Retrospective evaluation of cetuximab-related adverse events from claims databases—methodological concerns
Authors: S. Maier, G. Peltz, J.R. Penrod, K.P. Sugarman
Journal: Annals of Oncology (2010)

Foley et al. [1.Foley K.A. Wang P.F. Barber B.L. et al.Clinical and economic impact of infusion reactions in patients with colorectal cancer treated with cetuximab.Ann Oncol. 2010; 21: 1455-1461Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar] use insurance claims data to retrospectively estimate infusion reaction (IR) rates in patients receiving cetuximab for metastatic colorectal cancer. They conclude that ‘8.4% experienced IRs requiring resource-intensive medical intervention, a rate that is two to three times higher than that of severe IRs reported in the cetuximab prescribing information (3%)’. IRs are important safety events and occur with many monoclonal antibodies, including cetuximab and panitumumab [2.Chung C.H. Managing premedications and the risk for reactions to infusional monoclonal antibody therapy.Oncologist. 2008; 13: 725-732Crossref PubMed Scopus (175) Google Scholar]. IRs present with a variety of signs and symptoms and have variable clinical impact. Underestimation or overestimation may have major consequences for prescribing physicians and patients. Therefore, IRs must be described with high scientific rigor. The cetuximab label reports severe [National Cancer Institute—Common Toxicity Criteria (NCI–CTC) grades 3–4] IRs in 2%–5%. Serious reactions requiring medical intervention and immediate permanent discontinuation of cetuximab occurred in ∼3%. These data, collected prospectively in well-controlled clinical trials, are consistent with postmarketing surveillance. A direct comparison of the events described by Foley et al. and the IRs reported in the cetuximab label is inappropriate because the authors did not ascertain, confirm, or grade events in the same manner: they did not employ NCI–CTC criteria to identify severe events or the criteria for serious IRs described in the cetuximab label. Events requiring medical intervention are not necessarily severe or serious. Indeed, of the events identified by Foley et al., 31.9% resulted in no interruptions of cetuximab; 34.1% had some but not permanent disruption; and only 34% permanently discontinued cetuximab. Only 39.4% required an emergency room visit or hospitalization. In well-controlled closely monitored clinical trials and extensive postmarketing experience, ∼90% of severe IRs occurred with the first infusion compared with only 41% of the events described by Foley et al., suggesting that many of these may not have been severe or serious or not related to cetuximab. Several diagnoses and treatments used to identify the IRs do not establish the definitive diagnosis of an IR and may alternatively indicate other illnesses, complications of metastatic colon cancer, or reactions to other therapies. Also, including events up to the second day post-infusion may also have led to overestimation of the number of reactions. While it is possible to identify claims data sources that can be matched to more detailed data such as medical records, such combined data sets were not employed in this study, nor has the algorithm, to our knowledge, been validated in claims data previously. Thus, while retrospective investigations can help to describe adverse events in medical practice, the conclusions drawn in Foley et al. are not supported by the analysis. Potential limitations are described insufficiently, and in the absence of a balanced discussion, their conclusions may be misleading for physicians and patients. IR rates reported in the cetuximab label are based on extensive clinical trial experience as well as vigilant postmarketing surveillance, both of which have been reported to and reviewed by regulatory authorities. Eli Lilly and Company and Bristol-Myers Squibb continue to closely monitor the reporting rate of this important safety event in medical practice. Funding to pay the Open Access publication charges for this letter to the editor was provided by Bristol-Myers Squibb.