Introduction
Over the past decade, monoclonal antibodies have gained attention as a
systemic anticancer therapy1 and are now widely used
in the treatment of various malignancies. In general, monoclonal
antibodies are less toxic and better tolerated than conventional
cytotoxic chemotherapeutic agents. However, as with other injected
anticancer agents, monoclonal antibodies can cause infusion-related
reactions (IRRs).1–3 Most IRRs are mild and include
chills, fever, nausea, skin rash, and pruritus. Severe side effects are
less frequent but can include low blood pressure, tracheal spasm, and
angioedema and can be fatal without proper care.2,4IRRs usually develop within the first few minutes of the first
infusion.5,6
Trastuzumab, a humanized monoclonal antibody developed to block human
epidermal growth factor receptor type 2 (HER2) from binding to tyrosine
kinases,7 is used for treating cancers that
overexpress HER2.1 Currently, it is the first-line
treatment for almost all stages of breast cancer as well as advanced or
recurrent gastric cancer.8–13 The HER2 gene,HER2/neu (c-erbB-2 ), was first discovered by Schechter et
al. in 1984,14 and this receptor is overexpressed in
25–30%15 of early-stage breast cancers and
10–34%14 of invasive breast cancers. Overexpression
of HER2 adversely affects clinical outcomes.8,16However, the prognoses of these malignancies have remarkably improved
with the introduction of trastuzumab, a monoclonal antibody against the
extracellular domain of HER2. Trastuzumab has shown efficacy as a
monotherapy17 in metastatic breast cancer as well as
in combination with chemotherapy in metastatic and early-stage breast
cancer, reducing the recurrence rate by up to 50%, regardless of age or
other prognostic factors.9,18–20
The probability that a patient will develop an IRR depends on the type
of monoclonal antibody used and the disease.21Estimates of IRR rates for common agents range from 2% to
15%,22 whereas those for taxanes and platinum are
40% and 16%, respectively. The IRR rates for monoclonal antibodies
rituximab, trastuzumab, and cetuximab are 77%, 40%, and 20.5%,
respectively, which are relatively high.2,23 The
incidence of IRR for the same drug varies from report to report. A
report revealed the IRR incidence of trastuzumab to range from
3.4%24 to 5.9%.25 Trastuzumab is
generally considered to be a safe drug, as there have been no reports of
hematologic toxicity commonly associated with
chemotherapy10; moreover, trastuzumab has demonstrated
favorable safety profiles in patients older than 70
years.25 However, IRRs and cardiac
toxicity10 have emerged as major safety
concerns.18,19,26–28 Cook et al. reported that 0.3%
of breast cancer patients experienced a serious IRR in response to
trastuzumab, based on postmarketing surveillance
data.28 Therefore, it is imperative that clinicians
are aware of the potential for IRRs when administering trastuzumab and
implement protocols to prevent and manage these reactions to minimize
their impacts on further treatment.
The degree of antibody humanization influences the frequency of
IRRs,29 but the mechanisms underlying IRRs associated
with monoclonal antibodies remain to be elucidated.2IRRs after rituximab administration occur at a significantly higher rate
in patients with tumors than in patients with rheumatoid
arthritis.30,31 Byrd et al. reported increased levels
of cytokines, such as tumor necrosis factor-α, interleukin (IL)-6, IL-8,
and interferon-γ in patients with rituximab-induced IRRs compared to
those in a group without IRRs.32 Larger tumor loads
are known to promote more severe cytokine
release.33,34 Although IRRs occur almost exclusively
with the first infusion,1–3,35–37 IgE-mediated
hypersensitivity requires prior sensitization and is not expected to
occur with the first infusion of monoclonal antibodies.
Cytokine-dependent mechanisms in IRRs have been
proposed,2 since cytokines can cause a variety of
symptoms characteristic of IRRs and cytokine-dependent mechanisms are
independent of prior sensitization. Previous findings suggest that the
etiology of IRRs to monoclonal antibody preparations may involve
cytokine release due to tumor cell destruction, unlike IgE-mediated type
1 allergic reactions observed in patients with normal
hypersensitivity.1,2,5,35,36,38
There is little information on the risk factors for IRRs associated with
trastuzumab. Of all factors evaluated by Thompson et al., high body mass
index (BMI), stage IV, and no prior medication use (diphenhydramine,
meperidine, or hydrocortisone) were significantly associated with
increased IRR risk by multivariate logistic regression
analysis.39 However, their study did not analyze
effective premedications.
Premedications with histamine H1 receptor antagonist,
acetaminophen, or glucocorticoids are common methods to prevent IRRs
associated with the use of monoclonal antibodies.1,35Tokuda et al. reported a decreased incidence of IRR when a non-steroidal
anti-inflammatory drug (NSAID) was administered 30 minutes before
trastuzumab administration.40 In a study of cetuximab
plus irinotecan in heavily metastatic colorectal cancer that had
progressed on prior irinotecan therapy (MABEL trial), the effects of
premedication on the incidence of IRR were examined using retrospective
analysis. Histamine H1 receptor antagonist alone and
histamine H1 receptor antagonist plus glucocorticoids
were compared as prophylactic premedication; the incidence of IRRs in
any grade of colorectal cancer was 25.6% and 9.6%, respectively, and
the incidence of IRRs in Grade 3/4 cases was 4.7% and 1.0%,
respectively, suggesting the usefulness of glucocorticoids as
premedication for monoclonal antibody regimens to prevent
IRRs.41 Among all adult patients prescribed rituximab
for B-cell malignancies, the incidence of IRRs in patients premedicated
with glucocorticoids for the first infusion was significantly lower than
in patients who were not (8.3% versus 41.2%,p =0.017).37
To the best of our knowledge, the benefits of premedication with
glucocorticoids for trastuzumab treatments are not clear, as clinical
data have not demonstrated the efficacy of prophylactic administration
of glucocorticoids for IRR after trastuzumab.42 It is
common practice to slow down or interrupt the infusion rate when IRRs
occur. In addition, IRRs can cause logistic problems for infusion
centers. Patients with IRRs require an average of 54 minutes (range
10–100 minutes) of dose interruption, which can result in longer chair
time at the infusion center and delayed scheduled dosing for other
patients. These interruptions also affect the ability to move patients
within the center, often requiring additional medications, supplies, and
clinical staff time, creating an economic burden on the health care
system.39 Establishment of efficacious IRR prophylaxis
methods not only help to improve patient safety but also reduce
treatment time delays due to IRR occurrence and, ultimately, improve the
scheduling of chemotherapy departments. Prevention and management of
trastuzumab-induced IRRs has become increasingly important in recent
years, as registry data in Japan and the United Kingdom indicate that
breast cancer incidence is on the rise.43,44 In this
retrospective observational study, we aimed to determine the incidence
of IRRs during trastuzumab therapy in breast cancer patients as well as
the associated risk factors; we also aimed to validate the protective
effect of glucocorticoid premedication.