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C A S EREPORT

pISSN: 2384-3799 eISSN: 2466-1899Int J Thyroidol 2016 November 9(2): 210-214https://doi.org/10.11106/ijt.2016.9.2.210

Received August 20, 2016 / Revised November 14, 2016 / Accepted November 17, 2016Correspondence: Won Gu Kim, MD, PhD, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, KoreaTel: 82-2-3010-5883, Fax: 82-2-3010-6962, E-mail: wongukim@amc.seoul.kr

Copyright ⓒ 2016, the Korean Thyroid Association. All rights reserved. This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creative-

commons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Development of Tracheoesophageal Fistula after the Use of Sorafenib in Locally Advanced Papillary Thyroid Carcinoma: a Case Report

Eyun Song, Kyung Mee Song, Won Gu Kim and Chang Min ChoiDepartment of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Sorafenib, an oral multi-kinase inhibitor, is used for the treatment of patients with radioactive iodine (RAI)

refractory differentiated thyroid carcinoma (DTC) with favorable outcomes. Some unusual but fatal adverse

effects are known for this drug and tracheoesophageal fistula (TEF) is one of them, which has never been

reported in thyroid cancer patients. We present a successfully treated patient who had developed TEF

associated with rapid tumor regression during sorafenib treatment for locally advanced papillary thyroid

carcinoma (PTC). Sorafenib was discontinued and feeding jejunostomy tube was placed for nutritional support.

3 months later, the TEF had successfully healed and there was no visible fistula track or interval change of

the viable tumor during 15 months of follow-up. Identifying patients at high risk for this potential complication

and paying special attention when prescribing anti-angiogenics to these patients are crucial to prevent

associated morbidity and mortality.

Key Words: Tracheoesophageal fistula, Sorafenib, Thyroid cancer, Papillary

Introduction

The prognosis of differentiated thyroid carcinoma

(DTC) is known to be excellent after surgical treatment

and radioactive iodine (RAI) followed by thyrotropin

suppressive therapy.1) However, approximately half of

locally advanced or metastatic DTCs are refractory to

RAI therapy and have a very poor prognosis.2,3)

Sorafenib, an oral multi-kinase inhibitor that affects

both tumor cell proliferation and angiogenesis, has

emerged as an effective therapeutic option for patients

with advanced RAI-refractory DTC.4) It has a relatively

well-tolerated toxicity profile compared with conven-

tional cytotoxic chemotherapy. However, rare but fatal

adverse events, such as hemorrhage, myocardial in-

farction, sepsis, and sudden death, have been

reported.4,5) Tracheoesophageal fistula (TEF), which is

one of them, is a life threatening complication in malig-

nancy such as lung, esophagus, or head and neck

cancer.6-10) TEF formation because of DTC is ex-

tremely rare and there have been no previous reports

of this phenomenon as a complication of using

sorafenib. Herein, we report a patient with TEF asso-

ciated with rapid tumor regression of locally advanced

papillary thyroid carcinoma (PTC) after treatment with

sorafenib.

Case Report

A 71-year-old woman presented with a 1-week

history of hemoptysis and progressive dyspnea

Tracheoesophageal Fistula after Sorafenib

211 Int J Thyroidol

Fig. 1. Locally advanced papillary thyroid carcinoma inthe tracheoesophageal groovewith esophagus and trachealinvasion before sorafenib treatment (A, B). (A) Neck CT image. (B) Bronchoscopic ima-ge. After 1 month of treatmentwith sorafenib, the metastatictumor significantly decreasedin size (C, D). (C) Neck CT image. (D) Bronchoscopic ima-ge.

(modified Medical Research Council grade 4). 15

years ago, she had undergone total thyroidectomy

and subsequent RAI ablation for the treatment of PTC.

After 10 years of disease-free period, a single meta-

static PTC in brain was found and surgical mass ex-

cision was done. There was no evidence of disease

in other lesions at that time.

4 years later, she was admitted to a local hospital

because of recurrent hemoptysis and dyspnea. On

neck computed tomography (CT) and bronchoscopy,

there was a 5.0-cm-sized mass in her right trache-

oesophageal groove that invaded into the cervical

esophagus and mid-trachea causing near total ob-

struction of the trachea (Fig. 1A, B). Several cervical

lymph nodes were enlarged and core needle biopsy

confirmed metastatic PTC. She underwent an 8 Gy

single dose of external beam radiotherapy and sub-

sequent high dose steroid therapy for the metastatic

mass. However, her symptoms did not improve and

she was referred to our hospital.

To treat the endotracheal metastatic mass, a twice

daily regimen of 400 mg sorafenib was initiated, 28

days after the initial radiotherapy. After 1 month of sor-

afenib administration, the mass had decreased by

50% of its initial size on follow-up CT and broncho-

scopy (partial response according to Response Evalua-

tion Criteria In Solid Tumors (RECIST) criteria, Fig. 1C,

D). Accordingly, her symptoms were much improved.

However, after 4 months of sorafenib treatment, she

returned to our clinic with a complaint of recurrent

aspiration. A tracheobronchial CT scan revealed new-

ly developed TEF at the level of the metastatic tumor

(Fig. 2A, B). The fistula opening was right below the

upper esophageal sphincter and esophageal stent in-

sertion was not feasible. She underwent insertion of a

feeding jejunostomy tube (Fig. 2C) and sorafenib was

discontinued. She was followed by TSH suppression

by thyroxine supplementation.

Eyun Song, et al

Vol. 9, No. 2, 2016 212

Fig. 2. Development of tracheoesophageal fistula (TEF) at 4 months after sorafenib treatment (A, B). (A) Tracheobronchial CTimage. (B) Three-dimensional reconstruction image. (C) Successful insertion of a feeding jejunostomy tube. Regression of TEF at 3 months after discontinuation of sorafenib and jejunostomy in esophagography (D), tracheobronchial CT image (E), and 3-dimensional reconstruction image (F).

Follow up CT image was performed every 1 month

after feeding through the jejunostomy tube to evaluate

the change in TEF and its size. After 3 months, esopha-

gography showed no extraluminal leakage of contrast

media (Fig. 2D) and TEF was found to be in a healing

state on tracheobronchial CT (Fig. 2E, F). She started

oral feeding and jejunostomy tube was removed.

Our patient remains alive without signs of recurrent

TEF, and the tumor remains stable at 15 months after

the discontinuation of sorafenib. She underwent radio-

frequency ablation for a right level II cervical lymph

node metastasis after withdrawal of sorafenib and this

lesion has also been stable up to the most recent fol-

low-up.

Discussion

Patients with RAI refractory DTC have a poor prog-

nosis and a long-term overall survival of only 10%.11)

No definite therapeutic option was available until sor-

afenib was first approved by Food and Drug Adminis-

tration (FDA) for these patients. Sorafenib, a multi-

kinase inhibitor that mainly targets angiogenesis, sig-

nificantly improved progression-free survival for 5

months compared with placebo group.4)

Hand-foot syndrome, diarrhea, alopecia, and rash

are some of the most common adverse effects of

sorafenib.12) TEF formation is very rare and direct

cancer invasion of the trachea or esophagus, prior

radiation therapy, and instrumentation of the trachea

or esophagus are known to be high risk factors for

its’ development.13) A previous study reported three

cases of aerodigestive fistula formation after the treat-

ment of thyroid cancer with antiangiogenic tyrosine

kinase inhibitors (TKI), including TEF after 3 months of

cabozantinib, trachea-tumor fistula after 6 weeks of

Tracheoesophageal Fistula after Sorafenib

213 Int J Thyroidol

sunitib, and esophago-tumor fistula after 6 months of

lenvatinib.13) All of the three cases had progressive

thyroid cancer that directly invaded the esophagus or

trachea. Two cases had a history of external beam

radiation, both a total dose of 66 Gy in 33 daily frac-

tions over 48 days and 46 days respectively. Our pa-

tient also had a progressive, locally advanced PTC

with direct invasion of the endotracheal space and a

previous history of external radiation therapy which

are all relevant to risk factors of TEF formation.

Notably, the TEF occurrence in our current case was

associated with tumor regression after sorafenib treat-

ment and not with tumor progression. During the first

month of treatment with sorafenib, her tumor size de-

creased dramatically. This suggests that a good re-

sponse to sorafenib treatment could also be a risk

factor for TEF formation when the tumor directly in-

vades to the trachea or esophagus.

Optimal treatment for TEF associated with malig-

nancy is not established – esophageal stent or gas-

trotomy/jejunostomy is generally performed although it

should be carefully chosen considering patient’s per-

formance status and the location of TEF. Surgical in-

tervention is not preferred in terms of advanced ma-

lignancy and poor performance status of the patients.6,14)

The prognosis of a patient who develops TEF as

a complication of a malignancy is very poor. In the

previously reported cases by Blevins et al.13), all of the

patients died within 2 months of the formation of aero-

digestive fistulas that resulted from hemorrhage, in-

fection, or respiratory distress. Our present case sug-

gests that early diagnosis of TEF and immediate ther-

apeutic interventions for enteric feeding to prevent life

threatening complications, such as aspiration pneu-

monia, are critical to improve the survival outcomes

and quality of life.

In conclusion, TEF formation can be a progressively

deteriorating complication in patients administered an-

tiangiogenic agents with tumors directly invading vital

organs including esophagus and trachea, previous

radiation therapy, and instrumentation of the trachea

or esophagus. As sorafenib grows in importance in

the treatment of RAI refractory DTC and more anti-

angiogenic TKIs are being developed, greater aware-

ness when using these drugs in high risk patients

should be made for this potential complication.

Acknowledgments

This study was supported by the National Research

Foundation (NRF) of Korea Research Grant (NRF-

2015R1C1A1A02036597).

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