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Cetuximab Infusion Reactions: French Pharmacovigilance Database Analysis
Cetuximab Infusion Reactions: French Pharmacovigilance Database Analysis
2012–12:46pm] [1–8]
{SAGE}OPP/OPP 457965.3d (OPP) [PREPRINTER stage]
Journal of
Oncology
Pharmacy
Original Article Practice
J Oncol Pharm Practice
0(0) 1–8
Aurélie Grandvuillemin
Centre Régional de Pharmacovigilance de Bourgogne, CHU de Dijon, Dijon, France
Anne Disson-Dautriche
Centre Régional de Pharmacovigilance de Bourgogne, CHU de Dijon, Dijon, France
Ghada Miremont-Salamé
Centre Régional de Pharmacovigilance, CHU de Bordeaux, France; Département de
Pharmacologie, Université Victor Segalen Bordeaux 2, France, INSERM U657, Bordeaux, France
Annie Fourrier-Reglat
Département de Pharmacologie, Université Victor Segalen Bordeaux 2, France, INSERM U657,
Bordeaux, France
Catherine Sgro
Centre Régional de Pharmacovigilance de Bourgogne, CHU de Dijon, France, EA 4184, Dijon,
France
The Réseau des Centres Régionaux de Pharmacovigilance
Français
Abstract
Objectives: To compare characteristics of patients exhibiting cetuximab infusion reactions or another adverse drug
reaction related to cetuximab and to identify factors associated with the severity of cetuximab infusion reactions.
Methods: All cases of adverse drug reaction reported with cetuximab from 1985 to 2010 were extracted from the French
Pharmacovigilance database. The severity of infusion reactions was assessed according to the NCI-CTCAE criteria (v4.0).
Multiple logistic regression analysis was performed to identify factors associated with the severity of infusion reactions.
Results: Among the 602 adverse drug reaction reported with cetuximab during the study period, 374 infusion reactions were
identified. Indication is more likely to be head and neck than colorectal cancer among patients experiencing an infusion
reaction (p < 0.001). Among the seven deaths related to an infusion reaction, five patients were treated for head and neck
cancer. Infusion reactions were more likely to be severewhen theyoccurred during the first administration (OR ¼ 7.40 95% CI
[2.21–24.71]), adjusted for age, sex, region of France, quarter of the year, indication, year of occurrence, and premedication.
Conclusion: Our study found that reports of infusion reactions more often concerned patients treated for head and
neck cancer, that in these patients the adverse drug reaction was more often fatal and severe infusion reactions were
more likely during the first administration. In daily practice, the close monitoring of patients during the first infusion,
especially patients with head and neck cancer, is recommended. Considering the possible immunoglobulin E–mediated
mechanism, reliable tests for their detection need to be readily available.
Keywords
Cetuximab, infusion reaction, severity, hypersensitivity
Corresponding author:
Aurélie Grandvuillemin, Centre de Pharmacovigilance de Bourgogne,
14 rue Paul Gaffarel, 21079 Dijon Cedex, France.
Email: [email protected]
Grandvuillemin et al. 3
Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-like substances from mast cells, causing a hypersensitivity immune response.
Death
Death
reactions, we considered reactions grade 1 to 3 non-
severe and grade 4 and 5 severe.
5
Statistical analysis
Life-threatening consequences;
Characteristics of patients and adverse drug reactions
were described using percentages for categorical vari-
ables and means and standard deviations for continu-
ous variables. Comparisons were made by Chi-square
or Fisher’s exact test for categorical variables.
Severity was considered the dependent variable for
the analysis. Associations between the potential risk
factors and the seriousness of the infusion reaction
4
Clinically, it presents with breathing difficulty, dizziness, hypotension, cyanosis and loss of consciousness and may lead to death.
Results
Intervention or infusion interruption
(AR)’’ (n ¼ 228).
The characteristics of infusion reactions and other
AR are reported in Table 2.
The proportion of serious reports was higher for
infusion reactions than for other AR (p < 0.001). The
—
2
Table 2. Characteristics of cases of infusion reactions related indicated precisely, the average time to onset of infu-
to cetuximab and other adverse reactions related to cetuximab sion reactions was 22 minutes (median 15 minutes).
recorded in the French pharmacovigilance database between In 76.2% of reports, symptomatic treatment was
1 January 1985 and 31 December 2010. administered after discontinuation of cetuximab: anti-
Other histamines and/or corticosteroids (59.6%), adrenaline
Infusion adverse intravenously (16.3%), oxygen and/or aerosols
reactions reactions (25.9%), fluids/macromolecules (15.2%), other symp-
N ¼ 374 N ¼ 228 p Value tomatic treatment such as paracetamol or antiemetics
(12.6%). In 9.1% of reports, no symptomatic treatment
Age n (%) 0.479
was necessary.
<65 212 (56.7) 133 (58.3) Cetuximab was reintroduced in 52 cases (13.9%). In
65 162 (43.3) 90 (39.5) 16 cases, reintroduction was done the day of the initial
Sex n (%) <0.001 reaction, in 18 cases 1 week later, and in 6 cases 2 weeks
Male 305 (81.5) 152 (66.7) later. The severity of the initial reaction was grade 1 in
Female 69 (18.5) 76 (33.3) 2 cases, grade 2 in 5 cases, grade 3 in 39 cases, and
Region n (%) 0.029 grade 4 in 6 cases. Infusion reactions reappeared in 23
North East 78 (20.9) 43 (18.9) cases (44.2%). In 9 cases, the reintroduction led to a
South East 60 (16.0) 46 (20.2) more severe reaction (from grade 3 to grade 4). Among
South West 107 (28.6) 48 (21.0) the 29 cases with a reaction-free reintroduction, pre-
North West 69 (18.4) 35 (15.3)
medication was increased in 10 cases: corticosteroid
added to the antihistamine (given alone before the
Paris 60 (16.0) 56 (24.6)
first administration) in 6 cases; corticosteroid dose
Year n (%) <0.001
increased in 2 cases; other antihistamine given in
2004 19 (5.1) 33 (14.5) 1 case; and premedication administrated for 3 days
2005 14 (3.7) 36 (15.8) before reintroduction in 1 case. In 9 other cases, the
2006 32 (8.6) 23 (10.1) infusion rate was decreased (halved in 6 cases while
2007 45 (12.0) 26 (11.4) the first administration was based on the SPC guideline
2008 67 (17.9) 51 (22.4) which is 5 mL/min).
2009 100 (26.7) 44 (19.3) Among the 374 reports of infusion reactions, 243
2010 97 (25.9) 12 (5.3) (65.0%) were classified as non-severe (1.3% grade 1,
Trimester n (%) 0.327 10.2% grade 2, 53.5% grade 3) and 131 as severe
Jan–Mar 86 (23.0) 59 (25.9) (35.0%) (33.2% grade 4 and 1.9% grade 5).
Apr–Jun 76 (20.3) 46 (20.2)
After univariate analysis (Table 3), the severity of
the infusion reaction was no different according to the
July–Sept 104 (27.8) 70 (30.7)
premedication in bi- or monotherapy (bitherapy vs.
Oct–Dec 106 (28.3) 49 (21.5)
monotherapy OR ¼ 1.26 CI 95% [0.65–2.43]), or the
Indication n (%) <0.001 indication (p ¼ 0.252).
Colorectal 145 (38.8) 156 (68.4) In multivariate analysis, severe infusion reactions
Head and neck 155 (41.4) 44 (19.3) were more likely to occur during the first cycle (cycle
Other 28 (7.5) 18 (7.9) 1 vs. cycle 2 or more OR ¼ 7.40 CI 95% [2.21–24.71],
Unknown 46 (12.3) 10 (4.4) p ¼ 0.005) after adjustment for age, sex, region of
Cycle n (%) <0.001 France, quarter of the year, indication, and year of
1st 250 (66.8) 79 (34.6) occurrence and premedication.
2 38 (10.2) 130 (57.0) A fatal outcome (grade 5) was reported in 13 cases,
Seriousness n (%) <0.001 including 7 directly related to the infusion reaction and
Serious 292 (78.1) 106 (46.5)
4 where the latter may have contributed to the death.
Two deaths were not considered to be related to the
Hospit./prolong. hospit. 154 (41.2) 60 (26.3)
infusion reaction. No deaths were found in other-AR
Life-threatening 100 (26.4) 16 (7.0)
reports.
Death 7 (1.9) 11 (4.8) Of the 7 deaths related to the reaction, 5 patients
Disability/incapacity 1 (0.3) 9 (3.9) were treated for head and neck cancer and 1 for colo-
Important medical event 29 (7.7) 9 (3.9) rectal cancer (1 unknown). The reaction occurred in the
Serious without precision 1 (0.3) 1 (0.4) first cycle for five cases (two unknown). Premedication
Non-serious 82 (21.9) 122 (53.5) consisted of a corticosteroid and antihistamine in
4 cases and monotherapy in 1 case (1 unknown).
Grandvuillemin et al. 5
Table 3. Univariate comparison of infusion reactions related to cetuximab in the French Pharmacovigilance
database according to their severity.
Non-severe
(grade I–III) Severe (grade IV–V) Odds ratio
N ¼ 243 N ¼ 131 (%) [CI 95%] P Value
In 4 cases, the death occurred despite resuscitation and 1 case. The causes of death were probable pulmonary
administration of epinephrine. In one case, the patient embolism (death 2 hours after the initial reaction,
died following acute pulmonary oedema with heart fail- which had completely resolved); disseminated intravas-
ure. One patient presented two successive cardiac cular coagulation in the aftermath of cardio-respiratory
arrests, the second was fatal. arrest (death within 12 hours following the initial reac-
Among the four deaths where the infusion reaction tion); multiple organ failure 11 days after the initial
may have contributed to the death of the patient, the reaction that led to heart failure; and pulmonary
indications were head-neck in 3 cases and colorectal in infection acquired under mechanical ventilation
(death 27 days after the initial reaction which required deaths more often concerned patients with head and
intubation). neck cancers (5 of 7 deaths). This could be explained
by the location of the tumor, which may interfere with
intubation, the poor nutritional and general status of
these patients, or a lesser response to the corrective
Discussion
treatment of the reaction. Radiotherapy did not seem
We found that 62% of adverse events related to cetux- to be involved as infusion reactions appeared mostly in
imab recorded in the French Pharmacovigilance the first cycle of cetuximab, which is administered
Database until 31 December 2010, were infusion reac- before radiotherapy. Tobacco and alcohol may also
tions. The characteristics of these ARs were compar- play a role, as head and neck cancers are associated
able to current data (literature and ErbituxÕ SPC). with tobacco and alcohol consumption.14 Several stu-
Most of the infusion reaction reports in our study dies found a positive association between alcohol con-
were serious and severe. This was potentially related sumption and total IgE levels and various allergic
to the more spontaneous reporting of serious or reactions, but no clear mechanisms were elucidated.21
severe ARs. Patients exposed to tobacco smoke are more likely to
Our study population consisted of 76% men, which have respiratory symptoms as already suggested by
is consistent with the target population of cetuximab in O’Neil et al.6 The role of tobacco in atopy has not
its official statements. Indeed, head-neck cancers occur been established, although some studies found a dose-
predominantly in males (80% of new cases in France dependent association between exposure to environ-
are men14), colorectal cancer also affects men (55% in a mental tobacco in the first months of life and IgE
population-based study carried out in two French sensitization to food allergens.22
departments15). This result is also consistent with the The mechanism of infusion reactions is not clearly
data provided by the Agence de Traitement de understood but an IgE-mediated reaction was demon-
l’Information Hospitalière (ATIH) (involving French strated for the first time by Chung et al. in 2008.4 The
Public Hospitals and private health-care institutions): antigen identified was an oligosaccharide located in
over the period 2009–2010, 70.4% of patients treated the Fab portion of the heavy chain of cetuximab: the
with cetuximab were men.16 In our study, infusion reac- galactose-a-1,3-galactose (a3Gal). These IgE were
tions seemed to be more likely in males, but the indi- found in some patients before any contact with cetuxi-
cation was probably a confounding factor as shown in mab. This may explain the occurrence of these reactions
a previous study.7 Nevertheless, sex could have an during the first cycle. Sensitization could occur through
impact as males were also more likely to have a history food (pork and beef), some parasites, or tick bites.4,18
of atopy.17 Premedication is actually ineffective in preventing this
We found no association between the severity of type of reaction. It is also interesting to note that a
infusion reactions and age, which is consistent with French study found a significantly higher prevalence of
results from other studies5–7 or with the region of IgE anti- galactose-a-1,3-galactose in men.18
occurrence (unlike in the USA4). We found no evidence This IgE-mediated hypothesis may be reflected by
of seasonality that could have correlated with periods the relative inefficiency of the premedication shown in
associated with environmental allergies (spring), as other studies6,7,23 as well as in ours. However, this
atopy has already been mentioned.6 result in our study should be interpreted with caution
Infusion reactions were more likely to occur in indi- given the large amount of missing data. The positive
cations of head and neck cancer, while other ARs were association between severity and first administration
more likely to occur in indications for colorectal cancer. could have been related to lighter premedication
This is not related to the number of treated patients as, before the first administration than before subsequent
according to the ATIH data, the number of patients cycles. However, the recommendation of the SPC is bi-
treated with cetuximab for head and neck cancer or premedication (antihistamine and corticosteroid), and
for colorectal cancer was similar over the period in our study, the proportions of patients receiving com-
2009–2010: 4782 patients treated for head and neck bination therapy in the first cycle or in all subsequent
cancer vs. 4612 patients treated for colorectal cycles were no different (p ¼ 0.682).
cancer.17 This association has been shown only once The ability of bi-premedication to reduce the inci-
before.7 dence and severity of infusion reactions has been
Fatal outcomes in infusion reactions are rare but shown in one clinical trial24 (study funded by the
have already been reported.1,2,18–20 In our study, maker of ErbituxÕ ) and in the analysis done by the
drug-related deaths were all in the infusion reaction maker of ErbituxÕ in Europe with pooled data of
group. Even though the indication was not associated 2 major trials in colon cancer setting (CRYSTAL and
with the severity of infusion reactions, drug-related MABEL).18
Grandvuillemin et al. 7
This IgE-mediated hypothesis is probably not the In conclusion, analyses of ADR reported with cetux-
only mechanism of infusion reactions seen with cetux- imab to the French Pharmacovigilance database shows
imab. Indeed it is surprising not to find more severe that reports of infusion reactions more often concerned
reactions beyond cycle 2 (sensitization during first patients treated with cetuximab for squamous cell car-
administration). The large proportion of reaction-free cinoma of the head and neck than for patients treated
reintroductions (55.8%) also goes against the hypoth- for colorectal cancer, that the outcome in these patients
esis of an initial IgE-mediated reaction. There were only was more often fatal and that severe infusion reactions
a few cases of reintroductions (52 out of 374), which were more likely during the first treatment cycle.
may be explained by the fact that severe reactions led to Further investigations are needed to assess differences
a definite contraindication to cetuximab. in support care between the two indications.
Another assumption is another mechanism such as an Considering the possibility that these reactions are
anaphylactoid reaction or another antigen. When IgE mediated, reliable tests for their detection need to
reports of cetuximab infusion reactions were compared be readily available. The interest of identifying patients
with other ARs reported with this drug, we found a sig- at risk before starting treatment should be investigated.
nificant difference for the year of occurrence. Moreover, A prospective study may be helpful to identify other
we noted an increasing tendency since 2007. This raises risk factors such as medical history and previous
the question of the new formulation of ErbituxÕ author- chemotherapy. In daily practice, the fatal outcome of
ized in February 2007.25 ErbituxÕ 2 mg/mL was these immediate reactions may be prevented by very
replaced by ErbituxÕ 5 mg/mL, which contains new close monitoring of patients during the first infusion,
additives to reduce aggregates, among them is polysor- especially patients with head and neck cancer.
bate 80. This vehicle has been identified as a cause of
immediate reactions with several drugs, including doce- Acknowledgments
taxel26 and omalizumab.27 An anaphylactoid mechan- The authors acknowledge Dr Côme Lepage and Dr Hervé
ism has been demonstrated with polysorbate 80, without Watier for the medical contribution, Véronique
involvement of IgE.28 This new formulation was author- PIZZOGLIO and Pascal AURICHE from AFSSAPS for
ized in January 2007, but it is difficult to date the com- the extraction of the French Pharmacovigilance database,
plete cessation of the old formulation. and Mr Cédric Collin from AFSSAPS for the ATIH data.
This increase may also be a bias linked to increased
awareness of this reaction leading to more frequent Funding
reporting by health professionals even though such reac- This research received no specific grant from any funding
tions are no more frequent than other reactions. agency in the public, commercial, or not-for-profit sectors.
However, there have been no communications from the
French or other national authorities on this kind of reac- Conflict of interest
tion induced by cetuximab. Nevertheless, the French None.
Health authorities published a warning about other
monoclonal antibodies (panitumumab VectibixÕ in References
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