Epistaxis during Treatment with Paclitaxel

Abstract

The purpose of this study was to determine the incidence and severity of epistaxis in patients treated with paclitaxel. Patients who were treated with paclitaxel filled a questionnaire regarding their general health, medications and incidents of epistaxis. Relevant clinical information was obtained from the patients' charts. Forty-seven consecutive patients were recruited to the study. Twenty-four (51%) of the patients reported epistaxis during paclitaxel therapy. Twenty-three of 39 (59%) patients who received weekly paclitaxel had epistaxis at least once during treatment, compared with one out of eight patients who were treated every 3 weeks (P = 0.045). All episodes of epistaxis were mild, occurred with normal platelets counts and did not require blood product transfusions or treatment modification. The majority of the patients experienced the first episode of epistaxis on the third week of weekly paclitaxel treatment and then repeatedly throughout therapy. It is concluded that epistaxis is a common mild side-effect of weekly paclitaxel that has not been reported previously. In this trial, epistaxis did not have any major clinical consequences. However, when paclitaxel is combined with other drugs that may cause bleeding, such as bevacizumab, physicians should be alerted to the potential risk of this phenomenon.

Full text

© 2009 The Authors
Doi: 10.1111/j.1742-7843.2008.00372.x
Journal compilation
© 2009 Nordic Pharmacological Society
. Basic & Clinical Pharmacology & Toxicology
,
104
, 259–261
Blackwell Publishing Ltd
Epistaxis during Treatment with Paclitaxel
Nirit Yarom, Arnoldo Cyjon, Svetlana Kovel, Adelya Yachnin, Avishay Sella and Ella Evron
Oncology Department, Assaf-Harofeh Medical Center, Zerifin 70300, Israel
(Received July 9, 2008; Accepted October 14, 2008)
Abstract:
The purpose of this study was to determine the incidence and severity of epistaxis in patients treated with
paclitaxel. Patients who were treated with paclitaxel filled a questionnaire regarding their general health, medications and
incidents of epistaxis. Relevant clinical information was obtained from the patients’ charts. Forty-seven consecutive
patients were recruited to the study. Twenty-four (51%) of the patients reported epistaxis during paclitaxel therapy. Twenty-
three of 39 (59%) patients who received weekly paclitaxel had epistaxis at least once during treatment, compared with one
out of eight patients who were treated every 3 weeks (P = 0.045). All episodes of epistaxis were mild, occurred with normal
platelets counts and did not require blood product transfusions or treatment modification. The majority of the patients
experienced the first episode of epistaxis on the third week of weekly paclitaxel treatment and then repeatedly throughout
therapy. It is concluded that epistaxis is a common mild side-effect of weekly paclitaxel that has not been reported previously.
In this trial, epistaxis did not have any major clinical consequences. However, when paclitaxel is combined with other drugs
that may cause bleeding, such as bevacizumab, physicians should be alerted to the potential risk of this phenomenon.
Key words: XX.
Paclitaxel is an effective chemotherapy for a variety of solid
malignancies. Traditionally, paclitaxel has been administered
every 3 weeks. The most common side-effects reported with
its administration have been bone marrow suppression,
neuropathy, alopecia, mild nausea, vomiting and diarrhoea.
In the late-1990s, weekly administration of the drug was
introduced which has become a well-established treatment
in many solid malignancies [1,2]. In breast cancer, weekly
administration of paclitaxel is more active and less toxic
than the every 3-weeks schedule [3,4].
We noted that epistaxis was a common complaint of the
breast cancer patients during weekly paclitaxel treatment.
Therefore, we initiated a prospective study to evaluate the
incidence and the clinical impact of epistaxis associated
with paclitaxel chemotherapy.
Materials and Methods
Patients who were treated with paclitaxel at our institution signed
an informed consent before being recruited to the study. At the
beginning of therapy they were asked about their history of
epistaxis, other episodes of bleeding, regular medications and
chronic medical problems. During the course of chemotherapy and
at completion, all participants filled a questionnaire. They were spe-
cifically asked about episodes of epistaxis, the duration, severity
and the measures taken to control the bleeding. Epistaxis was
defined as any amount of blood dripping from the nose (even a few
drops). Relevant medical information regarding disease parameters,
performance status, compounding medical problems, medications
and laboratory tests were obtained from the medical charts.
Statistics.
This is a prospective observational study. Based on our
preliminary estimations, to detect a 15% incidence of epistaxis
during paclitaxel therapy, with power = 80%,
α
= 0.05, 48 patients
had to be recruited to the trial. Fisher’s exact test was used to
compare between patients on weekly paclitaxel and those treated in
every 3 weeks.
Results
Forty-seven patients were recruited to the study and answered
the questionnaire. Their median age was 50 years (range 29–
79 years). Patient characteristics are shown in table 1.
Thirty-nine breast cancer patients were treated with
weekly paclitaxel at 80 mg/m
2
, six patients with lung cancer
and two with ovarian cancer received paclitaxel every 3
weeks at 175–225 mg/m
2
. Twenty-six patients received adju-
vant chemotherapy for stage II breast cancer, nine patients
received neoadjuvant chemotherapy for locally advanced
breast cancer, four patients received palliative chemotherapy
for stage IV breast cancer, eight patients received a combi-
nation of paclitaxel and carboplatin chemotherapy for lung
or ovarian cancer (three in the adjuvant setting and five for
palliation).
Twenty-four (51%) patients reported episodes of epistaxis
during paclitaxel therapy. In the weekly paclitaxel group, 23
Author for correspondence: Nirit Yarom, Oncology Department,
Assaf-Harofeh Medical Center, Zerifin 70300, Israel (fax +972 8
9779714, e-mail nirit.yarom@gmail.com)
Table 1.
Patients’ characteristics.
Weekly
paclitaxel
Paclitaxel every
3 weeks
Number of patients 39 8
Median age (range) 49 (29–71) 61 (44–79)
Epistaxis during paclitaxel (%) 23 (59%) 1 (12.5%)*
Past history of epistaxis 5 (12.8%) 1 (12.5%)
Adjuvant/neoadjuvant 26/9 3
Palliative 4 (10.2%) 5 (62.5%)
Paclitaxel/paclitaxel + carboplatin 39/0 0/8
Nadir of platelets 228,052 288,000
*Statistically significant difference.

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NIRIT YAROM
ET AL.
© 2009 The Authors
Journal compilation
© 2009 Nordic Pharmacological Society.
Basic & Clinical Pharmacology & Toxicology
,
104
, 259–261
of 39 (59%) patients experienced epistaxis at least once
during the treatment, compared to 1 of 8 (12.5%) patients
who were treated every 3 weeks (P = 0.045).
Five of 24 (21%) patients who experienced epistaxis
during paclitaxel therapy (4 on the weekly schedule and 1
on the 3 weeks schedule) reported episodes of epistaxis in
the past, as compared to 1 (on the weekly schedule) of 23
(4%) patients who did not experience epistaxis during
therapy (P = 0.1). The episodes of nose bleeding usually
started on the third week of chemotherapy (median 3 weeks,
range 1–9 weeks) and were always recurrent. Eleven of 24
(46%) patients had recurrent nose bleedings on all subsequent
chemotherapy courses. Epistaxis usually continued intermit-
tently for 3 days (range 1–7 days). Six patients (four on the
weekly regimen and two on the every three weeks regimen)
reported of mild bleeding from other sites like the anal
canal and gingival.
Epistaxis was always mild and self-limiting, and did not
require medical intervention. There was never a need for
platelets or red cells transfusions, and no treatment modifi-
cation was required. Episodes of epistaxis were not associated
with a drop in platelets count. The median platelets number
during therapy was 232,500/
μ
l (range: 126,000–407,000/
μ
l)
and the nadir platelet count did not differ significantly
between the two groups. None of the patients received con-
comitant anticoagulant therapy. One patient was taking
clopidogrel (a platelet aggregation inhibitor given for acute
coronary syndrome).
Discussion
We report for the first time of a common mild toxicity of
paclitaxel. In this prospective, observational study, a large
proportion of patients (51% of the patients) experienced
grade I epistaxis during paclitaxel chemotherapy.
Epistaxis was reported by 23 (59%) of 39 patients who
received weekly paclitaxel, as compared with 1 (12.5%) of
the 8 patients who received the drug every 3 weeks. This dif-
ference was statistically significant (P = 0.045). Admittedly,
the two groups were not balanced and differed in the
number of patients, type of malignancies and stages of the
disease (more patients in the every 3 weeks group had
advanced disease and received chemotherapy for palliation).
Episodes of epistaxis were frequent and recurred during
subsequent courses of the weekly regimen. All episodes were
mild and easily controllable by local pressure on the nostril.
They did not lead to any medical consequences and did not
affect the schedule of chemotherapy.
Five (21%) of 24 patients who had epistaxis during
therapy reported of episodes of epistaxis in the past, implicating
that past history of epistaxis might be predictive of epistaxis
with paclitaxel therapy. As shown in table 1, we could not
identify other parameters such as age, stage of disease or
platelet counts that were associated with increased likelihood
of epistaxis. It is interesting to note that metastatic disease
was not a risk factor for epistaxis in this trial, in spite of the
coagulopathy that often accompanies advanced cancer [5].
As shown, epistaxis during single agent paclitaxel was
mild. However, it is possible that when combining paclitaxel
with other drugs, epistaxis may become more severe and
clinically significant. In the last decade, targeted biological
medications came into routine use. Monoclonal antibodies
and tyrosine kinase inhibitors proved active in many types
of cancers and are now part of the standard treatments for
these diseases [6].
Antiangiogenic medications including bevacizumab, a
monoclonal antibody directed against vascular endothelial
growth factor, and sunitinib, a tyrosine kinase inhibitor, as
well as others, have been reported to cause epistaxis when given
as single agents [7]. A number of studies have shown that
low concentrations of paclitaxel had antiangiogenic activity
[8–10], which might explain the mechanism of epistaxis
during the weekly lower-dose regimen. The efficacy of targeted
biological agents was usually modest when given alone, and
improved when they were combined with chemotherapy [11].
As expected, combinations of biological drugs with chemo-
therapy increased toxicity as well. Recently, the combination
of bevacizumab and paclitaxel proved active in the treatment
of metastatic breast cancer [12]. Increased incidence of
haemorrhagic events was reported in that work but the sites
of bleeding were not specified. Since bevacizumab alone may
cause epistaxis in up to 20% [13] it is possible that the pacl-
itaxel/bevacizumab regimen might increase the frequency
and severity of epistaxis, which should be further investigated.
In conclusion, epistaxis is a common side-effect of paclit-
axel that has not been reported and studied before. It is
more frequently associated with weekly administration than
with an every 3 weeks schedule. Episodes of epistaxis are
mild and do not affect the course of therapy. Patients
presenting with this symptom should be reassured.
References
1 Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Mar-
com PK
et al
. Randomized phase III trial of weekly compared
with every-3-weeks Paclitaxel for metastatic breast cancer, with
Trastuzumab for all HER-2 overexpressors and random assign-
ment to Trastuzumab or not in HER-2 non overexpressors: final
results of Cancer and Leukemia Group B protocol 9840. J Clin
Oncol 2008;
26
:1642–9.
2 Lombardi D, Crivellari D, Scuderi C, Magri MD, Spazzapan S,
Sorio R
et al
. Long-term, weekly one-hour infusion Paclitaxel
in patients with metastatic breast cancer: a phase II monoinsti-
tutional study. Tumori 2004;
90
:285–8.
3 Green MC, Smith T, Nuhad KI, Valero V, Rosales MF, Booser
DJ
et al
. Weekly Paclitaxel improves pathologic complete remis-
sion in operable breast cancer when compared with Paclitaxel
once every 3 weeks. J Clin Oncol 2005;
23
:5983–92.
4 Loo WT, Fong JH, Cheung MN, Chow LW. The efficacy of
Paclitaxel on solid tumour analysed by ATP bioluminescence
assay and VEGF expression: a translational research study.
Biomed Pharmacother 2005;
59
:S337–9.
5 Patrocinio LG, Batista de Paula Silva J, Rodrigues Santos Junior J,
Antonio Patrocinio J. Severe epistaxis and thrombocytopathy in
oncology patient. Int Arch Otorhinolaringol 2005;
9
:235–8.
6 Press MF, Lenz HJ. EGFR, HER2 and VEGF pathways:
validated targets for cancer treatment. Drugs 2007;
67
:2045–75.

EPISTAXIS DURING TREATMENT WITH PACLITAXEL
261
© 2009 The Authors
Journal compilation
© 2009 Nordic Pharmacological Society.
Basic & Clinical Pharmacology & Toxicology
,
104
, 259–261
7 Morales JMCJ, Kreis H, Mourad G, Eris J, Schena FP, Grinyo
JM
et al
. Sirolimus-based therapy with or without
Cyclosporine: long-term follow-up in renal transplant patients.
Transplant Proc 2005;
37
:693–6.
8 Pasquier E, Honore S, Pourroy B, Jordan MA, Lehmann M,
Briand C
et al
. Antiangiogenic concentrations of Paclitaxel
induce an increase in microtubule dynamics in endothelial cells
but not in cancer cells. Cancer Res 2005;
65
:2433–40.
9 Pasquier E, Carre M, Pourroy B, Camoin L, Rebai O, Briand C
et al
. Antiangiogenic activity of Paclitaxel is associated with its
cytostatic effect, mediated by the initiation but not completion
of a mitochondrial apoptotic signaling pathway. Mol Cancer
Ther 2004;
3
:1301–10.
10 Belotti D, Vergani V, Drudis T, Borsotti P, Pitelli MR, Viale G
et al
. The microtubule-affecting drug Paclitaxel has antiangiogenic
activity. Clin Cancer Res 1996;
2
:1843–9.
12 Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez
EA
et al
. Paclitaxel plus Bevacizumab versus Paclitaxel alone
for metastatic breast cancer. N Engl J Med 2007;
357
:2666–76.
13 Mayer EL, Lin NU, Burstein HJ. Novel approaches to
advanced breast cancer: Bevacizumab and Lapatinib. J Natl
Compr Canc Netw 2007;
5
:314–23.