Discussion
In this retrospective observational study, we tested whether
premedication with dexamethasone is effective in preventing
trastuzumab-associated IRR in patients with HER2-positive breast cancer
based on electronic medical record data. To the best of our knowledge,
this study is the first to show that dexamethasone premedication is
effective in preventing IRRs caused by trastuzumab.
In our study, premedication with dexamethasone reduced the incidence of
IRR (final model OR=0.616; 95%CI, 0.440-0.861; p =0.005) (Figure
3). Hemophagocytic lymphohistiocytosis occurring in rheumatic disease
(macrophage activation syndrome) is treated with glucocorticoids, IL-1
blockade, or cyclosporine A.48,49 Glucocorticoids
remain the first-line drugs for adult-onset Still’s disease
characterized by excessive cytokine production.50Thus, the results of this study showing that dexamethasone was effective
in preventing IRRs caused by trastuzumab support the hypothesis that
IRRs are cytokine-dependent. In a previous observational study, IRRs
were prevented when all patients received an intravenous histamine
H1 receptor antagonist (5 mg of dichlorpheniramine) as a
premedication and 6.6 mg premedication with dexamethasone as an
antiemetic agent for cetuximab therapy.51 The
dexamethasone premedication used in the patients in our study was also
intended as an antiemetic for other chemotherapy regimens administered
in combination with trastuzumab, at doses of 6.6 mg or 8.25 mg. These
suggest that doses such as those used as antiemetics are effective in
reducing IRR risk with cetuximab and trastuzumab. There is little
information on the addition of premedication to regimens that do not
traditionally require premedication, such as trastuzumab
monotherapy.39 Because unnecessary premedication may
result in dexamethasone-induced adverse events, it is necessary to
identify patients at high IRR risk and determine the need for
dexamethasone premedication. For example, preoperative status and
high-dose trastuzumab (i.e., first course patients) were identified as
risk factors for trastuzumab-induced IRR, and these patients may require
premedication with dexamethasone. A previous observational study
revealed no differences in IRR prophylaxis for cetuximab between
dexamethasone doses of 6.6 mg and 13.2 mg.51 Our
results show that the OR was 0.616 per 1 mg increase in dexamethasone,
which indicates that if 8 mg were premedicated, the OR would be 0.02, or
a 1 in 50 risk of IRR occurrence. Further studies are needed to
determine the optimal dose of dexamethasone to avoid unnecessary
exposure.
In the current study, the risk of IRR in patients with breast cancer was
higher in preoperative patients and in patients receiving high
trastuzumab doses (Figure 3). The frequency of IRRs after rituximab
administration is clearly higher in patients with tumors than in
patients with rheumatoid arthritis.30,31Administration of rituximab to patients with a large number of tumor
cells in the blood may increase the likelihood of a severe initial
IRR.33,34 In a study investigating IRRs in response to
rituximab in patients with B-cell lymphoma, multivariate logistic
regression analysis confirmed that low-grade lymphomas (OR=2.81;p =0.017) and bulky disease (OR=2.52; p =0.037) were
independent risk factors.52 The IRR risk factor
identified in the present study, preoperative status, reflects a high
tumor count, and a higher dose of trastuzumab indicates more tumors to
be destroyed. In other words, these reports are consistent with the
results of the present study, as they indicate patients with high
cytokine release. Conversely, patients who received postoperative
adjuvant chemotherapy have fewer tumor cells than preoperative patients
and therefore do not release as many cytokines; postoperative immune
dysfunction may be the reason for their low IRR risk.
Of all factors evaluated in a study by Thompson et al., high BMI, stage
IV, and no prior medication use (diphenhydramine, meperidine, or
hydrocortisone) were significantly associated with higher risks of
trastuzumab-induced IRRs in breast cancer patients.39In contrast, in our results, BMI was not associated with IRR risk. We
attribute the differences between these studies to differences in BMI
distribution in our cohort. The numbers of patients with BMI
(kg/m2) <18.5, 18.5–24.9, 25.0–29.9, and
30≤ were 0, 60, 55, and 82, respectively. In the previous study, they
were 17, 113, 36, and 10, respectively, at baseline. The lower
distribution of BMI in the present study may account for the disparities
in results. Cochran-Armitage trend testing in our study also showed a
statistically significant trend towards increased IRR incidence with
advancing stage (Table 2). Furthermore, stage IV (i.e. metastasis) was
associated with higher risk of IRR in univariate analysis (Figure 2) but
not statistically significant in multivariate analysis. There are
several possible reasons for this. First, metastasis was not detected
because of the higher IRR risk of preoperative or trastuzumab dosage
used as variables in this study. Second, the variables used in the
multivariate analysis were different. Third, the patient background,
such as BMI, was different. However, the details underlying this finding
are not known, and the IRR risk in patients with stage IV breast cancer
needs further investigation.
In the present study, high eosinophil levels were a risk factor for IRR
occurrence in univariate analysis (Figure 2), but no statistically
significant association was found when adjusted for other factors by
multivariate analysis (Figure 3). In a previous study, low eosinophil
levels were associated with trastuzumab-induced IRR in breast cancer
patients.53 High eosinophil counts were a risk factor
for cetuximab-induced IRR in patients with squamous cell carcinoma of
the head and neck.42 Therefore, the influence of blood
eosinophils on the development of IRRs caused by monoclonal antibody
preparations shows conflicting results. In addition, eosinophil levels
being used as a baseline characteristic in our study may have been a
factor in the lack of associations with increased IRR risk. Because
eosinophil data was not available for each infusion in our study, we
were unable to obtain eosinophil levels at a consistent time point prior
to each trastuzumab infusion, rather than at baseline, to assess the
role of eosinophils in IRR development as a micro-level variable.
Although the risk of IRR is clearly higher with monoclonal antibody
preparations at the first dose,37,39 course was not
associated with the development of IRRs in during multivariate analysis
(Figure 3). Since the dose of trastuzumab treatment was higher at the
first dose (8 mg/kg) than at the maintenance dose (6 mg/kg), the same
patient is at higher risk for IRRs with the first dose.
In this retrospective study of breast cancer patients treated with
trastuzumab, the overall incidence of IRR was 3.4% of all infusions.
Most IRRs occurred during the first dose (53 of 58 patients, 91.4%).
The incidence of IRRs was higher with the first course and the first
dose of 8 mg/kg, which is consistent with previous
reports.3 Previous studies have reported a relatively
high incidence of IRRs with trastuzumab (40%,23.4%,24 or 5.9%).25 Although the
incidence of IRR in our study was on the low side, the wide range in IRR
incidence between different reports seems to result from differences in
comorbidities or premedication use.37 The use of
trastuzumab has expanded to salivary gland and colorectal cancers, and
the differences in IRR occurrence by disease state should be examined in
the future.
There are several limitations to our study. First, we cannot distinguish
whether the IRRs that occurred were due to trastuzumab or other
chemotherapy. To minimize this effect, we qualified IRRs only as those
symptoms that developed within 120 minutes of the start of trastuzumab
infusion, based on reports that most trastuzumab IRRs occur during
trastuzumab administration or within 2 hours after
initiation.2 Second, it is not known from our study
whether dexamethasone premedication affects the efficacy with
trastuzumab. While previous studies have shown that pretreatment with
glucocorticoids does not affect the efficacy of rituximab at 24 weeks in
the treatment of rheumatoid arthritis,54 there is no
similar evidence for trastuzumab for breast cancer. However, studies
using BT-474 breast cancer cells suggest that dexamethasone at least
partially inhibits the growth-suppressing effects of
trastuzumab;55 therefore, clinical evaluations are
needed.
In conclusion, to investigate how to prevent trastuzumab-induced IRR in
breast cancer, we analyzed a model adjusted for patient background and
found that premedication with dexamethasone is effective in preventing
trastuzumab-induced IRR. However, the current lack of information on the
risks of dexamethasone-induced adverse events and its effect on
trastuzumab efficacy makes it impractical to unreservedly recommend
premedication with dexamethasone based solely on this study. It is
essential to select patients at high risk for IRR for dexamethasone
premedication, such as those of preoperative status and who are
receiving high trastuzumab doses based on the results of this study. In
addition, dexamethasone should be limited to a minimal dose to lower IRR
risk and avoid prolonged infusion time, and dexamethasone premedication
should not be used in patients at high risk for dexamethasone-associated
adverse events. Future studies are needed to determine the optimal dose
of dexamethasone to prevent IRRs and the impacts of dexamethasone on the
efficacy of trastuzumab in breast cancer.