PD-1 Inhibitor and Anlotinib Combined With Multimodal Radiotherapy in Recurrent or Metastatic Anaplastic Thyroid Cancer

Thyroid cancer (TC) is the most common malignant tumor of the endocrine system. It is more common in women and accounts for approximately 4% of all new malignancies in women. TC can be classified according to its pathological type: papillary carcinoma, follicular carcinoma, Hurthle cell carcinoma, medullary carcinoma, and anaplastic thyroid carcinoma (ATC). ATC is more aggressive than other types and tends to metastasize at an early stage. Although ATC accounts for only 1.6%-4% of all TC, the mortality rate is 14%-40%. According to the American Joint Committee on Cancer (AJCC) staging criteria, all ATC is considered stage IV once diagnosed, regardless of the size of the primary site or lymph node metastasis. Until now, the best treatment options for ATC have been unclear, and currently, a combination of treatment options is used. However, the efficiency of treatment is less than 15% and most patients experience recurrence and distant metastases. There is an urgent need for safe and effective treatment options for patients with ATC.

Radiotherapy, as one of the important local treatments, can reduce the tumor load and alleviate local symptoms. Several studies have demonstrated that radiotherapy can improve the prognosis of patients with ATC. The results of a meta-analysis covering 17 studies with a total of 1147 patients showed that postoperative radiotherapy improved the prognosis of patients with ATC compared to those who underwent surgery only. Meanwhile, the results of another large retrospective study showed that radiotherapy resulted in sustained local progression-free survival and overall survival in the treatment of patients with locally advanced ATC and that a radiotherapy dose of ≥60 Gy was an independent prognostic factor (p=0.01). The prognostic role of radiotherapy and different radiotherapy doses was also confirmed in another meta-analysis from the National Cancer Database (NCDB), which showed that patients with inoperable ATC may benefit from radiotherapy at higher irradiation doses (60-70 Gy vs 45-59.9 Gy). It can thus be seen that both operable and inoperable ATC patients, may benefit from radiotherapy and that the dose of radiotherapy may correlate with their survival benefit.

For the systemic treatment of patients with ATC, the NCCN guidelines recommend first-line regimens including paclitaxel combined with carboplatin, doxorubicin combined with doxorubicin, single-agent paclitaxel and single-agent doxorubicin, but patients with ATC respond poorly to treatment and there is no recommended optimal regimen for patients who develop recurrence or metastasis after first-line therapy. In recent years, PD-1/PD-L1 has been used in melanoma and a variety of other solid tumors have demonstrated promising efficacy. The results of a retrospective study in 2017 showed positive PD-1 expression in all specimens of the 16 ATC patients observed, while almost all patients (13/16) were positive for PD-L1 expression. In vitro experiments have also shown that PD-1 blockers can reinvigorate the cytotoxic effects of NK cells, thereby enhancing the killing effect on tumor cells. This lays the theoretical foundation for the use of PD-1/PD-L1 blockers in the treatment of ATC. Multi-target tyrosine kinase inhibitors have shown significant anti-tumor effects in a variety of tumor types, including thyroid cancer, by inhibiting angiogenic and proliferative signaling. Anrotinib is a small molecule multi-target complex kinase inhibitor developed in China and has been reported to be safe and effective in the treatment of patients with advanced refractory solid tumors. In addition to this, the anti-tumor activity of anrotinib in ATC has been In vivo and in vitro assays have demonstrated that anlotinib inhibits ATC cell proliferation and inhibits the migration of thyroid cancer cells in vitro and the growth of xenograft thyroid tumors in mice.

The findings suggest that there may be synergy between PD-1/PD-L1 blockers and complex kinase inhibitors and that PD-1/PD-L1 blockers may improve the tumor microenvironment in ATC, thereby increasing the efficacy of complex kinase inhibitors. This suggests that the combination of PD-1/PD-L1 blockers and complex kinase inhibitors may be an effective treatment option for ATC and that PD-1/PD-L1 blockers may improve resistance to complex kinase inhibitor therapy. PD-L1 blockers may improve the resistance that occurs with complex kinase inhibitor therapy. Meanwhile, the combination of PD-1/PD-L1 blockers with radiotherapy has been shown to have a synergistic effect in several studies. Radiotherapy combined with immunotherapy can activate specific T-cell immune responses and alter the suppressive effect of the tumor microenvironment on the immune system, resulting in durable anti-tumor activity. Combining radiotherapy with PD-1/PD-L1 blockers for the treatment of undifferentiated thyroid cancer may demonstrate better therapeutic outcomes.