DEVELOPMENT OF UPPER AERODIGESTIVE TRACT COMPLICATIONS IN PATIENTS WITH STAGE IV THYROID CANCER RECEIVING TYROSINE KINASE INHIBITORS

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1 Case Report DEVELOPMENT OF UPPER AERODIGESTIVE TRACT COMPLICATIONS IN PATIENTS WITH STAGE IV THYROID CANCER RECEIVING TYROSINE KINASE INHIBITORS Christopher Perdoni, MD 1 ; Clara Olcott, MD 1 ; David C. Lieb, MD, FACE, FACP 2 ; Daniel W. Karakla, MD, FACS 1 ABSTRACT Objective: Tyrosine kinase inhibitors (TKIs) are a class of systemic chemotherapy used in patients with radioactive iodine-refractory metastatic thyroid cancer. TKIs have been linked with impaired wound healing, but their association with upper aerodigestive tract complications is not well defined. The objective of this case series was to demonstrate that upper aerodigestive tract complications can occur in thyroid cancer patients receiving TKIs. Methods: A retrospective chart review was conducted on 3 cases involving patients with stage IV differentiated or medullary thyroid cancer treated between the years from 2000 to Each patient received surgical management, external beam radiation therapy, and subsequent TKI therapy and they also developed upper aerodigestive tract complications during their clinical course. Results: Patient 1 received TKIs for radioactive iodine-refractory pulmonary metastases and developed a tracheoesophageal fistula 1 year after initiation of chemotherapy. Patient 2 received TKIs for pulmonary metastases and developed a tracheoesophageal fistula several months Submitted for publication July 30, 2017 Accepted for publication December 7, 2017 From the 1 Department of Otolaryngology-Head and Neck Surgery, Eastern Virginia Medical School, Norfolk, Virginia, and 2 Department of Medicine, Strelitz Diabetes Center for Endocrine and Metabolic Disorders, Eastern Virginia Medical School, Norfolk, Virginia. Address correspondence to Dr. Christopher Perdoni, 600 Gresham Drive, Suite 1100, Norfolk, VA perdoncj@evms.edu. DOI: /ACCR To purchase reprints of this article, please visit: after initiation of chemotherapy. Patient 3 was placed on TKIs for progressive metastatic disease 9 years after initial intervention and later developed laryngeal necrosis. Conclusion: Systemic TKIs can offer a clinical benefit in patients with metastatic thyroid cancer. However, clinicians should monitor patients for upper aerodigestive tract fistula formation and tissue necrosis during and after TKI therapy. Although a history of external beam radiation therapy may place patients at increased risk for fistula development, further investigation is needed to determine the relative risk associated with subsequent TKI exposure in these patients. (AACE Clinical Case Rep. 2018;4:e270-e274) Abbreviations: DTC = differentiated thyroid cancer; EBRT = external beam radiation therapy; MKI = multikinase inhibitor; MTC = medullary thyroid cancer; RAI = radioactive iodine; TEF = tracheoesophageal fistula; TKI = tyrosine kinase inhibitor; VEGFR = vascular endothelial growth factor receptor INTRODUCTION Nearly 10% of thyroid cancer patients will develop metastatic disease. Approximately half of these patients will become refractory to radioactive iodine (RAI) therapy, and this RAI-refractory state is associated with a 10-year survival rate of 10 to 20% and mean survival of 3 to 5 years (1,2). The majority of patients with metastatic thyroid cancer are observed, with either thyroid stimulating hormone suppression (in the case of differentiated thyroid carcinoma, DTC) or without thyroid stimulating hormone suppression (as with medullary thyroid cancer, MTC) (3-4). Treatment for progressive or symptomatic metastatic lesions may include the use of external beam radiation therapy (EBRT) or tyrosine kinase inhibitors (TKIs). e270 AACE CLINICAL CASE REPORTS Vol 4 No. 4 July/August 2018

2 UADT complications and TKIs, AACE Clinical Case Rep. 2018;4(No. 4) e271 TKIs are a class of systemic chemotherapeutic agents approved for use in patients with RAI-refractory metastatic thyroid cancer. The U.S. Food and Drug Administrationapproved TKIs for the treatment of DTCs (including papillary thyroid carcinoma and follicular thyroid carcinoma) include sorafenib (5) and lenvatinib (6), while cabozantinib (7) and vandetanib (8) are approved for use in MTC. Additional TKIs such as sunitinib (9) have shown efficacy in early clinical trials but their use in thyroid cancer is currently off-label. The antineoplastic efficacy of these TKIs results from their antagonistic action on oncogenic targets such as the vascular endothelial growth factor receptor (VEGFR) family of tyrosine-kinase receptors and a resulting inhibitory effect on angiogenesis (10), thus describing their classification as VEGFR multikinase inhibitors (MKIs). The use of these drugs has been shown to significantly prolong progression-free survival when compared to placebo for both DTC (10.8 versus 5.8 months for sorafenib (5); 18.3 versus 3.6 months for lenvatinib (6)) and MTC (11.2 versus 4.0 months for cabozantinib (7); 30.5 versus 19.3 months for vandetanib (8)). Adverse effects are common during TKI therapy and include hand-foot syndrome (70%) and mucositis (35%). It is estimated that 15% of patients will eventually require discontinuation of TKI therapy due to medication intolerance (11). Less commonly, TKIs have been linked with the development of gastrointestinal perforations in patients being treated for solid tumors (12,13). Prior reports have also suggested an affiliation between VEGFR MKIs and upper aerodigestive tract fistulas in patients being treated for advanced thyroid cancer and other head and neck cancers (14,15). In a phase III trial of cabozantinib for MTC treatment, 0.9% and 3.7% of treated patients developed gastrointestinal and non-gastrointestinal fistulas, respectively, although the extent to which these nongastrointestinal fistulas involved the upper aerodigestive tract was not stated (7). In the present case report, we describe 3 patients with metastatic thyroid cancer who developed upper aerodigestive tract complications following the implementation of VEGFR MKI treatment. CASE REPORT Three cases of tracheoesophageal fistula (TEF) were identified by recollection in the senior author s clinical practice. All 3 patients carried a diagnosis of stage IV differentiated cancer or MTC and received care between the years of 2000 to Retrospective chart review was conducted for these 3 cases including review of office notes, surgical procedures, and radiation/medical oncology treatment plans. Each patient received a combination of surgical excision, EBRT, and TKI therapy. Given the case report nature of this retrospective review and its inclusion of only 3 patients, it did not meet criteria as a research study by our institutional review board. Case 1 Patient 1 was a 49-year-old female diagnosed with T4N1bM1 columnar cell variant papillary thyroid cancer. She presented with bulky metastasis at the left lung apex with pleural involvement, and underwent total thyroidectomy, left selective neck dissection (SND), sternotomy, and mediastinal dissection with resection of her left apical metastasis. Pathology revealed tumor invasion at the anterior and posterior left tracheoesophageal groove. She received post-operative RAI therapy (150 mci) 1 month after resection, with post-treatment whole-body scans revealing residual uptake in the thyroid bed and possible nodal metastasis at the submental region but no evidence of distant disease (Fig. 1 A). She subsequently began EBRT 1 month later at 69.3 Gy in 33 fractions, with completion of therapy 4 months after initial resection. Follow-up imaging at 6 months was without evidence of disease, but imaging at 9 months revealed extensive pulmonary metastases. She was started on sunitinib but transitioned to sorafenib after 6 months due to findings of a new lung nodule on workup for dyspnea. She developed nausea and anorexia after 3 months of sorafenib therapy, and chemotherapy was withheld for 1 month prior to a second round of RAI therapy (150 mci). Post-treatment whole-body scans were suggestive of recurrent carcinoma at the thyroid bed (Fig. 1 B). Given her disease progression and adverse reactions to sorafenib, she was transitioned to pazopanib 1 month following her second round of RAI therapy. She was hospitalized with dysphagia and hemoptysis approximately 1 year after VEGFR MKI initiation, and computed tomography angiography of the chest revealed a TEF (Fig. 2) not present on prior imaging. She underwent esophageal stent placement, during which the TEF was noted to be located 5 cm above the carina. She passed away the following month from complications secondary to aspiration pneumonia and had remained on pazopanib throughout the remainder of her clinical course. Case 2 Patient 2 was a 57-year-old female diagnosed with T3N1bM0 columnar cell variant papillary thyroid cancer. She underwent total thyroidectomy, central-left selective neck dissection, superior mediastinal dissection, and tracheal resection with primary anastomosis. Her tumor was noted to penetrate but not perforate her tracheal mucosa. She completed post-operative RAI therapy (142 mci) 6 weeks after resection, with post-treatment wholebody scans revealing no evidence of residual or distant disease (Fig. 1 C). The following month she underwent EBRT at 60 Gy over 30 fractions with completion of therapy 4 months after initial resection. Follow-up imaging at 9 months did not reveal any evidence of active disease. She complained of dyspnea at her 1-year follow-up, and bronchoscopy

3 e272 UADT complications and TKIs, AACE Clinical Case Rep. 2018;4(No. 4) A B C Fig. 1. Post-treatment whole-body scans. These images depict wholebody scans obtained after radioactive iodine treatment. (A) Results from patient 1 at 1 month after surgical resection revealing residual uptake in the thyroid bed and possible nodal metastasis at the submental region but no evidence of distant disease. (B) Results from patient 1 at 18 months after surgical resection suggestive of recurrent carcinoma at the thyroid bed. (C) Results from patient 2 at 6 weeks after surgical resection without evidence of residual or distant disease. revealed posterior tracheal wall fibronecrotic changes but no evidence of TEF on esophagoscopy. Imaging at 1 year revealed new and progressive pulmonary nodules for which the patient was started on sunitinib. Two months later, she developed worsening dyspnea and aspiration pneumonia. Tracheostomy was performed, at which time a 4-cm TEF was noted and further evaluated on computed tomography imaging (Fig. 3). The patient remained on sunitinib at the time of TEF diagnosis but was transitioned to comfort care prior to leaving the hospital. Case 3 Patient 3 is a 51-year-old female diagnosed with sporadic TxN1bM1 MTC who underwent total thyroidectomy with bilateral selective neck dissection and subsequent EBRT. She was followed over the next 6 years for stable pulmonary nodules and started on sorafenib after these nodules progressed. Carcinoembryonic antigen and calcitonin levels obtained after nodule progression were 9.7 and 971, respectively. Prior values were not obtainable as the patient was receiving care by an outside oncologist. Calcitonin levels decreased to 340 within 1 month of sorafenib therapy. She remained on sorafenib for the next 2 years, but reported progressive gastrointestinal adverse effects and was transitioned to sunitinib which she remained on for the following 5 years until discovery of liver metastases. She was then transitioned to cabozantinib. Four months after starting cabozantinib she began reporting dyspnea and dysphagia. Barium swallow revealed the absence of anatomic abnormalities or aspiration. She was diagnosed with non-obstructive dysphagia and received esophageal balloon dilation at the time of diagnostic upper endoscopy. Due to progressive dyspnea and inability to lie Fig. 2. Tracheoesophageal fistula formation in patient 1. This computed tomography image demonstrates an abnormal communication (arrow) between the trachea and esophagus at the level of the clavicle in a patient previously treated with sunitinib, sorafenib, and pazopanib. supine, the patient opted for tracheostomy. Laryngoscopy at the time of tracheostomy revealed posterior laryngeal wall necrosis with involvement of the post-cricoid mucosa. Surveillance imaging 2 months later revealed progression of several pulmonary nodules and she was transitioned to vandetanib. Surveillance laryngoscopies revealed stabilization of the laryngeal necrosis with eventual transition to fibrous stenosis for which she has received serial laryngeal dilation procedures in an attempt to achieve decannulation. Two years later, she currently remains on vandetanib for her metastatic disease and is followed clinically for her laryngeal stenosis for which she remains tracheostomy-dependent. DISCUSSION We describe 3 patients with metastatic thyroid cancer who all received various VEGFR MKIs at some point in time following initial resection and adjuvant EBRT (Fig. 4) and who later developed TEFs (patients 1 and 2) or laryngeal necrosis (patient 3). Associations between VEGFR MKIs and upper aerodigestive tract complications have been described previously (14,15), and fistula development outside of the gastrointestinal tract occurred in 3.7% of treated patients participating in a phase III trial of cabozantinib for MTC (7). In a study of 43 head and neck cancer patients receiving bevacizumab, 5 developed TEFs (16). Although bevacizumab falls within a distinct drug class from TKIs, it is thought to exert similar effects on angiogenesis and wound repair as several VEGFR MKIs such as sorafenib and cabozantinib (10). Reviewing prior reports of upper aerodigestive tract complications in patients receiving TKIs, a case series by Blevins et al (14) described 3 patients with metastatic thyroid cancer who developed upper aerodigestive tract fistulas while on VEGFR MKI therapy. In a large retrospective review of 140 thyroid cancer patients treated with VEGFR MKIs (17), 9 patients developed clinically apparent hemoptysis. Although TEFs were not reported in this study, the authors identified airway invasion, poorly

4 UADT complications and TKIs, AACE Clinical Case Rep. 2018;4(No. 4) e273 Fig. 3. Imminent tracheoesophageal fistula formation in patient 2. A computed tomography scan was performed 1 month prior to discovery of tracheoesophageal fistula in this patient, who had been receiving sunitinib at the time of its formation. Area of eventual tracheoesophageal fistula is depicted here. differentiated pathology, and exposure to EBRT as risk factors for hemoptysis in the setting of antiangiogenic TKI therapy. The mechanism for these potential complications likely involves mucosal breakdown and impaired wound healing resulting from VEGFR inhibition. As an important mediator of angiogenesis, VEGFR inhibition may impair post-surgical and post-radiation healing which would place tracheal and neighboring esophageal tissue at risk for such complications (10). It could be argued that EBRT, independent of TKI exposure, places patients at increased risk for the complications described in our 3 patients. Although EBRT is often utilized for locoregional control of persistent disease, it is of uncertain value in many patients with thyroid carcinoma, including both DTC and MTC, and is associated with complications such as dermatitis, esophagitis, and mucositis (18). In a study of 131 DTC patients undergoing EBRT without subsequent TKI exposure, however, there were no reports of TEF formation over a 5-year surveillance period (19), thus suggesting that EBRT may not be an independent risk factor for TEF formation. Interestingly, Barney et al (12) analyzed a group of 76 patients receiving radiation therapy for various abdominal cancers, 20 of which received TKIs within 2 years of radiation therapy. Of the 7 patients who developed bowel ulceration or perforation, all had previously received TKIs. Additionally, there may soon be alternatives to the current U.S. Food and Drug Administration-approved VEGFR MKIs that are without anti-angiogenic properties and therefore carry a theoretical reduced risk for TEF development. These include the selective BRAF V600E inhibitors dabrafenib and vemurafenib. Although these agents are currently approved for use in patients with melanoma, their safety and efficacy have been reported in patients with metastatic RAI-refractory DTC (20,21). These TKIs have been shown to have clinical benefit without reports of fistula development, and work through inhibition of the mutated BRAF kinase commonly seen in patients with DTC. Patients believed to be at higher risk for fistula development, especially those with known BRAF V600E mutations, may thus benefit from consideration for participation in a clinical trial involving these agents. Similarly, there are highly-selective RET kinase inhibitors that are currently in development that may also show promise in the treatment of MTC, without the risks associated with VEGFR inhibition (22). VEGFR MKIs have a clear role in the treatment of advanced thyroid cancer and are currently considered standard of care for patients with metastatic or progressive RAI-refractory disease. Nevertheless, in patients receiving VEGFR MKIs, especially those who had locally advanced disease and tracheal wall invasion, signs of upper aerodigestive tract complications should be investigated thoroughly in an effort to prevent TEF formation or detect it at its early stages. This is of vital importance in patients who develop radiation-induced airway or esophageal stenosis, as dilation procedures or other related interventions would increase the likelihood of perforation or fistulization. If identified early, TEFs may be managed conservatively using enteral feeding and surveillance imaging with eventual esophagography to confirm resolution of the fistula (15). We believe a serious discussion of the ongoing risks and benefits regarding continuation of TKI therapy should take place in patients who develop these complications. Fig. 4. Timeline of clinical events of the 3 patients. EBRT = external beam radiation therapy; TEF = tracheoesophageal fistula.

5 e274 UADT complications and TKIs, AACE Clinical Case Rep. 2018;4(No. 4) CONCLUSION At our institution, we have begun utilizing a vascularized muscle (sternocleidomastoid or pectoralis) flap within potential tracheoesophageal communication sites in patients deemed to have high-risk, locally aggressive disease and who are likely to receive future EBRT or TKI therapy. As newer agents are introduced and approved for use in the treatment of metastatic thyroid cancer, we need to determine the risk for TEF in each of our patients prior to any treatment. We recommend and advocate for a multidisciplinary approach for the care of these patients, involving surgeons, endocrinologists, oncologists, and radiation oncologists. Such an approach may lead to different surgical approaches, as described above, or to a particular patient s enrollment in a clinical trial utilizing a potentially safer TKI. Systemic TKIs can offer a clinical benefit to patients with metastatic thyroid cancer. However, clinicians should monitor patients for upper aerodigestive tract fistula formation and tissue necrosis during and after TKI therapy. Given that our report did not involve a retrospective review of all patients at our institution treated with EBRT and TKIs, we are unable to draw conclusions regarding the relative risk of these exposures and subsequent TEF rates. Accordingly, further work is needed to identify risk factors for TEF formation in patients receiving TKIs, particularly case-control studies investigating increased risk in patients with and without prior EBRT. DISCLOSURE The authors have no multiplicity of interest to disclose. REFERENCES 1. Shoup M, Stojadinovic A, Nissan A, et al. Prognostic indicators of outcomes in patients with distant metastases from differentiated thyroid carcinoma. J Am Coll Surg. 2003;197: Durante C, Haddy N, Baudin E, et al. 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