Carboplatin desensitization

1. Successful Carboplatin Desensitization in Patients
with Proven Carboplatin Allergy
Ronit Confino-Cohen, M.D.
1
Amiram Fishman, M.D.
2
Marco Altaras, M.D.
1
Arnon Goldberg, M.D.
1
1
The Allergy and Clinical Immunology Unit, Meir
General Hospital, Kfar Saba, affiliated with Sackler
School of Medicine, Tel-Aviv University Tel-Aviv,
Tel-Aviv, Israel.
2
Gynecologic Oncology Unit, Meir General Hospi-
tal, Kfar Saba, affiliated with Sackler School of
Medicine, Tel-Aviv University Tel-Aviv, Tel-Aviv,
Israel.
Address for reprints: Ronit Confino-Cohen, M.D.,
Allergy and Clinical Immunology Unit, Meir General
Hospital, 44281 Kfar Saba, Israel; Fax: (011) 972-
9-7472362; E-mail: ronitco@clalit.org.il
Received November 29, 2004; revision received
January 25, 2005; accepted February 11, 2005.
BACKGROUND. Carboplatin is one of the most useful and well tolerated cytotoxic
drugs for gynecologic malignancies. Hypersensitivity to carboplatin is not rare
among patients receiving multiple recurrent treatments with this drug. The aim of
the current study was to offer a safe and convenient carboplatin desensitization
strategy to patients with a proven allergic reaction to this drug.
METHODS. Patients with an immediate objective allergic reaction to carboplatin
were skin tested with the drug. A 6-hour carboplatin desensitization protocol was
administered to the patients with a carboplatin-positive skin test on each of the
following treatment courses.
RESULTS. Twenty-three patients with an allergic reaction to carboplatin and a
positive skin test were included in the current study. Twenty patients (86.9%) were
desensitized. One patient developed a mild urticarial rash. Nineteen patients
tolerated 80 desensitization courses uneventfully.
CONCLUSIONS. The data presented a successful desensitization protocol for indi-
viduals with a proven allergic reaction to carboplatin. The protocol was safe and
convenient and offered an effective therapeutic strategy to patients who required
this drug. Cancer 2005;104:640–3. © 2005 American Cancer Society.
KEYWORDS: carboplatin, hypersensitivity, allergy, carboplatin desensitization.
Carboplatin has been the mainstay chemotherapy of gynecologic
malignancies over the past decade. It is usually well tolerated,
easily administered, and associated with mild side effects.1
Neverthe-
less, with the extensive use of carboplatin, it has become evident that
recurrent courses of the drug expose patients to the risk of developing
hypersensitivity reactions.2–6
These reactions can be either mild cu-
taneus eruptions or more serious anaphylactic symptoms such as
hypotension, bronchospasm, and cardiovascular collapse.7
The cur-
rent data suggest that most of the reactions are immunologically
mediated. The symptoms tend to appear after four to six treatment
courses and persist in further treatments.7,8
Most of them occur
during or immediately after infusion of the drug. The symptoms,
which are anaphylactic in nature and the skin tests with carboplatin
that are usually positive, suggest an immediate immunoglobulin E
(IgE)mediated reaction. Different management approaches have
been suggested to solve this adverse reaction of carboplatin treat-
ment. They include avoiding use of the drug in future chemotherapy,
reintroducing carboplatin with premedication,8
and using a desensi-
tization protocol.9–12
We present a large group of patients with gyne-
cologic malignancies who have developed allergic reactions to carbo-
platin as manifested by the clinical symptoms and proved by a
positive skin test.As carboplatin was essential for these patients, they
underwent a desensitization protocol with carboplatin. Most patients
640
© 2005 American Cancer Society
DOI 10.1002/cncr.21168
Published online 23 June 2005 in Wiley InterScience (www.interscience.wiley.com).

2. tolerated it uneventfully and the drug could be admin-
istered thereafter, in the following treatment courses,
with the same protocol without any symptom of hy-
persensitivity.
MATERIALS AND METHODS
Patients
During the years 1996–2004, 228 patients with ovarian
carcinoma or primary peritoneal carcinoma and 26
patients with serous papillary carcinoma of the endo-
metrium were treated in the Gynecologic-Oncology
Unit, Meir General Hospital (Kfar-Saba, Israel) with
either carboplatin as a single agent or a carboplatin-
based combination chemotherapy regimen. Of the 228
patients with ovarian carcinoma, 112 had recurrence
of the disease. Fifty-seven of them received carbopla-
tin or carboplatin-based chemotherapy as second-line
chemotherapy.
Those who developed objective symptoms of hy-
persensitivity reaction during or immediately after the
infusion of carboplatin were further evaluated by skin
tests. If skin tests were positive, a desensitization pro-
tocol was offered for the subsequent treatment
courses.
Objective symptoms of hypersensitivity included
diffuse erythema, urticaria, angioedema, hypotension
(systolic pressure Ͻ 80 mm Hg), wheezing, and bron-
chospasm. Subjective symptoms of pruritus, shortness
of breath, abdominal pain, and general discomfort
were considered to be hypersensitivity symptoms only
if they were combined with at least 1 objective symp-
tom. Reactions were divided into two groups: mild,
and moderate to severe, according to recently pub-
lished grading.13
Mild reactions included all cutane-
ous reactions, not accompanied by symptoms affect-
ing other organ systems. Moderate to severe reactions
included reactions involving one or more body sys-
tem, with or without skin involvement. Eleven patients
developed delayed reactions (appearing Ͼ 3 hours
after the infusion). The reactions included mild
rashes, pruritus, abdominal pain, or discomfort. These
patients were not included in the current study.
Skin Tests
All suspected hypersensitive patients were skin tested
after informed consent was obtained. Intradermal skin
tests were performed with carboplatin at concentra-
tions of 0.1 and 1 mg/mL as previously described.9
Histamine and saline served as positive and negative
controls, respectively. Skin tests were read 20 minutes
after the intradermal injection. They were considered
positive if the wheal diameter was Ͼ 5 mm compared
with the negative control and had a surrounding flare.
Desensitization Protocol
A 6-hour desensitization protocol included 4 carboplatin
solutions. The first 3 infusion bags contained 1/1000,
1/100, and 1/10 of the total dose diluted in 150 mL of
D5W solution (Teva Medical, Ashdod, Israel). The last
bag contained the remainder of the undiluted drug dose.
Each dilution was delivered in drip infusion over 90
minutes, starting with the 1/1000 solution. The next
higher concentration was delivered immediately after
successful completion of the preceding infusion. Pa-
tients were premedicated with antiemetics (ondansetron
hydrochloride) and dexamethasone as indicated for rou-
tine carboplatin chemotherapy. The same protocol was
used in all future treatment courses with carboplatin.
RESULTS
Twenty-three patients treated with carboplatin for gy-
necologic malignancy were included in the current
study. Their median age was 54.8 years (range, 37–76
years). All had objective symptoms of a hypersensitiv-
ity reaction and demonstrated a positive skin test to
carboplatin. Eight patients (34.7%) had mild reactions
and 15 patients (65.2%) had moderate to severe reac-
tions involving Ն 2 organ systems (Table 1).
As demonstrated in Table 2, hypersensitivity reac-
tions appeared relatively late along the carboplatin
treatment (mean, 9 treatments; range, 2–17 treat-
ments). Seventeen (74%) patients developed their hy-
persensitivity reaction during the second or third line
of carboplatin treatments after 1 or 2 prolonged no-
treatment intervals while disease remission had been
achieved. There was no correlation between the sever-
ity of the initial hypersensitivity reaction and the num-
ber of the previous treatment courses or the number
of prolonged no-treatment intervals (data not shown).
TABLE 1
Clinical Characteristics of the Patients and the Adverse Reactions
Characteristics
No. of patients
(n ‫؍‬ 23) (%)
Mean age (yrs) (range) 54.8 (37–76)
Diagnosis
Ovarian carcinoma 15 (65.2)
Primary peritoneal carcinoma 6 (26.1)
Endometrial carcinoma 2 (8.7)
Hypersensitivity reaction
Milda
8 (34.7)
Moderate to severeb
15 (65.2)
a
Mild reactions included all cutaneous reactions not accompanied by symptoms of other body
systems.
b
Moderate to severe reactions included all reactions involving one or more organ systems, with or
without skin involvement.
Carboplatin Desensitization/Confino-Cohen et al. 641

3. Skin tests to carboplatin were positive in all pa-
tients.
After the initial reaction and skin testing, 20 (86.9%)
patients continued chemotherapy with carboplatin ac-
cording to the desensitization protocol (Table 3). For two
of three patients who were not desensitized, carboplatin
was discontinued due to progression of their malignancy
.One patient was lost to follow-up.
There was no difference in the severity of the
initial hypersensitivity reaction between the desensi-
tized and the women who were not treated.
Of 81 desensitization treatments, 80 were toler-
ated uneventfully. In one patient, the first desensiti-
zation treatment was discontinued because of mild
urticarial reaction and further carboplatin treatment
was not attempted.
Nineteen of 20 women (95%) tolerated well 80
desensitization treatments (mean, 4.05 desensitization
treatments per patient; range, 1–13 desensitization
treatments per patient). No reductions in the chemo-
therapy dose were required. No additional premedi-
cation was administered.
DISCUSSION
Carboplatin therapy is the standard treatment for
ovarian and other gynecologic malignancies. Although
the drug has a favorable safety profile, hypersensitivity
reactions to carboplatin are not rare.2–6
We showed
that in women with an apparent allergic reaction to
this drug and a positive skin test to carboplatin, read-
ministration of the drug with a desensitization proto-
col is safe. Moreover, with this strategy, multiple treat-
ments are feasible without allergic side effects.
Hypersensitivity is defined as an unexpected re-
action with signs and symptoms inconsistent with the
known toxicity of the drug. Previous reports on hyper-
sensitivity reactions included both immediate and de-
layed reactions, as well as various nonspecific clinical
presentations.7,8,10
A prerequisite for an immediate
immune-mediated reaction includes symptoms com-
patible with an allergic reaction, signs appearing dur-
ing or immediately after the administration of the
drug, and documented preexposure to the offending
drug. Indeed, all the adverse reactions in our study
fulfilled these criteria. Thus, all the reactions coin-
cided with administration of the drug and included
the typical symptoms of an allergic reaction. Preexpo-
sure to carboplatin was evident in all patients before
the adverse reaction to the drug. As previously de-
scribed,5,7,8,10
reactions to carboplatin tended to ap-
pear after a large number of treatment courses, usu-
ally after more than six treatment courses. Our group
of patients fits into this observation, with a mean
number of nine treatment courses before the first
adverse reaction. Our observations support the sus-
pected immunologic mechanism underling carbopla-
tin hypersensitivity in these patients. This is sup-
ported, in addition, by the finding that all patients had
a positive skin test to carboplatin. The skin test is an
accepted diagnostic tool when an immediate allergic
reaction is suspected.14
Carboplatin skin testing has
been used previously for the diagnosis and prediction
of hypersensitivity reactions to this drug.9,15,16
Mark-
man et al.16
showed that a negative test substantially
decreased the incidence of severe reactions. They also
suggested that this test be used as a method of pre-
dicting the risk of developing an adverse reaction be-
fore carboplatin treatment. Although the positive pre-
dictive value of a positive skin test to carboplatin has
not been defined, the combination of an immediate
adverse reaction together with a positive skin test is
highly indicative of an IgE-mediated reaction. Conse-
quently, two operative strategies should be consid-
ered: avoiding the use of carboplatin in the future or
using the desensitization protocol. The essential need
for carboplatin in these patients and previous success-
ful experience with different desensitization proto-
cols4,9–11
encouraged us to offer a desensitization pro-
tocol to our patients. Indeed, desensitization was well
tolerated by most (95%) of our patients. These results
are in agreement with previous publications, most of
TABLE 2
Timing and Severity of Carboplatin Hypersensitivity Reaction
No. of carboplatin courses before
the allergic reaction No. of patients (%)
Յ 5 5 (21.7)
Ͼ 6 18 (78.3)
Severity of the allergic reaction
Mean no. of carboplatin courses
before the allergic reaction
Mild 9.3
Moderate to severe 8.8
TABLE 3
Desensitization Protocol
Premedication:
Dexamethasone: 8–12 mg (i.v.) single dose immediately before the infusion of
carboplatin
Ondansetron hydrochloride: (i.v.) single dose immediately before the infusion of
carboplatin
Carboplatin—each solution diluted in 150 mL D5W
1/1000 of the total dose—in 150 mL D5W over 1.5 hrs. If tolerated:
1/100 of the total dose—in 150 mL D5W over 1.5 hrs. If tolerated:
1/10 of the total dose in—150 mL D5W over 1.5 hrs. If tolerated:
The remainder of the dose in—150 mL D5W over 1.5 hrs.
i.v.: intravenously; D5W: dextrose 5% in water.
642 CANCER August 1, 2005 / Volume 104 / Number 3

4. them including only case reports.3–5,17
Two studies
reported small groups of patients that were desensi-
tized successfully. Markman et al.11
reported success-
ful desensitization in four of five patients with either a
hypersensitivity reaction or a positive skin test to car-
boplatin. All patients were premedicated extensively
for 5 days before desensitization. Robinson et al.10
reported a high rate of success in desensitization to
different chemotherapy agents. Eight patients with
clinical carboplatin hypersensitivity were included in
that study. Four of them underwent intravenous de-
sensitization and tolerated further treatment courses
with the drug. An allergic reaction was not confirmed
by a skin test in that study. In contrast to these studies,
Choi et al.18
recently reported their experience with
desensitization in eight patients allergic to carbopla-
tin. In 2 patients, a 6-hour desensitization protocol
was attempted without success. Nevertheless, all pa-
tients tolerated uneventfully a longer infusion proto-
col.
The current study presents a large group of pa-
tients with a clinical allergic reaction to carboplatin
confirmed by a positive skin test. The majority of the
patients had moderate to severe reactions. The com-
mon attitude in such circumstances would have been
to withhold carboplatin treatment in these patients.
However, because carboplatin was an indispensable
treatment, the majority of these patients were desen-
sitized successfully and tolerated further treatments
thereafter. The protocol we used is simple and short
and does not require overnight hospitalization or ad-
ditional premedication.
To our knowledge, the current study is the first
large report of a successful desensitization protocol for
a large sample of individuals with a proven allergic
reaction to carboplatin. The data presented offer safe,
convenient, and effective therapeutic strategy to pa-
tients who need this drug.
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