Lenvatinib for Anaplastic Thyroid Cancer and Lenvatinib-Induced Thyroid Dysfunction

Anaplastic thyroid cancer (ATC) is one of the most aggressive cancers, and death usually occurs within a few months after diagnosis [1]. Surgery is the most effective treatment to improve the prognosis [2-4]; however, most cases cannot be managed because of locally extensive disease or distant metastases at the initial diagnosis. Current chemotherapies have limited efficacy and cannot demonstrate a significant increase in overall survival [5]. Thus, new therapeutic strategies are required to improve the prognosis.

Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1–3, FGFR1–4, RET, KIT, and PDGFRβ [6-8]. It was associated with a marked improvement in progression-free survival in patients with radioiodine-refractory differentiated thyroid cancer [9]. Lenvatinib also has the possibility of improving disease control and prognosis in ATC [10, 11]. However, the efficacy and safety of ATC have not been sufficiently considered. In Japan, lenvatinib was approved for the treatment of unresectable ATC in 2015; therefore, we could use lenvatinib to treat patients with ATC.

Tyrosine kinase inhibitors frequently present several specific adverse effects, such as fatigue, diarrhea, rash, and endocrine-related disorder [12, 13]. Treatment-related hypothyroidism is a major adverse effect of other tyrosine kinase inhibitors [14]. The reported rates of hypothyroidism range from 53 to 85% for sunitinib, 20 to 36% for sorafenib, and 10 to 29% for pazopanib [14]. Treatment-related hypothyroidism from lenvatinib for thyroid cancer has been rarely reported; most patients undergo total thyroidectomy prior to lenvatinib treatment [10]. Therefore, treatment-related hypothyroidism from lenvatinib for untreated thyroid cancer has never been discussed.

Between June 2015 and December 2016, 5 patients diagnosed with unresectable ATC were enrolled in this study. The pathological diagnosis was determined by a pathologist from fine-needle aspiration cytology. Liquid-based cytology and cell block cytology techniques were combined with the conventional technique. Only case 5 was histologically diagnosed using lymph node biopsy because of insufficient information from fine-needle aspiration cytology. Lenvatinib 24 mg once daily was administered until disease progression, unmanageable toxicity, withdrawal, or death occurred. Dose modification was performed based on the adverse reaction management guideline on the lenvatinib website. The management of treatment-related adverse effects was performed with the cooperation of a medical oncologist. We retrospectively analyzed the objective response rate (ORR), time to progression (TTP), overall survival, and safety. ORR was evaluated based on the Response Evaluation Criteria in Solid Tumor version 1.1 with computed tomography. Radiological evaluation was first performed 4–8 weeks after the first administration of lenvatinib and repeated every 4–8 weeks thereafter. Safety of the treatment was evaluated based on the Common Terminology Criteria for Adverse events, version 4.0. The protocol of the investigation was approved by the Institutional Review Board of Tottori University Hospital (No. 1706A061).

Five male patients with a mean age of 58.8 years were enrolled in this study (Table 1). Four patients were newly diagnosed with de novo ATC, and the other patient experienced anaplastic transformation from poorly differentiated thyroid cancer. The 4 de novo ATC patients had received no treatment prior to lenvatinib; the remaining patient (case 2) had undergone total thyroidectomy and radioactive iodine treatment prior to receiving lenvatinib. The 4 patients except case 1 were diagnosed with unilateral recurrent laryngeal nerve paralysis, and unilateral recurrent laryngeal nerves were resected at initial surgery in case 2. Case 5 was first diagnosed as unknown primary squamous cell carcinoma by cervical lymph node biopsy and was treated with 2 cycles of cetuximab, cisplatin, and 5-fluorouracil. Subsequently, a biopsy specimen from the thyroid revealed ATC with squamous cell and papillary cell carcinoma.

Three of the 5 patients (60%) had a partial response, and 2 (40%) had stable disease; therefore, the ORR was 60% (Fig. 1). The clinical benefit rate was 100%. Case 1 showed remarkable tumor reduction at 4 and 12 weeks after lenvatinib treatment compared with the baseline (Fig. 2). The median TTP was 88 days, and the median overall survival was 165 days. One patient continued over 6 months of treatment with lenvatinib because of a continued partial response. Two patients who presented unilateral recurrent laryngeal paralysis at diagnosis developed bilateral recurrent laryngeal paralysis. However, tracheostomy was performed only in case 5 due to tracheal obstruction by the tumor. Hypothyroidism was a common treatment-related adverse effect; 4 patients (80%) had hypothyroidism of any grade within 4 weeks after the initiation of lenvatinib (Fig. 1). These 4 patients had not undergone total thyroidectomy, and the thyroid organ was preserved during lenvatinib administration. The treatment-related adverse effects of any grade were hypertension in 80% of patients, hand-foot syndrome in 20%, diarrhea in 40%, fatigue in 80%, decreased appetite in 80%, proteinuria in 100%, and weight loss in 80% (Table 2). There was no discontinuation of treatment due to adverse effects of lenvatinib. Adverse effects were manageable by dose modification, temporary treatment interruption, and the addition of therapeutic medication. The clinical course of case 1 is shown in Figure 3.

Treatment efficacy of lenvatinib for ATC has been reported in only one phase 2 study, which reported an ORR of 24% [10]. A high ORR was seen in the present study, indicating that lenvatinib is an effective treatment for ATC. The difference in ORR between the 2 studies might have resulted from the patient characteristics, especially in a previous treatment prior to lenvatinib. In the previous study, most patients received multiple treatments with surgery, chemotherapy, and radiotherapy prior to lenvatinib, which might have induced acquired resistance to chemotherapy [15]. The median TTP was 88 days, which is slightly higher than that with the use of other drugs (i.e., less than 2 months) [16, 17]. The median survival with ATC was reported to be 147 days for stage IVB and 81 days for stage IVC [1]. In the study, median overall survival was 168 days; therefore, lenvatinib may show promise to potentially extend survival. Most patients with ATC present at a very advanced stage, with a high-volume tumor invading the surrounding organs and resulting in several symptoms, such as neck pain, neck stiffness, airway obstruction, hoarseness, and dysphagia [18]. Tracheotomy should be considered carefully because tracheotomy for patients with unresectable ATC impairs their quality of life because of tumor plugging, erosion, and bleeding [19]. The incidence of tracheotomy affected 30% of patients with ATC [20]. In the present study, only 1 patient (20%) underwent tracheostomy due to airway obstruction by the tumor. Therefore, lenvatinib may improve the quality of life of patients with ATC by controlling tumor growth and avoiding tracheotomy.

The adverse effect profiles were similar to those in previous studies of lenvatinib [9, 10]. Most of the patients presented with hypertension, diarrhea, fatigue, decreased appetite, and proteinuria of any grade. However, adverse effects were manageable by dose modification, temporary interruption of treatment, and the addition of therapeutic medication. A major difference between the present study and previous studies regarding adverse effects is that 80% of the patients had hypothyroidism. In previous studies, most patients had undergone total thyroidectomy prior to participation, and thyroid hormone was replaced by oral levothyroxine [9, 10]. In the present study, the 4 patients who presented with hypothyroidism had not received any treatment prior to lenvatinib, and the thyroid organ was preserved as it was. Several studies reported that tyrosine kinase inhibitors induce hypothyroidism through various mechanisms, such as destructive thyroiditis and tissue ischemia [14, 21]. In this study, the difference in thyroid gland integrity may have resulted from treatment-related hypothyroidism, which was induced by the mechanisms mentioned above. Hypothyroidism was observed within 4 weeks after the initiation of lenvatinib, and therefore we should frequently examine thyroid function in the early period after the initiation of lenvatinib.

Lenvatinib is an effective treatment for ATC and shows promise to potentially improve the prognosis; however, overlooked hypothyroidism might decrease quality of life. Therefore, the physician should pay attention to treatment-related hypothyroidism if the patient has a residual thyroid organ.

Lenvatinib is an effective treatment for ATC and may improve the prognosis of unresectable ATC. Four out of 5 patients had hypothyroidism, which may have been associated with treatment-induced injury of the thyroid gland. The patients had many treatment-related adverse effects, most of which were manageable by dose modification and medical therapy.

We gratefully acknowledge the work of past and present members of our department.

The authors have no conflicts of interest in relation to this study.