Neoadjuvant lenvatinib for inoperable thyroid cancer: A case report and literature review

Abstract Background Poorly differentiated thyroid cancer (PDTC) is now classified as a separate thyroid tumor entity. It has male predominance and poor prognosis compared to differentiated TC. Case We report a case of a patient with PDTC who was previously deemed inoperable. A trial of neoadjuvant lenvatinib therapy was given to the patient after that the tumor become operable and the surgery went successfully. Conclusions Lenvatinib is a feasible option in patients with inoperable TC and can stabilize the lesion size or even reduce it, leading to a more favorable surgical outcome.


| INTRODUCTION
Thyroid cancer (TC) is a common malignancy in over 50 000 newly diagnosed patients annually in the United States alone. 1 Globally, the most common histological subtype of TC is papillary TC, followed by follicular TC. 2 Other TC subtypes are relatively rare. 2 Poorly differentiated TC (PDTC) was historically considered a tumor with intermediate characteristics between differentiated TC and anaplastic TC, and in 2004, it was classified as a separate thyroid tumor entity. 3,4 It has male predominance and poor prognosis compared to differentiated TC. Patients with PDTC tend to be older in age, with advanced locoregional or metastatic disease at presentation. 5 In these cases, the decision of surgery as an initial management can be challenging due to potential morbidity without achieving complete resection. 6 A limited number of case reports have investigated the role of tyrosine kinase inhibitors (TKIs) in PDTC or differentiated TC as neoadjuvant therapy for inoperable TC in order to facilitate complete resection with subsequent surgery. Lenvatinib is an oral TKI approved by the US Food and Drug Administration for radioactive iodine (RAI)-refractory TC. 7 In 2016, the landmark SELECT trial concluded that lenvatinib demonstrates significant response rates and progressionfree survival in the treatment of RAI-refractory progressive TC and should be considered in the setting of clinically relevant or symptomatic disease progression. 8 Herein, we report a case of a patient with PDTC who was previously deemed inoperable but was later successfully operated on with complete excision after a trial of neoadjuvant lenvatinib therapy. We also present a series of cases from the literature that utilized neoadjuvant TKIs in the setting of inoperable TC.

| CASE REPORT
The patient was a 56-year-old woman with diabetes mellitus, hypertension, and a history of right breast cancer treated with right mastectomy, six cycles of chemotherapy, and three sessions of external beam radiation therapy (EBRT). She had been in remission since 2015.
In May 2018, she presented to the otorhinolaryngology clinic after F I G U R E 1 Axial and sagittal images from the CT examinations of the neck with contrast performed before and after Lenvatinib therapy. Axial (A) and sagittal (C) images before Lenvantinib treatment. Axial (B) and sagittal (D) images after Lenvatinib therapy. The axial images (A) and (B) demonstrate decreased mass effect on the trachea with widening of its lumen (arrows). Similar changes are noted on the right internal jugular vein (asterix). On the sagittal images The patient received one cycle of paclitaxel (300 mg) and carboplatin (500 mg); however, carboplatin was switched to doxorubicin within 1 month due to poor tolerability as the patient developed generalized pain, rash, mucositis, and numbness. However, the same side effects occurred with doxorubicin; therefore, chemotherapy was stopped after only one additional cycle. Four months later, she was started on a sorafenib therapy trial (400 mg), but this was stopped within a week due to generalized body pain and fatigue. At this stage, CT with intravenous contrast was repeated and showed a stable tumor burden similar to that of CT prior to chemotherapy.
The patient was later commenced on lenvatinib 10 mg once daily, which she tolerated well with no significant side effects, except for

| DISCUSSION
In this case report, we demonstrated the potential of neoadjuvant TKI therapy for inoperable TC. Studies have shown that aggressive surgery in patients with TC exhibit gross ETE results in satisfactory locoregional control. 9 However, in cases where surgeries with curative intent are not possible, neoadjuvant TKI therapy shows promising results. Initially, in our patient, lenvatinib was used as a palliative option, but it showed a therapeutic effect over the course of treatment (Figures 1 and 2). Lenvatinib targets vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors 1-4, RET, c-kit, and platelet-derived growth factor receptor α. Its antitumor activity is thought to be due to its antiangiogenic properties and direct antitumor effects. 10 Lenvatinib and sorafenib have been reportedly used preoperatively in patients with differentiated TC and in those with PDTC (as in our patient) to shrink the tumor size in order to facilitate ensuing surgery and to spare the patient from the morbidities of a more aggressive resection possibly including laryngectomy, tracheostomy, and esophageal reconstruction.  lenvatinib also resulted in a significant quality of life benefit as it prevented the necessity for a laryngectomy procedure. The positive effect of neoadjuvant TKI was also noted in metastatic lesions, including metastatic lymph nodes and lung metastasis. 14,17 Our patient did not receive a repeated chest CT after the lenvatinib therapy period. Instead, it was performed 6 months later when mild progression of pulmonary metastasis was observed; therefore, it is difficult to judge the effect of lenvatinib on the lung lesions in our case.

| CONCLUSION
In summary, we report a case of PDTC, initially considered inoperable, that was fully resected after preoperative lenvatinib treatment without any major perioperative complications. TKI therapy, such as lenvatinib, is a feasible option in patients with inoperable TC and can stabilize the lesion size or even reduce it, leading to a more favorable surgical outcome. In order to determine the maximum efficacy and outcome of neoadjuvant lenvatinib and sorafenib, further studies including larger samples are needed to investigate the optimal dosing and duration. Furthermore, it is necessary to determine the appropriate candidates and tumor factors for such a regimen.