Oxaliplatin (Eloxatin) is a thirdgeneration
compound complexed to
1,2-diaminocyclohexane in the trans-
R,R or L configuration with an oxalate
ligand as a leaving group. It
forms intra- and interstrand DNA
platinum adducts which inhibit DNA
synthesis, induce apoptosis, and inhibit
tumor cell growth and protein
synthesis.[1,2] Oxaliplatin has been
used as a single agent and in combination
with fluorouracil (5-FU) in
colorectal cancer.[3,4] It has also
shown activity in various other malignancies
such as advanced ovarian
carcinoma, astrocytoma, breast cancer,
non-Hodgkin's lymphoma, melanoma,
non-small-cell lung cancer, and head
and neck malignancies.[5-9] Oxaliplatin
is not cross-resistant with cisplatin
and carboplatin (Paraplatin) in
human ovarian cell lines, both in vitro
and in vivo.
The range of oxaliplatin toxicity varies
from acute reversible sensory symptoms
such as cold-sensitive dysesthesia
to cumulative peripheral neurotoxicity.
In general, oxaliplatin lacks nephrotoxicity
and is less myelotoxic than cisplatin
and carboplatin, making it an
ideal candidate for combination therapy.
The dose-limiting neurotoxicity is
reversible within a few months of discontinuation
of the drug.
There are few reports in the literature
describing oxaliplatin hypersensitivity,
unlike other platinum compounds such as cisplatin and carboplatin.[
12-15] The incidence of allergic
reactions to carboplatin and
cisplatin is approximately 5%. For
oxaliplatin, the incidence of severe
anaphylactic reaction is estimated to
be 0.5%, whereas the incidence of
other hypersensitivity reactions in
clinical practice is estimated to be 12%
to 13%.[13,14] These reactions are
often self-limited but, as discussed
below, may be unpredictable. They
are rarely life-threatening.
We conducted a retrospective analysis
of patients treated with oxaliplatin
for gastrointestinal malignancies at
Roswell Park Cancer Institute and here
report the incidence, clinical features,
and management of hypersensitivity
reactions in this group of patients. A
desensitization schedule used for one
patient who experienced life-threatening
hypersensitivity is also discussed.
Incidence and Management
The objective of this investigation
was to assess the incidence and management
of hypersensitivity reactions
to oxaliplatin. We reviewed all clinical
records, including charts, case
report forms, and chemotherapy infusion
notes of patients enrolled in two
clinical trials of oxaliplatin. These patients
were treated between January 1,
2000, and July 31, 2002. Institutional
review board approval was obtained
for this study.
All patients were treated with a
combination of oxaliplatin and 5-FU.
The first protocol consisted of oxaliplatin
followed by a 2-day schedule
of bolus 5-FU and infusional leucovorin/
5-FU (FOLFOX-4) for colorectal
cancer. The second protocol was
for esophageal cancer, consisting of
radiotherapy and infusional 5-FU
along with oxaliplatin. In each instance,
oxaliplatin was administered
over 2 hours and preceded by dexamethasone
(10 mg) and ondansetron
(Zofran, 8 mg).
A total of 169 patient records were
reviewed. Data regarding hypersensitivity
reactions to oxaliplatin were
obtained from the chemotherapy
records, clinic notes, and case report
forms. Cold-induced symptoms, including
layngospasm and neuropathy,
were excluded. The spectrum of symptoms
and signs related to hypersensitivity
is very broad, varying from mild
cutaneous inflammation to life-threatening
anaphylaxis. The following reactions were considered as probable
hypersensitivity reactions: skin rash,
flushing, pruritus, lacrimation, blurred
vision, wheezing, chest discomfort,
fever, chills, slurred speech, hypotension,
and anaphylactic shock.
Overview of Data
Among 169 patients, 32 experienced
one or more hypersensitivity
reactions to oxaliplatin. These data
are described in Table 1.
Five patients experienced more than
one reaction: Three developed fever
and rash, two had respiratory symptoms
including wheezing-one of these
patients also developed ocular irritation-
and the other developed skin
rash. Twenty-two patients developed
erythematous, macular skin rash, which
was the most common reaction. Skin
rash occurred after a median of three
infusions. Other skin reactions included
facial flushing, palmar erythema,
urticaria, and generalized pruritus.
Most of these skin reactions were selflimited
and treated successfully with
antihistamines and/or a single dose of
dexamethasone. In none of the cases
was oxaliplatin discontinued due to this
complication. Five of these 22 patients
had a recurrence of skin reaction with
subsequent infusions. However, the
type of skin reaction varied with subsequent
After a median of two cycles, five
patients developed febrile reactions
following oxaliplatin infusion. In all
of these cases, fever developed within
24 hours of infusion and infectious
etiology was ruled out. Fever (above
38oC) was treated with acetaminophen.
In one instance, the patient
was hospitalized and treated with intravenous
fluids. He defervesced within
24 hours. Oxaliplatin therapy was
continued in all five patients. One of
these patients experienced repeat episodes
of fever with two subsequent
infusions, which were treated with
Five patients experienced respiratory
symptoms, including wheezing,
shortness of breath, and chest tightness,
during oxaliplatin infusion.
These were treated with diphenhydramine
and dexamethasone. One patient
with underlying asthma and
another with fibrosis and pneumonia
experienced shortness of breath during
infusion. These events were not
included as hypersensitivity reactions,
because it was difficult to exclude the
underlying disease process as a cause
of these symptoms.
Two patients experienced ocular
symptoms; one had lacrimation following
oxaliplatin infusion and the
other reported blurring of vision. The
patient with lacrimation experienced
respiratory symptoms at the same
time. This patient received a subsequent
infusion of oxaliplatin over
6 hours without recurrence of symptoms.
The other patient refused further
One patient experienced an anaphylactic
reaction after his sixth infusion.
He developed swelling of the tongue
and face, shortness of breath, itching,
chills, and slurred speech. The patient
was treated with diphenhydramine,
meperidine, dexamethasone, and intravenous
fluids. Chemotherapy infusion
was stopped. He was treated with oral
dexamethasone and diphenhydramine
for the next 3 days, and his symptoms
resolved uneventfully. However, 2 weeks
later this patient was re-treated with
a regimen based on the carboplatin
desensitization protocol described earlier.[
19,20] Treatment with oxaliplatin
was administered in the intensive care
unit as four gradually escalating doses
over 10.5 hours as follows:
(1) 0.1% of the full dose administered
over 90 minutes preceded by
dexamethasone (8 mg), diphenhydramine
(50 mg), and famotidine
(20 mg) intravenously. These premedications
were repeated prior to each
of the following 3 infusions.
(2) 1% of the full dose infused over
(3) 10% of the full dose administered
over 90 minutes.
(4) Remainder of the full dose
(140 mg) administered over 6 hours.
The patient tolerated the above regimen
well and experienced no toxicity.
Subsequent oxaliplatin infusions were
administered in full dose (158 mg) over
6 hours, and the patient tolerated three
such infusions after undergoing desensitization.
diphenhydramine, and H2 blockers
were administered with each infusion.
However, during the fourth infusion
after desensitization-after receiving
one-fifth of the due dose-the patient
developed itchiness, rash, flushing, and
slurring of speech.
No subsequent oxaliplatin was administered
to this patient.
Hypersensitivity or anaphylactic
reactions are characterized by the
contraction of smooth muscles and
dilatation of capillaries due to the release
of biologically active amines as a
result of the reaction between antigens
and mast cell bound antibodies (eg,
immunoglobulin [Ig]E). These reactions
usually follow multiple doses,
indicating the need for repeated exposure
to antigen for eliciting the immune
response. Occurrence of these reactions
after initial exposure is consistent with
IgE-mediated type I hypersensitivity.
Idiosyncratic reactions are abnormal
reactions to a drug that are not antibody-
related, the onset of which may
be delayed instead of immediate.
Hypersensitivity reactions to platinum
compounds have been well documented.
Such reactions were reported
in platinum refinery workers as early
as 1945 and have been specifically
described for cisplatin and carboplatin.[
12-15,17] Newman Taylor et
al demonstrated that HLA phenotype
has an important role in sensitization
to inhaled haptens of complex platinum
salts, thus placing certain individuals
at higher risk.
Incidence of Hypersensitivity
Most reactions noted in our study
were suggestive of type I hypersensitivity.
Fever and respiratory symptoms
occurring hours after completion
of the infusion, however, suggest an
idiosyncratic effect and were also
noted in our study. It is currently believed
that most idiosyncratic reactions
are immune-mediated and
caused by immunogenic conjugates
formed from the reaction of a reactive
metabolite of a drug with cellular
proteins. Tumor necrosis
factor (TNF)-alpha and interleukin
(IL)-6 are elevated during these reactions.[
20] Oxaliplatin (behaving as a
hapten) has been associated with immunohemolytic
anemia inducing IgG
antibodies bound to red cell membrane,
which demonstrates its immunogenic
Brandi et al evaluated the incidence
of hypersensitivity reactions to oxaliplatin
and reported 17 hypersensitivity
reactions in 124 patients (13%
incidence), occurring after mean infusion
number 9.4 (range: 2-17). The
incidence of hypersensitivity reactions
in our study was 18.9%. The occurrence
of hypersensitivity was at median
infusion number 3 in our study. The
reason for early development of reactions
in our study is unclear. However,
individual case reports describe hypersensitivity
reactions during cycles
3 through 12.
These reactions were treated symptomatically
with antihistamines (H1
blockers) and antipyretics. If patients
developed hypersensitivity symptoms
during oxaliplatin infusion, they were
treated with intravenous diphenhydramine
and dexamethasone, and the
infusion was slowed or discontinued
depending upon the severity of the
reaction. If a reaction such as rash,
itching, or fever appeared later or at
home, patients were instructed to take
oral diphenhydramine and evaluated
in the outpatient clinic. These patients
were premedicated with antihistamines
for subsequent infusions.
Pulmonary symptoms such as
wheezing, shortness of breath, and
chest tightness were also noted in our
study. These symptoms are presumably due to bronchospasm. Uncommonly,
oxaliplatin can cause acute
lung injury as demonstrated by bronchoalveolar
lavage. This syndrome
resolved with steroid therapy.
The solitary severe anaphylactic
reaction observed in our study occurred
during the sixth infusion and
consisted of tongue swelling, slurring
of speech, chest tightness, and
hypotension. As the patient had not
experienced any previous allergic reactions,
we can postulate that this
event may have resulted from sensitization
during previous infusions.
This reaction may be IgE-mediated,
with the platinum compound behaving
as a hapten. A component of non-
histamine release may also have been
responsible: Platinum salts can release histamine directly from mast cells and
basophils. Desensitization strategies
have been employed when
continued administration of the offending
agent or allergen is deemed
The mechanism of desensitization
is not completely understood. It is
thought that when very dilute allergen
is administered, it stimulates the
production of IgG and IgA. These
immunoglobulins then act as blocking
antibodies to bind and neutralize
much of the allergen before it can
bind to the deeper cell-bound IgE on
the mast cells in the connective tissue.
The allergen also appears to suppress
production of IgE by inducing
tolerance and/or by activating T8-suppressor
We employed a strategy to "desensitize"
this patient, based on a desensitization
protocol employed for
However the patient developed a similar
reaction during the 10th infusion
(4th after desensitization).
Recurrence of hypersensitivity reactions
after desensitization has been
described with carboplatin. Rose et
al, reported their experience with carboplatin
desensitization in 33 patients
with documented hypersensitivity.[
26] Twenty-nine patients were successfully
rechallenged (88%), whereas
four developed recurrent symptoms
precluding further administration.
Three additional patients developed
symptom recurrence after two, three,
and six subsequent courses. Thus, 21%
of patients (7/33) developed recurrence
despite desensitization procedure.
This may have also been the
case with our patient and does not
necessarily reflect failure of the desensitization
Two case reports describe successful
results using a similar desensitization
protocol for oxaliplatin.[13,27]
Interestingly, all the patients in this
study were premedicated with dexamethasone
and ondansetron as a component
of a "standard antiemetic"
regimen prior to the oxaliplatin infusion.
Dexamethasone may have influenced
the severity and time course
of the hypersensitivity reactions observed.
As a result, we may have
missed minor reactions.
Reducing and Predicting
Measures to decrease hypersensitivity
reactions may include prolongation
of infusion time to 6 hours and
chronomodulation. When the infusion
of oxaliplatin is prolonged to 6 hours
or more, hypersensitivity reactions
decrease in incidence as seen in some
of our patients. Giacchetti et al reported
one hypersensitivity reaction
among 100 patients treated with a
6-hour oxaliplatin infusion.
Chronomodulation may also lead
to decreased hypersensitivity. It has
been shown that peak levels of histamine
and other mediators occur between
midnight and 4 AM, leading to
exacerbation of asthma during those
hours. Several trials employed the
concept of chronomodulation with
oxaliplatin, 5-FU, and leucovorin to
improve therapeutic efficacy in gastrointestinal
Fewer hypersensitivity reactions were
noted in these trials.[31,32]
Intradermal skin testing may help
determine hypersensitivity. Zanatti et
al described a skin-testing protocol
for carboplatin hypersensitivity.
Garufi et al studied 20 patients with
advanced colorectal carcinoma and
showed that an intradermal test could
be used to predict hypersensitivity to
Our study supports the conclusion
that hypersensitivity reactions secondary
to oxaliplatin are frequent despite
the routine use of dexamethasone.
Given that oxaliplatin is well established
in the treatment of gastrointestinal
and gynecologic malignancies,
we are likely to encounter more hypersensitivity
reactions in the future.
Our findings also demonstrate the benign
nature of most occurrences. Fatal
anaphylactic reactions are
uncommon; desensitization protocols
and methods to predict hypersensitivity
using skin testing need further investigation.
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