Abstract: Preclinical studies have demonstrated that Apatinib, major targeting vascular endothelial growth factor receptor-2 (VEGFR-2), could inhibit the proliferation of anaplastic thyroid carcinoma (ATC) cells in vitro and in vivo. The efficacy and safety in ATC patients, however, remains unknown. Here, we report the case of a 93-year-old female with advanced ATC who initially treated with Apatinib. The tumor shrank notably 4 weeks after the initiation of therapy, which sustained for more than 30 weeks. The cervical CT illuminated a stable disease with a best response of 19.7% of the primary lesion and shrinkage of the metastatic lymph node. Adverse events, including hypertension, dental ulcer, hand-foot syndrome, fatigue, and anorexia, were observed and lightened with supportive treatment and dose reductions. The overall survival of the patient was 41 weeks. This is the first report describing the effectiveness of the VEGFR-2 inhibitor for the treatment of advanced ATC, warranting clinical trials to further ascertain its utility in this challenging setting.
Keywords: anaplastic thyroid carcinoma, vascular endothelial growth factor receptor, Apatinib
Anaplastic thyroid carcinoma (ATC), one of the most lethal malignant tumors, is characterized by rapid proliferation, extrathyroidal invasion, and distant metastasis. It is the major cause of thyroid carcinoma-related deaths, with a median survival of 5 months and a 1-year survival rate of 20%.1 Surgery and chemoradiation are recommended if the tumor were locoregionally confined,1–3 but more than half of all patients present with advanced disease at the time of diagnosis, and the efficacies of traditional therapies are very poor.4,5 Therefore, new therapeutic strategies urgently need to be explored.
Apatinib, a tyrosine kinase inhibitor, can inhibit multiple tumor-related kinases, such as vascular endothelial growth factor receptor-2 (VEGFR-2), c-Kit, and c-Src6. Our group and others have investigated its safety and efficacy in radioiodine-refractory differentiated thyroid cancer (RR-DTC) patients, which demonstrated an overwhelming metabolic and structural response and tolerable toxicity.7–9 Moreover, preclinical studies demonstrated that Apatinib could inhibit the proliferation of ATC cells in a dose- and time-dependent manner, suggesting a potential in the treatment of patients with ATC.10,11 We, hereby, report an initial attempt to clinically treat ATC with Apatinib.
A 93-year-old woman with a rapidly growing left-sided neck mass and hoarseness was referred to our department. Baseline computed tomography images showed a 7.6 × 4.2 cm thyroid mass involving the trachea (Figure 1). Laryngoscope indicated left vocal cord fixation. An ultrasound-guided core-needle puncture followed by pathological examinations including immunohistochemical studies with negative for Epithelial Membrane Antigen, Thyroglobulin, Thyroid Transcription Factor-1, Cytokeratin (CK) 19, CK 20 and Villin, but positive for CKpan, Vimentin, CK 7, Ki 67 (60% +), which revealed the diagnosis of ATC with positive expression of VEGFR-2 (Figure 2; rabbit polyclonal antibody, 1:100 dilution; ZSGB-BIO, China). The staging was performed with a positron emission tomography/CT fusion image showing the hypermetabolic thyroid mass and a left lateral neck lymph node metastasis (Figure 3).
After the Eastern Cooperative Oncology Group performance status of 3 was obtained, the patient was then started on 250 mg Apatinib twice a day as an off-label use with ethical permission and informed consent in January 2018. The mass shrank notably 4 weeks after the initiation of therapy (Figure 4). Along with the cheerful effect, some unpleasant side effects emerged after 2 weeks of treatment, which were evaluated by Common Terminology Criteria for Adverse Events Version 4.0.12 Hypertension first appeared with the highest blood pressure of 170/100 mmHg (grade 3, which was elevated compared to the blood pressure of <150/90mmHg before Apatinib initiation). A dental ulcer (grade 2) and hand-foot syndrome (grade 3) caused notable pain. Other adverse events included fatigue (grade 3) and anorexia (grade 3). Compromising of these undesirable effects, the patient immediately received a calcium ion antagonist (amlodipine, 5 mg daily) and an external use hormone ointment (fluocinonide ointment, twice a day), and a reduced dose of 250 mg daily 4 weeks after the beginning of the treatment was applied. The patient tolerated treatment well thereafter, except for refractory anorexia.
The therapeutic response sustained more than 30 weeks when cervical CT illuminated a stable disease with a best response of 19.7% of baseline in the longest diameter of the primary lesion and shrinkage of metastatic lymph node according to Response Evaluation Criteria in Solid Tumors version 1.1 (Figure 1). No progression evidence was found during the Apatinib treatment. Unfortunately, she died from pneumonia and respiratory failure when the total duration of Apatinib treatment was 41 weeks.
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