Severe hypersensitivity reactions to antineoplastic agents are quite rare, occurring 5% of the time across all agents.1 Despite this, the impact to the patient can be quite significant, resulting in discomfort and distress, hospitalization, treatment discontinuation, and even death. Unlike most adverse reactions, which often can be predicted, infusion reactions are unexpected and variable. Although rare, nearly every antineoplastic drug has been associated with a hypersensitivity reaction.
It is estimated that an average of $177.4 billion is spent annually in the United States on managing adverse drug reactions.2 Although infusionrelated reactions make up a small percentage of adverse drug reactions, they still carry a significant economic impact. Infusion-related reactions may lead to prolonged infusion times, dose reductions, dose delays, and/or discontinuation of the drug.3,4 They also can lead to hospitalizations and compromise optimal cancer therapy outcome. For this reason, it is important for all oncologists, nurses, and pharmacists to have a fundamental background in the prevention and management of infusion reactions.
Classification of hypersensitivity reactions
Hypersensitivity reactions are classified into two categories: type A and type B. Type-A reactions are adverse side effects caused by drug properties. For example, the use of vincristine may cause constipation. In contrast, type-B reactions are considered immune mediated. The classic mechanism of im - mune-mediated hypersensitivity reactions involves the formation of im munoglobulin E (IgE) antibodies from drug exposure. Subsequently, IgE binds to mast cells, which can lead to the release of numerous cytokines.5 Hypersensitivity reactions may also be non-IgE mediated, but the manifestations are identical.6 An infusion reaction is a type of hypersensitivity reaction that develops during or shortly after administration of a drug. Signs and symptoms may include pruritus, urticaria, fever, rigors/chills, diaphoresis, bronchospasms, and cardiovascular collapse. The Cancer Therapy Evaluation Program has developed grading criteria based on presentation (Table 1).7
Incidence of infusion-related reactions
Severe hypersensitivity reactions are rare occurrences with the use of proper preventive measures. The overall incidence varies across drug classes and agents. In addition, incidence rates have been variable across time and studies. For example, earlier reports of cisplatin infusion reactions cite a 10% to 27% overall incidence.1 Modern infusion techniques with slower infusion rates and improved premedication with dexamethasone have resulted in a much lower rate of infusion reactions.
Historically, the most common drug classes associated with hypersensitivity reactions were the taxanes, platinum compounds, and monoclonal antibodies.8 Specific antineoplastics reported to carry a significant risk include denileukin diftitox, liposomal doxorubicin, etoposide, ixabepilone, teniposide, and Lasparaginase. Anti neo plastics that rarely result in hyper sensitivity reactions in - clude the anthracyclines, bleomycin, 6-mercaptopurine, azathioprine, and various alkylating agents, including dacarb - azine and melphalan.9 Table 2 lists the agents by class with overall reported rates of hypersensitivity reactions.
Exact mechanisms of hypersensitivity reactions with antineoplastic agents remain unclear. They can be immuneor nonimmune-mediated reactions. The cause may be related to the drug compound, the drug vehicle, or patient-related risk factors (ie, disease site, tumor burden). This article will focus on three chemotherapy classes commonly associated with infusion reactions: taxanes, platinum compounds, and monoclonal antibodies.
Taxanes
The two most frequently used taxanes are paclitaxel and docetaxel. Hypersensitivity to paclitaxel typically occurs within 10 minutes of infusion but may extend to 12 hours.27 It is not known whether the cause of infusion reactions is the drug or the polyoxyethylated castor oil solvent. For this reason, nanoparticle albuminbound paclitaxel is manufactured with human albumin as the solvent. Docetaxel is suspended in a polysorbate 80 vehicle.28 Hypersensitivity reactions to docetaxel are unpredictable. It is possible that polysorbate 80 is the culprit. Newer formulations are under development to maximize antitumor activities and minimize the risk of hypersensitivity reactions.29
Platinum agents
Oxaliplatin, carboplatin, and cisplatin are the platinum compounds available in the United States. Most of the hypersensitivity reactions associated with their use are IgE mediated and, as a result, reaction incidence increases with subsequent cycles.30 For oxaliplatin, the average time between first drug exposure and reaction has been reported as 217.7 days (cycles 9-10).31 The average time to reaction for carboplatin has been found to be five to six cycles.32 The cause and timing of reactions for cisplatin have not been elucidated.
Monoclonal antibodies
The incidence of hypersensitivity reactions to monoclonal antibodies is variable. The immunogenicity of each specific agent is an important determinant of the overall risk of a patient experiencing a hypersensitivity reaction. The murine antibodies contain no human proteins, whereas chimeric antibodies contain approximately 65% to 90% human amino acids, humanized antibodies contain >90% human amino acids, and fully humanized antibodies contain 100% human amino acids. Murine antibodies carry the highest risk of an immune reaction and thus are not used for solid tumors and only in a limited capacity for hematologic malignancies.
Cetuximab, a chimeric mousehuman IgG1 monoclonal antibody against the epidermal growth factor receptor, is used to treat a variety of solid tumors. A retrospective study suggested that infusion reactions to cetuximab are mediated via IgE antibodies directed at the oligosaccharide, galactose- -1,3-galactose, which is present on the fragment antigen binding portion of the cetuximab molecule.33 In phase 2 and 3 clinical trials, reactions to cetuximab most commonly occurred during the first infusion.15 The overall risk of severe infusion reaction to cetuximab is reported at 3% in national and international studies, but follow-up reports have described this rate to be variable across demographic areas of the United States.8,34 For example, in Tennessee and North Carolina the risk of severe infusion reaction was found to be 22%, whereas in the Northeast it was <1%.14 It has been proposed that this is because individuals in specific geographic areas have increased expose to mouse antigen and develop IgE antibodies against cetuximab.33
Rituximab is a chimeric monoclonal antibody indicated for hematologic malignancies. The reported overall incidence of hypersensitivity reactions to rituximab is 77% with the first infusion, but by the eighth infusion, the rate decreases to only 14%.35 Rituximab reactions appear to be positively correlated with tumor necrosis factor- and interleukin-6 serum concentrations.36 Risk factors for the development of an infusion reaction include lymphocyte counts >50 109/L and high numbers of circulating CD20+ cells.36 The most common adverse effects include fever, chills, rash, and nausea occurring during the first infusion. Infusion reactions typically occur within 30 to 120 minutes and resolve with discontinuation of the infusion and supportive care.19
Humanized monoclonal antibodies, such as trastuzumab and bevacizumab, have a lower rate of hypersensitivity reactions than murine and chimeric monoclonal antibodies, and premedication is often not required. The exact mechanism of infusion reactions to trastuzumab has not been elucidated. Signs and symptoms reported in clinical trials include fever, chills, nausea, vomiting, headache, dizziness, dyspnea, hypotension, rash, and asthenia. No risk factors have been identified to predict which patients are likely to develop reactions.21 Bevacizumab is a monoclonal antibody that targets the vascular endothelial growth factor. Patients may present with hypertension rather than hypotension, as seen with other monoclonal antibodies.18 Fully human panitumumab has an extremely low incidence of hypersensitivity reactions and is well tolerated.8,34 Ofatumumab, a novel CD20 monoclonal antibody, however, has a high incidence with the first two doses because of cytokine release, but it appears from an interim analysis that long-term administration is well tolerated.17
Prevention and treatment
Patients who are about to begin treatment need to have their medical history reviewed, which must include analysis of previous therapies and allergic reactions. A thorough evaluation may reveal previous allergic reactions that can lead to an increased risk of hypersensitivity reactions during chemotherapy infusion. Obtaining a complete assessment of a patient’s allergies beforehand may prompt therapeutic interventions to decrease the risk of infusion-related reactions. Other factors that may increase the risk of hypersensitivity reactions that should be reviewed before the initiation of chemotherapy include age, race, sex, geographic location, malignancy, and previous chemotherapy administration.9,14,37 Counseling should also be a mainstay of a patient’s chemotherapy treatment. Patients should be educated on the drug’s possible side effects and informed of infusion- related reactions that may occur during their course of therapy.
Most infusion-related reactions to taxanes can be prevented by using premedications. Use of histamine H1- and H2-receptor antagonists and corticosteroids can decrease the occurrence of infusion-related reactions to less than 10%.1 Dex amethasone is used to reduce the incidence and severity of fluid retention from docetaxel infusions.38 Pre medications for monoclonal antibodies vary. In most cases, antihistamines are used as the mainstay of premedication regimens. However, a retrospective study evaluated the use of antihistamines versus steroids and antihistamines for premedication before cetuximab administration and showed a substantial decrease in infusion-related reactions.38 Mild-to-moderate infusion reactions may be managed by holding the drug and then restarting the infusion at a slower rate, adding antihistamines for symptom management, and/or adding corticosteroids. Patients should be monitored during their infusion, with cessation of infusion if the patient experiences noticeable chest pain, cardiac issues, or anaphylaxis. Appropriate supportive care should be initiated.
Anaphylaxis
The incidence of anaphylaxis during infusion of antineoplastic or biologic agents varies as does severity and symptomatology. Anaphylaxis is a lifethreatening reaction that can either be generalized or systemic based on its etiology. It is characterized by an unexpected onset of symptoms that may include an increase in anxiety similar to a panic disorder as well as changes in the patient’s airway status, breathing, and/or circulation.39 Other possible symptoms include throat or tongue swelling, stridor, hoarseness, wheezing, increased respiratory rate, fatigue, hypoxia, hypotension, dizziness, and loss of consciousness.40 Some patients may experience systemic allergy symptoms such as angioedema and urticaria, which are usually less severe. In all cases, prompt attention and an immediate response to the patient’s initial hypersensitivity reaction are essential.
In cases of severe anaphylaxis, death can occur within 30 minutes from the time of the patient’s initial exposure to the drug.41 Criteria for treatment should be available at each infusion center to expedite measures and antidotes for treatment. Guidelines for the management of anaphylaxis have been developed by the American Heart Association and the Oncology Nursing Society (Table 3).39,40,42 At the first sign of a reaction, the chemotherapy should be stopped with prompt intervention by the medical and healthcare staff:
• Recline the patient to a comfortable position, leaving the legs elevated
• Administer oxygen at high flow rates
• Continue to evaluate vital signs
Desensitization
Numerous chemotherapy agents can cause infusion-related reactions, with some patients exhibiting severe reactions during chemotherapy. In some cases, the patient may require the chemotherapy, even after experiencing a reaction because of the limited choice of therapeutic alternatives. The use of desensitization protocols for these patients provides an option to continue with their chemotherapy. Desensitization protocols have been used to treat hypersensitivity reactions to most chemotherapy agents, including taxanes, platinoids, anthracyclines (including doxorubicin), and, to a lesser extent, monoclonal antibodies. Thegeneral principle is gradual reintroduction of small amounts of drug antigens. Rapid desensitization induces temporary clinical toleration and is achieved by administering small incremental diluted doses of the drug to the full therapeutic dose within several hours.43,44 Initial rapid desensitization should be performed only in settings under the guidance of a physician, with one-onone nurse –patient care and where resuscitation personnel and resources are readily available. Repeated desensitization can be safely performed in outpatient settings with similar conditions, which allow patients to continue their treatment schedule without a change in the efficacy of treatment.45
Summary
Infusion-related reactions occur with numerous chemotherapy agents in a wide variety of treatment regimens. Hypersensitivity reactions may be specific to drug classes and biologic agents. Most patients who exhibit infusion- related reactions are able to be rechallenged either by changes to premedications or through desensitization pro tocols. The next decade should bring new biologic and antineoplastic oncology agents that will need to be continually evaluated for infusion reactions. The expected increase in patients being diagnosed with cancer will likely increase the number of patients being treated with chemotherapy. Developing a plan that prevents infusion-related reactions at your institution requires developing a process that educates healthcare staff to the signs and symptoms of these reactions, counseling patients on the adverse effects of therapy, and creating protocol guidelines for managing reactions when they occur. Implementation of these procedures for infusion centers can provide proper management to prevent and treat reactions in a timely manner. !
References
1. Syrigou E, Makrilia N, Koti I, et al. Hyper - sensitivity reactions to antineoplastic agents: an overview. Anticancer Drugs. 2009; 20:1-6.
2. Ernst FR, Grizzle AJ. Drug-related morbidity and mortality: updating the cost-of-illness model. J Am Pharm Assoc (Wash). 2001; 41:192-199.
3. Schwartzberg LS, Stepanski EJ, Fortner BV, Houts AC. Retrospective chart review of severe infusion reactions with rituximab, cetuximab, and bevacizumab in community oncology practices: assessment of clinical consequences. Support Care Cancer. 2008;16:393-398.
4. Schwartzberg LS, Stepanski EJ, Walker MS, et al. Implications of IV monoclonal antibody infusion reaction for the patient, caregiver, and practice: results of a multicenter study. Support Care Cancer. 2009;17:91-98.
5. Schnyder B, Pichler WJ. Mechanisms of druginduced allergy. Mayo Clin Proc. 2009;84:268- 272.
6. Castells MC. Hypersensitivity to antineoplastic agents. Curr Pharm Des. 2008;14:2892-2901.
7. Cancer Therapy Evaluation Program, Common Terminology, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Dept of Health and Human Services. Common terminology criteria for adverse events (CTCAE) and common toxicity criteria (CTC). August 9, 2006. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Assessed February 23, 2010.
8. Lenz HJ. Management and preparedness for infusion and hypersensitivity reactions. Oncologist. 2007;12:601-609.
9. Gobel BH. Chemotherapy-induced hypersensitivity reactions. Oncol Nurs Forum. 2005; 32:1027-1035.
10. Taxotere [package insert]. Bridgewater, NJ: sanofi-aventis; 2008.
11. Paclitaxel [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2007.
12. Gradishar WJ, Krasnojon D, Cheporov S, et al. Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol. 2009;27:3611-3619.
13. Wendtner CM, Ritgen M, Schweighofer CD, et al; for the German CLL Study Group (GCLLSG). Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission—experience on safety and efficacy within a randomized phase III trial of the German CLL Study Group (GCLLSG). Leukemia. 2004;18:1093-1101.
14. O’Neil BH, Allen R, Spigel DR, et al. High incidence of cetuximab-related infusion reactions in Tennessee and North Carolina and the association of atopic history. J Clin Oncol. 2007;25:3644-3648. 15. Erbitux [package insert]. Princeton, NJ: Bristol- Myers Squibb; 2010.
16. Zevalin [package insert]. Irvine, CA: Spectrum Pharmaceuticals, Inc; 2009.
17. Osterborg A, Kipps TJ, Mayer J, et al. Ofatumumab (HuMax-CD20), a novel CD20 monoclonal antibody, is an active treatment for patients with CLL refractory to both fludarabine and alemtuzumab or bulky fludarabine- refractory disease: results from the Planned Interim Analysis of An International Pivotal Trial. Blood (ASH Annual Meeting Abstracts). 2008;112:Abstract 328.
18. Vectibix [package insert]. Thousand Oaks, CA: Amgen Inc; 2008.
19. Rituxan [package insert]. South San Francisco, CA: Biogen Idec Inc. and Genentech Inc; 2010.
20. Bexxar [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005.
21. Herceptin [package insert]. South San Francisco, CA: Genetech Inc; 2009.
22. Olsen E, Duvic M, Frankel A, et al. Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. J Clin Oncol. 2001;19:376-388.
23. Foss FM, Bacha P, Osann KE, et al. Biological correlates of acute hypersensitivity events with DAB(389)IL-2 (denileukin diftitox, ONTAK) in cutaneous T-cell lymphoma: decreased frequency and severity with steroid premedication. Clin Lymphoma. 2001;1:298-302.
24. Alberts DS, Garcia DJ. Safety aspects of pegylated liposomal doxorubicin in patients with cancer. Drugs. 1997;54:30-35.
25. Yardley DA. Proactive management of adverse events maintains the clinical benefit of ixabepilone. Oncologist. 2009;14:448-455.
26. Billett AL, Carls A, Gelber RD, Sallan SE. Allergic reactions to Erwinia asparaginase in children with acute lymphoblastic leukemia who had previous allergic reactions to Escherichia coli asparaginase. Cancer. 1992;70:201-206.
27. Kintzel PE. Prophylaxis for paclitaxel hypersensitivity reactions. Ann Pharmacother. 2001; 35:1114-1117.
28. Eisenhauer EA, Vernmorken JB. The taxoids. Comparative clinical pharmacology and therapeutic potential. Drugs. 1998;55:5-30.
29. Engels FK, Mathot RA, Verweij J. Alternative drug formulations of docetaxel: a review. Anticancer Drugs. 2007;18:95-103.
30. Van Gerpen R. Chemotherapy and biotherapy- induced hypersensitivity reactions. J Infus Nurs. 2009;32:157-165.
31. Brandi G, Pantaleo MA, Galli C, et al. Hypersensitivity reactions related to oxaliplatin (OHP). Br J Cancer. 2003;89:477-481.
32. Markman M, Kennedy A, Webster K, et al. Clinical features of hypersensitivity reactions to carboplatin. J Clin Oncol. 1999;17:1141.
33. Chung CH, Mirakhu B, Chan E, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose--1,3-galactose. N Engl J Med. 2008;358:1109-1117.
34. Carney PH, Ollom CL. Infusion reactions triggered by monoclonal antibodies treating solid tumors. J Infus Nurs. 2008;31:74-83.
35. Chung CH. Managing premedications and the risk for reactions to infusional monoclonal antibody therapy. Oncologist. 2008;13:725-732.
36.Winkler U, Jensen M, Manzke O, et al. Cytokine-release syndrome in patients with Bcell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8). Blood. 1999;94:2217-2224.
37. Azmi SS, Sachdev J, Kronsih L, et al. Hyper - sensitivity to cetuximab: is there an association with race, region, or both? J Clin Oncol. 2008;26(May 20 suppl):Abstract 14002.
38. Chan S, Winterbottom L, Gardner S. Re - sponse to dexamethasone in patients with fluid retention after docetaxel. Lancet. 1996; 347:1486-1487.
39. Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary report—second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006;117:391-397.
40. American Heart Association. Guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 10.6: anaphylaxis. Circulation. 2005;112:IV-143–IV-145.
41. Drain KL, Volcheck GW. Preventing and managing drug-induced anaphylaxis. Drug Saf. 2001;24:843-853.
42. Hypersensitivity and anaphylaxis. In: Polovich M, White JM, Kelleher LO, eds. Chemotherapy and Biotherapy Guidelines: Recommendations for Practice. 2nd ed. Pittsburgh, PA: Oncology Nursing Society; 2005:83-87.
43. Castells M. Rapid desensitization for hypersensitivity reactions to chemotherapy agents. Curr Opin Allergy Clin Immunol. 2006;6:271-277.
44. Castells MC, Tennant NM, Sloane DE, et al. Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases. J Allergy Clin Immunol. 2008;122:574-580.
45. Lee CW, Matulonis UA, Castells MC. Rapid inpatient/outpatient desensitization for chemo - therapy hypersensitivity: standard protocol effective in 57 patients for 255 courses. Gynecol Oncol. 2005;99:393-399.
