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Symptom Management and Supportive Care |
University of Southern California, Los Angeles, California, USA
Key Words. Hypersensitivity • Infusion reactions • Monoclonal antibodies • Taxanes • Platinum • Rechallenge
Correspondence: Heinz-Josef Lenz, M.D., F.A.C.P., USC/Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Room 3456, Los Angeles, California 90033, USA. Telephone: 323-865-3955; Fax: 323-865-0061; e-mail: lenz{at}usc.edu (cc to assistant: ramirez4{at}usc.edu)
Received January 8, 2007; accepted for publication February 28, 2007.
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LEARNING OBJECTIVES
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Learning Objectives
Abstract
Introduction
Characteristics of...
Management of Hypersensitivity...
Conclusions
Disclosure of Potential...
Acknowledgments
References
After completing this course, the reader will be able to:
| ABSTRACT |
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Methods. MEDLINE was searched for recent studies and reviews pertaining to hypersensitivity reactions with monoclonal antibodies (cetuximab, rituximab, trastuzumab, panitumumab, bevacizumab), platinum compounds (carboplatin, oxaliplatin), and taxanes (paclitaxel, docetaxel). Emphasis was placed on articles that provided practical information on hypersensitivity reaction management. Data found in the literature were supplemented with information from the package insert for each agent.
Results. Severe hypersensitivity reactions are rare, with an incidence of
5%, provided patients receive proper premedication, close monitoring, and prompt intervention when symptoms occur. Hypersensitivity reactions to platinum compounds are generally consistent with type 1 hypersensitivity, occurring after multiple cycles of therapy. Reactions to taxanes and monoclonal antibodies produce similar symptoms, but are generally immediate, occurring during the first few minutes of the first or second infusion. However, 10%30% of reactions to monoclonal antibodies are delayed, and may occur in later infusions, indicating the importance of close observation of the patient following administration. Mild-to-moderate reactions can be managed by temporary infusion interruption, reduction of the infusion rate, and symptom management. Rechallenge should be considered after complete resolution of all symptoms. Severe reactions may require treatment discontinuation.
Conclusion. Hypersensitivity or infusion reactions to platinum compounds are acquired; reactions to taxanes and monoclonal antibodies are immediate and typically occur during the first few minutes of the first infusion. The different time of onset should be considered when developing strategies for preventing and managing hypersensitivity reactions. The decision to rechallenge or discontinue treatment after a reaction occurs depends on the severity of the reaction and other clinical factors.
Disclosure of potential conflicts of interest is found at the end of this article.
| INTRODUCTION |
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This article reviews the clinical features and current management strategies of hypersensitivity reactions and of milder infusion reactions for selected, commonly used platinum compounds (carboplatin, oxaliplatin), taxanes (paclitaxel, docetaxel), and monoclonal antibodies (cetuximab, trastuzumab, rituximab, bevacizumab, and panitumumab). A MEDLINE search was conducted for studies and reviews pertaining to hypersensitivity reactions to these agents. Supplemental information was obtained from the product information provided for each agent. Emphasis was placed on practical information regarding prevention and management of hypersensitivity, and how the occurrence of these reactions affects further treatment.
| CHARACTERISTICS OF HYPERSENSITIVITY REACTIONS |
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Some chemotherapy agents, their metabolites, and vehicles interact directly with mast cells and basophils, producing an anaphylactoid response that is indistinguishable from an IgE-mediated response [1]. The taxanes paclitaxel and docetaxel produce reactions that are clinically similar to type 1 hypersensitivity, but evidence suggests that these reactions are not mediated by IgE [9, 10]. Instead, these reactions may be caused by direct effects on immune cells or other mechanisms. Cremophor EL (polyoxyethylated castor oil), the excipient found in paclitaxel (but not docetaxel), has also been shown to induce histamine release and hypotension and may therefore be responsible in part for hypersensitivity reactions [1, 11]. An albumin-bound form of paclitaxel that does not contain Cremophor EL has been associated with little to no incidence of severe hypersensitivity reactions, even in the absence of premedication [12].
Treatment with monoclonal antibodies has been associated with infusion reactions, some of which are severe. The National Cancer Institute Common Toxicity Criteria (NCI-CTC) distinguish between hypersensitivity reactions and acute infusion reactions induced by cytokine release (Table 1) [13, 14]. The exact mechanism responsible for infusion reactions to monoclonal antibodies is not known, but like the taxanes, these reactions are unlikely to be true, type 1 IgE-mediated hypersensitivity reactions [15]. Theoretically, infusion reactions to chimeric and humanized monoclonal antibodies may be a result of their ability to elicit human antichimeric antibodies (HACAs) and human anti-human antibodies (HAHAs), respectively [16]. This theory is supported by the observation that the incidence of infusion reactions to panitumumab, a fully human monoclonal antibody that targets the epidermal growth factor receptor, is in the range of 1%5% [17, 18]. However, a correlation between infusion reactions and HACAs or HAHAs has not been demonstrated [1921].
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In contrast, nearly 95% of all reactions to taxanes occur during the first or second infusion, suggesting a nonIgE-mediated mechanism [1, 5, 11]. These reactions occur rapidly, with up to 80% of patients developing symptoms within the first 10 minutes of the infusion [1, 34]. Similarly, infusion reactions to monoclonal antibodies occur primarily during the first infusion [20, 21, 27, 30]. Approximately 90% of severe infusion reactions with cetuximab were observed during the first infusion [20]. For rituximab, the incidence of any-grade infusion reactions during the first, fourth, and eighth infusion was 77%, 30%, and 14%, respectively [27]. This rate of 10%30% of delayed events in subsequent doses indicates the importance of close monitoring following administration of any infusion.
| MANAGEMENT OF HYPERSENSITIVITY AND INFUSION REACTIONS |
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Prevention
Pharmacological prophylaxis with antihistamines, corticosteroids, or both is generally recommended to reduce the frequency and severity of hypersensitivity reactions (Tables 3 and 4) [1, 11, 35]. For example, standard premedication for paclitaxel includes dexamethasone, diphenhydramine, and an H2 antagonist (cimetidine, famotidine, or ranitidine), although other simplified approaches have been used successfully [11, 36]. Premedication with diphenhydramine is recommended before each infusion of cetuximab [20]. Timoney et al. [37] recently reported that premedication can be safely discontinued after the first infusion of cetuximab if no hypersensitivity reaction is observed. At University of Southern California (USC), diphenhydramine is often replaced by loratadine, a nonsedating antihistamine, in patients who do not experience an infusion reaction during the first infusion of cetuximab.
Patients should be monitored closely during and immediately after all infusions. Particularly close monitoring is warranted when the risk of hypersensitivity reactions is higher, such as during the first infusion of taxanes or monoclonal antibodies or after multiple cycles of platinum therapy. Vital signs should be checked before, during, and after the infusion [5]. The possibility of a delayed reaction, which may occur hours or days after an infusion, should also be considered. In addition to careful monitoring, patients should be strongly encouraged to notify a clinician immediately if they notice any discomfort during the infusion.
Hypersensitivity reactions are unpredictable and can occur at any time, despite preventive measures. Therefore, clinicians should be prepared for a reaction to occur during each administration [1]. Standing orders should be in place to allow immediate intervention if a reaction occurs, without waiting for a physician [5]. A "crash cart" with the resources needed for resuscitation should be readily available. This includes not only pharmacological agents such as epinephrine and aerosolized bronchodilators, but also medical equipment such as oxygen tanks, tracheostomy equipment, and a defibrillator. Sufficient medical resources should be available to sustain a patient who experiences a severe infusion reaction until they can be admitted [38].
Management
Prompt recognition and immediate medical attention are essential to reducing the risk of severe symptoms [3]. Oncology nurses administering medication should have a protocol on hand that outlines the emergency management of hypersensitivity reactions [5]. At USC, for example, we have developed standing orders that include specific interventions for symptoms of hypersensitivity (Fig. 1). These protocols allow for immediate intervention by the nursing staff if a reaction occurs, without waiting for a physician. When an infusion reaction occurs, the infusion should be interrupted and supportive care should be administered until the symptoms resolve. In most cases, mild-to-moderate reactions will resolve after a brief infusion interruption and the administration of supportive care.
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Mild-to-moderate reactions to platinum compounds generally do not require treatment discontinuation [7]. Many patients can continue therapy or be rechallenged after symptoms have resolved using pretreatment with antihistamines and corticosteroids [4, 5, 7, 23]. However, rechallenge with platinum compounds is generally less successful than with taxanes: approximately 50% of patients rechallenged with platinum compounds experience recurrent hypersensitivity reactions despite premedication [1].
Similar to taxanes, desensitization protocols modifying infusion times have been used with success to reduce the risk of a second reaction to platinum agents [2, 4, 8, 40]. Some of these protocols are based on reinstating treatment at a low concentration and progressively increasing the concentration of the drug by administering a sequence of serial dilutions (i.e., 1:104, 1:103, 1:102, 1:10), over extended infusion periods. This approach has been successful in rechallenging patients who had experienced reactions to carboplatin and oxaliplatin. As those patients undergo safe infusions after a reaction, premedications can be used for subsequent doses [41].
In any circumstance, the decision to rechallenge with any agent should be based on several clinical factors, including the risk for a serious recurrent reaction and the potential clinical benefit of further treatment. For example, if the drug is given as salvage therapy or as palliative care, the long-term clinical benefits of continued treatment are likely to be small and may not warrant the risk for severe toxicity. In this case, switching to an alternative agent, if available, may be appropriate. However, continuing active treatment should be a priority for patients who have mild-to-moderate reactions, and strategies that safely allow continuation should be considered, particularly if the goal of therapy is to prolong survival. The decision to continue or discontinue treatment must be made on a case-by-case basis after weighing all of the relevant clinical factors. Accurate grading of hypersensitivity and infusion reactions, including distinguishing between moderate and more severe reactions, may be critical to determine the best treatment plan following resolution of symptoms.
| CONCLUSIONS |
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The risk for severe hypersensitivity reactions can possibly be reduced by checking for a history of drug allergies, adequate premedication, careful patient monitoring, and prompt intervention when signs of hypersensitivity occur. Accurate grading of reactions is essential in determining how to proceed with treatment. Mild-to-moderate reactions are managed by temporarily interrupting the infusion and administering supportive care for symptoms. Most patients can be safely rechallenged with the drug following complete resolution of symptoms using a reduced infusion rate, premedication, and/or a desensitization protocol. For severe reactions, the infusion should be stopped, supportive care should be provided, and, in most cases, treatment should be discontinued.
| DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST |
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| ACKNOWLEDGMENTS |
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| REFERENCES |
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