Research Article
The Effect of Corticosteroid Eye Drops on the Prevention of Eye Disorders Caused by High-Dose Cytarabine Therapy
Tetsuo Kume1*, Kana Akiyama1, Shigeyo Sakata1, Takahiro Mochizuki1, Ikue Shiki2, Satoshi Motokawa1,3, Michihiro Shino1 and Takashi Ikeda2
1Department of Pharmacy, Shizuoka Cancer Center, Japan
2Department of Hematology and Stem Cell Transplantation, Shizuoka Cancer Center, Japan
3Department of Pharmacy, Kushiro City General Hospital, Japan
*Corresponding author: Tetsuo Kume, Department of Pharmacy, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan
Published: 24 Mar, 2017
Cite this article as: Kume T, Akiyama K, Sakata S,
Mochizuki T, Shiki I, Motokawa S, et al.
The Effect of Corticosteroid Eye Drops
on the Prevention of Eye Disorders
Caused by High-Dose Cytarabine
Therapy. Clin Oncol. 2017; 2: 1246.
Abstract
Side effects of high-dose cytarabine (HDCA) treatment include cytarabine syndrome with
symptoms such as fever, muscle pain, and conjunctivitis. The use of corticosteroid eye drops to
prevent eye disorders caused by HDCA has been previously reported. However, previously reported
prophylactic methods include the administration of corticosteroid eye drops combined with other
eye droups, we retrospectively examined the prophylactic effect of 0.1% fluorometholone eye drops
(FM) as a monotherapy to prevent eye disorders caused by HDCA. The subjects were hospitalized
patients who received HDCA at doses of at least 1 g/m2 between April 2011 and December 2014 at
a Japanese cancer treatment center. Patients taking HDCA once a day received FM every 6 h in both
eyes, starting from the first HDCA dose and continuing until 48 h after the last dose. Patients taking
HDCA twice a day were administered FM every 4 h in both eyes, starting from the first HDCA dose
and continuing until 48 h after the last dose. The incidence of Grade 1 and Grade 2 eye disorders was
2.8% and 2.3%, respectively, and Grade 3 eye disorders were not detected. The use of FM as a single
agent appears to prevent eye disorders caused by HDCA, with the added advantage that it is a simple
technique, which can be managed by the patients themselves.
Keywords: Eye disorders; Fluorometholone eye drops; High-dose cytarabine; Prophylactic effect; Simple technique
Introduction
High-dose cytarabine (HDCA) is used to treat acute myeloid leukemia, acute lymphoblastic
leukemia, and as a salvage treatment for malignant lymphoma [1–3]. Side effects of HDCA
include cytarabine (AraC) syndrome, which manifests as fever, muscle pain, and conjunctivitis.
Eye disorders resulting from AraC treatment present symptoms such as eye pain, foreign body
sensation, photophobia, and conjunctivitis, and it has been reported that these symptoms develop
when AraC is transported from the blood into tear fluid, inhibiting the division of corneal epithelial
cells. The plasma half-life of HDCA is 2–3 h in the β-elimination phase, and approximately 3 h in
tears. Even when AraC concentration in tears is approximately one tenth of the concentration in
blood, it exerts a cytotoxic effect on corneal epithelial cells, leading to eye disorders [4–6].
The use of corticosteroid eye drops to prevent eye disorders caused by HDCA has been
previously reported. Published prophylactic methods include the administration of corticosteroid
eye drops combined with artificial tears, and using corticosteroid eye drops with sterile saline as an
eye rinse [5,7,8]. However, combining prophylactic methods is more complex than using a single
agent. Therefore, in this study we used a simple method to prevent eye disorders caused by HDCA,
the administration of 0.1% fluorometholone eye drops (FM) as monotherapy, and examined the
prophylactic effects retrospectively.
Materials and Methods
Patients and medication
The Shizuoka Cancer Center (SCC) Ethics Committee approved our study design and
publication of the results. The Ethics Committee waived the requirement for informed consent
because of the retrospective nature of the study. The study population comprised patients who were
hospitalized and treated with HDCA at a dose of 1g/m2 or more at the SCC between April 2011 and
December 2014.Considering the incidence of side effects such as increased intraocular pressure, we selected 0.1% FM administered as corticosteroid eye drops to
prevent the occurrence of eye disorders caused by AraC. During the
instillation period, considering the plasma half-life of AraC, patients
who were administered HDCA once a day received FM every 6 h in
both eyes, starting from the first HDCA dose and continuing until 48
h after the last HDCA dose. Patients who were administered HDCA
twice a day received FM every 4 h in both eyes, starting from the first
HDCA dose and continuing until 48 h after the last HDCA dose. The
two treatment regimens are shown in (Figure 1A and 1B).
Assessment and grading
The items assessed included AraC dosage, presence or absence
of Total Body Irradiation (TBI), and eye disorders. These data were
retrieved from the medical records of the patients. To assess the
eye disorders, we, along with an ophthalmologist, evaluated our
departmental findings in reference to the Common Terminology
Criteria for Adverse Events, version 4.0. Assessment criteria were as
follows: Grade 0, none; Grade 1, eye discharge, mild symptoms of
conjunctivitis, and no intervention indicated; Grade 2, symptomatic,
medical intervention indicated; Grade 3, limiting self-care and
activities of daily living. The assessment period lasted from the
first HDCA dose until 7 days after the last HDCA dose, or until
the complete resolution of any eye disorder. The highest-grade eye
disorder during that period was noted. Eye disorders were assessed
retrospectively based on medical records compiled by pharmacists,
nurses, and physicians.
Statistical analysis
We used Fisher’s exact test, and p values <0.05 were considered statistically significant. All statistical analyses were performed with
EZR version 3.2.2. EZR is a modified version of “R Commander”
which includes statistical functions frequently used in biostatistics.
Figure 1
Figure 1
(A) Administration method of 0.1% fluorometholone eye drops 4 times a day. (B) Administration method of 0.1% fluorometholone eye drops 6 times a day.
DEX: Dexamethasone; CPA: Cyclophosphamide; VP-16: etoposide; AraC: Cytarabine.
Table 1
Table 2
Table 3
Results and Discussion
Eye disorders caused by AraC have been reported to occur
when AraC is transported from the blood into tear fluid, where
it subsequently inhibits the division of corneal epithelial cells [5].
In the current study, we examined the prophylactic effect of 0.1%
FM as a single agent against eye disorders caused by AraC. Patient
characteristics are shown in (Table 1). Of the four patients who
underwent TBI, two received an AraC dose of 2g/m2, and two received
3g/m2. In one patient with an AraC dose of 2g/m2, a Grade 1eye
disorder was confirmed. Of the patients who were administered FM six
times a day, one patient self-administered eye drops inappropriately
by allowing the applicator to contact the eyelid and eyelashes, and
one patient confirmed symptoms of central nervous system toxicity
due to AraC. There was no difference in the incidence of eye disorders
based on a single AraC dose. Therefore, we postulate that there is no
relationship between a single dose of AraC and the incidence of eye
disorders. On the other hand, there is a possibility that the incidence
of eye disorders increases with duration of exposure to AraC.
Eye disorder grades and AraC doses at the time of eye disorder
expression are shown in (Table 2). No Grade 3 eye disorders were
identified in any patients who received HDCA either once a day or
twice a day. Since no Grade 3 eye disorders were detected in our
cohort, we believe that FM as monotherapy is an effective treatment
for preventing eye disorders caused by AraC.
Previously investigated methods to prevent eye disorders include
the use of corticosteroid eye drops combined with artificial tears or
a sterile saline eye rinse, but it is difficult to compare those results
with the findings of this study. In addition, the administration period
and type of prophylactic eye drops used differ between our study
and previous studies [5,7,8] (Table 3). Itoh et al. [5] administered
prophylactic eye drops from the first AraC dose until 10 days after
the last AraC dose, using 0.1% betamethasone as a single agent. In
the current study, we administered prophylactic eye drops from
the first AraC dose until 48 h after the last AraC dose, using FM as
monotherapy. There was no change in the instillation schedule in
most cases. Although Grade 2 or lower eye disorders were detected
even with FM administration, symptoms could be controlled with
treatment according to the prescribed schedule. Therefore, our use
of FM as a single agent to prevent eye disorders was simpler than
other methods, and was shown to have a sufficient prophylactic effect
despite the presence of minor eye disorder symptoms.
Our study did have some limitations. First, the package insert
for cytarabine states, “eye disorders can be prevented and reduced
by corticosteroid eye drops.” Therefore, it was ethically difficult
to set up a comparison group that did not use corticosteroid eye drops. Second, the administration of prophylactic eye drops was
essentially managed by the patients. The tip of the eye drop applicator
touched the eyelashes and eyelid at the time of instillation in one
case. It is possible that there were other instances of inappropriate
administration of eye drops that were overlooked. Therefore,
inappropriate administration of eye drops could have led to some eye
disorders. Third, in this study we did not confirm the technique of
eye drop administration used. It has previously been reported that
instructions on eye drop administration from pharmacists resulted
in the appropriate use of eye drops [5,9] Therefore, it is possible
that pharmacists’ instructions on the appropriate use of eye drops
and confirmation of use of the correct technique by medical staff
could have avoided the eye disorders observed in our study. Fourth,
previous studies have reported that washing eyes with betamethasone
and saline, in combination with the use of HDCA and TBI, reduced
the severity of eye disorders [7]. This study did not include many
patients who underwent TBI; therefore, further investigation should
be undertaken with a study population including a larger number of
patients who undergo TBI.
In conclusion, a prophylactic method using FM as a single agent
to prevent eye disorders caused by HDCA is simpler than previously
reported methods. Since we did not compare FM with other
corticosteroid eye drops under the same conditions in this study,
further verification is warranted.
Acknowledgments
We thank Dr. Kazuto Ogura, M.D. (previously in the Division of Hematology and Stem Cell Transplantation, Shizuoka Cancer Center), and the nursing staff on the fourth floor of the East Ward, Shizuoka Cancer Center, for their cooperation.
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