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.