In our analysis, we found five predictors for longer survival: the absence of distant metastasis at the time of diagnosis, surgery, complete resection (R0), a radiation dose of 50 Gy or higher and multimodal therapy (surgery, radiotherapy and chemotherapy). According to multivariate analyses, the best predictor of survival was a high radiation dose (≥ 50 Gy). Besides, even for patients with stage IV C (distant metastases) a radiation dose of at least 50 Gy could provide longer survival, whereas surgery and chemotherapy did not.

The guidelines of the National Comprehensive Cancer Network (NCCN) as well as the ATA (American Thyroid Association) guidelines recommend surgery (total thyroidectomy with therapeutic lymph node dissection), if resectable, with adjuvant radiotherapy and optional (radiosensitizing) chemotherapy for stage IVA and IVB [3, 8]. For unresectable disease they recommend radiotherapy and chemotherapy or molecularly targeted neoadjuvant therapy for borderline resectable disease. Depending on the response, surgery may follow. For stage IVC the guidelines distinguish aggressive from palliative treatment.

In the NCCN guideline aggressive treatment consists of surgery (total thyreoidectomy + lymphnode dissection, if resectable), locoregional radiation and chemotherapy plus molecular testing to check if a targeted therapy, such as dabrafenib/trametinib is considered [3]. Clinical trials should be initiated. Palliative therapy includes locoregional radiation as well as surgery and radiation of metastases. Tracheostomy and best supportive care may need to be performed as palliation or in transition before radiochemotherapy demonstrates effects. Following, cross-sectional imaging (CT, MRI with contrast), FDG PET/CT and disease monitoring should be continued.

The ATA guidelines focuse less on surgery and more on palliative cytotoxic chemotherapy and/or radiation for aggressive therapy in stage IVC disease [8]. They point out the importance of molecular testing and targeted therapies, already at the time of diagnosis.

In our study, a radiation dose of at least 50 Gy showed the strongest association with an improved survival, in accordance with the literature [9, 10]. However, an even more aggressive radiotherapy with a radiation dose of 60 Gy or higher should be delivered. In an analysis of 1288 ATC patients from the NCDB database, Pezzi et al. observed a significant benefit in survival for patients who received 60–75 Gy (HR = 0.419, 95% CI: 0.339–0.517) compared to cases who received 45–59.9 Gy (HR = 0.596, 95% CI:  0.479–0.743) and < 45 Gy (HR = 0.843, CI: 0.718–0.988) [11]. Comparable results can be found in other studies [2, 12, 13]. The NCCN guidelines also suggest a radiation dose of 60–66 Gy for adjuvant radiotherapy [3].

We also aimed to explore the difference in survival time and toxicity according to the radiation method. The advantage of IMRT and VMAT lies in the fact that a higher radiation dose can be delivered to the tumor while surrounding normal tissue can be better spared when compared to 3D-conformal techniques [2, 14]. Moreover, toxic side effects such as xerostomia can be reduced [15]. In their study on 41 ATC patients, Park et al. demonstrated a longer overall survival and progression-free survival using IMRT in comparison to 3D-conformal technique (HR for IMRT = 0.30) [2]. In addition, they could deliver a significant higher radiation dose using IMRT (66 vs. 60 Gy, p = 0.005), while toxicities were fewer than when compared to 3D-conformal technique.

In our cohort, a significantly higher radiation dose of 47.5 Gy versus 41.5 Gy could be delivered when using IMRT or VMAT. The toxic side effect of radiation was significantly better when IMRT or VMAT was used. Conversely, the risk of dysphagia was lower when a higher radiation dose was applied. This finding may be explained by the use of more toxic higher single doses (hypofractionation) in the radiotherapy concepts with lower total doses. Also, the OS was not improved using VMAT or IMRT compared to conventional radiotherapy. However, it must be pointed out that just a small number of our patients (13 out of 63) received IMRT or VMAT.

Moreover, surgery was a significant predictor for longer OS. Likewise, in almost every study we found, any kind of surgery extended overall survival and progression-free survival significantly, whereas radical surgery shows better outcomes [16,17,18,19].

For chemotherapy, we could not find any significant benefit in terms of survival. In the literature, various, but mostly disappointing outcomes, can be found [10, 20, 21].

On the other hand, regarding multimodal therapy, which includes chemotherapy as well as surgery and radiotherapy, we found a significant effect on survival, in accordance with the literature [2, 17, 22, 23]. Fan et al. explored the OS and progression-free survival (locoregional and distant) in 104 patients. Trimodal therapy was associated with an improved locoregional progression-free survival (HR = 0.060, p = 0.017) [13].

In our observation there was no advantage of survival in the most recent treatment periods (Table 2). The median OS in the last 10 years was six months, as well as in the period from 1989 until 1999. Compared to our older study from 2008, there was no difference in survival time (Fig. 3) [6].

Still, over the past years, treatment options have improved. Because of the high rate of BRAF V600E mutations in ATC recent advances have suggested the use of BRAF inhibitors, like dabrafenib and MEK inhibitors, such as trametinib [24].

In our cohort, three patients received targeted therapy. However, this number is too small and the observation period too short to draw any meaningful conclusions. The NCCN and ATA guidelines suggest dabrafenib plus trametinib for BRAF V600 mutated carcinoma, larotrectinib or entrectinib if NTRK gene fusion is positive and pralsetinib or selpercatinib for RET-fusion positive ATC [3, 8]. In case of a PD-21 expression or more than 10 mutations they also recommend checkpoint inhibitors such as pembrolizumab. Besides, the ATA guidelines name crizotinib and certinib for ALK-mutated tumors [8].

Several recent studies prove the positive effect of targeted therapy and immunotherapy [3, 25,26,27,28,29,30,31]. If there are mutations, which is the case in almost all the cases of ATCs, targeted therapies may be a promising therapeutic option or adjunct [3, 32]. The most frequent mutations are TP53, RAS and BRAF [32].

In our opinion, the future of ATC-therapy will be surgery plus individually planned high-dose radiotherapy and new targeted therapy. Even neoadjuvant concepts may become part of the therapeutic options in near future.

Our study was limited by the small number of patients. However, compared to other single center studies, 63 cases over 31 years still is a considerate number. Also, the results are biased by comorbidities or unresectable tumor which we tried to avoid by adjusting with Karnofsky score and building subgroups like the stage IVC group.

Due to the rareness of ATC prospective studies are very hard to perform. Hence, research is important to improve the therapy options and outcome of this extremely lethal disease.