Complications of TreatmentInfectious complications in cancer patients treated with anti-EGFR monoclonal antibodies cetuximab and panitumumab: A systematic review and meta-analysis
Introduction
The epidermal growth factor receptor (EGFR), which is a member of the ErbB receptor tyrosine kinases, is composed of an extracellular ligand-binding domain, a hydrophobic transmembrane domain and an intracytoplasmic tyrosine kinase domain. Binding of ligands, such as epidermal growth factor (EGF) and transforming growth factor alpha (TGF-α), leads to receptor dimerization and autophosphorylation of key tyrosine residues within the receptors which initiates intracellular signaling. EGFR signaling plays an important role in cancer cell proliferation, inhibition of apoptosis, differentiation, adhesion and migration [1], [2]. Approximately 30% of cancers overexpress EGFR, which has been associated with advanced disease, recurrence, metastasis and poor survival [3], [4].
Accordingly, monoclonal antibodies (mAbs) that target the extracellular ligand-binding domain of EGFR have been developed. Cetuximab is a chimeric mAb with the Fv regions of a murine anti-EGFR antibody and human IgG1 heavy and kappa light-chain constant regions. Panitumumab is a fully human anti-EGFR mAb [5], [6]. Currently, the United States Food and Drug Administration (FDA) has approved cetuximab for the treatment of advanced/metastatic colorectal cancer and squamous cell carcinoma of the head and neck (SCCHN) [5]. Panitumumab has been approved for the treatment of patients with EGFR-expressing metastatic colorectal cancer [6].
With the use of anti-EGFR mAbs, some unique adverse events have been reported. For instance, previous meta-analyses have shown an increased risk of rash, nail changes, hypokalemia, hypomagnesemia and venous thromboembolism [7], [8], [9], [10], [11]. Additionally, infectious complications associated with anti-EGFR mAbs have been reported in randomized controlled trials (RCTs). Lee et al. performed an observational study to assess the association between cetuximab therapy and infection events requiring hospitalization. They used a national cohort of 1083 patients with head and neck cancers identified through the National Health Insurance Research Database in Taiwan. With a median follow-up duration of 6.5 months, 20.3% (32/158) patients receiving cetuximab and 10.1% (93/925) patients not receiving cetuximab had infection events. Though the propensity score analysis revealed a higher risk of infection with cetuximab (OR, 2.27; 95% CI, 1.46–3.54), the instrumental variable analysis (IVA) showed no increased risk of infection with cetuximab (OR, 0.87; 95% CI, 0.61–1.14) [12]. There were limitations to their study. First, despite their efforts to simulate the randomization situation with IVA, confounding variables may not have been adequately controlled. Second, their sample size was relatively small. Since they only included patients with head and neck cancers, we do not know its risk in other cancer types. Especially, a risk of high-grade infection with cetuximab has been reported with a substantial variation in randomized controlled trials. For instance, Pirker et al. [13] and Alberts et al. [14] reported a higher incidence of infection with cetuximab compared with control in their trials, while Sobrero et al. [15] and Lynch et al. [16] did not report a significant difference in infectious risk. RCTs have reported a risk of high-grade infection with panitumumab inconsistently as well [17], [18]. Thus, the risk of high-grade infection with anti-EGFR mAbs has not yet been fully elucidated. Therefore, we conducted an up-to-date systemic review and meta-analysis of RCTs to determine the overall risk of high-grade infection associated with the use of anti-EGFR-mAbs cetuximab and panitumumab.
Section snippets
Data source
We conducted an independent review of PubMed from January 1966 to January 2014. We limited our search to anti-EGFR monoclonal antibodies approved by the FDA. Searches were performed by using the keywords “cetuximab” or “panitumumab” and were limited to randomized clinical trials. We searched abstracts and virtual meeting presentations from the American Society of Clinical Oncology (ASCO) conferences held up to January 2014 utilizing the same search terms in order to identify relevant trials. An
Search results
Our search strategy yielded 272 potentially relevant publications in the PubMed and ASCO databases. 244 publications were excluded. This selection process and reasons for study exclusion are shown in Fig. 1. Thus, a total of 28 randomized clinical trials were considered eligible for the meta-analysis, including 16 phase III trials, 11 phase II trials and one phase II/III trial. 27 trials were open-label whereas the only one was double-blind placebo controlled. From the abstracts presented at
Discussion
This meta-analysis of 28 RCTs including a total of 14,957 patients evaluated the risk of high-grade infection and febrile neutropenia in patients with cancer receiving anti-EGFR mAbs. Our pooled results demonstrated a significantly increased risk of high-grade infection and febrile neutropenia with anti-EGFR mAbs compared with the controls with RR of 1.49 (95% CI, 1.33–1.66; P < 0.001) and RR of 1.27 (95% CI, 1.09–1.48; P = 0.002), respectively. Infection seems to be a class-type adverse effect of
Conflict of interest
The authors declare no competing financial interests.
Role of the funding source
This study was not funded by any sponsors.
Authorship
T.F. designed research, collected data, analyzed and interpreted data, and wrote the manuscript. M.S. contributed to collection of data and revision of the manuscript. K.T. participated in the elaboration of the research design and revision of the manuscript.
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