9. Anaplastic thyroid carcinoma – Thyroid Cancer
Anaplastic thyroid carcinoma (ATC) is a very rare, highly aggressive disease that is usually presenting with rapidly growing mass in the neck often accompanied by other symptoms such as difficulty swallowing, hoarseness and dyspnea on initial presentation. The clinical suspicion is confirmed by cervical sonography. Immediately, imaging is performed to assess the extent of the disease in parallel with histological confirmation. Treatment is a challenge due to the aggressiveness of the disease and the very limited data available. A distinction can be made between resectable disease (stage IVA according to UICC) and non-resectable and/or primarily metastatic disease (stage IVB and IVC according to UICC). Treatment is multimodal and consists of surgery, radiotherapy and chemotherapy. Other therapeutic approaches include targeted therapy (e.g. BRAF and MEK, RET and NTRK inhibitors). There is also data on PDL1 inhibition, which has shown efficacy. The care of ATC patients includes experts in palliative medicine and psycho-oncology.
9.1 Preoperative diagnostics
9.1.1 Clinical examination
Anaplastic thyroid carcinoma (ATC) can present clinically as a rapidly progressive cervical mass with sudden hoarseness and shall be subjected to further work-up immediately.
- Consensus
- Strong consensus (100%)
Clinical suspicion of ATC are sudden hoarseness and difficulty swallowing. Other typical symptoms are a rapidly growing cervical tumor and shortness of breath. B symptoms such as weight loss and night sweats have also been described as initial symptoms in retrospective studies [1191].
The physical examination serves to assess the general condition using ECOG (Eastern Cooperative Oncology Group) status [1192] as well as specific examinations depending on the initial symptoms. The physical examination of the neck can provide relevant information such as the extent of the tumor, palpable metastases or infiltration of the skin. Overall, the physical examination is not primarily used for diagnosis, but for further treatment planning [1193].
9.1.2 Laboratory studies
Laboratory diagnostics are used to assess the general health status and the functional status of the thyroid gland. If a surgical procedure is planned, the functional status of the parathyroid glands shall also be evaluated.
- Consensus
- Strong consensus (100%)
There is no specific tumor marker for anaplastic thyroid carcinoma. Thyroglobulin, which is used as a progression parameter in differentiated and poorly differentiated thyroid carcinoma, is not useful in ATC, as there is complete dedifferentiation and this is accompanied by a loss of thyroglobulin expression, among other things [1194]. Thyroglobulin should nevertheless be determined during the initial diagnosis, as a lack of thyroglobulin production can support the diagnosis of ATC [337].
9.1.3 Sonography
Sonography examination is discussed in Chapter Imaging.
9.1.4 Imaging (CT, MRI, PET/CT)
Staging shall be performed using suitable imaging. Local tumor spread can be detected using sonography, CT or MRI.
Whole-body PET/CT with [¹⁸F]FDG should be performed to detect distant metastases and local tumor spread.
If brain metastases are suspected, a head MRI should be performed.
- Consensus
- Strong consensus (100%)
Accurate and rapid assessment of the extent of the histologically confirmed ATC is essential for adequate treatment planning. Immediately after initial diagnosis or histological confirmation of the ATC, the extent of the disease must be determined using suitable methods of cross-sectional imaging in order to plan next therapeutical steps (surgery and/or radiotherapy) [1195] and to predict if local resectability is feasible [1196], [49], [1197]. Local resectability is given if surgical R0 or R1 resection can be achieved. This is the case with intrathyroidal ATC or extrathyroidal infiltration limited to surrounding soft and fatty tissue, recurrent laryngeal nerve and superficial trachea. In contrast, ATC with cervical multivisceral infiltration (vessels, nerves, aerodigestive tract, substernal space) is usually irresectable [1198], [258], [1199], [1200].
Due to the rapid progression of the disease, if there is sufficient clinical suspicion, imaging can be planned and performed before histological confirmation is available in order to avoid delaying treatment; this applies in particular to impending local complications. If there are indications of airway involvement, CT cross-sectional imaging is the modality of choice. The most suitable imaging modality for detecting whole-body tumor status is positron emission tomography/computed tomography (PET/CT) with [¹⁸F]FDG. PET/CT is clearly superior to CT in the detection of metastasis-suspected lesions (detection rates 99% vs. 62%); PET/CT allows the initially planned treatment regimen to be adjusted in up to 25% to 50% of cases [1201], [1202], [1203]. Using [¹⁸F]FDG-PET/CT, ATC metastases can be better differentiated from (coincidental) DTC metastases , which impacts the treatment regimen [1204], [1205]. ATC expresses Glut-1 more strongly, which results in a higher accumulation of the radiopharmaceutical tracer in lesions suspicious for metastases [1206]. If a CT scan is performed, there is no reason to hold off contrast, as neither diagnosis nor treatment with radioiodine is possible (with regard to the prognostically relevant anaplastic tumor components). For the detection of brain metastases, MRI appears to be superior to other imaging modalities, in particular CT [1207], [1208]. For the detection of bone metastases [¹⁸F]FDG PET/CT is the modality of choice [1209], [1203].
9.1.5 Esophagoscopy
An esophagoscopy (i.e. endoscopy), possibly with additional endosonography, shall be performed if the clinical presentation and/or imaging is suspicious for infiltration of the esophagus.
- Consensus
- Strong consensus (100%)
An esophagoscopy (i.e. endoscopy) and, if necessary, endosonography allows for an exact assessment of suspected esophageal infiltration. In addition, a biopsy can be performed if the findings are conspicuous. In the case of advanced infiltration of the digestive tract, the tumor would be irresectable. Depending on the findings, the indication for pre-therapeutic stent implantation can be evaluated with regard to palliative radiotherapy [1210].
9.1.6 Tracheobronchoscopy
A tracheobronchoscopy shall be performed if the clinical presentation and/or imaging is suspicious for infiltration of the trachea.
- Consensus
- Strong consensus (100%)
A tracheobronchoscopy allows for an exact assessment of suspected tracheal infiltration based on clinical or imaging findings. In addition, a biopsy can be performed if the findings are not decisive. The findings are also relevant with regard to the assessment of resectability. In the case of advanced airway infiltration, the tumor would not be resectable. Depending on the findings, the indication for pre-therapeutic stent implantation can be evaluated with regard to palliative radiotherapy [1211], [1212].
9.1.7 Further diagnostics
As soon as the diagnosis is made by core or, if necessary, incisional biopsy, rapid genetic testing of the tumor and immunohistochemical determination of PD-L1 expression shall be performed for treatment planning.
- Consensus
- Consent (91,3%)
For ATC, targeted therapies requiring proof of a specific genetic alteration have been approved by the EMA or FDA (e.g. RET fusion, BRAF V600E mutation). Further biomarker analyses for targeted therapies, approved for advanced tumors regardless of tumor entity (tumor-agnostic), can also be considered as treatment options (e.g. NTRK fusion [1037], microsatellite instability). Large series of genomic analyses of ATCs have revealed genetic alterations in different signaling pathways or DNA repair genes amenable to targeted therapies that are approved for other solid tumors or available in clinical trials. In an analysis of 196 ATC tumors, TP53 (65%) and TERT mutations (65%) were most frequently found to be prognostically relevant. 41% had BRAF mutations and 27% RAS mutations [1213]. Currently, the BRAF mutation, which is detected in 11-45% of ATCs in different series [1191], can be targeted by combined BRAF and MEK inhibition, which is approved by the FDA. Other genetic alterations have been targeted effectively in case reports (e.g. ALK translocation [1214], ROS1 fusions [1215], or nonsense TSC2 mutation [1216]).
In the context of evolving personalized oncology care, initial genetic testing (panel sequencing of the important signaling pathways including fusions, TMB, HRR) of formalin-fixed and paraffinized (FFPE) tumor assessed by the pathologist is recommended. This applies in particular in the context of rapid disease progression considering the time genetic testing takes.
The routine use of whole exome (WES) or whole genome (WGS) sequencing cannot be recommended at this time due to the quantity and quality requirements of DNA/RNA and the longer time for results to come in, if performed outside studies.
Assessment of PD-L1 expression can be used to leverage off-label immune checkpoint inhibitor therapy, shown effective in studies or case reports (e.g. in combination therapy with tyrosine kinase inhibitors (TKIs), see below). For this purpose, the common scores for immunohistologic PD-L1 analysis (IC, CPS, TPS) shall be reported by the pathologist.
9.2 Therapy of resectable ATC
9.2.1 Surgery
For local tumor control and to improve outcome, radical surgery should be attempted in cases of local resectability (R0 to possibly R1 resection). Depending on the findings, this includes lobectomy or total thyroidectomy, possibly with diagnostic and/or therapeutic central lymph node dissection.
- Consensus
- Strong consensus (100%)
Local resection may also be indicated in metastatic disease due to local symptoms or the threat of secondary complications in the context of local tumor progression. Tumor debulking should be avoided if possible and may only be indicated in rare exceptions [1198], [258], [1217], [1218].
If ATC is locally resectable, surgery shall be attempted for local tumor control and to improve the chances of survival. Local radical (R0) resection is the goal. If there is localized extrathyroidal tumor growth, surgery shall be attempted to achieve local tumor control and improve the chances of survival. Alternatively, a neoadjuvant concept with systemic therapy can be attempted with the aim of secondary surgery.
The extent of resection depends on the local findings and the presence of metastatic disease. Unilateral intrathyroidal ATC can be resected by lobectomy if possible, depending on the findings; in most cases a thyroidectomy is required for complete tumor removal. The significance of locoregional lymph node dissection of the central compartment from a diagnostic and therapeutic point of view is assessed inconsistently. Lateral lymph node dissection should only be considered in cases of clinical involvement. For all types of resection, adjuvant early postoperative locoregional external radiotherapy should is essential to ensure surgical outcome.
9.2.2 Radiotherapy
9.2.2.1 Indication for primary or postoperative radiotherapy
After R0 or R1 resection, patients with ATC with good performance status and no evidence of metastatic disease shall be offered normofractionated intensity-modulated radiotherapy (IMRT) with simultaneous systemic therapy.
- Consensus
- Strong consensus (100%)
Despite the poor prognosis of ATC, percutaneous radiotherapy is an essential local treatment option with a predominantly palliative character. Locoregional tumor control is achieved in 60-80% of percutaneously irradiated patients [1219], [1220], [523], [1221], so that death by asphyxiation can usually be prevented. In a large retrospective series, the combination of surgery and percutaneous radiotherapy was an independent prognostic factor for tumor-specific survival [1222]. The benefit of aggressive local therapy was found in patients with locoregionally advanced or distant metastatic disease, but not with only intrathyroidal tumor extension. Even in the presence of distant metastasis, local tumor control appears to prolong survival [1223]. Primary or postoperative radiotherapy is therefore generally indicated for ATC.
In patients without distant metastases in whom complete tumor resection is possible, combined radio-chemotherapy (in the sense of trimodal therapy) with three-year survival rates of at least 50% [1224], [1225], [1226] may even represent a curative treatment approach. Preoperative and postoperative radiochemotherapy yielded comparable results [1224], [1220], [1226], meaning that both sequences are justifiable in principle. Both pre- and postoperative radiotherapy ("split course") is not recommended [1220]. In a larger case series (104 patients, period 1984-2017), a 1-year survival of 45% was described after surgery and combined radio-chemotherapy (doxorubicin in 74%, paclitaxel with or without pazopanib in 24%) [1227].
A recent meta-analysis (17 non-randomized observational studies, 1,147 patients) looked at the value of postoperative radiotherapy after ATC resection (R status not specified) [1228]. Postoperative radiotherapy reduced the risk of death compared to surgery alone with an HR of 0.556 (95% CI, 0.419-0.737; p<0.001). The benefit was most pronounced in patients with stage IVA (HR 0.364; p=0.012) and IVB disease (HR 0.460; p=0.059). In a further meta-analysis (10 studies, 1,163 patients), a reduction in the risk of death with HR 0.51 (95% CI: 0.36-0.73, p=0.0002) was reported after surgery + radiotherapy compared to surgery alone [1229].
9.2.2.2 Implementation of radiotherapy
Radiotherapy shall be planned and started as soon as the patient has recovered sufficiently from the neck surgery, usually within two to three weeks after the surgery.
- Consensus
- Strong consensus (100%)
Patients receiving radiotherapy for ATC (irresectable or postoperative) shall be treated with intensity-modulated radiotherapy (IMRT).
- Consensus
- Strong consensus (95,7%)
In patients treated with radiotherapy (at least 50 Gy), simultaneous chemotherapy with a combination of taxane (paclitaxel, docetaxel) and/or anthracycline (doxorubicin) and/or platinum (cisplatin, carboplatin) should be used.
- Consensus
- Strong consensus (100%)
Patients with ATC in poor performance status shall preferably be offered palliative dosed locoregional radiotherapy.
- Consensus
- Strong consensus (100%)
The effectiveness of percutaneous radiotherapy for ATC is dose-dependent. The total dose is usually 40-70 Gy; when choosing the fractionation, a short total treatment duration (acceleration, e.g. through hypofractionation) shall be aimed for in view of the usually short survival times. Hyperfractionated radiation (e.g. two fractions per day) can be used as part of intensified radio-chemotherapy protocols.
In retrospective analyses, survival time and local control were significantly improved when total doses above 30 Gy or 40 Gy (cut-off value for comparison in the respective study) were used [1223], [1221].
In smaller series, accelerated, in some cases hyperfractionated, radiation protocols were investigated, which only achieved median survival times of around 3 months without simultaneous chemotherapy, despite total doses of around 60 Gy [1219].
A recent meta-analysis of the National Cancer Data Base with 1,228 patients shows a clear correlation between total dose of radiotherapy and overall survival (compared to no radiotherapy: radiotherapy with <45 Gy: HR 0.834; with 45-59.9 Gy: HR 0.596; with 60-75 Gy: HR 0.419 [1230]. The effect was confirmed in a propensity score-matched analysis. The 1-year survival after radiotherapy with 60-75 Gy was 31% and with 45-59.9 Gy 16% (p=0.008).
Percutaneous radiotherapy of ATC should be performed as intensity-modulated radiotherapy (IMRT) to minimize toxicity, although the urgency of starting treatment or a highly palliative situation may also justify simpler radiotherapy techniques.
In a retrospective analysis of 41 patients with ATC, multivariate analysis showed an advantage in overall survival for patients treated with IMRT vs. patients treated with 3D-conformal radiotherapy (HR 0.33, 95% CI 0.15-0.72, p=0.005) [1231]. IMRT patients received a higher total dose compared to the 3D technique (66 Gy vs. 60 Gy), but did not show increased toxicities.
9.2.3 Systemic therapy
Adjuvant chemotherapy can be carried out after R0/R1 resection and radiochemotherapy in patients without evidence of residual tumor disease and/or metastasis.
- Consensus
- Strong consensus (100%)
Survival of patients with anaplastic thyroid carcinoma is stage-dependent [1205], [1232]. Patients in the non-metastatic stages IVA and IVB have a significantly better survival than patients with metastatic stage IVC disease. In retrospective studies, multivariate analyses showed an advantage for patients with IVA and IVB disease after tumor resection followed by adjuvant radiotherapy and chemotherapy [1193], [1233].
In a large Japanese retrospective multicenter study with 547 ATC cases, patients with stage IVB disease who received multimodal therapy consisting of surgery, radiotherapy and adjuvant chemotherapy had significantly better survival, compared to patients with stage IVA disease [1205]. The median overall survival of stage IVA patients was 389 days with resection and adjuvant radiotherapy versus 314 days with surgery, radiotherapy and chemotherapy. In stage IVB patients, on the other hand, the median survival was 194 versus 420 days with the same treatment sequence. In a retrospective series of 104 ATC patients treated between 1984 and 2017, the median 1-year survival after surgery, radiotherapy and adjuvant chemotherapy was 54.7% compared to 12.8% for patients who received only two or one of the three treatment modalities [1227]. Derbel et al. [1234] studied 44 ATC patients. The majority (35/44) received multimodality therapy and 14 patients achieved complete remission after therapy completion. These 14 patients had an initially stage IVA or IVB disease. The substances administered were doxorubicin in combination with cisplatin, or carboplatin, or paclitaxel monotherapy.
The efficacy of chemotherapy regimens for the adjuvant treatment of stage IVA and IVB anaplastic thyroid carcinoma patients has not been investigated in prospective studies. Several retrospective case series have analyzed the efficacy [1191]. Seto et al. investigated the efficacy of docetaxel (75mg/m²) and cisplatin (75mg/m²) every 4 weeks for 6 cycles [1235]. Included were 8 patients, including 2 patients in stage IVB for postoperative adjuvant therapy. Both patients received adjuvant radiotherapy after R0 and R1 resection, respectively. One patient died of local recurrence 3 years after receiving 5 cycles of chemotherapy and the second patient remained free of recurrence after receiving 6 cycles at the time of publication (>5 years after diagnosis). In a French study, 30 patients were treated with multimodal therapy [1226]. An R0 or R1 situation after surgery was achieved in 12 patients. The 12 patients received adjuvant radiotherapy postoperatively and were treated with 2-9 cycles of doxorubin (60mg/m²) and cisplatin (120mg/m²). Overall survival varied widely between 4 and 78 months (median 24.5 months).
Long-term systemic therapy of resectable ATC without evidence of residual disease in imaging after completion of multimodal therapy is not recommended [1191].
9.3 Treatment of non-resectable or incompletely resected and/or metastasized ATC
9.3.1 Neoadjuvant therapy
In the non-resectable situation, patients with a BRAF V600E mutation should undergo neoadjuvant therapy.
- Consensus
- Strong consensus (100%)
In a case series of 57 ATC patients with a BRAF V600E mutation at the MD Anderson Cancer Center, Texas, from 2017 to 2021, primary tumors became resectable in approximately 70% of patients after at least one month of combination therapy with dabrafenib and trametinib (DT) [1236]. If DT treatment was only given after surgery (n=12), the outcome was slightly worse than in patients (n=32) who received DT treatment in the neoadjuvant setting.
In a further study including 13 patients, surgery could not be performed due to insufficient response (n=9) after DT, insufficient AZ (n=2). Two patients refused surgery. In the DT + surgery group, the median OS [CI 39.2 months - NA) was not reached, the 1- and 2-year OS was 93.6% and 80.3% respectively. In the group without surgery + DT, the 1- and 2-year OS was 38.5% and 15.4%, respectively. In patients with preoperative DT treatment, the 1-year and 2-year OS was 74.1% and 74.1%.
A British study [1237] included 17 patients with unresectable disease and BRAF V600E tumor positivity, who were treated with DT between August 2018 and October 2021. 12 patients underwent surgery after DT, 4 had an R0 resection, 7 had an R1 resection and one had an R2 resection. The median OS was 12 months (range 3 to 43). Although the real-world outcome data is worse than of the ROAR basket study, it is still improved better compared to other retrospective data. In addition to stricter inclusion criteria in studies, delayed access to DT is also mentioned as a possible explanation.
Studies with other drug combinations have been initiated:
DT plus pemprolizumab (30 patients, phase II study; NCT04675710),
MD Anderson Cancer Center immune checkpoint inhibitor atezolizumab combined with the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib (VCA) (n=17).
If effective neoadjuvant therapy results in resectability of the primary tumor with an expected benefit for the patient, surgical therapy should be following.
- Consensus
- Strong consensus (100%)
A primary tumor that was considered irresectable can become resectable after radiation, chemotherapy combined radio-chemotherapy or targeted therapy [1224], [1238], [1239]. In the re-evaluation of resectability with the aim of avoiding local recurrence and preventing locoregional complications, the overall prognosis, the increased surgical difficulty, especially after local radiotherapy with the associated increased risk of complications and the individually expected benefit of resection should be taken into account, as data on disease-free and overall survival are lacking.
9.3.2 Surgical treatment of extrathyroidal ATC without multivisceral infiltration
For local tumor control and to improve the chances and quality of survival in patients with extrathyroidal ATC without multivisceral infiltration, complete tumor removal shall be attempted in cases of local resectability (R0 to possibly R1 resection). Depending on the findings, this includes lobectomy or total thyroidectomy, possibly with diagnostic and/or therapeutic lymph node dissection.
- Consensus
- Strong consensus (100%)
In ATC with extrathyroidal spread but without cervicovisceral infiltration, extended resection is indicated if it can achieve local tumor control and improve survival and/or quality of life [1198], [258], [1200]. Selected patients have experienced prolonged recurrence-free survival and/or overall survival after surgery for locoregional disease [1223], [1198], [1240].
9.3.3 Surgical treatment of extrathyroidal ATC with multivisceral infiltration
In the case of multivisceral ATC infiltration, surgery should generally not be performed, but can be performed in individual cases to debulk the tumor and prevent local complications (e.g. tracheal compression).
- Consensus
- Strong consensus (100%)
If multivisceral infiltration is present in ATC with extrathyroidal spread and only tumor debulking (R2 resection) can be performed, surgery is not recommended. If non-surgical palliative measures do not provide sufficient symptomatic improvement, tumor debulking surgery may be indicated on an individual basis, e.g. to avoid secondary complications, e.g. to secure the airway or enable a tracheostoma to be placed. A prophylactic tracheostomy shall be avoided [1090], [1198], [258].
9.3.4 Recurrence surgery
Completion surgery for adequate or complete primary tumor resection of an ATC should be attempted if R0/R1 resection can be achieved. Re-surgery for ATC recurrence should be evaluated if the benefits of local tumor control or prevention of secondary complications are considered advantageous in the case of resectability, taking into account the overall situation.
- Consensus
- Strong consensus (100%)
If ATC is only diagnosed postoperatively and no form of tumor-adequate resection or radical primary tumor resection has been performed (subtotal resection, lobectomy with R1/R2 resection), the possibility of completion surgery of both the ATC component and possible tumor components of other entities should be examined as a completion surgery, as R0 resection improves the overall prognosis [1222][1241]. Whole-body imaging and the locoregional tumor extent should be assessed to demonstrate resectability and establish an advantage for the patient.
ATC recurrence within primary tumor bed should be evaluated in the context of resectability as in the primary situation. The risk factors for recurrence as well as the overall disease and prognosis must be taken into account.
The considerations for local progression control and prevention of secondary locoregional complications due to tumor growth apply in principle to completion surgery and recurrence surgery for ATC in the same way as for primary surgery, but the increased degree of difficulty and risk of complications must also be taken into account as limiting factors.
9.3.5 Radiotherapy
After R2 resection or in the case of resectable non-metastatic ATC, patients with good performance status who prefer a radical approach shall be offered normofractionated radiotherapy in the form of intensity-modulated radiotherapy (IMRT) with simultaneous systemic therapy. For patients with BRAF mutations, treatment with BRAF/MEK inhibitors can be considered as an alternative.
- Consensus
- Strong consensus (100%)
9.3.6 Systemic therapy
Multimodal therapy should be offered to patients with metastatic/non-resectable ATC (chemotherapy in addition to and, if necessary, following radiotherapy) if no targetable mutations are present.
- Consensus
- Strong consensus (100%)
To date, only one ATC phase III trial has been published, which was terminated prematurely due to recruitment difficulties [1242]. However, several retrospective cohort studies have shown significantly longer overall survival in patients who received multimodal treatment. In all retrospective studies, a clear systematic bias in the allocation of chemotherapy can be assumed [1243], [1232], [1233]. Patients with good performance status, should be treated with cytotoxic chemotherapy [1198]. Reliable data on the most suitable regimen is not yet available. However, with a view to early and sufficiently high-dose radiotherapy, it is advisable to choose a chemotherapy that can be started as a radiosensitizer before or during radiotherapy and continued after it. A typical regimen that is used internationally and also in Germany is carboplatin (AUC2) and paclitaxel (50 mg/m²) as weekly chemotherapy in parallel with radiotherapy, which is adjusted in dose and treatment interval after completion of radiotherapy: paclitaxel 135-175 mg/m² at three to four-week intervals, carboplatin AUC 5-6) [1244]. This regimen can also be used if radiotherapy is omitted. Due to the low rate of objective response and toxicity, doxorubicin is not recommended despite existing approval.
Inclusion in a suitable treatment study should be offered when a non-resectable/metastatic ATC is diagnosed and during the course of treatment, if available.
- Consensus
- Strong consensus (100%)
Due to the rarity of ATC and the lack of evidence-based recommendations as well as the development of new, currently mainly molecularly-targeted and immunotherapy approaches, as many patients as possible should be included in studies. In addition to the gain in knowledge, treatment within a trial offers the advantage for patients that they are closely monitored during the trial and potentially benefit from a new therapy. For this reason, early contact with a center experienced in this entity is recommended.
BRAF-mutated ATC should be treated with a combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib.
- Consensus
- Strong consensus (100%)
If an ATC with a RET fusion is detected, treatment with the RET inhibitor selpercatinib can be administered.
- Consensus
- Strong consensus (100%)
If an ATC with an NTRK fusion is detected, treatment with an NTRK inhibitor (larotrectinib or entrectinib) can be given.
- Consensus
- Strong consensus (100%)
Based on a phase 2 trial in BRAF-mutated ATC, the combination of dabrafenib 150 mg twice daily in combination with trametinib 2 mg daily was approved in the USA for ATC patients with this molecular alteration. In the study, an objective tumor response (partial remission) was observed in 10 of 16 patients; after a median follow-up of 12 months, 8 of the 10 patients continued to have a response [1245]. In an update only available as a congress report, 28 patients were included, the median progression-free survival was 60 weeks, the overall survival 86 weeks. Therefore, patients with BRAF-mutated ATC and good performance status (ECOG performance status ≤2) who are able to take oral medication should urgently consider treatment with this therapy, which is not approved in the EU (as of 07/2021), as part of an individualized treatment trial. The combination therapy is currently not approved for this indication in the EU, but has been approved in the USA by the FDA since 2018 and by the English NHS since 2022.
The selective RET inhibitor selpercatinib was investigated in a total of 162 thyroid cancer patients with an RET mutation or fusion in a phase 1-2 study [1034]. Two ATC patients were included. One ATC patient had stable disease and the other ATC patient had a partial response. The results of this study were the basis for approval for the treatment of advanced medullary thyroid carcinoma with RET mutation. However, in non-medullary thyroid cancer with RET fusions, selpercatinib is only approved as second-line therapy after lenvatinib and/or sorafenib therapy. Further data on selpercatinib in the treatment of ATC are available in the form of a case report [1246].
The NTRK inhibitors larotrectinib and entrectinib have been approved by the EMA for the treatment of patients with tumors with NTRK fusion [1247]. Data for the treatment of ATC patients with an NTRK fusion with an NTRK inhibitor is scarce. Larotrectinib was investigated in a study with 55 patients, including 5 thyroid cancer patients. All 5 patients responded to the therapy with a complete or partial remission. The histology of these patients was not reported. A report from the annual meeting of the European Society of Medical Oncology (ESMO) summarizes the results of a study of the efficacy of larotrectinib in 28 thyroid cancer patients, including 7 ATC patients [1248]. The primary endpoint was best overall response. Two of the seven ATC patients had a partial response, 1/7 had stable disease and 3 of 7 patients had progressive disease.
Efficacy has been shown for other targeted therapies, for example, there are promising case reports on the ALK inhibitor crizotinib [1214] and the mTOR inhibitor everolimus [1216]. These therapeutic options can be utilized in an indvidual treatment approach and ideally by inclusion in corresponding studies.
The tyrosine kinase inhibitors lenvatinib and sorafenib are approved for the systemic treatment of radioiodine-refractory differentiated thyroid carcinoma. Similar to other tyrosine kinase inhibitors, these have also been used in smaller studies in ATC [1244], [1249]. Lenvatinib showed an objective tumor response rate of 24% with a progression-free survival of 7.4 months and a median overall survival of 10.6 months in a phase 2 trial in Japan with 17 patients [1250]. This led to the approval of lenvatinib for the treatment of ATC in Japan, but not yet in Europe or the USA. In an international phase 2 trial of the International Thyroid Oncology Group with 33 patients, which is not yet available as a full publication, a confirmed partial remission with lenvatinib was observed in only one case (NCT02657369). A recent multicenter open-label phase II study investigated the efficacy of lenvatinib monotherapy in 34 patients. The best overall response showed a partial response in 1/34 patients, stable disease in 17/34 patients and progressive disease in 9/34 patients [1251].
The role of immunotherapy in ATC has not been conclusively investigated. Various combination therapies, for example of tyrosine kinase inhibitors with immune checkpoint inhibitors, are currently being investigated [1252], [1253]. In a German retrospective study, a total of 8 patients with metastatic disease, 6 with ATC and 2 with PDTC, were treated with a combination of lenvatinib and the PD-L1 inhibitor pembrolizumab [1054]. All patients had prior treatments including surgery, radiotherapy, chemotherapy or radioiodine therapy. In the first imaging follow-up 3-4 months after initiation of therapy, 4 of the 6 included ATC patients showed complete remission, 1 patient had stable disease and 1 patient had progressive disease. Overall survival in the 4 ATC patients with an initial complete remission was 11, 19, 26 and 40 months.
9.3.7 Management of individual issues
The indication for surgical and/or local ablative therapy in metastatic stage IVC versus the initiation of systemic therapy should be determined individually and by interdisciplinary consensus, taking into account the mostly palliative situation.
- Consensus
- Strong consensus (100%)
ATC in the metastatic stage is associated with an unfavorable prognosis. In autopsy studies and retrospective cohort studies, distant metastasis is reported in around 75% of patients and more than one organ system is affected in around 80% [1205], [1254], [1255], [1256]. The 1-year survival in stage IVC is around 8% [1204]. In the rare case of oligometastatic disease, the effects of local ablative and/or surgical therapy have not been investigated.
9.3.7.1 Lung metastases
Disseminated lung metastases shall be treated systemically.
- Consensus
- Strong consensus (100%)
The lung is the most frequently affected organ system in metastatic ATC patients, with a frequency of 70-80% [1255], [1256]. The majority of patients have multiple lung metastases and at least one other affected organ system [1254], so systemic therapy shall be preferred over local ablative therapy. For systemic therapy of lung metastases, please refer to Chapter Systemic therapy.
9.3.7.2 Bone metastases
In the case of symptomatic bone metastasis, local ablative and/or surgical therapy should be offered.
- Consensus
- Strong consensus (100%)
A stable vertebral body metastasis without myelon compression can be treated conservatively.
- Consensus
- Strong consensus (100%)
In the presence of bone metastases, antiresorptive therapy with bisphosphonates or RANK ligand antibodies should be carried out.
- Consensus
- Strong consensus (100%)
Bone metastases occur in 5% of ATC patients, usually in combination with at least one other affected organ system [1255]. The treatment of bone metastases in ATC patients has only been investigated in small case series. In a series of 14 thyroid cancer patients with myelon compression, 4 had histologically confirmed ATC [1257]. The patients were irradiated without primary surgical intervention. There was a response rate of 79% for all thyroid cancer patients. In a retrospective study, a total of 79 thyroid cancer patients with bone metastases were examined, including 10 patients with histologically confirmed ATC [1258]. Six of the 10 patients died in the first year after bone metatases diagnosis.
The aim of the specific treatment of bone metastases is to prevent skeletal complications such as pathological fractures, spinal compression syndrome, bone pain and hypercalcemia. The treatment options are pharmacological pain management, local radiation, surgical intervention and systemic tumor therapy.
Bisphosphonate therapy or therapy with RANKL inhibitors for osteoprotection has not been investigated in ATC patients. In individual cases, osteoprotective therapy with bisphosphonates can be discussed in analogy to other aggressive tumor diseases. Please refer to the interdisciplinary cross-sectional guideline "Supportive therapy in oncology patients".
9.3.7.3 Brain metastases
The treatment of brain metastases should be determined individually by interdisciplinary consensus in view of the poor prognosis.
- Consensus
- Strong consensus (100%)
Brain metastases are rare in ATC patients with a frequency of 1-5%, but are associated with a particularly unfavorable prognosis [1207]. Data on therapy are only available in the form of retrospective cohort studies with small numbers of cases. Salvati et al. [1208] retrospectively examined 12 thyroid cancer patients, including 5 with an ATC, with a single brain metastasis. In 4 of the 5 patients, more than one organ system was affected. The time between diagnosis of the primary disease and brain metastasis was between 7 and 13 months. In all patients, treatment consisted of resection of the metastasis followed by whole-brain radiotherapy. Overall survival was 8.8 months from ATC diagnosis.
Another study included a total of 47 thyroid cancer patients with brain metastases, including 11 ATC patients [1207]. The lesions were multifocal in 80% of the ATC patients and more than one organ system was affected in 80% of the patients. Survival after diagnosis of brain metastases was 1.3 months in ATC patients, which was significantly shorter than that of patients with differentiated thyroid carcinoma at 12.4 months.
No valid conclusions can be drawn from the available data due to the retrospective study design and the small number of patients. The prognosis after diagnosis of brain metastatic disease is dismal, i.e. the indication should be made as part of an interdisciplinary consensus. Treatment options include resection, radiotherapy and/or systemic therapy.
9.3.7.4 Surgery for metastatic disease
Depending on the localization, metastasectomy can be offered symptomatically or as a preventive measure against complications, if necessary, in addition to other therapeutic approaches.
- Consensus
- Strong consensus (100%)
Disseminated distant metastatic disease to one or more organ systems requires a systemic therapeutic approach. A role for surgery arises in individual cases depending on the localization and existing or impending symptoms or complications that cannot be controlled by therapeutic means or are complementary to them. This is most likely to be the case with bone metastases, cervical, mediastinal, skin and visceral metastases.
9.3.7.5 Further metastasis
In autopsy studies, metastases were found in a variety of organs in patients with anaplastic thyroid carcinoma [1254], [1256]. In addition to metastases in the lungs, bones and brain, lesions were also found in the liver in 20-30%, in the adrenal gland in 21-24%, in the cardiovascular system in 18%, in the stomach in 7% and in the pancreas in 6.7% of ATC patients. More than one organ system was affected in 80% of patients. It is not clear which metastases were already known before death and to what extent they were relevant for the clinical course. However, the studies show that metastases can occur in almost all organ systems.
Folllowed by lungs, the liver is the second most affected organ. However, metastases usually occur multifocally, so that surgical or local ablative therapy is not possible. In this case, systemic therapy should be considered as an option, as described in Chapter Systemic therapy.
9.4 Follow-up care for anaplastic thyroid carcinoma
9.4.1 Requirements for evaluation of therapy response
Patients with anaplastic thyroid carcinoma should receive cross-sectional imaging of the skull, neck, thorax, abdomen and pelvis after initial staging and treatment and without evidence of structural tumor disease if further treatment is desired. The recommended intervals are 1 - 3 months within the first year, then every 3 - 4 months within the following year and then every 6 months for a further 2 - 3 years. In addition to [¹⁸F]FDG PET/CT, which is particularly suitable for whole-body staging, CT with contrast and MRI are suitable modalities.
- Consensus
- Strong consensus (96%)
In patients with anaplastic thyroid carcinoma, imaging with [¹⁸F]FDG-PET/CT should be performed as part of follow-up care. It is used to detect small metastases that may alter treatment. In addition, [¹⁸F]FDG-PET/CT can enable a response assessment to decide on change in treatment in the case of persistent structural disease.
- Consensus
- Strong consensus (95,7%)
Patients with anaplastic thyroid carcinoma should receive cross-sectional imaging of the skull, neck, thorax, abdomen and pelvis or other affected organs/regions after initial staging and treatment and with evidence of persistent structural tumor disease if further treatment is desired. The choice of modality (CT with CA, MRI, [¹⁸F]FDG-PET/CT) depends on the individual findings and the need for therapy monitoring or therapy planning. The intervals should be 1 - 3 months.
- Consensus
- Strong consensus (100%)
Despite all therapeutic efforts, the majority of patients with ATC eventually develop tumor progression usually within a short period of time, and succumb to the disease. Approximately one third of patients already have distant metastases at the time of initial diagnosis and a further third develop distant metastases during the course of the disease. Supportive therapy is therefore important (see Chapter Rehabilitation). Approximately one third of patients die with locoregional disease, one quarter with distant metastases and more than 40% with both. Distant metastasis mainly affects the lungs (80% - 85%), the bones (5% - 10%) and the brain (5% - 10%). Lack of locoregional tumor control is found early on within 3 months in 20% to 40% of patients [1259], [1260], [1261], [1262], [1263], [1264], [1223], [1265], [1266], [1267], [520], [1268], [1269], [1226], [1221], [1270]. In this overall situation, cross-sectional imaging is a suitable procedure for the follow-up of both locoregional and distant tumor control. The start and intervals of diagnostic imaging depend on the initial tumor stage, the response to therapy and the time since diagnosis.
After initial successful therapy with no evidence of residual tumor, sectional imaging using CT or MRI of the brain, neck (plus sonography if necessary), thorax, abdomen and pelvis should be performed at intervals of 1 - 3 months for the first 6 to 12 months. Thereafter at intervals of 4 - 6 months for the following year. Additional examinations may be necessary in individual contexts. If the patient refuses further therapeutic measures, imaging procedures can be used in close consultation with the patient in a symptom-oriented manner [1198].
If there is no tumor after 2 years, the intervals can be extended to 6 months for another 2 to 3 years. In the event of tumor persistence or recurrence, sectional imaging should be performed in accordance with the clinical situation.
CT, MRI and, if necessary, sonography for the neck are suitable for anatomical response assessment using sectional imaging. The same procedures shall be used for follow-up exams according to the organ-specific requirements and availability. Reference can be made to the explanations in Chapter Imaging (CT, MRI, PET/CT) on morphological cross-sectional imaging. The RECIST response assessment requires a complete CT, which can also be acquired as part of a PET/CT examination. Study protocols may also require other/additional modalities for response assessment (e.g. PET-based criteria, see below).
¹⁸F]FDG-PET/CT is an additional well-suited procedure for tumor follow-up. In the case of persistent tumor burden, (whole-body) [¹⁸F]FDG-PET/CT offers the highest diagnostic accuracy [1198]. In particular, with discordant imaging, the metabolic activity measured in [¹⁸F]FDG-PET can be more informative than the sole assessment of tumor size in CT [1202], [1203], [1271], [1272]. It is also possible to assess the response to systemic therapy and radiotherapy [1202], [1271], [1272].
9.4.2 Terminology of therapy response
The evaluation of treatment response in patients with anaplastic thyroid carcinoma should be based on the RECIST 1.1 criteria for the treatment of solid tumors.
- Consensus
- Strong consensus (100%)
There are no studies evaluating treatment response criteria specifically for anaplastic thyroid carcinoma. Current studies on systemic therapy for anaplastic thyroid carcinoma use the RECIST criteria [549], [1273], [1252].
There are no tumor markers for response evaluation in anaplastic thyroid carcinoma.
A negative [¹⁸F]FDG-PET with a new lesion confirmed by CT during the course is assessed as progression if the new lesion is detected at a new site.
PET-based criteria (PERCIST) [1274] for assessing treatment response have been validated for many solid tumors and are characterized by higher sensitivity and diagnostic accuracy compared to RECIST. Individual observations suggest that this also applies to anaplastic thyroid carcinoma, even if there are no systematic studies on this entity [1275]. Newly detected lesions without [¹⁸F]FDG uptake are assessed according to the RECIST 1.1 criteria.
9.4.3 TSH target
The thyroid metabolism in ATC patients should be euthyroid with a target TSH in the reference range.
- Consensus
- Strong consensus (100%)
Anaplastic thyroid carcinoma is an undifferentiated carcinoma that is characterized, among other things, by the loss of expression of the sodium iodide symporter on the basolateral membrane [1276]. A growth stimulus through the pituitary TSH has not been proven and would be implausible, so that no growth-inhibiting effect through exogenous TSH suppression is to be expected.
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