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.