (60%) patients rated as ECOG-PS 0, and 8 (40%) presenting with an ECOG-PS of 1.

Clinical characteristics before BM diagnosis
The primary therapeutic strategy differed between the histological subtypes. Overall, 15/18 patients with DTC had received RAI therapy during the course of the disease. The median number of RAI treatments was 2.5 (range 0-10), with a median dose of 101.45 mCi (range101-1,487 mCi-) being administered. Six patients received a dose of > 600 mCi, however, information about the received RAI dose was only available for 11/20 patients. The patient with MTC had received chemotherapy (substance unknown) after thyroidectomy and the patient with ATC received two cycles of doxorubicin before diagnosis of BM.
In total, 8/20 (40%) patients had organ metastases at TC diagnosis; two had both pulmonary and osseous metastases and 6 had pulmonary, osseous and BM. Hence, all patients, who presented with distant metastases at primary diagnosis, had at least two sites of distant metastases (lung, bones and/ or brain) and none presented with BM as the only metastatic disease. At diagnosis of BM, all patients had pulmonary metastases. Interestingly no patient had a singular pulmonary lesion but 18/20 patients had several (at least three) lesions located in one lung and two patients had bilateral, disseminated pulmonary lesions. Ten patients had bone metastases including eight patients with a singular bone Seven patients received additional systemic therapies. Of those, three patients were treated with chemotherapy for metastatic TC (two DTC, one ATC) before 2007 (i.e., before approval of TKIs). The patient with ATC received doxorubicin. The CHT regimen for the DTC patients remained unknown. Three patients with BM from DTC diagnosed after 2017 were treated with lenvatinib after progression upon RAI therapy. Lenvatinib was started before diagnosis of BM for one and after diagnosis of BM for two patients. No objective intracranial response was observed but patients remained stable for 2, 4 and 5 years respectively and two of these patients were still alive at time of analysis after a median follow up time of 75 months. Finally, one patient with FTC received temozolomide. This approach, however, was not successful as the therapy had to be discontinued after one cycle due to severe side effects (hematologic toxicities). See Table 1 for detailed clinical characteristics, treatment and outcome of patients with BM and TC.

Outcome after BM diagnosis
The overall PFS time after the first BM-specific treatment was two months for patients with PTC, 7 months for patients with FTC, 139 months for the MTC and only 2.6 months for the ATC patient (p = 0.266).
The median survival after diagnosis of DTC was 6.5 years (range 0.2-42 years) and the median survival after diagnosis of BM was 15 months (range 1.8-188 months, see Fig. 1). The patient with MTC lived 33 years after diagnosis of TC and 12 years after diagnosis of BM. The patient with ATC lived nine months after diagnosis of TC and 2.6 months after diagnosis of BM. Patients with FTC had a numerically shorter OS from BM compared to patients with PTC (13 vs. 26 months, p = 0.309). Ten patients died due to intracranial progression. Patients undergoing surgery had a better long-term outcome with a longer median OS compared to patients who didn't have a surgical resection, however, this was not statistically significant (4 vs. 33 months, p = 0.406). This was also observed in the DTC only cohort (4 vs. 42 months, p = 0.11). Patients with singular brain lesions (n = 12) had a trend for longer survival than patients with more than one brain lesion (26 vs. 13 months, p = 0.22).

Discussion
According to the literature, the development of BM constitutes a rare event in TC patients, documented in approximately 1% of DTC, 4% of MTC and 10% of ATC patients. In view of the rarity of BM in TC and the lack of systematic data regarding management and clinical outcome, we have retrospectively reviewed the Vienna Brain Metastases (p = 0.74). The median age at diagnosis of BM was 68 years (range 35-75 years). Patients with FTC developed BM at a numerically slightly younger age compared to patients with PTC (median age at diagnosis of BM: 62 vs. 72 years, respectively). The patient with MTC was 71 and the patient with ATC 66 years old at diagnosis of BM. The ECOG-PS was worse at diagnosis of BM compared to the ECOG-PS at diagnosis of TC. Two out of 20 patients (10%) had an ECOG-PS of 0 (compared to 12 patients at diagnosis of TC), 16 (80%) patients had an ECOG-PS of 1 (compared to 8 patients at diagnosis of TC) and two (10%) patients had an ECOG-PS of 2.

Neurological symptom burden, BM characteristics and treatment
Notably, almost all BM were symptomatic at initial manifestation (19/20, 95%). In detail, 11 patients presented with neurological deficits, five had symptoms of increased intracranial pressure and three had epileptic seizures. Only one patient with FTC had asymptomatic BM diagnosed coincidentally on a routine screening after RAI therapy. Regarding BM pattern, 13/20 patients had singular BM predominately located in the left hemisphere (8/13), three BM were located in the right hemisphere and two in the cerebellum. Two patients had two BM, in both patients located in the left and in the right hemisphere, 3/20 patients had three BM and two patients had more than three BM. Information about the size of BM was available for 13/20 patients. The size of BM ranged from 0.3 to 7 cm (patient with FTC). Seven patients had BM with a diameter of < 2 cm. The others had BM sizes between 3 and 7 cm. See Table 1 for a detailed list of BM-characteristics.
The most common upfront treatment for BM was total resection (n = 7), followed by stereotactic radiosurgery (SRS, n = 4), resection and SRS (n = 4), whole brain radiotherapy (WBRT, n = 3) and best supportive care (BSC, n = 2). If only looking at the DTC cohort, this distributed as follows: among the PTC patients, two patients had a resection, two a SRS, three a SRS and resection and one a WBRT; among the FTC patients, five patients had a resection, one a SRS, one a SRS and resection, one a WBRT and two patients with FTC were treated with BSC. Regarding the four patients with combined therapy, one patient with a singular BM was surgically resected and the resection area was subjected to subsequent SRS and three patients had multiple lesions, of which the biggest were surgically removed and the smaller BMs were treated with SRS. In total, 8/20 patients had a second BM treatment (SRS n = 5, resection n = 1, and WBRT n = 2). Only three patients had a third BM specific treatment (surgery, SRS and WBRT). No DTC patient received RAI for treatment of active BM.
BM to be more common in PTC [30][31][32][33][34][35]. Of clinical relevance is the fact that we also observed an earlier development of BM in FTC compared to the PTC cohort (2 vs. 10 years, respectively), suggesting that one should probably be more alert in these patients if neurological symptoms occur. Interestingly, no patient with oncocytic or poorly differentiated carcinoma was documented in our database, which is in contrast to other publications [4,8,9,[20][21][22][23][24][25][26]. See Table 2 for an overview of comparable patient cohorts reported in the literature.
The observed time from diagnosis of TC to BM was wide with a range from synchronous presence to up to 42 years from diagnosis of TC, again underscoring the different prognosis depending on the histological TC subtype. The median time to BM diagnosis was 36 months in the entire cohort with 6 patients presenting with synchronous BM and 102 months in patients who without BM at TC diagnosis.
Registry to investigate BM distribution, neurological symptom burden and BM-directed therapies in this highly distinct cohort of patients.
Our findings again underscore the exceedingly rare occurrence of BM from TC, with only 20/6047 patients (0.3%) in the Vienna Brain Metastases Registry having an underlying diagnosis of TC. The large majority was related to DTC (18/20, 90%) with only one patient each presenting with MTC and ATC. The predominance of DTC is in keeping with epidemiological data but analysis of subtypes of DTC requires further notice. In our cohort, 10/18 DTC patients (55%) had FTC, underscoring the more aggressive nature of FTC which only accounts for roughly 20% of all TC cases. Data in the literature regarding this observation, however, are conflicting: Shaha et al. reported that distant metastases including BM occurred more often in FTC (22%) compared to 10% in PTC, while other series reported lenvatinib experienced improved QoL and were still alive at time of analysis.
Relatively promising are data for intracranial activity of recently approved novel driver mutation based targeted therapies. Selective RET-inhibitors such as selpercatinib and pralsetinib are effective therapeutic options for RET -altered tumors, and both compounds have shown considerable intracranial efficacy of 91% in RET fusion-positive NSCLC in the pivotal studies [39,40]. RET alterations occur in over 60% of sporadic MTC, 98% of hereditary MTC and 10-20% of PTC [41], thus rendering these compounds of interest in selected patients with TC and BM. In addition, the NTRK inhibitors larotrectinib and entrectinib are approved for NTRK fusion positive DTC and MTC and particularly entrectinib is characterized by a high central nervous system penetration. An intracranial response rate of 64% was reported for entrectinib in the combined ALKA/ STARTRK trial [42]. While NTRK fusions are extremely rare in TC (< 2%), these data still support NGS testing at least following standard therapy. Furthermore, BRAF V600E mutations are a common finding in PTC and ATC associated with a more aggressive course. BRAF V600E can be targeted by BRAF +/-MEK inhibitors which show relevant intracranial control with most data again deriving from NSCLC. However, BRAF-targeted therapy is currently only FDA approved in ATC and in our cohort, only two PTC patients had a BRAF V600E mutation. Both had a short OS from diagnosis of TC of only 3 and 26 months, respectively. No patients in our cohort were treated with checkpoint inhibitors (CPI), and data regarding TC and CPIs remain scarce. First cohorts such as in the ATLEP study (lenvatinib and pembrolizumab for ATC) are being defined and based on experience of other tumor entities intracranial control is expected for CPI therapy also in TC [43].
Regarding OS, the median OS in our series after diagnosis of BM was 15 months (range 1.8-188 months) for patients with DTC, with a median OS of 6 years after initial diagnosis of TC (range 0.3-42 years). Again, FTC patients had a shorter OS from BM compared to the PTC cohort (13 vs. 26 months). These figures appear to be roughly in line with other series, with a median OS from diagnosis of BM reported to be between 7 and 33 months, depending on histological subtype, patient's performance status, the time from TC to BM diagnosis, number of BM sites and BM specific treatment [9,20,23,26,32].
The retrospective nature, the small sample size of only 20 patients with mixed histologies (while being in the medium range compared to other single center cohorts, see Table 1), as well as the absence of systematic assessment of further pathological characteristics such as BRAF/RET mutations or NTRK fusions are caveats of our analysis. Furthermore, due to the BM-specific focus of the underlying registry, these Interestingly, we observed BM only in patients with additional distant metastases, but not as an isolated event. Current guidelines do not support routine screening for BM in TC patients, and our data also do not suggest screening for BM in asymptomatic patients. However, in the subgroup of FTC and/or patients with distant metastases and neurological symptoms the treating physicians should be alert of the possibility of BM. This is further supported by the fact that all but one patient presented with neurological symptoms leading to diagnosis of BM (n = 11 with neurological deficits, 5 with increased intracranial pressure, 3 with seizures). Most patients presented with singular lesions (13/20), which were most commonly located in the left hemisphere (8/13). Finally, one could also consider brain imaging in patients with elevated tumor markers and absence of radiological extracranial lesions or progression, given the high sensitivity and specificity of biomarkers in DTC and MTC.
In general, local therapies appear to effectively control BM in the majority of patients judging from the scarce data in the literature [33]. Some authors reported a statistically significant longer BM-specific survival among patients who underwent resection compared to patients who did not [4,8,9,30,33]. In keeping with this, our patients treated with surgery had a better long-term outcome compared to patients who could not undergo resection (median OS from BM: 33 vs. 4 months). This also applied to the specific cohort of DTC patients (4 vs. 42 months, p = 0.11). Even though the difference was not statistically significant in our cohort, a significant difference was reported by other authors [1][2][3][4][5].
This again supports open surgery as the treatment of choice for BM, even in patients with impaired general condition [8]. While SRS could also be shown as effective in our series in line with literature reports [20,32], we and several authors found resection to be an independent covariate for prolonged survival [4,30,33,34,36]. In analogy to other series, our analysis does not allow for estimation of RAI therapy as a therapeutic option for BM, which has only been anecdotally reported in the literature [35].
TKIs are increasingly being used in patients with radioiodine refractory TC but little is known about their intracranial efficacy. To date, several multi-TKIs are approved for DTC and MTC. Effects for controlling BMs and improvement of QOL have only occasionally been reported [37,38]. The potential risk of intracranial bleeding in BM treated with multi-TKIs implicating anti-angiogenic effects needs to be considered but appears limited based on available data [38]. Also, our data do not allow for additional extrapolation on the value of TKIs in patients with BM, as only three patients received a TKI (lenvatinib) in our cohort. Lenvatinib was started before diagnosis of BM in one and after diagnosis of BM in two patients. Whereas no objective intracranial response was observed, two of three patients treated with Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons. org/licenses/by/4.0/. data do not allow extrapolation of prognostic and predictive factors rendering TC patients more prone to developing BM or regarding the general incidence of BM in TC patients.
Our analysis nevertheless provides a real-world analysis of a rare patient cohort treated at a tertiary referral center. We confirm that BM-development is associated with the histological subtype of TC and cautiously hypothesize that, in contrast to ongoing guidelines, screening for BM might be indicated for selected patients at individual intervals. This is supported by the finding that many patients present with symptomatic singular lesions, suggesting the possibility of improved local treatment options if detected early enough. This is underscored by the fact that aggressive (local) BM-specific treatment, preferable neurosurgery, appears to provide the best control for TC BM. In addition, we observed BM only in patients with additional distant metastases, which might be a further indicator for patient selection and screening. Finally, following recent data on personalized medicine approaches, we encourage NGS testing in all patients with advanced disease.
In conclusion, BM constitute a generally poor prognostic factor in TC patients, but individual patients experience long-term survival following local therapy. More information about clinical, pathological and molecular risk factors is needed to allow provision of distinct guidelines for the management of BM in TC. For the time being, patients should be managed on an individual basis in a tertiary referral center with access to (neuro-) surgery.
Funding There is no specific funding to report for this investigation. Open access funding provided by Medical University of Vienna.

Data Availability
Enquiries for further data can be directed to the corresponding author.

Conflict of Interest
The authors report no relevant conflicts of interest for this paper. LW has no conflicts of interest to declare. AS received travel support from Merck. PP has no conflicts of interest to declare-KD has no conflicts of interest to declare. BG has no conflicts of interest to declare. GW has no conflicts of interest to declare. MP received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers