Locally advanced TC generally refers to gross extrathyroidal extension (gETE) of primary tumor who passes the thyroid capsule and infiltrates the surrounding tissues. According to the 8th edition AJCC Cancer Staging Manual, gETE invasion into subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve from a tumor of any size is defined as T4a category, and the presence of gETE invading the prevertebral fascia, encasing carotid artery or mediastinal vessels is T4b . Extensive gETE portends an increased incidence of local recurrence, regional and distant metastasis . Though management is controversial, it is well known that the most significant approach is to remove the neoplasm en bloc for local control and disease-free survival. However, the balance between radical surgery and functional preservation of the anatomical structures involved was required to be taken into account . There is no doubt, surgical therapy of this locally advanced DTC is challenging and the resection scope remains controversial for lack of high-level evidence.
Research shows that free margins (R0) have better local control  compared with close or positive microscopic margins (R1), while incomplete resection has been associated with increased mortality [5, 9]. Besides, lower local control was observed in recurrent tumor versus initial tumor, and the contribution of postoperative adjuvant radiation therapy is limited . In conclusion, attaining an R0/R1 resection by comprehensive operative clearance is critical and bound up with superior outcomes in T4 disease. Back to this case, demolitive surgery with reconstruction of the esophagus not only considerably aggravated the notable surgical trauma and postoperative complications, but also significantly decreased the patients' quality of life. Above all, the patient's acceptance to undergo such procedures seemed vacillating.
In this particular case, which methods can we try to reduce the tumor volume for improved resection margins and narrow the scope of surgery on the basis of R0/R1 resection? Neoadjuvant therapy for thyroid cancer still has not had an established role and not be mentioned in the 2015 ATA guideline . Historically, only a few similar cases were found on review of the literature. Besic et al presented that preoperative ChT decreased the tumor size by > 50% in 45% patients (13/29) of FTC or HCTC, and in 44% (7/16) of locally advanced PTC [10, 11]. A case published in 1998 reported that preoperative 131I treatment is beneficial for inoperable TC . Besides, one locally unresectable patient underwent a total thyroidectomy after neo-adjuvant EBRT . Nonetheless, the large number of studies focused on targeted therapies, especially tyrosine kinase inhibitors (TKIs). For instance, surgical clearance was achieved in patients with locally advanced DTC after 14 months treatment of sorafenib and lenvatinib , or after 13months of sorafenib monotherapy , or after 22 weeks of lenvatinib monotherapy ; the usage of lenvatinib for better local control of poorly DTC during waiting period for operation because of patient comorbidities ; a similar situation come up in medullary thyroid cancer (MTC) with sunitinib , or even in anaplastic thyroid cancer (ATC) with dabrafenib plus trametinib . Nowadays, vandetanib and cabozantinib are approved by FDA for patients with progressive, metastatic, or unresectable MTC, while sorafenib and lenvatinib are for DTC patients with RAI-refractory. All these findings revealed that neoadjuvant therapy could potentially reduce the extent of invasion and risks of residual disease after surgical resection. In certain cases, it might be a valuable option when treatment is limited .
Pathological angiogenesis is an important characteristic and essential for tumor growth, invasion and metastasis, especially for solid tumor . Vascular endothelial growth factor (VEGF) is a crucial and positive regulator in physiological processes. VEGFR-2, mainly expressing on endothelial cells, is the key signaling receptor of the pathway for mediating the mitogenic, angiogenic and permeability-enhancing effects of VEGF. Thus, the therapy of targeting VEGF or VEGFR is mainly to focus on anti-angiogenesis. Apatinib, also known as Aitan (brand name in China) and developed independently by Shanghai Hengrui Pharmaceutical Co., Ltd (Shanghai, China) , is a typical representative of anti-angiogenesis agents for antineoplastic functions, which could induce apoptosis and suppress tumor proliferation either alone or in combination with chemotherapy across a variety of advanced solid malignancies [23–28]. What needs to be emphasized is that, the efficacy of apatinib is comparable to that of sorafenib or lenvatinib, but with more manageable safety profile and faster therapeutic response [26, 29–31].
Back to this case, the treatment of apatinib (orally 500 mg qd)  showed significant effect and least complications in a very short time. Just after treatment for 6 weeks and drug withdrawal for 10 days, a complete operation with total thyroidectomy, left central lymph node dissection and the muscular layer resection of the esophagus were performed. Tg detection and CT scan were applied to reassess the disease. Thankfully, there was no postoperative complication, such as wound dehiscence or fistula formation. At present, the role of TKIs is limited to those thyroid cancer cases that still progress after surgery, radioiodine or local ablation therapies. And there is no data to certify the use of antiangiogenic TKIs as neoadjuvant therapy in DTC. Thus, there are still many problems, including drug categories, dosage, time of adding medicine, withdrawal time before surgery and methods of disease reassessment, worthy to be further studied.
A recent article reported an initially unresectable, end-stage and BRAF-mutated ATC case, which responded well to combined medicine of dabrafenib, trametinib and pembrolizumab preoperatively, and then the tumor was completely resected . Jennifer et al. illustrated that dabrafenib plus trametinib was feasible and effective as a neoadjuvant approach for locoregionally advanced BRAFV600E-mutated ATC . Furthermore, the therapy role is generally limited when a single chemotherapy is used in thyroid cancer. Hence, it is worth considering whether monotherapy or combination with conventional therapies are effective.
To our knowledge, this is the first report that VEGFR-2 TKI apatinib monotherapy was effective, safe and economical for unresectable locally advanced DTC preoperatively. The emergence of this neoadjuvant concept has changed the landscape of management to locally advanced TC. We believe that it's time to propose preoperative neoadjuvant targeted therapy for those inoperable DTCs to achieve extensive resection of extrathyroidal tissues and guarantee quality of life simultaneously. Yet, more cohort studies, randomized controlled trials and even related mechanism research are necessary.