Lenvatinib in multimodal therapy for unresectable radioactive iodine‐naïve differentiated thyroid cancer: A case report with literature review

Abstract Background Patients with unresectable or metastatic differentiated thyroid carcinoma (DTC) are rare and require individualized therapy. This may require approaches not typically used in resectable disease. We report a patient treated with lenvatinib and external beam radiation therapy. Case An 87‐year‐old woman presented with cT4N1aM1 papillary thyroid carcinoma with tracheal invasion. She was not a candidate for surgery, radioactive‐iodine, or radiation, so a trial of lenvatinib was offered. Her tumor showed clinical, biochemical, and radiological response after 5 months of lenvatinib, and she subsequently received external beam radiation. She enjoys good quality of life without evidence of cancer progression off therapy 21 months post‐initiation of treatment. Conclusion Lenvatinib may be effective in RAI‐naïve advanced DTC patients as a component of individualized multimodal therapy when conventional options are not feasible.


| BACKGROUND
Differentiated thyroid cancer (DTC) accounts for 3% of all cancer diagnoses in the United States. 1 Five-year survival rates in DTC range from nearly 100% in early-stage disease to 51% in stage IV disease. 2 Approximately 15% demonstrate extracapsular spread, and this tendency is greater in older patients with the papillary subtype. 3 Papillary thyroid carcinoma is usually cured with thyroidectomy, but postoperative radioactive iodine (RAI) may offer improved survival and recurrence rates in cases with pathological risk factors or iodine-avid distant metastases. 4 For unresectable or metastatic RAI-refractory disease, options to provide disease control and palliation include external beam radiation therapy (EBRT), chemotherapy, or targeted therapy. 5 Vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs) are effective in RAI-refractory DTC; and sorafenib, lenvatinib, and recently cabozantinib (in the second-line setting) have been studied in randomized trials and approved for use in these patients. [6][7][8] Lenvatinib appears to be the most potent drug with a response rate of 64.8% (compared to 1.5% with placebo). 7 With their consent, we report the case of a RAI-naïve patient treated initially with lenvatinib followed by EBRT for locally advanced unresectable and metastatic papillary thyroid cancer and review the literature in this domain.

| OBJECTIVE
To describe a case of sustained response to lenvatinib therapy in a patient with RAI-naïve DTC.

| CASE REPORT
An 87-year-old female was referred to our cancer center for management of locally advanced and metastatic papillary thyroid carcinoma.
She reported a six-month history of increasing stridor, shortness of breath, and hemoptysis, which prompted investigation with a biopsy of her left thyroid and computed tomography (CT) of the neck and chest. Imaging showed a 4.2 cm left thyroid mass indenting and displacing the cervical trachea, an enlarged left supraclavicular node, a 4.0 cm right adrenal mass, and bilateral pulmonary nodules suspicious for metastases ( Figure 1). She was staged as cT4N1aM1, corresponding to stage IVB. The patient declined surgery due to her desire for voice preservation. She was not a candidate for RAI given her intact thyroid gland and nondebulked primary tumor. There was tepid enthusiasm for EBRT given the size of the treatment field. Lenvatinib was thus  Initially the patient was monitored weekly, and lenvatinib was well-tolerated with gradual disappearance of stridor and dyspnea. Following EBRT, thyroglobulin was 25.7 μg/L and TSH 0.01 mIU/L, and CT showed stability of the thyroid mass ( Figure 3B). In this context, lenvatinib was not restarted, and she has since been observed.
At her last follow-up 2 years after initiating lenvatinib, she was very satisfied with her quality of life and had resumed her usual activities with only mild residual dysphagia from EBRT.

| DISCUSSION
The optimal therapeutic approach for the rare patient with unresectable and/or metastatic DTC is uncertain, may not be curative, and is usually individualized. Our patient was elderly, had metastatic and locally advanced disease threatening her airway, and refused sur-  (Table 1). In all cases, patient or tumor factors initially made surgery and RAI too morbid or contraindicated, thereby prompting consideration of neoadjuvant lenvatinib to improve patient functional status or reduce tumor burden. [11][12][13][14][15][16] The patient who was managed most similarly to ours was treated nonsurgically with lenvatinib followed by EBRT and RAI, but unfortunately deteriorated secondary to malignant pleural effusion while receiving lenvatinib. 15 In a retrospective study of TKI use in unresectable, RAI-naïve DTC, the only patient who received first-line lenvatinib had treatment withdrawn due to grade 3 asthenia, and another who received second-line lenvatinib after pazopanib achieved stable disease. 17 Our patient is unique in that lenvatinib, as a primary therapy rather than an adjunct, writingoriginal draft (equal); writingreview and editing (equal).

CONFLICT OF INTEREST
Eric Winquist has served in a consulting/advisory role for Amgen, Bayer, Eisai, Ipsen, Merck, and Roche; and received research funding (institution) from Roche/Genenetech, Merck, Pfizer, Eisai and Ayala Pharmaceuticals. The other authors have no disclosures.

DATA AVAILABILITY STATEMENT
All data concerning this study are presented in this manuscript.

ETHICS STATEMENT
Informed consent was obtained to use images and information from the patient whose case is published in this study.