Platinum hypersensitivity

Platinum
Hypersensitivity
Pairach Supsongserm, MD
6-9-2019

Outline
• Case
• Introduction
• Mechanism
• Incidence
• Risk Factors
• Symptoms and Signs
• Evaluation and Prevention
• Treatment
• Desensitization
• Taxane Hypersensitivity

Case
• ผู้หญิง อายุ 60 ปี
• นัดมารับ PT regimen cycle 3
• Underlying diseases:
1. HT, DLP
2. CA ovary (Poorly differentiated
adenocarcinoma) Dx ปี 2560
- TAH with BSO with surgical staging ปี 2560
- PT regimen รวม 6 Cycles (มิ.ย.-ธ.ค. 2560) อาการ
ปกติ
• Free interval 1 ปี 4 เดือน
• F/U พบ CA-125 rising จึงให้ Re-
induction PT regimen
- Cycle 1 (28/5/62) ไม่มีอาการผิดปกติระหว่างให้
แต่กลับบ้านไป 1 วันมีอาการหน้าร้อนผ่าว ไม่มีผื่น
- Cycle 2 (19/6/62) ไม่มีอาการผิดปกติ

Case
• นัดมาให้ PT regimen cycle 3 (10/7/62)
- Paclitaxel 260 mg in 5% D/W 500 ml in 3 hr ไม่มีอาการผิดปกติ
- Carboplatin 460 mg in 5% D/W 200 ml in 1 hr หลังให้ 15 นาที (54 ml) หน้าและแขนแดง คันที่
ปลายนิ้วมือ ไม่มีผื่น ไม่คัดจมูกหรือน้ามูกไหล แน่นอก อาเจียน ไม่ปวดท้อง ไม่มีไข้ T 36.7 BP 60/41 P 86 R 20
O2sat (RA) 90% L: clear Skin: flushing at face and forearms
Dx: Anaphylatic shock
Mx: Off Carboplatin, Adrenaline (1:1000) 0.5 ml IM*1 dose, CPM 10 mg IV, Ranitidine
50 mg IV, Dexamethasone 10 mg IV, NSS IV
หลังจากนั้น 10 นาที อาการดีขึ้น BP 140/75 P 80 O2 sat 100% จึง Admit observe

Carboplatin Hypersensitivity???

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 of cancer cells, thus
killing these cells
Shingo M et al., Japanese Journal of Clinical Oncology, 2015, 45(9) 795–804

Introduction
• Widespread use of platinum
antineoplastic agents has led to an
increased incidence of
hypersensitivity reactions
• Allergic reactions can appear after a
significant number of infusions
with no prior clinical signs
• Carboplatin-based chemotherapy is
often administered over 6 cycles, and
hypersensitivity reactions are usually
observed during re-treatment, after a
period of remission
• Allergic crossreactivity between
cisplatin and carboplatin has been
reported, but the number of cases is
insufficient to establish the true
incidence
J.Boulanger et al, Curr Oncol, 2014, Vol.21, pp. e630-641

Cisplatin
• A first-generation platinum agent
• A non-natural compound
• Treatment be discontinued after a
maximum of 6 cycles when treating
non small cell lung cancer

Carboplatin
• A second-generation platinum agent
• Can be administered to patients with reduced
kidney function
• It does not require large-volume transfusion
• It can be administered to outpatients
• In ovarian cancer, carboplatin is used as a
standard primary treatment
• In cases in which relapse occurs >6 months
following this primary treatment, retreatment
with carboplatin-containing chemotherapy
yields favorable results

Oxaliplatin
• A third-generation platinum agent
• An integral drug used for colorectal
cancer and pancreatic cancer
• It is administered either until treatment
discontinuation due to toxicity or is
continually administered until
progression
• Increased frequency of cold-sensitive
dysesthesia and peripheral neuropathy

Hypersensitivity Reactions (HSRs)
• An unforeseen reaction whose signs and symptoms cannot be explained by
the known toxicity of the drug
• Clinicians must choose whether to continue with the same treatment or to
suspend treatment and to search for other treatment options
• As continued readministration of these platinum agents contributes to
prolonged survival periods, clinicians contemplate rechallenge with these
platinum agents

Approaches to Address HSRs
• Reducing the infusion rate
• Administering premedication
• Switching to a different platinum agent
• Skin testing
• Desensitization

Mechanism
• Allergic reactions (Immunological mechanism)
• Non-allergenic (Cytokine release syndrome)

Type 1 Allergic Reaction Cytokine Release Syndrome

Mechanism
• The mechanism has not yet been clearly elucidated
• Generally reported as immediate Type I allergies
• Mast cells and basophils react via IgE and release chemical messengers such
as histamine, leukotrienes and prostaglandins
• A variety of symptoms including anaphylaxis

October 1998-March 2003
126 patients
A total of 717 carboplatin skin tests (Median per patient 4 tests)
• Of the 668 negative tests (93% of
the total performed)
- 10 were associated with evidence of
carboplatin hypersensitivity (1.5%
false-negative rate; 95% CI, 0.6% to
2.4%), none of which were severe
• NPV 98.5%
• Of the 41 positive tests
- The decision was made to not deliver the
drug to 32 patients (7 patients ultimately
underwent a future attempt at re-treatment
with a platinum agent using a desensitization
program)
- In 7 episodes where patients received the
carboplatin despite the finding of a positive
test, 6 were associated with the development
of symptoms of anaphylaxis (none severe)

Mechanism
• Case reports present the possibility that cytotoxic (Type II) hypersensitivity
and immune complex (Type III) hypersensitivity contribute to HSRs to
platinum agents
• It has been suggested that cisplatin and carboplatin also induce Type IV
hypersensitivity through delayed T-cell sensitization

Mechanism
• Santini et al. 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 a superantigen to
stimulate the release of these cytokines

Incidence
• Immediate type hypersensitivity and asthma were occurring in workers at
platinum refinement plants who repeatedly inhale platinum-containing dust
• HSRs due to the use of anticancer agents have been reported since the
1970s

Risk Factors
• Risk factors of carboplatin HSRs:
- Age <70 years
- A history of allergies to environmental stimuli or drugs
- Administration with carboplatin at 650 mg or more
- A long platinum-free interval

Most patients who developed carboplatin HSR had a deleterious
BRCA1/2 mutation (93%) vs 50% in patients without HSR
(P<0.0001)
Mutation carriers had onset of carboplatin HSR at lower
cumulative exposure (P=0.003)

• Carboplatin may act as a hapten that
binds to serum proteins to elicit an
immunologic reaction
• Patients may be sensitised to the
protein–platinum adduct beginning
with the first-line treatment, with
immunologic restimulation during
subsequent regimens
• The DNA–platinum adduct itself may
be immunogenic
• Loss of normal BRCA function impairs
homologous recombination required for error-free
repair of DNA double-strand breaks that may
occur secondary to torsion caused by or excision of
interstrand platinum–DNA adducts
• Dysfunctional BRCA1 also disrupts nucleotide
excision repair, the mechanism through which
platinum adducts are repaired
• Impaired DNA repair may contribute to increase in
the DNA–platinum adducts, subsequently
augmenting exposure and possible HSRs to
carboplatin

Risk Factors
• The calypso study showed that hypersensitivity occurred more often among
patients receiving a carboplatin–paclitaxel combination than among those
receiving carboplatin combined with pegylated liposomal doxorubicin
(18.8% vs. 5.6%)
• Markman et al. showed that, compared with single-agent carboplatin, the
combination of pegylated liposomal doxorubicin and carboplatin reduced
the frequency of hypersensitivity reactions (0% vs. 30%)

• It takes time to develop an allergy to platinum salts as has been seen with
increasing IgE antibodies over time in workers exposed to platinum salts
• However, that does not fully explain why a greater platinum-free interval
would expose a patient to a greater risk of HSR
• Sensitization or tachyphylaxis to the allergic effects of platinums occurs with
constant exposure and the increased time between retreatment reintroduces
sensitivity

Risk Factors
• The risk factors for the onset of HSRs to oxaliplatin:
- Young age
- Female gender
- Use of oxaliplatin as a second-line or higher therapy
• The total dose of oxaliplatin administered and oxaliplatin-free interval have
been reported to be associated with HSRs

Symptoms and Signs
• Fever and/or shaking chills
• Cutaneous manifestations (80-90%)
• Gastrointestinal manifestations
• Respiratory manifestations
• Circulatory manifestations
• Most manifestations only mild to moderate

Evaluation and Prevention:
Skin Test
• All patients receiving carboplatin be tested before each treatment after the 6th
cycle
• Patients who experience hypersensitivity symptoms and a positive skin-test
result should undergo a desensitization protocol
• Skin testing can be used to evaluate the potential for cross-reactions between
two platinum drugs
- Those with a positive result have a greater risk of experiencing cross-reactivity
between platinum salts

Infusion Time
• O’Cearbhaill et al. noted that administration of a 3-hour carboplatin infusion
together with premedication (instead of the standard 30-minute infusion)
could reduce the risk of hypersensitivity (3.4% vs. 21%)

Premedication
• Routine premedication with antihistamines and steroids is not recommended
before commencement of platinum-based therapy
• A small retrospective study showed that premedication (diphenhydramine,
dexamethasone, granisetron, and famotidine vs. dexamethasone and
granisetron) reduced hypersensitivity reactions associated with modified
folfox6 (leucovorin, 5-fluorouracil, oxaliplatin)

Treatment
• Early perception of changes in the patient’s condition
• The administration of drugs is then ceased
• Physiological saline
• A rapid evaluation of the patient’s circulation, airway, breathing, state of
consciousness and skin, oxygen

Treatment
• Antihistamines alleviate symptoms such as itching, urticarial and angioedema
but have no life-saving effect
• Glucocorticoids may also alleviate delayed reactions, but the therapeutic
effects occur after some hours, and these drugs also have no life-saving effect
• Epinephrine is used as the primary treatment, particularly for anaphylaxis,
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

Treatment
• Extra attention should be paid to anaphylaxis cases in which biphasic
anaphylaxis may occur several hours after cessation of treatment and
resolution of symptoms

Confounding Factors of Diagnosis of
HSRs to Platinum
• Patients receiving cancer therapy are prescribed many drugs that can cause
HSRs
• The cancer itself acts directly on mast cells to produce similar symptoms to
those of an HSR
• Several epidemiological studies have found that certain cancers have been
shown to increase the risk of allergies
• If possible, diagnosis may be made based on the results of skin or challenge
testing

Desensitization
• The process in which the
concentration of an anticancer drug
acting as an antigen is increased in a
slow and step-wise manner to
induce a temporary tolerization state
toward the drug, until the target
dose is reached
• No standardized protocol for
desensitization

Desensitization
• 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
• The production of cytokines related to delayed onset reactions, like IL-6, was
also suppressed

• The same group reported alleviation of symptoms in 12 of 14 patients who had
HSRs during desensitization
• These patients were prescribed 325 mg of acetylsalicylic acid, a prostaglandin
blocker, and 10 mg of montelukast, a leukotriene blocker, both were administered 2
days prior to and on the day of desensitization
• The group on 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)

Recent HSR
(<3mo)
Remote HSR
(>9 mo)
Total Desensitization
ST positive 20 5 25 19
ST negative 4 9 13 11
Total 24 14 38 30
7/19 (37%)
had mild HSR
3/3 (100%) tolerated
a rapid protocol
without HSR and
remained ST negative
with repeated testing
6/8 (75%)
reacted during
desensitization
(More severe)
5/7 (71%) retested
became ST
positive before the
second
desensitization

Desensitization
• There have been few investigations of desensitization to oxaliplatin
• Many of these have a small number of cases

• Lee et al. conducted a retrospective analysis
of the results of 152 patients who had
experienced HSRs to oxaliplatin
• Undergone a premedication protocol with 20
mg of chlorpheniramine and 100 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%
• The success rate reached 86% when
desensitization was conducted
• XELOX regimen with a 3 week interval
was found to have a greater number of
administrations before the onset of an
initial HSR than FOLFOX regimen with a
2 week interval
• The actual time from the start of treatment
to the onset remained the same
• Rather than the number of administrations,
the length of treatment may be important

The Approach for HSRs during
Desensitization
• Discontinued
• Diphenhydramine or hydroxyzine
• If a severe reaction develops, oxygen and inhaled bronchodilators may be given
• H2-blockers and glucocorticoids are administered intravenously
• When necessary, epinephrine may also be considered
• Treatment may be restarted from where the desensitization process was interrupted,
with a reduced infusion rate or a reduced increment of dose

Taxane Hypersensitivity
• Originally derived from the Pacific yew tree
• Disruption of microtubule function
• Whether hypersensitivity can be attributed to the taxanes themselves or to
their formulation vehicles has not yet been established
• Paclitaxel is administered in a solution of ethanol and Kolliphor EL
(formerly Cremophor EL)
• The reaction to docetaxel has been attributed to its vehicle, polysorbate 80

• Risk factors:
- History of atopy
- History of mild skin reactions during earlier treatments
- The presence of respiratory dysfunction
- Overweight or obesity
- Menopausal or postmenopausal status

• Paclitaxel and carboplatin are often administered concomitantly, and so it can
be difficult to distinguish which drug has triggered a hypersensitivity reaction
• Diagnosis is facilitated by the clinical presentation and the time of
appearance because the reactions are different for and specific to each agent

Platinum hypersensitivity

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