Found it. Please excuse the inelegant paste-job -- I don't have time right now to make it pretty.
CAPECITABINE-INDUCED
ABNORMALITIES IN
THYROID FUNCTION
TESTS
To the Editor:
Drugs can have profound effects
on thyroid function tests (1). We report
a patient who developed marked
abnormalities in her thyroid function
tests while receiving capecitabine (2)
for treatment of metastatic breast
cancer.
A 58-year-old woman with hypothyroidism
and metastatic breast cancer
was first seen for management of
her hypothyroidism in April 2001;
she was euthyroid while taking levothyroxine
125g/d and tamoxifen 20
mg/d (Table). Similar values were obtained
in November 2001, following
which tamoxifen was discontinued
and she began taking capecitabine
3000 mg/d for 2 of every 3 weeks. Repeat
thyroid studies in June and July
2002 revealed elevated serum concentrations
of thyroid stimulating hormone
(TSH), total thyroxine (T4),
free thyroxine index, and thyroxinebinding
globulin, with normal values
for direct free T4 and total triiodothyronine
(T3), but a subnormal free T3
concentration (Table). Her dose of
levothyroxine was increased to 150
g/d, and serum TSH levels normalized
over the next several months,
with elevated total T4 levels and normal
free thyroxine index. Capecitabine
was stopped in November 2002.
In March 2003, serum TSH level was
slightly suppressed, with a mildly elevated
total serum T4 level and borderline
high free thyroxine index on the
same dose of levothyroxine (150 g/
d), but now off capecitabine. Her
dose of levothyroxine was decreased
to 125 g/d (her precapecitabine
dose), with return of serum TSH levels
to normal. In November 2003, she
was begun on chemotherapy with a
cyclophosphamide/methotrexate/5-
fluorouracil regimen, and in December
2003 her serum TSH and T4 levels
were again elevated with serum T3
and thyroxine-binding globulin levels
at the upper limit of normal.
Capecitabine is currently approved
for use in advanced breast and colon
cancer. Orally adminstered capecitabine
is converted in the liver and in
tumor cells to its active metabolite,
5-fluorouracil, which is responsible
for its antineoplastic activity. There
have been no reports of effects of
capecitabine on thyroid function tests
and no reports of interference by
5-fluorouracil or capecitabine in the
assays for TSH, total or free T4 or T3,
or for thyroxine-binding globulin.
Drugs can affect the production,
secretion, transport, and metabolism
of thyroid hormones and may also alter
the absorption of exogenously administered
thyroid hormone (1).
Beex et al (3,4) reported that euthyroid
patients receiving 5-fluorouracil
as part of combination chemotherapy
for breast cancer had thyroid function
test abnormalities somewhat
similar to our patient, with elevated
total serum T4 and T3 concentrations
but normal free T4 and normal TSH.
The most plausible explanation of
their results was that 5-fluorouracil
induced an increase in the serum
concentration of thyroxine-binding
globulin, the main serum carrier protein
for thyroid hormones. In accord
with those observations, our patient
demonstrated an increase in the serum
serum
concentration of thyroxinebinding
globulin, which raised the
total serum T4 concentration, as
expected. However, total serum T3
level, which should also have increased,
was normal, and free T3 concentration
was actually low; this raises
the possibility that capecitabine may
also interfere with the deiodination of
T4 to T3.
In our patient, adminstration of
capecitabine or, to a lesser extent,
5-fluorouracil, was associated with elevation
of serum thyroxine-binding
globulin; being hypothyroid, she was
unable to increase her thyroid hormone
production to compensate for
the increase in serum protein binding
sites for T4 and T3, thus leading to an
elevated serum TSH and necessitating
an increase in her thyroxine dose.
On discontinuing capecitabine, her
dose requirement for thyroxine decreased,
suggesting that capecitabine
was responsible for the observed
changes in thyroid function tests.
We did not see any abnormalities
in thyroid function tests in 5 euthyroid
patients receiving capecitabine
2000 mg/m2/d for 14 days of each 21-
day cycle in a combination chemotherapy
protocol for colon cancer.
This suggests that certain regimens
containing capecitabine may be more
likely than others to cause changes in
thyroid function tests. Alternatively,
it is possible that our patient was
uniquely sensitive to an effect of the
drug. Further study is needed to define
the factors that may influence the
effects of capecitabine on thyroid
function tests.
Harmeet S. Narula, MD
Harold E. Carlson, MD
Department of Medicine
Endocrinology Division
Stony Brook University
Stony Brook, New York
1. Surks MI, Sievert R. Drugs and thyroid
function. N Engl J Med. 1995;333:1688–
1694.
2. Capecitabine/Xeloda [package insert].
Available at:
www.Xeloda.com. Accessed
May 20, 2003.
3. Beex LV, Ross A, Smals AG, Kloppenborg
PW. 5-fluorouracil and the thyroid. Lancet.
1976;1:866–867.
4. Beex L, Ross A, Smals A, Kloppenborg P.
5-fluorouracil-induced increase of total serum
thyroxine and triiodothyronine. Cancer
Treat Rep. 1977;61:1291–1295