There is a need for better risk stratification. Identification of risk factors for severe IR will help clinicians to reduce the incidence and prevent more IRs. Atopic patients are generally at higher risk of developing anaphylactic reactions. Female gender, older age, history of pulmonary infiltrates, dyspnea at rest, malignancy-related pulmonary infiltrates, and chronic lymphocytic leukemia and mantlecell lymphoma have been identified as risk factors for severe IR in previous experiences with rituximab(Drug information on rituximab) and trastuzumab(Drug information on trastuzumab).[5,9]
One peculiar aspect of cetuximab(Drug information on cetuximab)associated infusion reactions in the United States is the markedly regional differences in incidence. O’Neil and colleagues confirmed an anecdotal observation that patients in specific regions of the southeastern United States treated with cetuximab-containing regimens in clinical trials at three institutions had a 22% frequency of grade 3 to 4 hypersensitivity. There was no association between race or gender and the risk of experiencing an IR. All reactions occurred during the first dose and despite the use of prophylactic use of H1 antagonists. Glucocorticoid administration prior to MoAb infusion did not prevent the allergic reaction. Furthermore, investigation into specific patient records demonstrated that a personal phenotype of atopy to a variety of other environmental and pharmaceutical agents was present in the majority of those who experienced cetuximab reactions. This phenomenon has also been observed in nearby South Carolina, northern Georgia, Arkansas, and Missouri, suggesting an exposure to an environmental antigen that cross-reacts with cetuximab in this geographic region.
Preexisting immunoglobulin IgE was initially postulated to cross-react with the amino acid mouse region of the cetuximab molecule; however, subsequent analysis has revealed IgE specific for galactose-α-1,3-galactose on both Fab segments of the heavy chain. As a consequence of this complication, the utilization of cetuximab in these geographic regions has been adversely affected, particularly when an alternative therapeutic agent is available.
An assay to prescreen patients being considered for treatment with this cetuximab has been developed (ImmunoCAP) and is currently being evaluated for approval by the US Food and Drug Administration. This assay is not expected to be necessary for all regions of the United States, nor will it capture all patients at risk for IRs. Cytokine-mediated IRs (ie, non–IgE-mediated) will still occur. In association with a thorough clinical history investigating prior atopy as well as an assessment of potential drug alternatives, the assay may, however, be clinically useful to significantly reduce the likelihood of this adverse event in IR endemic areas.
Another result of certain geographic regions in the United States carrying much higher risk of IRs is the clinical use of heavier premedication regimens, including H1 and H2 blockers and corticosteroids, by physicians practicing in high-risk areas. Although this practice may reduce the severity of cytokine-mediated reactions, it is not expected to affect IgE-mediated reactions.
A recent retrospective study presented at the 2008 annual meeting of the American Society of Clinical Oncology investigated the risk factors associated with IRs with cetuximab. Data regarding demographics and premedication history were collected from 51 colorectal cancer patients (27 males and 24 females) and 50 head and neck cancer patients (38 males and 12 females) who were treated with cetuximab. Seventy (69.3%) patients were Caucasian and 31 (30.7%) were African-American.
All patients were premedicated with diphenhydramine(Drug information on diphenhydramine) prior to cetuximab administration. Data regarding famotidine, dexamethasone(Drug information on dexamethasone), and hydrocortisone(Drug information on hydrocortisone) sodium succinate (AHydrocort, Solu-Cortef) premedication were available for 84 patients. Of these, 14 (16.7%) received famotidine(Drug information on famotidine), 32 (38.1%) received dexamethasone, and 25 (29.8%) received hydrocortisone sodium succinate. Twenty-four patients (48%) with head and neck cancer also received albuterol.
Eleven patients (10.9%) developed hypersensitivity reactions (HSRs). Serious grade 3/4 HSRs were seen in nine patients (8.9%). Race was strongly associated with HSR. All 11 patients who developed HSRs were Caucasian (Fisher’s exact P = .017). No grade 3/4 HSRs were seen in the group who received albuterol (Fisher’s exact P = .077). There were no statistically significant effects of premedication with dexamethasone, famotidine, or hydrocortisone sodium succinate on the risk of HSR, although the small numbers were limiting. Age and gender also had no effect on the risk of HSR. The authors concluded that race is a strong predictor for HSR. The authors also suggest that additional premedication with albuterol may prevent grade 3/4 HSRs.
One additional consequence of monoclonal antibody–related IRs in the United States is how these agents have been incorporated into treatment combinations using cytotoxics, rather than using MoAbs as single agents. If a given patient is unexpectedly intolerant of the targeted agent, the remaining drugs can be continued. This also fits the oncologic paradigm of using agents with different mechanisms of action together with the expectation of higher tumor response rates and avoiding overlapping toxicity.
The observed IR to monoclonal antibodies occurs primarily during the first infusion. Approximately 90% of severe infusion reactions with cetuximab were observed during the first infusion (Erbitux package insert, 2008). The rate of delayed events in subsequent doses ranges from 10% to 30%, indicating the importance of close monitoring following administration of any infusion.
There seems to be a consensus among oncologists that premedication with an antihistamine should be administered prior to the cetuximab loading dose and first weekly dose. It remains debatable whether routine use of antihistamines is beneficial prior to each subsequent dosing. A recent report by Timoney and associates suggests that administration of cetuximab without diphenhydramine premedication does not increase risk of severe IRs.
The European Union Experience
No obvious differences in the incidence of infusion-related reactions have thus far been reported within Europe. Such differences may exist, however, since the incidence of atopy and allergic asthma has been shown to be heterogeneously distributed over Europe. Significantly higher prevalence of atopy and allergic asthma were observed in the early 1990s among populations living in Western compared with populations in Eastern European countries. Changes in lifestyle after the fall of the communist system were associated with an increasing trend of atopic sensitization and hay fever in former East Germany only 6 to 8 years after the Germany reunification.
The increased prevalence of allergic asthma decades earlier in Western Europe than Eastern Europe is probably attributable to changes in lifestyle that had already occurred rather than to air pollution. The factors of a Western lifestyle (diet, hygiene, varied allergen exposure) that have determined the difference in allergic asthma prevalence across Europe are not yet fully identified. Whether the heterogeneous distribution of atopy across Europe translates into regional differences in infusion-related reactions is not yet known, but does certainly merit further investigations.
Rates of Mild and Severe IRs in the European Union
In European cancer studies, different rates of monoclonal antibody infusion-related reactions have been reported, as delineated in Table 3. Infusion-related reactions tended to be more commonly reported in trials where chimeric antibodies were given and appear to be less common when the structure of the administered antibody has more homology with the human protein. Adverse events with a fatal outcome are very rare. Nevertheless, there was a large difference in the reported IR incidence rates from different clinical trials. It is not known, whether this is due to regional differences, differences in premedication, or differences in the documentation and reporting of infusion-related adverse events and reporting.
Perspectives From the Clinic
With the increasing use of monoclonal antibodies in treating cancer in Europe, infusion-related reactions will be an increasing concern in the management of patients. European investigators should try to assess whether regional differences exist and whether specific factors associated with an increased risk for infusion-related reactions, such as history of atopy or specific preexisting IgE antibodies can be identified.[17,38] The importance of documentation and reporting of infusion-related reactions occurring within clinical trials and during routine administration should be reinforced.
With the use of chimeric and humanized antibodies, most centers in Europe give combined pharmacologic blockade of the histamine-1 and histamine- 2 receptors as premedication to reduce the probability or severity of an infusion-related reaction. This is an empiric approach and it is not clear how efficacious or for which patients this strategy is indicated.
In view of the increasing economic pressure that is put on treating physicians and institutions, time spent in the preparation and the administration of premedication and the observation of the patients postinfusion should also be considered in future pharmacoeconomic analyses comparing treatment strategies with and without monoclonal antibodies or treatments with different monoclonal antibodies.
Even with our best efforts, some IRs are unavoidable when using monoclonal antibodies therapeutically. Therefore, clinicians must accurately analyze the nature and severity of the reactions to avoid repeat reactions and to assess the feasibility of rechallenging a reacting patient with the reaction-associated agents.
Blood and Urine Tests—Timely measurement of urine histamine levels or serum tryptase levels can confirm the diagnosis of anaphylaxis, rather than relying on clinical signs and symptoms. This provides a more accurate assessment for physicians to use as a basis when formulating a subsequent treatment plan.
Test Doses—A lack of reaction to test doses of 20 mg of cetuximab is not a reliable predictor of severe infusion-related reaction. No data are yet available to identify patients more likely to have severe reactions to cetuximab infusion.