Japanese Journal of Clinical Oncology, 2015, 45(9) 795–804
doi: 10.1093/jjco/hyv081
Advance Access Publication Date: 7 June 2015
Review Article

Review Article

Platinum hypersensitivity and desensitization
Shingo Miyamoto1,*, Rika Okada2, and Kazumichi Ando3
1*For reprints and all correspondence: Shingo Miyamoto, Department of Medical Oncology, Japanese Red Cross Medical
Center, 4-1-22 Hiroo, Shibuya, Tokyo 150-8935, Japan. E-mail: aaa17580@pop06.odn.ne.jp
Received 21 February 2015; Accepted 3 May 2015

Abstract
Platinum agents are drugs used for various types of cancer. With increased frequency of administration of platinum agents, hypersensitivity reactions appear more frequently, occurring in over 25% ofcases from the seventh cycle or second line onward. It then becomes difficult to conduct treatmentusing these agents. Various approaches have been investigated to address hypersensitivity reactions
to platinum agents. Desensitization, which gradually increases the concentration of the anticancer
drug considered to be the antigen until the target dosage, has been reported as being particularly
effective, with a success rate of 80–100%. The aims of this paper are to present the current findings
regarding hypersensitivity reactions to platinum agents and to discuss attempts of using desensitization against hypersensitivity reactions worldwide.
Key words: platinum, hypersensitivity, desensitization

Introduction
Chemotherapy including platinum agents is effective against a large
number of cancers and is used widely. By forming crosslinks with
DNA bases within cancer cells, platinum agents act to inhibit DNA
replication; this leads to suppression of division and proliferation ofcancer cells, thus killing these cells.
Cisplatin, a first-generation platinum agent, is a non-natural compound that was serendipitously discovered during a work conductedby Rosenberg et al. (1). For its efficacy, it is recommended that treatment be discontinued after a maximum of six cycles when treating nonsmall cell lung cancer (2,3). On the other hand, some Phase 3 trials havebeen conducted using this agent for gastric cancer, in which it has been
administered continuously until progression (4,5), with a reported
median number of 4 cycles and a maximum of 11 cycles (4).
Carboplatin, a second-generation platinum agent, is administereddepending on kidney function because it can be administered to patients with reduced kidney function. Additionally, as it does not require large-volume transfusion, it can be administered to outpatientsand is used in place of cisplatin for the treatment of many types of cancer. In ovarian cancer, chemotherapy including carboplatin is used asa standard primary treatment. It has been reported that, in cases inwhich relapse occurs >6 months following this primary treatment, retreatment with carboplatin-containing chemotherapy yields favorable
results (6,7).
Oxaliplatin, a third-generation platinum agent, is an integral drug
used for colorectal cancer (8–11) and pancreatic cancer (12). It is administered either until treatment discontinuation due to toxicity or iscontinually administered until progression. One of the characteristicsof oxaliplatin that differentiates it from other platinum agents is an increased frequency of cold-sensitive dysesthesia and peripheral neuropathy, which may lead to discontinuation of treatment (10).
Clinicians occasionally encounter hypersensitivity reactions(HSRs) to platinum agents. Hypersensitivity to a chemotherapeutic
agent is defined as unexpected reactions that cannot be explainedby the known toxicity profile of the drug (13). It has been known
that, as the administration of platinum agents becomes more frequent, the incidence of HSRs will also increase (14). HSRs canlead to life-threatening conditions and thus require immediate treatment. Consequently, when patients have experienced HSRs, clinicians must choose, based on their consideration of the risk of
causing even more serious adverse reactions or anaphylaxis, whether
to continue with the same treatment or to suspend treatment and© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

795

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Department of Medical Oncology, Japanese Red Cross Medical Center, Shibuya, Tokyo, 2Department of Allergy andRheumatology, Japanese Red Cross Medical Center, Shibuya, Tokyo, and 3Department of Gynecology, Japanese Red
Cross Medical Center, Shibuya, Tokyo, Japan

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Platinum hypersensitivity and desensitization

Mechanism
Based on their mechanism of development, HSRs are classified intoeither allergic reactions, which involve an immunological mechanism,or non-allergenic cytokine release syndrome (21). Additionally, thetype of allergic reaction can be further classified into four categories(Table 1).
Allergic reactions and anaphylaxis are caused by an immunological mechanism and HSRs occur within a relatively short time of the administration of the drug. Such HSRs are of the ‘immediate type’ andare classified as Gell and Coombs Type I allergies (21,22). On theother hand, cytokine release syndrome occurs due to the binding of
the administered drug to circulating immune cells, such as monocytes
and macrophages, causing the release of cytokines (23).
Although the mechanism by which platinum agents cause HSRs
has not yet been clearly elucidated, they are generally reported as immediate Type I allergies (24). In Type I allergies, mast cells and basophils react via IgE and release chemical messengers such as histamine,leukotrienes and prostaglandins, which in turn cause a variety ofsymptoms. Among allergic reactions, those with the most severe andrapid onset and fatal large-scale or systemic reactions are called anaphylaxis. Although anaphylaxis is rare, its onset is life-threatening andnecessitates that careful attention and appropriate measures should betaken (25).
One reason why Type I reactions are believed to be closely involved in HSRs is that there exist reports stating that skin testing is effective in diagnosis and prediction of HSRs to platinum agents(19,26,27). Such methods include prick testing, where the skin is
pricked with a needle lightly enough such that bleeding does notoccur, and then, an antigen-containing fluid is applied at the pricksite. Another method is intradermal testing, where 0.02 ml of a diluted
antigen-containing fluid is injected into the skin. Some studies havebeen conducted using intradermal testing alone (26,27); however,other studies have been performed with the safer skin prick testing;these studies then used intradermal testing for the negative cases(19,28), with the latter approach being used in recent studies.
Markman et al. (26) reported skin testing as a useful method forpredicting HSRs, with anaphylaxis occurring in six of seven skin testpositive patients when retreated with carboplatin, resulting in a negative predictive value of 98.5%. Zanotti et al. (27) also reported that, ina study of 47 patients, those who were negative for the intradermal reaction had a reduced risk of developing HSRs to carboplatin and had
milder reactions even when HSRs did occur. However, it was foundthat the false-negative rate was ∼8% (26,29), indicating the limits ofthe test or the possibility that other mechanisms may contribute to
HSRs. At present, skin testing of anticancer drugs as sensitivity tests
in patients with no medical history of HSRs to platinum agents isthought to be unethical due to adverse events such as irritant reactions
and is not conducted routinely (30).
Rarely, case reports present the possibility that cytotoxic (Type II)
hypersensitivity and immune complex (Type III) hypersensitivity contribute to HSRs to platinum agents (15,31–34). Additionally, it has
been suggested that cisplatin and carboplatin also induce Type IV
hypersensitivity through delayed T-cell sensitization (14). Santini
et al. (35) reported that 20 min following the administration of oxaliplatin, cases with chills, stomach pain, diarrhea and fever showed increases in TNF-α and IL-6, suggesting that oxaliplatin may act like asuperantigen to stimulate the release of these cytokines. Similar findings have been reported in some other papers (36,37).
In other words, because the pathologies of HSRs to platinum
agents are not limited to Type I allergic reactions, clinicians must be

Table 1. Classification of allergic reactions (Gell and Coombs)
Type of HSRs

Antibody

AntigenMediators

Skin test

Symptoms

I

Immediate type

IgE

Exogenous antigen
e.g. house dust, pollen,
drug, mite

Immediate

Urticaria
Angioedema
Bronchospasm
Anaphylaxis

II

Cytotoxic type
Cytolytic type

IgG
IgM

III

Immune complex
type

IgG
IgM

Complement
Lysosomal enzyme

Delayed (h)IVDelayed type
Cellularimmunotype

Sensitized T
lymphocytes

Exogenous antigen (hapten)
e.g. drug
Cell- or matrix- associatedantigen
Exogenous antigen
e.g. drug, bacillus
Autoantigen
e.g. DNA
Exogenous antigen
e.g. bacillus, drug
Autoantigen

Histamines
Leukotrienes
Prostaglandins
Platelet activating
factor etc.
Complement

Cytokines

Delayed(days)

HSR, hypersensitivity reactions.

Hemolytic anemia
Thrombocytopenia
Goodpasture
syndrome
Serum sickness

Contact dermatitis

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to search for other treatment options, although it is possible thatchemotherapy with platinum agents is the only effective treatment
option. In recurrent ovarian cancer in particular, carboplatin is
associated with the ‘platinum-sensitivity relapse’ concept and oxaliplatin is used as the key drug for adjuvant therapy, first-line therapy
and second-line therapy for colorectal cancer. As continued readministration of these platinum agents contributes to prolonged
survival periods, clinicians contemplate rechallenge with these platinum agents.
Approaches to address HSRs include reducing the infusion rate(15), administering premedication (16), switching to a different platinum agent (17,18) and skin testing (19). However, in particular, desensitization is an effective method (20).
The aims of this paper are to present the current findings regarding
HSRs to platinum agents and to discuss attempts of using desensitization against HSRs worldwide.

Jpn J Clin Oncol, 2015, Vol. 45, No. 9
attentive to the possibility of a reaction occurring well after the administration of the agent (38–41).

797(56) reported that the median time to the onset was 70 min from starting administration, and Polyzos et al. (32) reported that more severe
HSRs occurred within 5–10 min from starting administration.

Incidence

Table 2. Incidence and severity of hypersensitivity to platinum drugs
Drug

Incidence(%)

SevereHSR
incidence(%)

Mediancycles ofinitialonset

Cisplatin

1–14

–

6

Carboplatin

1–44

2

8

Oxaliplatin

10–25

1.5–7

8

Incidence(%)<5 cycles>6 cycles<6 cycles>7 cycles
Front-line
Second-lineor higher

0
24
3.4
27
9
24

Risk factors
It is known that, in general, the incidence of HSRs to platinum agentsincreases as the number of administrations increases (21).
The reported risk factors for HSRs to carboplatin include age <70
years (61); a history of allergies to environmental stimuli or drugs(44,62); administration with carboplatin at 650 mg or more (63);and a long platinum-free interval (62–64). However, currently, studies
have not consistently identified any risk factors.
Recently, Moon et al. (65) reported a mutation in the tumor suppressor gene BRCA1/2 as a risk factor for HSRs. According to theirinvestigation, of 29 patients who either developed an HSR or had ahistory of HSRs, 27 had mutations in the BRCA gene, while of 31 patients with no mutations in the BRCA gene, only 2 patients developed
HSRs. Consequently, it is possible that genetic mutations have someeffect on the immune response.
Additionally, it has been reported that the combined use of liposomal doxorubicin and carboplatin is associated with a reduced HSR incidence rate when compared with combinations with paclitaxel(5.6 vs. 18.8%) and carboplatin alone (0 vs. 30%), which suggests
the possibility that liposomes have some impact on immune cells.
However, the underlying mechanism for this remains unclear (66,67).
Schwartz et al. (64) reported that the risk of a severe HSR to carboplatin was higher in the group in which the platinum-free interval
was 2 years or more than in the group in which the interval was lessthan a year (47 vs. 6.5%), although these results require further
verification.
Although there are a number of reports that have investigated therisk factors for the onset and severity of HSRs to oxaliplatin, as withcarboplatin, a clear theory remains to be established (56–58,68,69).
Kim et al. (56) suggested three risk factors for the onset of HSRs to
oxaliplatin, including young age, female gender and use of oxaliplatin
as a second-line or higher therapy. Female gender was also reported to
be a risk factor for HSRs in a multivariate analysis by Parel et al. (60).
Additionally, the total dose of oxaliplatin administered (57) andoxaliplatin-free interval (69) have been reported to be associatedwith HSRs, although further verification of these results is required.

Symptoms and treatment
The clinical manifestations of HSRs are both diverse and unpredictable. Cutaneous manifestations ( pruritus, urticaria, facial flushing,angioedema, palmar erythema, erythematous rush), fever and/or
shaking chills, gastrointestinal manifestations (abdominal pain,
diarrhea, nausea), respiratory manifestations (dyspnea, bronchospasm) and circulatory manifestations (heart rate and blood pressure
alterations) are generally found (13). However, cutaneous symptoms are found in 80–90% of patients with HSRs (25,70). Additionally, although most manifestations remain only mild to moderate,
there are reports of manifestations escalating into severe and fatal
manifestations (71).
The severity of symptoms is generally evaluated using the National
Cancer Institute Common Terminology Criteria for Adverse Events
v4.0 (Table 3).
Treatment of HSRs first involves early perception of changes in thepatient’s condition, and the administration of drugs is then ceased, andDownloaded from https://academic.oup.com/jjco/article-abstract/45/9/795/900229 by guest on 18 May 2020

Following the finding that immediate type hypersensitivity and asthma
were occurring in workers at platinum refinement plants who repeatedly inhale platinum-containing dust (42), HSRs due to the use of anticancer agents have been reported since the 1970s (43). The incidence
according to each agent is outlined in Table 2.
It is known that the HSR frequency increases with the number ofcarboplatin administrations (44,45). It has been reported that HSRs
occur in 1% of cases in which carboplatin is administered for fiveor fewer cycles (45), but they occur in as many as 27% of cases inwhich more than seven cycles are administered (44). Additionally, it
has been reported that HSRs occur in 44% of cases using secondand third-line therapies (46). In cases in which the clinician has ahigh probability of encountering HSRs, such as in ovarian cancer patients, it is expected that HSRs will be induced after retreatment with acarboplatin-containing regimen for relapses occurring after an intervalof 6 or more months from the completion of primary therapies thatincorporated carboplatin, hindering further treatment. Furthermore,
HSRs have been reported in intraperitoneal administrations as wellas transvenous administrations (47).
Similar to carboplatin, it is known that the HSR frequency increases with the number of cisplatin administrations (48,49); however,there are few reports of the frequency of HSRs, none of which are recent, with estimations ranging from 1 to 14% (50). Additionally, combination with radiation therapy increases the incidence of HSRs (51).
Gralla et al. (49) reported no HSRs with up to five cycles of therapy,
and yet, they reported that the incidence increased rapidly when thenumber of cycles reached six and above. However, there are few
cases of more than six cycles of cisplatin being used for many typesof cancer at present, and thus, HSRs may be encountered less frequently in cases of cisplatin administration.
When oxaliplatin was clinically adopted, the incidence of HSRs tothis agent was found to be very low at 0.55% (52). However, reportsof the HSR onset have increased with oxaliplatin use following thefinding that oxaliplatin is effective as adjuvant chemotherapy forcolon cancer as well as for unresectable or recurrent colon cancer,
with a reported recent incidence of 10–25% (32,53–60). Although
the majority of these were mild-to-moderate reactions, severe toxicity(Grade 3/4) cases occurred at a rate of ∼1.6–7.3%, and thus, caution is
warranted. The median number of administrations before the onset of
an HSR is ∼7–9, and similar to the other platinum agents, use of six ormore cycles has been found to increase the HSR incidence. Kim et al.

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Platinum hypersensitivity and desensitization

Table 3. National Cancer Institute—Common Terminology Criteria for Adverse Events v4.0 (CTCAE)
Adverse event

Grade
2

3

4

5

Allergic
reactionTransient flushing orrash, drug fever<38°C (<100.4°F);
intervention notindicated

Intervention or infusioninterruption indicated; responds
promptly to symptomatic
treatment (e.g. antihistamines,
NSAIDS, narcotics);
prophylactic medications
indicated for ≤24 h

Life-threatening
consequences; urgent
intervention indicatedDeath

Anaphylaxis––

Life-threatening
consequences; urgent
intervention indicatedDeath

Cytokinereleasesyndrome

Mild reaction; infusioninterruption notindicated;intervention notindicated

Therapy or infusion interruption
indicated but responds promptly
to symptomatic treatment (e.g.
antihistamines, NSAIDS,
narcotics, IV fluids);
prophylactic medications
indicated for ≤24 h

Prolonged (e.g. not rapidly
responsive to symptomatic
medication and/or brief
interruption of infusion);recurrence of symptoms following
initial improvement;
hospitalization indicated forclinical sequelae (e.g. renal
impairment, pulmonary
infiltrates)
Symptomatic bronchospasm, withor without urticaria; parenteralintervention indicated;allergy-related edema/angioedema; hypotension
Prolonged (e.g. not rapidly
responsive to symptomatic
medication and/or brief
interruption of infusion);recurrence of symptoms following
initial improvement;
hospitalization indicated forclinical sequelae (e.g. renal
impairment, pulmonary
infiltrates)

Life-threatening
consequences; pressor
or ventilatory support
indicated

Death

NSAIDS, non-steroidal anti-inflammatory drugs.

the infusion is then replaced with physiological saline. After a rapid
evaluation of the patient’s circulation, airway, breathing, state of consciousness and skin, oxygen is provided as required, and the venous
administration of antihistamines and glucocorticoids or the rapid administration of epinephrine is provided for anaphylaxis or other severecases (32). Antihistamines alleviate symptoms such as itching, urticaria and angioedema but have no life-saving effect (72). Glucocorticoids may also alleviate delayed reactions, but the therapeutic effects
occur after some hours, and these drugs also have no life-saving effect(72). Epinephrine is used as the primary treatment, particularly foranaphylaxis, and an intramuscular injection of 0.1% (0.01 mg/kg)
epinephrine (with a maximum of 0.5 mg for adults) is given immediately to the anterolateral side of the central thigh whenever there is adiagnosis or strong suspicion of anaphylaxis (73).
Although symptoms usually occur during or within a few hours ofadministration, the symptom onset can occur 1–2 days after administration in rare cases, and hence, it is critical to inform patients of thispossibility (22). Additionally, extra attention should be paid to anaphylaxis cases in which biphasic anaphylaxis may occur several
hours after cessation of treatment and resolution of symptoms (74).
The diagnosis of HSRs to platinum agents depends greatly on thepatient’s clinical course but is exceptionally difficult because ofmany confounding factors. First, patients receiving cancer therapy
are prescribed many drugs that can cause HSRs. Second, it is possible that the cancer itself acts directly on mast cells to produce similar symptoms to those of an HSR. Third, several epidemiologicalstudies have found that certain cancers have been shown to increase
the risk of allergies (75). Because platinum agents are invaluable
drugs in a number of cancers, and, unlike other drugs, they cannot
be easily replaced, clinicians must evaluate the clinical course of

HSRs very carefully to analyze the possible link to platinum agent
use. If possible, diagnosis may be made based on the results ofskin or challenge testing (76).
When the clinician judges that an HSR to a platinum agent has occurred, but the prospect of altering the current treatment is unlikely
because it has a firm basis and is effective, they must search for a treatment option that can be safely performed in cancer patients withallergy (75).

Desensitization
Since the report of desensitization to penicillin, the desensitization ofvarious agents has been studied (77,78). Desensitization is the process
in which the concentration of an anticancer drug acting as an antigen isincreased in a slow and step-wise manner to induce a temporary tolerization state toward the drug, until the target dose is reached. It is also a
useful approach for HSRs to platinum agents. No standardized protocol for desensitization has been established, and protocols differ byinstitution, with some even implementing it in outpatients (Table 4).
Although the mechanism of desensitization has not been fully
understood, one hypothesis states that the internalization of antigenspecific IgE plays an important role (79–81). This has been tested
through basic researches, and various in vitro and in vivo results
have been reported (82,83). High-affinity IgE receptors on the surfaceof mast cells and basophils (FcεRI) act as key inducers of allergic reactions. When re-exposed to the causative agent, drug-specific IgEs
bound to FcεRI bind to the drug and, through crosslinking of IgE, activate intracellular signaling to release chemical mediators such as histamine, leukotrienes, prostaglandins and cytokines in mast cells andDownloaded from https://academic.oup.com/jjco/article-abstract/45/9/795/900229 by guest on 18 May 2020

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Jpn J Clin Oncol, 2015, Vol. 45, No. 9799

Table 4. Main desensitization protocols for platinum hypersensitivity

Carboplatin

Premedication-dose-route

Steps

Duration

Completion rate

Confino-Cohen et al.
(107)

20

From 1:1000 to 1:1 infour steps

6h

95% of patients
99% of procedures

Hesterberg et al. (89)30

Nothing
Only antiemetics containing
dexamethasone
Fexofenadine 180 mg p.o. and/or
desloratadine 5 mg p.o.
Antiemetics containing
dexamethasone 10 mg p.o.

6.35 and 11 h

97% of patients
99% of procedures

Rose et al. (108)33

Skin testing negative
From 1:10 to 1:1 ineight steps
Skin testing positive
From 1:100 to 1:1 in
10 steps
From 1:1000 to 1:1 infour steps

16.5 h

79% of patients

Lee et al. (87)31

From 1:100 to 1:1 in
12 steps

5.8 h (inpatient)and 3.8 h (outpatient)

100% of patientsand procedures
85% without
symptoms

Castells et al. (70)60

From 1:100 to 1:1 in
12 steps

5.8 h100% of patientsand procedures
67% of procedures
without
symptoms

Takase et al. (88)20

From 1:1000 to 1:1 infour steps

4h

Lee et al. (92)38

Chlorpheniramin 20 mg i.v.
Hydrocortisone 100 mg i.v.

5.8 h or 8 h

Cortijo-Cascajares
et al. (91)21

Corticosteroids: 1 mg/kg/day;
Ranitidine: 300 mg/day;Cetirizine 20 mg/day;Montelukast: 10 mg/day the night
before and 30 min before
infusion

From 1:100 to 1:1 in
12 steps or from
1:10 000 to 1:1 5
steps
Total dose
administered in an
average of 14 steps

80% of patients
95% of procedures
81% of procedures
without
symptoms
89.5% of patients

Dexamethasone 20 mg p.o. or i.v.
6 h before
Dexamethasone 20 mg i.v. andDiphenhydramine 50 mg i.v.
30 min before
Diphenhydramine 25 mg i.v.
Famotidine 20 mg i.v. or ranitidine
50 mg i.v.
Lorazepam 1 mg (as needed foranxiety)
Diphenhydramine or hydroxyzine
25 mg p.o. or i.v.
Famotidine 20 mg i.v. or ranitidine
50 mg i.v.
Lorazepam 0.5–1 mg p.o. or i.v.
(as needed for anxiety)Dexamethasone 24 mg i.v.
ranitidine 50 mg i.v.
Diphenhydramine 50 mg p.o.

3–4 h

100%
89% of procedures
without
symptoms

i.v., intravenous; p.o., per orum.

basophils. These chemical mediators can induce vasodilation, bronchoconstriction and cardiac rate disturbances (84,85). In desensitization
therapy, increasing doses of the antigen are administered at fixed intervals. Using this procedure in mouse bone marrow-derived mast cells
sensitized to IgE specific to antigens such as dinitrophenyl and ovalbumin, the release of chemical mediators was suppressed (82). The production of cytokines related to delayed onset reactions, like IL-6, wasalso suppressed. This may explain why there are few reports of delayed
onset reactions in desensitization (82).
The most comprehensive study of desensitization is that conductedby Castells et al. (70), which reported rapid desensitization in 98 patients to various drugs over 12 stages. Among these subjects, 65 patients had ovarian cancer, and 59 were desensitized to carboplatin.
Three different concentrations of the solution were prepared and administered at four different infusion rates, with an administration timeof 15 min for each step, except for the final step. As a result, amongcases that underwent desensitization, HSRs occurred in 33% ofcases. Nonetheless, it was reported that most of these were mild

reactions and less severe than initial HSRs, and HSRs occurred in
51% of cases during the final step. Regarding the treatment of these
HSRs, one patient required epinephrine; however, all the cases completed the administration of carboplatin following recovery fromtheir HSRs through appropriate medical treatment.
Furthermore, the same group reported alleviation of symptoms in
12 of 14 patients who had HSRs during desensitization, and these patients were prescribed 325 mg of acetylsalicylic acid, a prostaglandin
blocker, and 10 mg of montelukast, a leukotriene blocker, both wereadministered 2 days prior to and on the day of desensitization. In 7 ofthese 12 patients, symptoms disappeared (86). Additionally, the groupon acetylsalicylic acid and montelukast showed a significant reduction
in symptoms compared with a historical control group using methylprednisolone as premedication (0.5 mg/kg intravenous).
Lee et al. (87) also conducted a 12-step rapid desensitization in
31 cases that had experienced moderate-to-severe HSRs to carboplatin. For safety, the first desensitization was performed in all the casesin an intensive care unit, followed by inpatient or outpatient care.

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Oxaliplatin

Patients

800

Platinum hypersensitivity and desensitizationsuggesting that rather than the number of administrations, the lengthof treatment may be important.
The approach for HSRs during desensitization is similar to the approach for HSRs in general; first, treatment is discontinued, and diphenhydramine or hydroxyzine is then administered. If a severereaction develops, oxygen and inhaled bronchodilators may be
given, and H2-blockers and glucocorticoids are administered intravenously. When necessary, epinephrine may also be considered (70). After
resolution of symptoms, while carefully verifying the safety, treatment
may be restarted from where the desensitization process was interrupted, with a reduced infusion rate or a reduced increment of dose.

Discussion
The time within which HSRs are likely to occur in chemotherapy depends on the drugs used. Although they may occur on the first administration of taxanes, reactions to platinum agents often occur on
readministration, and they are thus classified as the late onset (21).
On rare occasions, HSRs represent very serious adverse events thatcan lead to death (93).
Although careful consideration should be given to strategies to respond to HSRs, routine premedication with antihistamines and steroids before starting treatment for HSRs to platinum agents is widely
viewed in a negative light (53,94,95). Brandi et al. (53) reported that,even with premedication, five of six patients developed HSRs, and that
simple premedication alone is not a sufficient approach. It is also
worth considering switching to other platinum agents, and the efficacy
of switching to nedaplatin has also been reported in Japan (96,97).
However, this cannot be strongly recommended as methods of clinically investigating cross-reactivity between platinum agents are limited
and it is difficult to predict safety; most studies have been small-scale
and few have been prospective, and fatal cases have been reported(98,99). Skin testing may become false negative under the influenceof glucocorticoids to use in an antiemetic drug purpose of chemotherapy and induced as irritation when used extravascularly. Other problems include the risk of inducing anaphylaxis even when used at alow dose and the excessive exposure of medical staff to anticancer
drugs. Therefore, skin testing is by no means a requirement (100,101).
Although platinum agent cross-reactivity has been evaluated bymeans of skin testing and actual switching to other platinum agents,
it is difficult to perform skin testing in clinical care settings for the reasons listed above; therefore, the frequency of cross-reactivity has notbeen clarified (17,30). Although we cannot yet be used in everyday
clinical practice, the use of platin-specific IgE and basophil CD203c
has been investigated to predict and diagnose HSRs to platinum agents(30,102). Although investigations involved only small groups of patients with HSRs to platinum agents in combination with skin testingin these patients, the sensitivity of carboplatin-specific IgE was 58.3%
with a specificity of 100%, while both the sensitivity and specificity ofoxaliplatin-specific IgE were 75% (30). Interestingly, 67% of patientswith HSRs to oxaliplatin were also positive for carboplatin- andcisplatin-specific IgE despite not having been exposed to either ofthese. On the other hand, patients with HSRs to carboplatin but
without oxaliplatin exposure had a positive rate of 0% for oxaliplatinspecific IgE. The authors stated that oxaliplatin was more immunogenic, and that readily changing to other platinum agents in patients
who had HSRs to oxaliplatin should be avoided. CD203c is a specificsurface marker on basophils and mast cells and is known to be immediately upregulated on stimulation by an antigen. In an investigation
using the basophil surface marker CD203c, a sensitivity of ∼55%

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Administration to 13 outpatients of the 31 cases was made possible byreducing the amount of the solution and using a 3.8 h desensitization
protocol. Although HSRs occurred in 15% of the desensitized cases,
symptoms improved using, for example, antihistamines, and all cases
succeeded in reaching the target dose.
There are only few comprehensive reports from Japan, although
Takase et al. reported the use of a four-step, 4 h desensitization protocol in a group of 20 patients. They had a success rate of 80%, and its
implementation was comparatively safe, with only a single case experiencing a Grade 3 adverse event (88). The protocol was very simple andrapid, and with the assistance of an allergist, we have conducted similar desensitizations in hospitalized patients at our institution.
Hesterberg et al. (89) modified the desensitization protocol according to the results of skin testing. Interestingly, on investigating theimpact of the interval between the onset of initial HSRs and implementation of skin testing, they found that cases negative for the skin test
within 3 months of the HSR did not experience HSRs during rapid desensitization. However, of eight patients who had undergone the skintest 9 months after initial HSRs, five showed resensitization during theinitial rapid desensitization and tested positive before the second administration, and, even with long-term desensitization protocols,
HSRs were found in four cases. By including this skin testing, they concluded that patients who had a long interval between the initial HSR
and skin testing and who were converted from a negative to a positive
result were at an increased risk of HSRs during the desensitization
protocol. On investigating the reproducibility of the above results,
52% of patients who underwent skin testing converted from negative
to positive results, and, in 92% of these ‘converters,’ 6 or more months
had elapsed between their first HSR and skin testing (28). Additionally,
the frequency of HSRs in the skin testing converter group was also increased, and they suggested that repeated skin testing was important incases in which considerable time elapsed since their initial HSR.
O’Cearbhaill et al. conducted preventative desensitization over 3 h
in 174 patients undergoing the administration of carboplatin for morethan eight cycles. This desensitization involved premedication on the
day prior to treatment, and on the day of treatment, 1% of the total
infusion was administered over 1 h, and then, 9% of the infusion was
administered over another hour, with the rest being administered over
the third hour (90). Although this was a retrospective investigation,
they reported that the 3 h desensitization group had a clear reductionin the incidence of HSRs when compared with the incidence of thegroup undergoing standard treatment (3.4 vs. 21%), and the mediantime until the onset of HSRs was increased (16 cycles vs. 9 cycles).
Thus, it seems that these types of simple, preventative desensitizations
are also worth considering.
There have been few investigations of desensitization to oxaliplatin; however, many of these have a small number of cases. Reports
with 20 or more cases are shown in Table 4 (91,92).
Lee et al. (92) conducted a retrospective analysis of the results of
152 patients who had experienced HSRs to oxaliplatin and undergone
a premedication protocol with 20 mg of chlorpheniramine and100 mg of hydrocortisone given 1 h before administration and/or desensitization. The success rate of premedication alone in patients who
had severe HSRs was only 22.7%, and this is difficult to endorse.
However, the success rate reached 86% when desensitization was conducted, and it is recommended to perform desensitization from initialadministration in patients who experienced severe HSRs. Even moreinterestingly, XELOX regimen with a 3 week interval was found tohave a greater number of administrations before the onset of an initial
HSR than FOLFOX regimen with a 2 week interval. However, the actual time from the start of treatment to the onset remained the same,

Jpn J Clin Oncol, 2015, Vol. 45, No. 9

Conclusion
When retreating after encountering an HSR, clinicians should act after
thorough consideration of the risk of additional adverse events as well
as of the efficacy of platinum agents in chemotherapy. Additionally, it
is important to adequately explain the situation to patients who will
undergo retreatment.
If conducted by medical teams, desensitization is a safe and effective method. The overall survival and quality of life of patients with
HSRs to platinum agents can be improved through cooperative

medical practice by teams consisting of not only an oncologist but
also an allergist and other experienced medical staff.

Conflict of interest statement
None declared.

References
1. Rosenberg B, Vancamp L, Krigas T. Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode. Nature
1965;205:698–9.
2. Park JO, Kim SW, Ahn JS, Suh C, Lee JS, Jang JS, et al. Phase III trial of
two versus four additional cycles in patients who are nonprogressive after
two cycles of platinum-based chemotherapy in non small-cell lung cancer.
J Clin Oncol 2007;25:5233–9.
3. Smith IE, O’Brien ME, Talbot DC, Nicolson MC, Mansi JL, Hickish TF,
et al. Duration of chemotherapy in advanced non-small-cell lung cancer: arandomized trial of three versus six courses of mitomycin, vinblastine, andcisplatin. J Clin Oncol 2001;19:1336–43.
4. Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, et al.
S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol 2008;9:215–21.
5. Boku N, Yamamoto S, Fukuda H, Shirao K, Doi T, Sawaki A, et al. Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study. Lancet Oncol 2009;10:1063–69.
6. Parmar MK, Ledermann JA, Colombo N, du Bois A, Delaloye JF,
Kristensen GB, et al. Paclitaxel plus platinum-based chemotherapy versus
conventional platinum-based chemotherapy in women with relapsed
ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet 2003;361:
2099–106.
7. Pfisterer J, Vergote I, Du Bois A, Eisenhauer E; AGO-OVAR; NCIC CTG,
et al. Combination therapy with gemcitabine and carboplatin in recurrent
ovarian cancer. Int J Gynecol Cancer 2005;15:36–41.
8. André T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, et al.
Improved overall survival with oxaliplatin, fluorouracil, and leucovorin
as adjuvant treatment in stage II or III colon cancer in the MOSAIC
trial. J Clin Oncol 2009;27:3109–16.
9. Allegra CJ, Yothers G, O’Connell MJ, Sharif S, Petrelli NJ, Colangelo LH,
et al. Phase III trial assessing bevacizumab in stages II and III carcinoma of
the colon: results of NSABP protocol C-08. J Clin Oncol 2011;29:11–6.
10. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J,
et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line
treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938–47.
11. Rothenberg ML, Oza AM, Bigelow RH, Berlin JD, Marshall JL,
Ramanathan RK, et al. Superiority of oxaliplatin and fluorouracil–leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil–leucovorin: interim resultsof a phase III trial. J Clin Oncol 2003;21:2059–69.
12. Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y,
et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.
N Engl J Med 2011;364:1817–25.
13. Shepherd GM. Hypersensitivity reactions to chemotherapeutic drugs. Clin
Rev Allergy Immunol 2003;24:253–62.
14. Makrilia N, Syrigou E, Kaklamanos I, Manolopoulos L, Saif MW. Hypersensitivity reactions associated with platinum antineoplastic agents: a systematic review. Met Based Drugs 2010;2010:207084.
15. Maindrault-Goebel F, André T, Tournigand C, Louvet C, Perez-Staub N,
Zeghib N, et al. Allergic-type reactions to oxaliplatin: retrospective analysis of 42 patients. Eur J Cancer 2005;41:2262–67.
16. Kidera Y, Satoh T, Ueda S, Okamoto W, Okamoto I, Fumita S, et al. Highdose dexamethasone plus antihistamine prevents colorectal cancer
patients treated with modified FOLFOX6 from hypersensitivity reactions
induced by oxaliplatin. Int J Clin Oncol 2011;16:244–9.

Downloaded from https://academic.oup.com/jjco/article-abstract/45/9/795/900229 by guest on 18 May 2020

and a specificity of ∼90% have been reported (103). Although it is too
early to determine whether these results are sufficient for clinical use,further progress and development of these tests are anticipated in the
future.
Desensitization involves the induction of a state of temporary tolerance by continuous exposure to an agent. However, if exposure toan agent is once lost, this tolerance is also lost. Consequently, the patient must undergo desensitization each time (104). Dependence ontime and concentration desensitization appears to be key factors for
successful desensitization (105). Although one approach for HSRs
during desensitization involves reducing the infusion rate and using
a low-gradient concentration change, this increases the infusion
time. Such lengthy infusion times on each administration increases
the time in which patients and medical staff are under stress, resulting
in exhaustion. The search for an appropriate desensitization protocol
should be conducted daily and necessitates high-quality, positive
experimentation.
Nonetheless, a number of problems remain. HSRs are truly diverse, and patients with HSRs exhibit cutaneous, gastrointestinal, respiratory and circulatory symptoms, which make some cases difficult
to diagnose. Additionally, a diagnosis of HSRs to platinum agents isbased on clinical course and medical interviews to obtain information
regarding any exposure and event up to the time of the onset.
However, due to confounding factors such as the effects of advanced
age and cranial irradiation on cognitive function and the effects ofcombination with other agents, there are cases in which it is difficult
to make a diagnosis (75,106). Patil et al. (28) stated that, of 39 patients
who were previously diagnosed as having HSRs to carboplatin basedon the clinical course but were found to be negative in repeated skintestings, 11 (28%) had almost no HSRs during treatment conductedwithout any desensitization. In other words, it is possible that a certain
proportion of patients have had their treatments changed or been desensitized after HSRs, or conditions mimicking HSRs have occurredfrom some unknown origin. It is therefore necessary to investigate
diagnostic criteria using tools other than a patient’s clinical course
to extract patients with a true HSR to platinum agents.
Additionally, the standards for discontinuing and restarting desensitization following recovery via appropriate treatment of HSRs during desensitization and standards for the protocol for restarting
treatment (the infusion rate and concentration) are both required(88). If these standards are entrusted to each clinician, it will likely
cause large fluctuations in the completion rate that can be an endpointof the desensitization protocol. Although Castells et al. (70) restarted
treatment even in patients showing severe reactions during desensitization, it is generally appropriate to discontinue treatment for Grade 3
allergic reactions and anaphylaxis. Investigation of infusion times isalso necessary. If the frequent of HSRs necessarily causes longer infusion times while using the rapid desensitization protocol, then this may
weaken the significance of the rapidity and safety of such approaches.

801

802

Platinum hypersensitivity and desensitization
40. Leguy-Seguin V, Jolimoy G, Coudert B, Pernot C, Dalac S, Vabres P, et al.
Diagnostic and predictive value of skin testing in platinum salt hypersensitivity. J Allergy Clin Immunol 2007;119:726–30.
41. Ichikawa Y, Goto A, Hirokawa S, Kijima M, Ishikawa T, Chishima T,
et al. Allergic reactions to oxaliplatin in a single institute in Japan. Jpn J
Clin Oncol 2009;39:616–20.
42. Cleare MJ, Hughes EG, Jacoby B, Pepys J. Immediate (type I) allergic
responses to platinum compounds. Clin Allergy 1976;6:183–95.
43. Williams CJ, Whitehouse JM. Cis-platinum: a new anticancer agent. Br
Med J 1979;1:1689–91.
44. Markman M, Kennedy A, Webster K, Elson P, Peterson G, Kulp B, et al.
Clinical features of hypersensitivity reactions to carboplatin. J Clin Oncol
1999;17:1141–5.
45. Sliesoraitis S, Chikhale PJ. Carboplatin hypersensitivity. Int J Gynecol
Cancer 2005;15:13–8.
46. Morgan JS, Adams M, Mason MD. Hypersensitivity reactions to carboplatin given to patients with relapsed ovarian carcinoma. Eur J Cancer
1994;30A:1205–6.
47. Shukunami K, Kurokawa T, Kawakami Y, Kubo M, Kotsuji F. Hypersensitivity reactions to intraperitoneal administration of carboplatinin ovarian cancer: the first report of a case. Gynecol Oncol 1999;72:
431–2.
48. Robinson JB, Singh D, Bodurka-Bevers DC, Wharton JT,
Gershenson DM, Wolf JK. Hypersensitivity reactions and the utility oforal and intravenous desensitization in patients with gynecologic malignancies. Gynecol Oncol 2001;82:550–8.
49. Gralla RJ, Casper ES, Kelsen DP, Braun DW Jr, Dukeman ME, Martini N,
et al. Cisplatin and vindesine combination chemotherapy for advanced
carcinoma of the lung: a randomized trial investigating two dosage schedules. Ann Intern Med 1981;95:414–20.
50. Cheng E, Cvitkovic E, Wittes RE, Golbey RB. Germ cell tumors (II): VAB
II in metastatic testicular cancer. Cancer 1978;42:2162–8.
51. Koren C, Yerushalmi R, Katz A, Malik H, Sulkes A, Fenig E. Hypersensitivity reaction to cisplatin during chemoradiation therapy for gynecologic
malignancy. Am J Clin Oncol 2002;25:625–6.
52. Thomas RR, Quinn MG, Schuler B, Grem JL. Hypersensitivity and idiosyncratic reactions to oxaliplatin. Cancer 2003;97:2301–7.
53. Brandi G, Pantaleo MA, Galli C, Falcone A, Antonuzzo A, Mordenti P,
et al. Hypersensitivity reactions related to oxaliplatin (OHP). Br J
Cancer 2003;89:477–81.
54. André T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J,
Hickish T, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant
treatment for colon cancer. N Engl J Med 2004;350:2343–51.
55. Siu SW, Chan RT, Au GK. Hypersensitivity reactions to oxaliplatin: experience in a single institute. Ann Oncol 2006;17:259–61.
56. Kim BH, Bradley T, Tai J, Budman DR. Hypersensitivity to oxaliplatin: aninvestigation of incidence and risk factors, and literature review. Oncology
2009;76:231–8.
57. Shao YY, Hu FC, Liang JT, Chiu WT, Cheng AL, Yang CH. Characteristics and risk factors of oxaliplatin-related hypersensitivity reactions.
J Formos Med Assoc 2010;109:362–8.
58. Kim MY, Kang SY, Lee SY, Yang MS, Kim MH, Song WJ, et al.
Hypersensitivity reactions to oxaliplatin: clinical features and risk factors
in Koreans. Asian Pac J Cancer Prev 2012;13:1209–15.
59. Seki K, Senzaki K, Tsuduki Y, Ioroi T, Fujii M, Yamauchi H, et al.
Risk factors for oxaliplatin-induced hypersensitivity reactions inJapanese patients with advanced colorectal cancer. Int J Med Sci
2011;8:210–5.
60. Parel M, Ranchon F, Nosbaum A, You B, Vantard N, Schwiertz V, et al.
Hypersensitivity to oxaliplatin: clinical features and risk factors. BMC
Pharmacol Toxicol 2014;15:1.
61. Joly F, Ray-Coquard I, Fabbro M, Donoghoe M, Boman K, Sugimoto A,
et al. Decreased hypersensitivity reactions with carboplatin-pegylated
liposomal doxorubicin compared to carboplatin–paclitaxel combination:
analysis from the GCIG CALYPSO relapsing ovarian cancer trial. Gynecol
Oncol 2011;122:226–32.

Downloaded from https://academic.oup.com/jjco/article-abstract/45/9/795/900229 by guest on 18 May 2020

17. Callahan MB, Lachance JA, Stone RL, Kelsey J, Rice LW, Jazaeri AA. Useof cisplatin without desensitization after carboplatin hypersensitivity reaction in epithelial ovarian and primary peritoneal cancer. Am J Obstet
Gynecol 2007;197:199.
18. Kandel MJ, Loehr A, Harter P, Traut A, Gnauert K, du Bois A. Cisplatinum rechallenge in relapsed ovarian cancer patients with platinum reinduction therapy and carboplatin hypersensitivity. Int J Gynecol Cancer
2005;15:780–4.
19. Pagani M, Bonadonna P, Senna GE, Antico A. Standardization of skintests for diagnosis and prevention of hypersensitivity reactions to oxaliplatin. Int Arch Allergy Immunol 2008;145:54–7.
20. Castells M. Rapid desensitization for hypersensitivity reactions to chemotherapy agents. Curr Opin Allergy Clin Immunol 2006;6:271–7.
21. Lenz HJ. Management and preparedness for infusion and hypersensitivity
reactions. Oncologist 2007;12:601–9.
22. Zanotti KM, Markman M. Prevention and management of antineoplastic-induced hypersensitivity reactions. Drug Saf 2001;24:767–79.
23. Dillman RO, Hendrix CS. Unique aspects of supportive care using monoclonal antibodies in cancer treatment. Support Cancer Ther 2003;1:38–48.
24. Caiado J, Picard M. Diagnostic tools for hypersensitivity to platinum
drugs and taxanes: skin testing, specific IgE, and mast cell/basophil mediators. Curr Allergy Asthma Rep 2014;14:451.
25. Simons FE, Ardusso LR, Bilò MB, El-Gamal YM, Ledford DK, Ring J,
et al. World allergy organization guidelines for the assessment and management of anaphylaxis. World Allergy Organ J 2011;4:13–37.
26. Markman M, Zanotti K, Peterson G, Kulp B, Webster K, Belinson J. Expanded experience with an intradermal skin test to predict for the presenceor absence of carboplatin hypersensitivity. J Clin Oncol 2003;21:4611–4.
27. Zanotti KM, Rybicki LA, Kennedy AW, Belinson JL, Webster KD, Kulp B,
et al. Carboplatin skin testing: a skin-testing protocol for predicting hypersensitivity to carboplatin chemotherapy. J Clin Oncol 2001;19:3126–9.
28. Patil SU, Long AA, Ling M, Wilson MT, Hesterberg P, Wong JT, et al. A
protocol for risk stratification of patients with carboplatin-induced hypersensitivity reactions. J Allergy Clin Immunol 2012;129:443–7.
29. Gomez R, Harter P, Lück HJ, Traut A, Kommoss S, Kandel M, et al. Carboplatin hypersensitivity: does introduction of skin test and desensitization reliably predict and avoid the problem? A prospective single-center
study. Int J Gynecol Cancer 2009;19:1284–7.
30. Caiado J, Venemalm L, Pereira-Santos MC, Costa L, Barbosa MP,
Castells M. Carboplatin-, oxaliplatin-, and cisplatin-specific IgE: crossreactivity and value in the diagnosis of carboplatin and oxaliplatin allergy.
J Allergy Clin Immunol Pract 2013;1:494–500.
31. Garufi C, Vaglio S, Brienza S, Conti L, D’Attino RM, Girelli G, et al. Immunohemolytic anemia following oxaliplatin administration. Ann Oncol
2000;11:497.
32. Polyzos A, Tsavaris N, Gogas H, Souglakos J, Vambakas L, Vardakas N,
et al. Clinical features of hypersensitivity reactions to oxaliplatin: a
10-year experience. Oncology 2009;76:36–41.
33. Getaz EP, Beckley S, Fitzpatrick J, Dozier A. Cisplatin-induced hemolysis.
N Engl J Med 1980;302:334–5.
34. Marani TM, Trich MB, Armstrong KS, Ness PM, Smith J, Minniti C, et al.
Carboplatin-induced immune hemolytic anemia. Transfusion 1996;36:
1016–8.
35. Santini D, Tonini G, Salerno A, Vincenzi B, Patti G, BBrandiattistoni F,
et al. Idiosyncratic reaction after oxaliplatin infusion. Ann Oncol 2001;12:
132–3.
36. Tonini G, Santini D, Vincenzi B, Borzomati D, Dicuonzo G, La Cesa A,
et al. Oxaliplatin may induce cytokine-release syndrome in colorectal cancer patients. J Biol Regul Homeost Agents 2002;16:105–9.
37. Ulrich-Pur H, Penz M, Fiebiger WC, Schüll B, Kornek GV, Scheithauer W,
et al. Oxaliplatin-induced fever and release of IL-6. Oncology 2000;59:
187–9.
38. de Vries RS, Mattijssen EJ, van Sorge AA. Serious delayed hypersensitivity
reaction to oxaliplatin. Ann Oncol 2006;17:1723–4.
39. Masse MS, Caimmi D, Demoly P. A delayed reaction to oxaliplatin.
J Invetig Allergol Clin Immunol 2012;22:372–3.

Jpn J Clin Oncol, 2015, Vol. 45, No. 9

81. Shalit M, Levi-Schaffer F. Challenge of mast cells with increasing
amounts of antigen induces desensitization. Clin Exp Allergy 1995;
25:896–902.
82. Sancho-Serra Mdel C, Simarro M, Castells M. Rapid IgE desensitization isantigen specific and impairs early and late mast cell responses targeting
FcεRI internalization. Eur J Immunol 2011;41:1004–13.
83. Oka T, Rios EJ, Tsai M, Kalesnikoff J, Galli SJ. Rapid desensitization induces internalization of antigen-specific IgE on mouse mast cells. J Allergy
Clin Immunol 2013;132:922–32.
84. Metcalfe DD, Baram D, Mekori YA. Mast cells. Physiol Rev 1997;
77:1033–79.
85. Galli SJ, Tsai M. IgE and mast cells in allergic disease. Nat Med
2012;18:693–704.
86. Breslow RG, Caiado J, Castells MC. Acetylsalicylic acid and montelukast
block mast cell mediator-related symptoms during rapid desensitization.
Ann Allergy Asthma Immunol 2009;102:155–60.
87. Lee CW, Matulonis UA, Castells MC. Rapid inpatient/outpatient desensitization for chemotherapy hypersensitivity: standard protocol effective in
57 patients for 255 courses. Gynecol Oncol 2005;99:393–9.
88. Takase N, Matsumoto K, Onoe T, Kitao A, Tanioka M, Kikukawa Y,
et al. 4-step 4-h carboplatin desensitization protocol for patients withgynecological malignancies showing platinum hypersensitivity: a retrospective study. Int J Clin Oncol 2014 (epub ahead of print).
89. Hesterberg PE, Banerji A, Oren E, Penson RT, Krasner CN, Seiden MV,
et al. Risk stratification for desensitization of patients with carboplatin
hypersensitivity: clinical presentation and management. J Allergy Clin
Immunol 2009;123:1262–7.
90. O’Cearbhaill R, Zhou Q, Iasonos A, Hensley ML, Tew WP,
Aghajanian C, et al. The prophylactic conversion to an extended infusion
schedule and use of premedication to prevent hypersensitivity reactions in
ovarian cancer patients during carboplatin retreatment. Gynecol Oncol
2010;116:326–31.
91. Cortijo-Cascajares S, Nacle-López I, García-Escobar I, AguilellaVizcaíno MJ, Herreros-de-Tejada A, Cortés-Funes Castro H, et al. Effectiveness of oxaliplatin desensitization protocols. Clin Transl Oncol
2013;15:219–25.
92. Lee SY, Kang HR, Song WJ, Lee KH, Han SW, Cho SH. Overcoming oxaliplatin hypersensitivity: different strategies are needed according to theseverity and previous exposure. Cancer Chemother Pharmacol 2014;
73:1021–29.
93. Boulanger J, Boursiquot JN, Cournoyer G, Lemieux J, Masse MS,
Almanric K, et al. Management of hypersensitivity to platinum- andtaxane-based chemotherapy: cepo review and clinical recommendations.
Curr Oncol 2014;21:630–41.
94. Syrigou E, Triantafyllou O, Makrilia N, Kaklamanos I, Kotanidou A,
Manolopoulos L, et al. Acute hypersensitivity reactions to chemotherapy agents: an overview. Inflamm Allergy Drug Targets 2010;9:
206–13.
95. Polyzos A, Tsavaris N, Kosmas C, Arnaouti T, Kalahanis N, Tsigris C,
et al. Hypersensitivity reactions to carboplatin administration are common but not always severe: a 10-year experience. Oncology 2001;61:
129–33.
96. Arimoto T, Oda K, Nakagawa S, Kawana K, Tsukazaki T, Adachi K, et al.
Retreatment with nedaplatin in patients with recurrent gynecological cancer after the development of hypersensitivity reaction to carboplatin.
J Obstet Gynaecol Res 2013;39:336–40.
97. Michikami H, Minaguchi T, Ochi H, Onuki M, Okada S, Matsumoto K,
et al. Safety and efficacy of substituting nedaplatin after carboplatin hypersensitivity reactions in gynecologic malignancies. J Obstet Gynaecol Res
2013;39:330–5.
98. Zweizig S, Roman LD, Muderspach LI. Death from anaphylaxis to cisplatin: a case report. Gynecol Oncol 1994;53:121–2.
99. Dizon DS, Sabbatini PJ, Aghajanian C, Hensley ML, Spriggs DR. Analysis
of patients with epithelial ovarian cancer or fallopian tube carcinoma retreated with cisplatin after the development of a carboplatin allergy.
Gynecol Oncol 2002;84:378–82.

Downloaded from https://academic.oup.com/jjco/article-abstract/45/9/795/900229 by guest on 18 May 2020

62. Gadducci A, Tana R, Teti G, Zanca G, Fanucchi A, Genazzani AR. Analysis of the pattern of hypersensitivity reactions in patients receiving carboplatin retreatment for recurrent ovarian cancer. Int J Gynecol Cancer
2008;18:615–20.
63. Sugimoto H, Iwamoto T, Murashima Y, Tabata T, Sagawa N, Okuda M.
Risk factors contributing to the development of carboplatin-related delayed hypersensitivity reactions in Japanese patients with gynecologic cancers. Cancer Chemother Pharmacol 2011;67:415–19.
64. Schwartz JR, Bandera C, Bradley A, Brard L, Legare R, Granai CO, et al.
Does the platinum-free interval predict the incidence or severity of hypersensitivity reactions to carboplatin? The experience from Women and Infants’ Hospital. Gynecol Oncol 2007;105:81–3.
65. Moon DH, Lee JM, Noonan AM, Annunziata CM, Minasian L,
Houston N, et al. Deleterious BRCA1/2 mutation is an independent risk
factor for carboplatin hypersensitivity reactions. Br J Cancer 2013;109:1072–78.
66. Pujade-Lauraine E, Wagner U, Aavall-Lundqvist E, Gebski V, Heywood M,
Vasey PA, et al. Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sensitive
ovarian cancer in late relapse. J Clin Oncol 2010;28:3323–9.
67. Markman M, Moon J, Wilczynski S, Lopez AM, Rowland KM Jr,
Michelin DP, et al. Single agent carboplatin versus carboplatin plus pegylated liposomal doxorubicin in recurrent ovarian cancer: final survival results of a SWOG (S0200) phase 3 randomized trial. Gynecol Oncol
2010;116:323–5.
68. Shibata Y, Ariyama H, Baba E, Takii Y, Esaki T, Mitsugi K, et al.
Oxaliplatin-induced allergic reaction in patients with colorectal cancer
in Japan. Int J Clin Oncol 2009;14:397–401.
69. Mori Y, Nishimura T, Kitano T, Yoshimura K, Matsumoto S, Kanai M,
et al. Oxaliplatin-free interval as a risk factor for hypersensitivity reaction
among colorectal cancer patients treated with FOLFOX. Oncology
2010;79:136–43.
70. Castells MC, Tennant NM, Sloane DE, Hsu FI, Barrett NA, Hong DI,
et al. Hypersensitivity reactions to chemotherapy: outcomes and safetyof rapid desensitization in 413 cases. J Allergy Clin Immunol
2008;30:1160–5.
71. Wang JH, King TM, Chang MC, Hsu CW. Oxaliplatin-induced severe
anaphylactic reactions in metastatic colorectal cancer: case series analysis.
World J Gastroenterol 2012;18:5427–33.
72. Gaeta TJ, Clark S, Pelletier AJ, Camargo CA. National study of US emergency department visits for acute allergic reactions, 1993 to 2004. Ann
Allergy Asthma Immunol 2007;98:360–5.
73. Lieberman P, Nicklas RA, Oppenheimer J, Kemp SF, Lang DM,
Bernstein DI, et al. The diagnosis and management of anaphylaxis
practice parameter: 2010 update. J Allergy Clin Immunol 2010;126:
477–80.
74. Confino-Cohen R, Goldberg A. Allergen immunotherapy-induced biphasic systemic reactions: incidence, characteristics, and outcome: a prospective study. Ann Allergy Asthma Immunol 2010;104:73–8.
75. Pagani M. The complex clinical picture of presumably allergic side effects
to cytostatic drugs: symptoms, pathomechanism, reexposure, and desensitization. Med Clin North Am 2010;94:835–52.
76. Demoly P, Bousquet J. Drug allergy diagnosis work up. Allergy
2002;57:37–40.
77. Wendel GD Jr, Stark BJ, Jamison RB, Molina RD, Sullivan TJ. Penicillin
allergy and desensitization in serious infections during pregnancy. N Engl
J Med 1985;312:1229–32.
78. Sullivan TJ. Antigen-specific desensitization of patients allergic to penicillin. J Allergy Clin Immunol 1982;69:500–8.
79. Shalit M, Pickholz D, Levi-Shaffer F. Mast cells retain their responsivenessupon continuous and repetitive exposure to antigen. Immunology
1993;79:319–24.
80. MacGlashan D Jr. Subthreshold desensitization of human basophils
re-capitulates the loss of Syk and FcepsilonRI expression characterizedby other methods of desensitization. Clin Exp Allergy 2012;42:1060–70.

803

804

Platinum hypersensitivity and desensitization

100. Brockow K, Romano A. Skin tests in the diagnosis of drug hypersensitivity
reactions. Curr Pharm Des 2008;14:2778–91.
101. Vyas N, Yiannakis D, Turner A, Sewell GJ. Occupational exposure toanti-cancer drugs: a review of effects of new technology. J Oncol Pharm
Pract 2013;20:278–87.
102. Madrigal-Burgaleta R, Berges-Gimeno MP, Angel-Pereira D, FerreiroMonteagudo R, Guillen-Ponce C, Pueyo C, et al. Hypersensitivity and desensitization to antineoplastic agents: outcomes of 189 procedures with a
new short protocol and novel diagnostic tools assessment. Allergy
2013;68:853–61.
103. Iwamoto T, Yuta A, Tabata T, Sugimoto H, Gabazza EC, Hirai H, et al.
Evaluation of basophil CD203c as a predictor of carboplatin-related
hypersensitivity reaction in patients with gynecologic cancer. Biol
Pharm Bull 2012;35:1487–95.

104. Liu A, Fanning L, Chong H, Fernandez J, Sloane D, Sancho-Serra M, et al.
Desensitization regimens for drug allergy: state of the art in the 21st century. Clin Exp Allergy 2011;41:1679–89.
105. Morales AR, Shah N, Castells M. Antigen-IgE desensitization in signaltransducer and activator of transcription 6-deficient mast cells by suboptimal doses of antigen. Ann Allergy Asthma Immunol 2005;94:
575–80.
106. Simons FE. Anaphylaxis. J Allergy Clin Immunol 2010;125:S161–81.
107. Confino-Cohen R, Fishman A, Altaras M, Goldberg A. Successful carboplatin desensitization in patients with proven carboplatin allergy. Cancer
2005;104:640–3.
108. Rose PG, Fusco N, Smrekar M, Mossbruger K, Rodriguez M. Successful
administration of carboplatin in patients with clinically documented carboplatin hypersensitivity. Gynecol Oncol 2003;89:429–33.

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