ATC, accounting for only 1~2% of all TC, occurs mainly in the elder group [3]. Arora et al. collected 644 ATC patients from the SEER database and the median age was 61.55 years in ATC [4]. A cohort study of 677 ATC patients from 38 multicenter indicated that a majority of patients had acute symptoms, such as dysphonia, dyspnea, and dysphagia, due to rapidly growing tumors [7]. According to the 2022 version of NCCN guidelines, surgery is recommended for ATC patients with resectable mass in Stage IVA or IVB, and neoadjuvant therapy can be tried for individuals with unresectable ATC. The following treatments are advised for individuals with Stage IVC, including radiation therapy, systemic therapy, target identification, or palliative care [8]. The five-year disease-specific survival rate is 14.3% [9]. It accounts for 15~40% of TC deaths and has a relatively quick clinical course with poor treatment outcomes [10]. Maniakas et al. demonstrated significantly improved survival in the period of 2017-2019 as compared to previous years, with 61% of those patients receiving targeted therapy and 47% receiving immunotherapy [11]. The current model for ATC treatment is increasingly inclined towards multidisciplinary comprehensive treatments.
In this study, we enumerated a cohort of 61 ATC patients followed by our institution and provided detailed clinical and treatment parameters. The patients aged from 34 to 85 years, with a median age of 66. Due to the high degree of malignancy, half of the patients had tumors larger than 5cm. 49/61 (80.3%) patients had lymph node metastases and 41/61 (67.2%) had distant metastases. Iwao et al. found accompanying nodal or distant metastases were independent prognostic factors and associated with poor outcomes [7]. In addition, the results showing a majority of patients had a first diagnosis of stage IVB and stage IVC and had extrathyroidal invasion. ATC is insidious and difficult to detect in the early stage, and this disease seriously threatens patient health.
ATC is more prone to cancer-related deaths, accounting for more than half of all thyroid tumor-related deaths [12]. Due to the limited survival of ATC patients in the past, many patients were unable to have surgery. However, with the development of diagnosis and treatment options, patients can discover lesions early and pursue aggressive treatment to extend survival. Surgical resection can improve the quality of life [13], and should be considered as the first choice when patients’ physical conditions permit. Surgery has an opportunity to alleviate local compression and collect enough tissue samples for genetic testing and identification. In the analytical result, the patients who underwent surgery obtained a better prognosis and there was a statistically significant difference (P<0.05). Paolo et al. analyzed a cohort of 335 patients with ATC who underwent surgery and observed that aggressive resections were adapted for patients with stage IVA, but the patients with stage IVB or IVC should balance benefit and harm comprehensively before the operation [14]. In this study, survival was improved in IVA and IVB patients who underwent surgery, while no statistically significant was found in patients with IVC (P>0.05). Therefore, it is important to improve the relevant examinations and comprehensively evaluate the patient's chances of surgery.
Chemotherapy is a viable systemic therapeutic option according to guidelines. Previous studies had reported chemotherapy was an independent prognostic factor [15]. However, there is no consensus on the chemotherapy regimen. Anthracyclines, paclitaxel, and platins are major chemotherapy drugs in ATC [16]. Traditional chemotherapy regimens do not seem to appreciably improve patient outcomes, so further investigation into novel medication combinations or antineoplastic agents is necessary. Wendler et al. found that combining paclitaxel with pemetrexed had a significant anti-tumor effect in a small sample of ATC patients (P=0.001) [17]. Onoda et al. assessed the efficacy of weekly paclitaxel in ATC patients with a 21% objective response rate (ORR) and 73% clinical benefit rate (CBR) [18]. In addition, liposomal doxorubicin was a new form of anthracyclines, and a previous study reported a case that an ATC patient, who used liposomal doxorubicin alone, achieved excellent response (70% according to RECIST criteria) [19]. According to the guidelines, starting with cytotoxic chemotherapy may serve as a "bridge" to targeted therapy or immunotherapy [16]. Even though chemotherapy was not statistically significant in univariate analysis, chemotherapy presented encouraging efficacy on a surgery basis in our study.
Conventional chemotherapy seems to have no inability to control the progression of ATC and needs to develop new medical therapy. Molecularly targeted drugs appear constantly, providing a new idea for tumor treatment. Several targeted drugs are emerging as novel therapeutic strategies for ATC. The treatment of ATC is now stratified largely by BRAF status. A large retrospective cohort of ATC indicated the frequency of BRAF mutation was 45% (57/126) [15]. In the cohort of 32 patients treated with neoadjuvant BRAF-directed therapy and surgery, 1-year and 2-year overall survivals were 93.6% and 80.3% respectively [20]. Dabrafenib and trametinib, both tyrosine kinase inhibitors (TKI), were approved by Food and Drug Administration (FDA) in ATC. Dabrafenib is a BRAF inhibitor and trametinib is a MEK inhibitor. Since MEK is downstream of BRAF, it can be reasoned that MEK inhibition would be effective when BRAF is mutated and activated[21]. In 2017, a phase II trial recruited 16 patients with BRAFV600E-mutated ATC and the patients received continuous dabrafenib plus trametinib therapy. The result showed that the overall response rate was over 60% and dabrafenib plus trametinib therapy was a promising targeted therapy for patients with BRAFV600E-mutated ATC [22]. The ROAR study is also a study conducted in ATC patients with the BRAFV600E-mutated and the updated data reported the efficacy and safety data of dabrafenib plus trametinib in 36 patients with unresectable or metastatic ATC [23]. The investigator-assessed ORR was 56% (95%CI:38.1%-72.1%) and median progression-free survival (PFS) was 6.7 months. These data highlighted dabrafenib plus trametinib notably improved long-term survival and represented a meaningful treatment option. In addition, lenvatinib may also be used as a treatment option for ATC and the median PFS was 5.7 months [24]. The exploration of antiangiogenic drugs in ATC has been ongoing, such as androtini and apatinib [25]. However, antiangiogenic drugs for ATC are still in the basic research or clinical trial phase. 17 ATC patients were enrolled in a single-arm phase II study that evaluated the efficacy and safety of lenvatinib [26]. Oral lenvatinib has improved outcomes compared with traditional chemotherapy. The median PFS was 7.4 months and the median OS was 10.6 months. Molecular targeted therapy is the most promising emerging treatment for ATC and TKI is a hot topic for future research. 11/61 (18%) patients received targeted therapy in this study, but the results were no statistically difference regrettably. A minority of patients received a targeted agent, owing to several factors, such as the paucity of high-throughput technologies and targeted agents. This reflects the necessity of genetic testing for ATC patients. Thus, comprehensive molecular analysis to detect potential gene mutations should be performed prior to the initiation of targeted therapy. The prognosis of patients may improve if tumor lesions can be retrieved for genetic testing and customized targeted therapy.
As an emerging hotspot in tumor research, the immune system has been well concerned. Tumor cells resort to immune checkpoints for the purpose of evading the attack of immune cells. Programmed cell death ligand 1 (PD-L1) and programmed cell death (PD-1) were studied most and fully. By combining with PD-1 on immune cells, PD-L1 helps tumor cells escape from the immune system and survive [27]. Currently, an increasing number of researches had indicated that ATC was characterized by rich infiltration of tumor-associated macrophage, high tumoral expression of PD-L1, and tumor mutational burden [28-30]. These findings may be applicable for guiding immunotherapy for patients with ATC. Capdevila et al. carried out a clinical trial that enrolled advanced ATC patients who received immunotherapy and they observed the ORR was 35% in the subset of patients with PD-L1 ≥ 50% [31]. However, the median PFS and OS were 1.7 months and 5.9 months. These results suggested that single-agent immunotherapy has limited clinical activity in ATC. Combination therapy is also under active investigation currently. A clinical trial of pembrolizumab combined with chemoradiotherapy as the initial treatment for ATC had been completed [32]. Three patients were enrolled, but all patients died <6 months following therapy. The disappointing results led researchers to explore immunotherapy combined with targeted therapy. There were several studies confirmed that the combination of immunotherapy and targeted therapy had a synergized effect. Iyer et al. reported 12 ATC patients who were treated with pembrolizumab plus kinase inhibitors and the disease control rate was 75% (5 ATC patients had partial response, 4 ATC patients had stable disease) [33]. A retrospective study enrolled 6 ATC patients, who received a combination therapy of pembrolizumab and lenvatinib [34]. The median PFS was 16.5 months and the ORR was 66%. The results implicated that the combination of immunotherapy and targeted therapy might be effective in patients with ATC. The benefit of immunotherapy was also revealed in the results of this study, particularly in patients with ATC who had undergone surgery. There were 9 ATC patients treated with immunotherapy, the CBR of eight evaluable patients was 33.3%, and one of the patients had PFS for more than 21 months and tumor lesions assessed as stable. However, the effectiveness of immunotherapy plus targeted therapy was not observed in our study. The reasons for this discrepancy were likely multifactorial. Six patients received immunotherapy combined with TKI and four of them participated in a clinical trial treated with apatinib and camrelizumab. The efficacy of immunotherapy plus antiangiogenic drugs required further validation. Overall, patients responded to immunotherapy in a variety of ways and pabolizumab had a greater therapeutic potential. Thus, the use of biomarkers to help prognostication is important, such as using next-generation sequencing to find valuable or analyze the expression of immune indicators.
The article has some inherent limitations to acknowledge. First, it is a retrospective study at a single institution, accuracy and generalizability may be constrained, and the findings require confirmation by prospective studies. Second, since incidence is extremely rare, only a relatively small number of patients diagnosed with ATC range from 2003 to 2022. This is a longitudinal study design, but diagnostic and therapeutic approaches are improving consecutively as the further understanding of the disease, so the efficacy of targeted therapy and immunotherapy could not exhibit completely. A cross-sectional prospective study is worthy of anticipation compared to the various system therapies. Thirdly, due to the lack of data on therapeutic effects, side effects, biomarkers, and so on, the credibility of partial results could be impacted by them, hence additional research is required to confirm the results mentioned above.