Results
Study subjects
Of 229 patients identified during the 4-year study period (January 1,
2017, to December 31, 2020), 176 patients met the inclusion criteria and
received 2,320 infusions that could be evaluated. Patients were excluded
for the following reasons: missing information on HER2 status
(n =1); missing information on eosinophils (n =11); or first
infusion of trastuzumab before January 1, 2017 (n =41) (Figure 1).
Demographic and clinical characteristics of the
patients
The baseline patient and tumor characteristics of this cohort are
summarized in Table 1, and the treatment characteristics are described
in Table 2. The final sample (n =176) had a median age of 56 years
(interquartile range, IQR: 48–69 years), and most patients had
nonmetastatic disease (stages I–III, 85.8%). Of the 176 patients
evaluated, 58 patients (33.0%) experienced IRRs, and IRRs occurred in
80 infusions (3.4%) of the total 2,320 infusions. Dexamethasone was
administered as a premedication in 281 of the 2,320 trastuzumab
infusions (12.1%). However, these dexamethasone doses were intended to
prevent adverse events from concurrent chemotherapy (e.g., taxane prior
to trastuzumab infusion). Most patients received trastuzumab with a
loading dose of 8 mg/kg for 90 min, followed by 6 mg/kg for 30 min every
three weeks. Sixty-nine IRRs occurred during the 8 mg/kg loading dose
for 90 min (69 of 271, 25.5%), and no IRRs occurred during a 4 mg/kg
loading dose for 90 min (0 of 2, 0%). Eleven IRRs occurred during
maintenance infusions of 6 mg/kg for 30 min (11 of 2,025, 0.5%), and no
IRRs were documented with the 2 mg/kg maintenance dose (n =22) in
this cohort of patients.
Details of infusion-related
reaction
Information related to the IRRs in this cohort is shown in Table 3. Most
reactions occurred during the first dose (53 of 58, 91.4%). Symptoms
included chills (n =57), decreased SpO2(n =8), dyspnea (n =7), hypotension (n =1), pyrexia
(n =35), nausea (n =19), shivering (n =25), and
vomiting (n =6). Most of the reactions were grade 1 or 2 (79 of
80, 98.8%). One patient experienced grade 3 reactions. IRRs to
trastuzumab were effectively managed by temporarily discontinuing
infusion and/or administering supportive medications such as NSAIDs.
IRRs to trastuzumab occurred 60 minutes on median (IQR, 45–70 minutes)
after the infusion. Patients who had IRRs to trastuzumab spent
additional time in the chemotherapy center until their symptoms had
resolved. Symptoms related to IRRs were resolved in all patients.
Preventive effects of dexamethasone against
IRRs
Since the null model yielded an ICC of 0.36, it was determined that
analysis using the hierarchical structure was
necessary.47 Figure 2 shows the unadjusted risk of
developing IRR obtained by univariate multilevel logistic regression
analysis. Univariate analysis revealed that metastasis (odds ratio,
OR=2.72; 95% confidence interval, 95% CI, 1.13–6.55; p =0.026),
preoperative status (OR=4.74; 95% CI, 2.18–10.31;p <0.001), trastuzumab dose (mg/kg; per unit; OR=58.8;
95% CI, 22.0–157.0; p <0.001), and eosinophil (/µL;
per 100 units; OR=1.30; 95% CI, 1.04–1.63; p =0.020) were
significantly associated with increased risk of IRRs. On the other hand,
course (per unit; OR=0.79; 95% CI, 0.73–0.86;p <0.001) and postoperative status (OR=0.22; 95% CI,
0.10–0.47; p <0.001) were significantly associated with
a lower risk of IRRs.
The results of the multivariate multilevel logistic regression analysis
are shown in Figure 3. In model 1, which included micro-level variables,
dexamethasone and the four covariates that were statistically
significant by univariate analysis were included in the multivariate
analysis, and higher doses of dexamethasone premedication were
associated with significantly lower risks of IRR after starting
trastuzumab. In model 2, which included macro-level variables, higher
baseline eosinophil levels resulted in higher IRR risk. In model 3,
which included micro- and macro-level variables, dexamethasone and five
covariates that were statistically significant by univariate analysis
were incorporated to obtain an adjusted OR, which showed that
dexamethasone premedication suppressed IRRs after starting trastuzumab
(mg; per unit; OR=0.62; 95% CI, 0.44‒0.86; p =0.005). In
addition, preoperative status (OR=34.7; 95% CI, 5.0–242.0;p <0.001) and high dose of trastuzumab (mg/kg; per unit;
OR=59.6; 95% CI, 19.7–180.0; p <0.001) were
independent risk factors for IRR. VIFs were less than 2 in all models
and there was no multicollinearity among the explanatory variables
(max=1.85; min=1.01).
Goodness-of-fit
measures
Table 4 shows the results of a comparison of the data’s suitability for
the model. Based on the results of the AIC, BIC, or likelihood ratio
tests, the goodness-of-fit was high for model 1 and model 3, which
included micro-level variables.