Vortex keratopathy in a patient receiving vandetanib for non-small cell lung cancer.
ABSTRACT We report a case of vortex keratopathy in a patient treated with vandetanib for non-small cell lung cancer (NSCLC). A 44-year-old female who underwent two cycles of chemotherapy for NSCLC complained of visual blurring in both eyes after the initiation of vandetanib, an anti-epidermal growth factor receptor (EGFR) and anti-vascular endothelial growth factor receptor 2 protein tyrosine kinase inhibitor. On ophthalmic examination, visual acuities were 20 / 20 OU and, with the exception of diffuse vortex keratopathy in both eyes, other findings were unremarkable. Vandetanib is believed to have caused vortex keratopathy in this patient. Anti-EGFR properties affecting normal corneal epithelial cell migration and wound healing or drug associated metabolite deposition, which is the case in numerous drug-associated vortex keratopathies, may be possible underlying mechanisms in the formation of this corneal complication.
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ABSTRACT: During the last 20 years, biologicals have become increasingly relevant in oncologic therapy. Depending on the medication used, there are different profiles of ocular side effects. Although these can be present in up to 70% of patients, they are generally underreported in the literature. Therefore, the pathophysiological details of their development are often poorly understood. Herein we attempt to identify groups of biologicals to which a specific side effect profile can be assigned. We also tried to capture all relevant side effects and therefore conducted several database investigation including Medline, Cochrane library, and the drugs section of the US Food and Drug Administration (FDA), using the following search strings: "name of biological agent (both generic and commercial names)" AND "eye" OR "ocular". If we found a side effect that has been associated with a drug, we researched Medline using the following search string: "name of biological agent" (both generic and commercial names) AND "term for the specific side effect". Due to the wealth of material we report only the drugs that are approved by the FDA.OncoTargets and Therapy 01/2013; 7:69-77. · 2.07 Impact Factor
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ABSTRACT: When using molecularly targeted agents (MTAs), oncologists and patients face new and sometimes unexpected toxicities. Though ocular adverse events (OAEs) are not uncommon with chemotherapy, they are rarely severe or dose limiting. Ocular toxicity profile may differ with MTAs, indeed severe and dose limiting toxicities have been described with targeted therapies currently under investigation. Our study aimed to review OAEs experienced with MTAs approved in solid tumours. This review revealed that many OAEs, frequent and potentially severe, exist and concern most MTAs. The suggestion is prompt referral of patients with severe pain and/or visual impairment to the ophthalmologist since these symptoms can be associated with potentially severe OAE and need ophthalmic assessment. Oncologists must be aware of such events and their potential severity for better treatment and better diagnosis in daily practice as well as in clinical trials.European journal of cancer (Oxford, England: 1990) 11/2013; · 4.12 Impact Factor
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ABSTRACT: The inability to routinely monitor drug-induced phospholipidosis (DIPL) presents a challenge in pharmaceutical drug development and in the clinic. Several nonclinical studies have shown di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP) to be a reliable biomarker of tissue DIPL that can be monitored in the plasma/serum and urine. The aim of this study was to show the relevance of di-22:6-BMP as a DIPL biomarker for drug development and safety assessment in humans. DIPL shares many similarities with the inherited lysosomal storage disorder Niemann-Pick type C (NPC) disease. DIPL and NPC result in similar changes in lysosomal function and cholesterol status that lead to the accumulation of multi-lamellar bodies (myeloid bodies) in cells and tissues. To validate di-22:6-BMP as a biomarker of DIPL for clinical studies, NPC patients and healthy donors were classified by receiver operator curve analysis based on urinary di-22:6-BMP concentrations. By showing 96.7- specificity and 100- sensitivity to identify NPC disease, di-22:6-BMP can be used to assess DIPL in human studies. The mean concentration of di-22:6-BMP in the urine of NPC patients was 51.4-fold (p≤0.05) above the healthy baseline range. Additionally, baseline levels of di-22:6-BMP were assessed in healthy non-medicated humans and laboratory animals (rats, mice, dogs, and monkeys) to define normal reference ranges for nonclinical/clinical studies. The baseline ranges of di-22:6-BMP in the plasma, serum, and urine of humans and laboratory animals were species dependent. The results of this study support the role of di-22:6-BMP as a biomarker of DIPL for pharmaceutical drug development and health care settings.Toxicology and Applied Pharmacology 06/2014; · 3.98 Impact Factor
Korean J Ophthalmol 2011;25(5):355-357
pISSN: 1011-8942 eISSN: 2092-9382
Vortex Keratopathy in a Patient Receiving Vandetanib for
Non-Small Cell Lung Cancer
Jeeyun Ahn1, Won Ryang Wee2, Jin Hak Lee1, Joon Young Hyon1
1Department of Ophthalmology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
2Department of Ophthalmology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
We report a case of vortex keratopathy in a patient treated with vandetanib for non-small cell lung cancer (NSCLC).
A 44-year-old female who underwent two cycles of chemotherapy for NSCLC complained of visual blurring in both
eyes after the initiation of vandetanib, an anti-epidermal growth factor receptor (EGFR) and anti-vascular endothe-
lial growth factor receptor 2 protein tyrosine kinase inhibitor. On ophthalmic examination, visual acuities were 20 / 20
OU and, with the exception of diffuse vortex keratopathy in both eyes, other findings were unremarkable.
Vandetanib is believed to have caused vortex keratopathy in this patient. Anti-EGFR properties affecting normal
corneal epithelial cell migration and wound healing or drug associated metabolite deposition, which is the case in
numerous drug-associated vortex keratopathies, may be possible underlying mechanisms in the formation of this
Key Words: Epidermal growth factor, Vandetanib, Vortex keratopathy
ⓒ2011 The Korean Ophthalmological Society
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses
/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: December 10, 2009 Accepted: April 19, 2010
Reprint requests to Joon Young Hyon, MD. Department of Ophthalmology,
Seoul National University Bundang Hospital, #300 Gumi-dong, Bundag-
gu, Seongnam 463-707, Korea. Tel: 82-31-787-7375, Fax: 82-31-787-4057,
Vortex keratopathy is characterized by distinctive bilateral
corneal subepithelial whorls and is known to be associated
with Fabry disease and the use of various drugs. Amiodarone,
chloroquine, ibuprofen, indomethacin, naproxen, tamoxifen
and chloropromazine are just a few of the wide array of medi-
cations that have been identified so far . Herein, we report
a case of vortex keratopathy in a patient treated with vandeta-
nib, a dual epidermal growth factor receptor (EGFR) and
vascular endothelial growth factor receptor 2 (VEGFR2) in-
hibitor used in the treatment of non-small cell lung cancer
A 44-year-old woman was referred to the ophthalmology
consultation service in October of 2009 for episodes of inter-
mittent blurred vision in both eyes. Her ophthalmic history
was unremarkable. In January of 2009, the patient was diag-
nosed with NSCLC and after undergoing four cycles of com-
bined chemotherapy consisting of gemcitabine and cisplatin,
she was enrolled in a clinical trial for vandetanib (ZD6474), a
dual anti- EGFR and anti- VEGFR2 tyrosine kinase inhibitor.
After six one-month cycles of vandetanib at 300 mg/day, the
patient remarked that she felt as if a thin fog had spread in
front of both eyes and she sought ophthalmologic evaluation.
On initial evaluation, her visual acuities were 20 / 20 OU.
Intraocular pressures were normal in both eyes. Slit-lamp bi-
omicroscopy examination revealed diffuse subepithelial
haze with inferior subepithelial whorls in both corneas (Fig. 1).
No staining was observed with the application of fluorescein
dye. The conjunctiva was quiet OU and both anterior cham-
bers were deep and clear. Irides, lens and fundus examina-
tions were unremarkable in both eyes and pupillary reaction
and ocular motility were also normal. She had no previous
use of medications known to be associated with vortex
Although we recommended artificial tear drops for symp-
tomatic relief, the patient felt no dryness in her eyes and
wished to forgo the use of any topical medication. She was
asked to return to our clinic 3-months later.
This case demonstrated vortex keratopathy in both eyes
while receiving vandetanib for the treatment of NSCLC. As
Korean J Ophthalmol Vol.25, No.5, 2011
Fig. 1. Photograph of the anterior segment of the right (A) and left (B) cornea of a patient who was treated with vandetanib. Subepithelial cor-
neal haze and whorls are observed.
far as we know, this is the first reported domestic case of van-
detanib-induced vortex keratopathy.
Vandetanib (ZD6474) is one of the novel ‘target therapies’
which inhibit signaling pathways involved in the develop-
ment and progression of cancer . Specifically, it is the first
protein tyrosine kinase inhibitor to target both EGFR and
VEGFR2. EGFR is known to be over-expressed in the ma-
jority of NSCLC and to stimulate cell proliferation, survival,
migration and angiogenesis [3,4]. VEGF is the target of nu-
merous antiangiogenesis drugs that seek to limit tumor
growth by inhibiting the fundamental process of new blood
vessel formation, an essential process for tumor expansion
Epidermal growth factor (EGF) is a small polypeptide that
has potent stimulatory effects on epidermal cell proliferation
and differentiation [5,6]. In the eye, EGF is one of the main
growth factors involved in the maintenance of ocular surface
homeostasis . The molecule binds to the EGFR, which is
localized in the basal cell layer of the conjunctiva and cornea,
stimulates corneal epithelial cell proliferation and migration
and is known to play a pivotal role in corneal wound healing
[8-11]. Lacrimal EGF messenger RNA was found to be in-
creased in rabbits after corneal epithelial injury. Also, the or-
al administration of gefitinib (Iressa), an EGFR inhibitor, in
rats demonstrated significant effects on the maintenance of
normal corneal thickness, epithelial cell proliferation and
stratification during corneal epithelial wound healing [12,13].
Reports of ocular complications arising from EGFR in-
hibitors include reversible recurrent corneal erosions, con-
junctival hyperemia, telangiectasia of the eyelid margins,
meibomitis, tear film dysfunction, and tortuous eyelashes
associated with gefitinib, corneal opacification in animals
administered high doses of EGFR inhibitors and trichome-
galy and periorbital rash after erlotinib (Tarceva) use [14-17].
There have been only two reports of vortex keratopathy arising
after EGFR inhibitor use, namely vandetanib and suramin, an
antiparasitic medication that inhibits EGF, platelet-derived
growth factor, and tumor growth factor-beta activity [18,19].
Discontinuation of suramin resulted in clearing of the cornea
despite persistent corneal opacification and improvement in
the patient’s ophthalmic symptoms was observed after van-
detanib dose reduction. Interestingly, the patient using van-
detanib had underlying epithelial basement membrane dys-
trophy and a history of recurrent corneal erosions, which may
have predisposed her to the development of abnormalities in
corneal epithelial wound healing .
Vortex keratopathy is characterized by a whorl-like pat-
tern of grayish golden-brown deposits in the corneal epi-
thelium . Although the underlying pathogenesis is yet
unclear, intralysosomal lipid-bearing inclusion bodies have
been demonstrated in the corneal epithelium of both Fabry’s
disease and various drug-induced vortex keratopathy cases
[1,20]. Drug-induced vortex keratopathies typically share
cationic and amphiphilic properties, allowing them to penetrate
lysosomes and bind to cellular lipids, resulting in drug-lipid
complexes which are believed to be the intralysosomal in-
clusion bodies observed in the basal layers of the corneal epi-
thelium [20,21]. On the other hand, biopsies of corneal lesions
of suramin-induced vortex keratopathy reveal lysosomal ac-
cumulation of glycosaminoglycan . As a biopsy was not
performed in our patient, it remains unclear whether the
cause for vortex keratopathy was epithelial deposition of
vandetanib derived metabolites or defective epithelial turn-
over and migration due to EGFR inhibitory properties of the
Although this patient did not undergo ophthalmological
examination prior to the administration of vandetanib, we
could not find any offending factor that could trigger such
corneal changes as vortex keratopathy other than vandetanib.
Stopping or reducing the dose of vandetanib would have
provided better evidence for the establishment of a causal
relationship between vandetanib use and vortex keratopathy.
Nevertheless, it may be reasonable to assume that vortex
keratopathy with subepithelial haziness was induced by
vandetanib in this case.
‘Targeted therapies’ have revolutionized cancer treatment
J Ahn, et al. Vortex Keratopathy Related to Vandetanib Use
by preferentially targeting cancer cells over normal cells,
presumably resulting in better patient tolerability compared
to cytotoxic drugs. However, it may be expected that sys-
temic complications will arise from the inhibition of specific
signal transmission cascades and the recognition of these
drugs as potential causes for such adverse reactions is neces-
sary in light of the expanding use of these drugs in the field of
cancer treatment. Increased awareness regarding visual
symptoms and regular ophthalmic examination should be
deemed mandatory in patients receiving vandetanib for the
treatment of various solid malignancies.
Conflict of Interest
No potential conflict of interest relevant to this article was
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