Chemotherapy and Biotherapy Hypersensitivity Reactions Christine E Coyle

Chemotherapy and Biotherapy Hypersensitivity Reactions Christine E. Coyle, RN, BSN, OCN Alverno College MSN Student Spring 2011 coylece@alverno. edu

Navigating through Tutorial • To move to the next slide click • To move to the previous slide click • To go to the home page click • To go to the last slide viewed • Click or hover on any underlined words for more information All images are from Microsoft Clipart, 2007.

Learner Outcomes At the end of this presentation the learner will: • Identify factors that place a patient at risk for hypersensitivity reactions from cancer therapies, such as chemotherapy and biotherapy. • Review pathophysiology of hypersensitivity reactions, including allergic, anaphylaxis, and cytokine-release syndrome. • Discuss the management of hypersensitivity reactions, emphasizing the oncology nurse’s role.

Clinical Significance • Almost all cancer therapy infusions have been reported to cause HSR’s. • These reactions can be life-threatening and requires that nurses are prepared to manage them. • Encourages the nurse to consider his/her role in preventing reactions.

Hypersensitivity Reaction (HSR) An over expressed immune response that results in tissue harm or changes throughout the body in response to an antigen or foreign substance. This can include an allergic reaction, anaphylactic reaction or Cytokine-Release Syndrome.

Reactions…what’s the difference? • Allergic Reaction: An unpleasant response from exposure to an allergen. • Anaphylaxis Reaction: An acute inflammatory reaction which results from the release of histamine from mast cells, causing a hypersensitivity immune response. It can presents with shortness of breath (SOB), lightheadedness, hypotension, and loss of consciousness and can lead to death. • Cytokine-release syndrome : Caused by the release of cytokines- can cause nausea, headache, tachycardia, hypotension, rash, and SOB. It only occurs with Monoclonal Antibodies. National Cancer Institute, 2010

Click on a topic Genetics Immune Response Risk Factors for Hypersensitivity Reactions Case Study Management and Nurse Role Cytokinerelease syndrome Reactions and Stress References

Risk Factors • • • Type of Chemotherapy/Biotherapy Agent Previous History with the agent Allergies Age Genetics

Incidence of Reactions Agent Overall Grade 3 -4 Carboplatin (Paraplatin®) 2% none Cetuximab (Erbitux®) 15 -20%, dependent on 3% tumor type Docetaxel (Taxotere®) 5 -12% 2% Eloxatin (Oxaliplatin®) 15 -33% 2 -3% Paclitaxel (Taxol®) 41% 2% Rituximab (Rituxan®) 77% First infusion, 30% 10% fourth infusion, 14% eighth infusion Vogel, 2010

Time out…let’s reflect Of the drugs previously mentioned, which one has the highest incidence of HSR’s with the first infusion? Correct! Incorrect Rituxan Cetuximab Incorrect Paclitaxel Paraplatin

Review Patient’s History Assess your patient for previous reactions and/or allergies. Know your patient’s health history. Prior history of HSR’s increases risk to subsequent HSR’s ! Gobel, 2005 Allergies • Food • Drugs • Insect stings • Latex • Vaccines • Anesthesia Medications Other • Female gender • Cardiac, liver, kidney or pulmonary dysfunction • Older Age • Asthma diagnosis

Time out…let’s reflect! Which is an example of a drug where previous and/or multiple exposure increases the risk for reaction? Incorrect Docetaxel Incorrect Rituximab Incorrect Paclitaxel Correct! Eloxatin

Is the patient getting Rituximab for the first time? CHECK YOUR PATIENT’S LYMPHOCYTE COUNT! Elevated Lymphocyte count (>40%) = Increased risk for a reaction Check your protocol!

Drug Metabolism and Genetics • Primary site of drug metabolism is the liver • Cytochrome P 450 (CYP 450) is a specific enzyme that is responsible for drug metabolism • Some drugs can induce or increase the action specific to CYP 450 which effects how the drugs work in the body • Not all CYP 450’s are created equal

CYP 450 There are genetic differences in the way it works Possible Genetic Mutations CYP 450 CYP 2 C 19 CYP 2 C 9 Paclitaxel is metabolized by the CYP 450 pathway CYP 2 D 6 Metabolizers -Poor -Intermediate -Extensive -Ultra-rapid This provides a possible explanation as to why some patients tolerate drugs better than others

Immune Response Cytokine-Release Syndrome, allergic reaction, and anaphylaxis reaction all equate to an Immune Response

Immune Response -A coordinated response to cells and molecules in the immune system -The body’s protection from bacteria, viruses and foreign substances -Is normally protective but can cause unfavorable effects Porth & Matfin, 2009

Innate Immunity (non-specific) • The body ’s primary line of defense • Contains compliment proteins, granulocytes, mast cells, macrophages, dendritic cells and natural killer cells

Adaptive Immunity (specific) • Responds less rapidly than innate immunity but more effectively • Includes lymphocytes , T cells (in cell mediated immunity and B cells (in humoral immunity) • Immunologic memory; more rapid and efficient with subsequent exposure

Innate and Adaptive Immunity Cells Ad Click on the pictures to learn more… Innate Dendritic cell Mast Cell ve B Cell Macrophage Compliment Protein T Cell Natural Killer Cell Granulocytes

Adaptive Immunity: Two Types Cell-Mediated Immunity Humoral Immunity Functions to get rid of pathogens. T-cells develop receptors that identify the viral peptides displayed on the surface of infected cells and then turn on the destruction of infected cells One of the main parts of the immune system that triggers specific B-cells to produce and secrete large amounts of specific antibodies. These are created to fight a particular microorganism or virus. Porth & Matfin, 2009

Time out…let’s reflect! Adaptive immunity has to do with which cells… Mast Cells Nope, think again! B-Lymphocytes You’re correct! Is there another one? Macrophages Sorry, this is r/t innate T-Lymphocytes Way to go! Is there another one?

Normal Immune Response vs. Hypersensitivity Reaction (HSR) HSR’s are different from the normal immune response. There are four different types of immune responses. The Type 1 (Ig. E response is related to HSR’s. Type of Immune Response Mechanism of Action 1 Immediate Immunoglobulin E-mediated (Ig. E) reaction 2 Antibody-mediated reaction resulting in antibody –antigen complexes 3 Immune complexes form in the circulation and deposit in various tissues 4 Delayed reaction which involves activation of Tcells in the immune system Gobel, 2005

Ig. E Mediated Response Allergen Eosinophils Histamines Leukotrienes Antigen Presenting Cells Dendritic cells & B Cells Present processed peptides from the allergen Now What!? !? T Helper cells B Cells T cells are activated and release IL-4, IL 13 Mast Cells Isotypes are induced , generates Ig. E cytokines Mast cells bind to antigen via Ig. E antibody

What does this really mean? …your patient is in TROUBLE!!! Chemotherapy (Antigen) Infusing The body says, “HOLY MOLY, something is not right!” Ig. E antibodies are produced and bind to receptors on Mast cells Mast Cells basophils Histamines Leukotrienes, & prostaglandins start to circulate

Time out…Let’s reflect An allergic reaction is caused by an Ig. E response in cell-mediated immunity True or False?

What’s the problem? Histamines The first mediator to be released during and acute inflammatory reaction. Causes dilation of the arterioles and increases vascular permeability. Stimulates H 1 and H 2 receptors. -trigger contractions in the smooth muscles lining the trachea; their overproduction is a major cause of inflammation during a reaction. Leukotrienes are produced in the body from arachidonic acid. Enhance vasodilatation, increase mucous production, and contraction of smooth muscle Prostaglandins Leukotrienes Induce vasodilatation, viscous mucous production, hypotension, increased platelets begin to stick together

Signs/Symptoms of HSR’s Chest pain, palpitations, hyper/hypo-tension, edema, cardiac arrest Headache, dizziness, confusion, LOC, anxiety, Impending doom Nausea/Vomiting, Diarrhea, abd cramping, bloating Skin Quiz yourself by clicking on the system to see how each can be affected Cough, dyspnea, nasal congestion, wheezing, bronchospasms, hypoxemia, chest tightness, tacypnea Incontinence, uterine cramping, pelvic pain, renal impairment Rash, pruritis, urticaria, flushing, tearing

“Hey, Nurse could you get me a blanket, it’s freezing in here!” “I have a tickle in my throat. ” “I don’t know what is wrong, I just don’t feel right. ” Other signs that your patient may be reacting… Confusion Restlessness Anxiety

Time out…let’s reflect Your patient is midway through the infusion on her ninth cycle of carboplatin for ovarian cancer. She begins to complain of a “scratchy throat, ” palmar itching and slight shortness of breath. Based on her symptoms, you would suspect: A. Paresthesia of her vagus nerve cause by carbolatin B. An impending pulmonary embolus C. An hypersensitivity reaction to carboplatin

Grade Allergic Reaction Anaphylaxis 1 Transient flushing or rash, drug fever <38 degrees C (<100. 4 degrees F); intervention not indicated N/A 2 Intervention or infusion interruption indicated; responds promptly to symptomatic treatment (e. g. , antihistamines, NSAIDS, narcotics); prophylactic medications indicated for <=24 hrs N/A 3 Prolonged recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae (e. g. , renal impairment) Symptomatic bronchospasm, with or without urticaria; parenteral intervention indicated; allergy-related edema; Hypotension 4 Life-threatening consequences; urgent intervention indicated 5 DEATH National Cancer Institute, 2010

Cytokine-Release Syndrome (CRS) A cluster of symptoms associated with the use of monoclonal antibodies. It results from the release of cytokines from cells targeted by the antibody. As tumor cells are destroyed levels of cytokines and histamines increase. Breslin, 2007

Cytokines • A group of polypeptide proteins that are made and released by most cells in the body • Organize communication between cells • Manage responses among the innate and mediated immune responses • Trigger lymphocytes and other immune effector cells • Synchronize the damaged of cells targeted by Monoclonal Antibodies (MOAB’s) Breslin, 2007

Cytokine-Release Syndrome Cancer Cell Monoclonal Antibody Compliment Immune effector cells Cancer Cell Breslin, 2007 Cytokines release into blood stream Cell Death

Cytokines Release can cause… • • Fever Chills Rigors Nausea Vomiting Dyspnea Hypotension

Time out…let’s reflect! True! True or False, CYTOKINES: Are a group of polypeptide proteins that are produced and secreted by most cells in the body. Act as chemical messengers, facilitating communication between cells. Coordinate responses among the innate and mediated immune responses.

Clinical Symptoms of CRS Cytokine-Release Syndrome can present almost the same as type one (Ig. E) reactions and can develop into anaphylaxis-like reactions…the difference is the pathophysiology!

Grades of Cytokine-release syndome Grade 1 Mild reaction; infusion interruption not indicated; intervention not indicated Grade 2 Therapy or infusion interruption indicated but responds promptly to symptomatic treatment (e. g. , antihistamines, NSAIDS, narcotics, IV fluids); prophylactic Grade 3 Prolonged (e. g. , not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement. Grade 4 Life-threatening consequences; pressor or ventilatory support indicated Grade 5 DEATH National Cancer Institute, 2010

What else is going on during a reaction? Generalized Adaptation Syndrome (GAS) General: the effect has to do with a general systemic reaction Adaptation: the response is due to a stressor Syndrome: the physical manifestations are dependent on each other. Porth & Matfin, 2009

GAS and Reactions Three Stages Alarm: generalized stimulation of the Sympathetic Nervous System (SNS) Resistance: the body selects the most optimal way to respond Exhaustion: stressor is extended, start to see possible signs of systemic damage This response is triggered by a stressor. For cancer patients this could be external or internal factors such as medication, anxiety, environment, social support, &/or life experiences. Porth & Matfin, 2009

GAS and Reactions Have you ever thought that your patient’s stress or anxiety may have caused a reaction? Stress response depends on what a person expects to happen in a given situation based on previous learning experiences.

SNS in Stress!! Adrenal Medula releases Epinephrine and Norepinephrine Increased Blood pressure Increased Heart Rate Results in Increased pressure can damage artery lining Glucose, fat, cholesterol in blood clump together and create plaque All can lead to stroke/ MI Blood vessels increase muscle tissue to control increased blood flow

Time out…let’s reflect… What effect does the release of norepinephrine and epinephrine cause? Select all that apply: Correct! Incorrect Increase in BP Correct! Decreased in HR incorrect! Increase in HR Decrease in BP

Management and the Role of the Oncology Nurse

Nursing Interventions Are you ready to administer the Chemotherapy or Biotherapy infusion? Preventative Measures • Obtain baseline assessment & vitals • Assess for risk factors • Educate the patient about signs/symptoms of a HSR? • Make sure emergency medication/equipment supplies are readily available? • Confirm that the patient took their pre-treatment medications if ordered? • Administer pre-medications as ordered?

Emergency Supplies Equipment • • • Code Cart Oxygen supplies Ambu Bag Stethoscope Suction set-up Syringes/Needles Medications • • Normal Saline Epinephrine Albuterol Inhaler Diphenhydramine Famotidine Dexamethasone Hydrocortisone

Medications: Histamine Antagonist A histamine antagonist, commonly referred to as antihistamine, is a drug that inhibits action of histamines by blocking it from attaching to histamine receptors. Bind to H 1 and H 2 receptors and act competitively to antagonize many effects of the inflammatory response. It may be necessary to give H 1 and H 2 antagonists may be necessary to counteract the histamine release.

Medications: IV Fluids • Maintain IV line with Normal Saline (NS) • IV fluids should be given to maintain a systolic BP above 90 mm. Hg Watson, 2010

Your patient is reacting!. . . now what? Stay in Control!!!! -Stop the infusion -Maintain IV line with NS or appropriate solution -Stay with the patient and have co-worker activate emergency team or notify physician -Maintain Airway (administer O 2 if needed) -Monitor vital signs Q 2 minutes until patient the patient reaches near baseline vital signs -Administer emergency medications -Place the patient in supine position (if not vomiting or SOB) -Offer emotional support of patient and family Polovich et al, 2009

Documentation of HSR • Prompt and accurate documentation of a HSR is critical • Accurate grading will allow the prescriber to decide the next appropriate steps for treatment Vogel, 2010 • Pre-infusion assessment • Initial symptoms and course of progression • Timing of reaction and duration • Grade and type of HSR • Timing of interventions and patient response • Did the symptoms resolve? : when/how?

Let’s apply what you’ve learned! Case Study Mrs. Jones, age 68, arrives at the Hematology/Oncology clinic to receive her first chemotherapy for stage IV ovarian cancer. Her baseline vitals are: BP: 148/62, pulse: 80, respirations: 20, oxygen saturation: 98%. You administer premedications: dexamethasone 20 mg IV, diphenhydramine, 25 mg IV, famotidine, 20 mg IV, and zofran 8 mg, IV. The following chemotherapy was ordered: paclitaxel 175 mg/m 2 infusion over 3 hours and carboplatin AUC 6 (750 mg) over one hour. Five minutes after you begin the infusion, Mrs. Jones complains of itching, SOB and she is nauseated.

Vital signs are now: BP: 92/52, pulse: 120, Respirations: 30 and oxygen saturation is 82%. What is your immediate response? Incorrect Continue to monitor the patient Incorrect Slow the infusion down Incorrect Assure the patient she will feel better in no time Correct! Stop the infusion Myers, 2000

In conclusion… • How does this tutorial encourage you to change your practice when thinking about HSR’s? • Nurses play a key role in preventing HSR’s • Continue to be advocate for your patients! THANK YOU FOR VIEWING THIS TUTORIAL!!!

References • • • Bonosky, K. (2005). Hypersensitivity reactions to oxaliplatin: what nurses need to know. Clinical Journal of Oncology. 9 (3), 325 -330. Breslin, S. (2007). Cytokine-release syndrome: overview and nursing implications. Clinical Journal of Oncology. 11(1), 37 -41. Gobel, B. H. (2005) Chemotherapy-induced hypersensitivity reactions. Oncology Nursing Forum, 32, 1027 -1035. Gleich, G. J. , & Leiferman, K. M. (2009). Oncology infusion reactions associated with monoclonal antibodies. Oncology. 23 (2), 7 -13. Labovich, T. M. (1999). Acute hypersensitivity reactions to chemotherapy. Seminars in Oncology Nursing. 15 (3), 222 -231. Lemos, M. L. (2006). Acute reactions of chemotherapy agents. Journal of Pharmacology Practice. 12, (3), 127 -129. Liebermann, P. , Nicklas, R. , Oppenheimer, J. , Kemp, S. , & Lang, D. (2010). The diagnosis and management of anaphylaxis practice parameter: 2010 update. Journal of Clinical Immunology. 126 (3), 477 -488. Lenz, H. J. (2007) Management and preparedness for infusion and hypersensitivity reactions. The Oncologist. 12: 601 -609 Myers, J. S. (2000). Chemotherapy-induced hypersensitivity reaction. American Journal of Nursing. 100(4), 53 -55.

References • • National Cancer Institute. Common Terminology Criteria for Adverse Events v 4. 03 (CTAE). Published date June 14, 2010. Available at http: //evs. nci. nih. gov/ftp 1/CTCAE_4. 03_2010 -0614_Quick. Reference_8. 5 x 11. pdf. Accessed March 9, 2011. Polovich, M. , Whitford, J. M. , & Olsen, M. 2009. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. 3 rd edition. Oncology Nursing Society. Porth, C. M. , 2009. Pathophysiology, 7 th edition. Lippincott. Scripture, C. D. , Sparreboom, A. , & Figg, W. (2005). Modulation of cytochrome p 450 activity: implications for cancer therapy. The Lancet. 6; 780 -789. Timoney, J. , P. , Eagan, M. , & Sklarin, N. T. , Establishing clinical guidelines for the management of acute hypersensitivity reactions secondary to the administration of chemotherapy/biologic therapy. Journal of Nursing Care Quality, 18(1) 80 -86. Vogel, W. H. (2010). Infusion reactions: diagnosis, assessment and management. Clinical Journal of Oncology Nursing. 14, 10 -14. Viale, P. H. , & Yamamoto, D. S. (2010). Biphasic and delayed hypersensitivity reactions: implications for oncology nursing. Watson, L. E. (2010). Recognition, assessment and management of anaphylaxis. Nursing Standard. 24 (46), 35 -39.