C A S E R EP O R T
pISSN: 2384-3799 eISSN: 2466-1899 Int J Thyroidol 2016 November 9(2): 210-214 https://doi.org/10.11106/ijt.2016.9.2.210
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 Choi Department 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
farction, sepsis, and sudden death, have been reported.4,5) Tracheoesophageal fistula (TEF), which is
one of them, is a life threatening complication in maligThe prognosis of differentiated thyroid carcinoma
nancy such as lung, esophagus, or head and neck
(DTC) is known to be excellent after surgical treatment
cancer.6-10) TEF formation because of DTC is ex-
and radioactive iodine (RAI) followed by thyrotropin
tremely rare and there have been no previous reports
suppressive therapy. However, approximately half of
of this phenomenon as a complication of using
locally advanced or metastatic DTCs are refractory to
sorafenib. Herein, we report a patient with TEF asso-
ciated with rapid tumor regression of locally advanced
Sorafenib, an oral multi-kinase inhibitor that affects
papillary thyroid carcinoma (PTC) after treatment with
both tumor cell proliferation and angiogenesis, has
RAI therapy and have a very poor prognosis.
emerged as an effective therapeutic option for patients with advanced RAI-refractory DTC.4) It has a relatively
well-tolerated toxicity profile compared with conventional cytotoxic chemotherapy. However, rare but fatal
A 71-year-old woman presented with a 1-week
adverse events, such as hemorrhage, myocardial in-
history of hemoptysis and progressive dyspnea
Received August 20, 2016 / Revised November 14, 2016 / Accepted November 17, 2016 Correspondence: 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, Korea Tel: 82-2-3010-5883, Fax: 82-2-3010-6962, E-mail: [email protected]
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://creativecommons.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.
Tracheoesophageal Fistula after Sorafenib
(modified Medical Research Council grade 4). 15
she was referred to our hospital.
years ago, she had undergone total thyroidectomy
To treat the endotracheal metastatic mass, a twice
and subsequent RAI ablation for the treatment of PTC.
daily regimen of 400 mg sorafenib was initiated, 28
After 10 years of disease-free period, a single meta-
days after the initial radiotherapy. After 1 month of sor-
static PTC in brain was found and surgical mass ex-
afenib administration, the mass had decreased by
cision was done. There was no evidence of disease
50% of its initial size on follow-up CT and broncho-
in other lesions at that time.
scopy (partial response according to Response Evalua-
4 years later, she was admitted to a local hospital
tion Criteria In Solid Tumors (RECIST) criteria, Fig. 1C,
because of recurrent hemoptysis and dyspnea. On
D). Accordingly, her symptoms were much improved.
neck computed tomography (CT) and bronchoscopy,
However, after 4 months of sorafenib treatment, she
there was a 5.0-cm-sized mass in her right trache-
returned to our clinic with a complaint of recurrent
oesophageal groove that invaded into the cervical
aspiration. A tracheobronchial CT scan revealed new-
esophagus and mid-trachea causing near total ob-
ly developed TEF at the level of the metastatic tumor
struction of the trachea (Fig. 1A, B). Several cervical
(Fig. 2A, B). The fistula opening was right below the
lymph nodes were enlarged and core needle biopsy
upper esophageal sphincter and esophageal stent in-
confirmed metastatic PTC. She underwent an 8 Gy
sertion was not feasible. She underwent insertion of a
single dose of external beam radiotherapy and sub-
feeding jejunostomy tube (Fig. 2C) and sorafenib was
sequent high dose steroid therapy for the metastatic
discontinued. She was followed by TSH suppression
mass. However, her symptoms did not improve and
by thyroxine supplementation.
Fig. 1. Locally advanced papillary thyroid carcinoma in the tracheoesophageal groove with esophagus and tracheal invasion before sorafenib treatment (A, B). (A) Neck CT image. (B) Bronchoscopic image. After 1 month of treatment with sorafenib, the metastatic tumor significantly decreased in size (C, D). (C) Neck CT image. (D) Bronchoscopic image.
211 Int J Thyroidol
Eyun Song, et al
Fig. 2. Development of tracheoesophageal fistula (TEF) at 4 months after sorafenib treatment (A, B). (A) Tracheobronchial CT image. (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
nosis and a long-term overall survival of only 10%.11)
after feeding through the jejunostomy tube to evaluate
No definite therapeutic option was available until sor-
the change in TEF and its size. After 3 months, esopha-
afenib was first approved by Food and Drug Adminis-
gography showed no extraluminal leakage of contrast
tration (FDA) for these patients. Sorafenib, a multi-
media (Fig. 2D) and TEF was found to be in a healing
kinase inhibitor that mainly targets angiogenesis, sig-
state on tracheobronchial CT (Fig. 2E, F). She started
nificantly improved progression-free survival for 5
oral feeding and jejunostomy tube was removed.
months compared with placebo group.
Our patient remains alive without signs of recurrent
Hand-foot syndrome, diarrhea, alopecia, and rash
TEF, and the tumor remains stable at 15 months after
are some of the most common adverse effects of
the discontinuation of sorafenib. She underwent radio-
sorafenib.12) TEF formation is very rare and direct
frequency ablation for a right level II cervical lymph
cancer invasion of the trachea or esophagus, prior
node metastasis after withdrawal of sorafenib and this
radiation therapy, and instrumentation of the trachea
lesion has also been stable up to the most recent fol-
or esophagus are known to be high risk factors for
its’ development. 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
Patients with RAI refractory DTC have a poor prog-
cabozantinib, trachea-tumor fistula after 6 weeks of
Vol. 9, No. 2, 2016
Tracheoesophageal Fistula after Sorafenib
sunitib, and esophago-tumor fistula after 6 months of lenvatinib.
All of the three cases had progressive
ness when using these drugs in high risk patients should be made for this potential complication.
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 fractions over 48 days and 46 days respectively. Our pa-
This study was supported by the National Research
tient also had a progressive, locally advanced PTC
Foundation (NRF) of Korea Research Grant (NRF-
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 treatment and not with tumor progression. During the first month of treatment with sorafenib, her tumor size decreased dramatically. This suggests that a good response to sorafenib treatment could also be a risk factor for TEF formation when the tumor directly invades to the trachea or esophagus. Optimal treatment for TEF associated with malignancy is not established – esophageal stent or gastrotomy/jejunostomy is generally performed although it should be carefully chosen considering patient’s performance status and the location of TEF. Surgical intervention is not preferred in terms of advanced malignancy and poor performance status of the patients.
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 aerodigestive fistulas that resulted from hemorrhage, infection, or respiratory distress. Our present case suggests that early diagnosis of TEF and immediate therapeutic interventions for enteric feeding to prevent life threatening complications, such as aspiration pneumonia, are critical to improve the survival outcomes and quality of life. In conclusion, TEF formation can be a progressively deteriorating complication in patients administered antiangiogenic 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 antiangiogenic TKIs are being developed, greater aware213 Int J Thyroidol
References 1) Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995 [see comments]. Cancer 1998;83(12):2638-48. 2) Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 1994;97(5):418-28. 3) Durante C, Haddy N, Baudin E, Leboulleux S, Hartl D, Travagli JP, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab 2006;91(8):2892-9. 4) Brose MS, Nutting CM, Jarzab B, Elisei R, Siena S, Bastholt L, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet 2014;384(9940): 319-28. 5) Schutz FA, Je Y, Richards CJ, Choueiri TK. Meta-analysis of randomized controlled trials for the incidence and risk of treatment-related mortality in patients with cancer treated with vascular endothelial growth factor tyrosine kinase inhibitors. J Clin Oncol 2012;30(8):871-7. 6) Rodriguez AN, Diaz-Jimenez JP. Malignant respiratorydigestive fistulas. Curr Opin Pulm Med 2010;16(4):329-33. 7) Gschossmann JM, Bonner JA, Foote RL, Shaw EG, Martenson JA Jr, Su J. Malignant tracheoesophageal fistula in patients with esophageal cancer. Cancer 1993;72(5):1513-21. 8) Spigel DR, Hainsworth JD, Yardley DA, Raefsky E, Patton J, Peacock N, et al. Tracheoesophageal fistula formation in patients with lung cancer treated with chemoradiation and bevacizumab. J Clin Oncol 2010;28(1):43-8. 9) Goodgame B, Veeramachaneni N, Patterson A, Govindan R. Tracheo-esophageal fistula with bevacizumab after mediastinal radiation. J Thorac Oncol 2008;3(9):1080-1. 10) Gore E, Currey A, Choong N. Tracheoesophageal fistula associated with bevacizumab 21 months after completion of radiation therapy. J Thorac Oncol 2009;4(12):1590-1. 11) Regalbuto C, Frasca F, Pellegriti G, Malandrino P, Marturano I, Di Carlo I, et al. Update on thyroid cancer treatment. Future Oncol 2012;8(10):1331-48. 12) Shen CT, Qiu ZL, Luo QY. Sorafenib in the treatment of radioiodine-refractory differentiated thyroid cancer: a meta-
Eyun Song, et al analysis. Endocr Relat Cancer 2014;21(2):253-61. 13) Blevins DP, Dadu R, Hu M, Baik C, Balachandran D, Ross W, et al. Aerodigestive fistula formation as a rare side effect of antiangiogenic tyrosine kinase inhibitor therapy for thyroid cancer. Thyroid 2014;24(5):918-22.
14) Hu Y, Zhao YF, Chen LQ, Zhu ZJ, Liu LX, Wang Y, et al. Comparative study of different treatments for malignant tracheoesophageal/bronchoesophageal fistulae. Dis Esophagus 2009;22(6):526-31.
Vol. 9, No. 2, 2016