Chemotherapy and Biotherapy Hypersensitivity Reactions

Christine E. Coyle, RN, BSN, OCNAlverno College MSN Student

Spring 2011

coylece@alverno.edu

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All images are from Microsoft Clipart, 2007.

Learner OutcomesAt 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?

National Cancer Institute, 2010

• 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.

Immune Response

Management and Nurse Role

Case Study

References

Cytokine-release syndrome

Risk Factors for Hypersensitivity Reactions

Genetics

Click on a topic

Reactions and Stress

Risk Factors

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

Incidence of ReactionsAgent Overall Grade 3-4Carboplatin (Paraplatin®)

2 % none

Cetuximab (Erbitux®) 15-20%, dependent on tumor type

3%

Docetaxel (Taxotere®) 5-12% 2%

Eloxatin (Oxaliplatin®) 15-33% 2-3%

Paclitaxel (Taxol®) 41% 2%

Rituximab (Rituxan®) 77% First infusion, 30% fourth infusion, 14% eighth infusion

10%

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?

Rituxan Paclitaxel

Cetuximab Paraplatin

Correct!

Incorrect Incorrect

Incorrect

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 !

Allergies• Food• Drugs• Insect stings• Latex • Vaccines• Anesthesia Medications

Other • Female gender• Cardiac, liver, kidney or pulmonary

dysfunction• Older Age• Asthma diagnosis

Gobel, 2005

Time out…let’s reflect!

Which is an example of a drug where previous and/or multiple exposure increases the risk for reaction?

Docetaxel Rituximab Paclitaxel Eloxatin

Correct!Incorrect

Incorrect Incorrect

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 P450 (CYP450) is a specific

enzyme that is responsible for drug metabolism

• Some drugs can induce or increase the action specific to CYP450 which effects how the drugs work in the body

• Not all CYP450’s are created equal

CYP450There are genetic differences in the way it works

CYP450 Possible Genetic Mutations

CYP2C9

CYP2D6

CYP2C19 -Poor-Intermediate

-Extensive -Ultra-rapid

Metabolizers

This provides a possible explanation as to why some patients tolerate drugs

better than others

Paclitaxel is metabolized

by the CYP450 pathway

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

Innate Adaptive

Click on the pictures to learn more…

Dendritic cell

Compliment Protein

Mast Cell

Macrophage

Natural KillerCell

Granulocytes

B Cell

T Cell

Adaptive Immunity: Two Types

Cell-Mediated 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

Humoral ImmunityOne 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!

MacrophagesSorry, this is r/t

innate

B-LymphocytesYou’re correct! Is

there another one?

T-LymphocytesWay 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 (IgE

response is related to HSR’s.Type of Immune Response

Mechanism of Action

1 Immediate Immunoglobulin E-mediated (IgE) 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 T-cells in the immune system

Gobel, 2005

IgE Mediated ResponseAllergen

Dendritic cells & B Cells

Antigen Presenting Cells

T Helper cells

BCells

Present processed

peptides from the allergen

T cells are activated and

release IL-4, IL-13

Mast Cells

Isotypes are induced ,

generates IgE

Eosinophils

Mast cells bind to antigen via IgE antibody

HistaminesLeukotrienes

cytokines

Now What!?!?

What does this really mean?…your patient is in TROUBLE!!!

Chemotherapy (Antigen) Infusing

Mast Cells

The body says, “HOLY MOLY, something is not right!”

basophils

IgE antibodies are produced and bind to

receptors on Mast cells

HistaminesLeukotrienes, & prostaglandins start to circulate

Time out…Let’s reflect

An allergic reaction is caused by an IgE response in cell-mediated

immunityTrue or False?

What’s the problem?Histamines

Leukotrienes

Prostaglandins

The first mediator to be released during and acute inflammatory reaction. Causes dilation of the arterioles and increases vascular permeability. Stimulates H1 and H2 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

Induce vasodilatation, viscous mucous production, hypotension, increased platelets begin to stick together

Signs/Symptoms of HSR’sChest pain, palpitations, hyper/hypo-tension, edema, cardiac arrest

Headache, dizziness, confusion, LOC, anxiety, Impending doom

Skin Rash, pruritis, urticaria, flushing, tearing

Nausea/Vomiting, Diarrhea, abd cramping, bloating

Cough, dyspnea, nasal congestion, wheezing, bronchospasms, hypoxemia, chest tightness, tacypnea

Incontinence, uterine cramping, pelvic pain, renal impairment

Quiz yourself by clicking on the system to see how each can be affected

Other signs that your patient may

be reacting…

“Hey, Nurse could you get me a blanket, it’s freezing in here!”

“I don’t know what is wrong, I just don’t feel right.”

“I don’t know what is wrong, I just don’t feel right.”

Restlessness

“I have a tickle in my throat.”

“I have a tickle in my throat.”

Confusion 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, drugfever <38 degrees C (<100.4degrees F); intervention notindicated

N/A

2 Intervention or infusion interruption indicated; responds promptly to symptomatic treatment (e.g., antihistamines, NSAIDS, narcotics);prophylactic medicationsindicated for <=24 hrs

N/A

3 Prolonged recurrence of symptomsfollowing initial improvement;hospitalization indicated forclinical sequelae (e.g., renalimpairment)

Symptomatic bronchospasm, with or without urticaria; parenteral interventionindicated; allergy-related edema;Hypotension

4 Life-threatening consequences;urgent intervention indicated

Life-threatening consequences;urgent intervention indicated

5 DEATH 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 SyndromeCancer

CellMonoclonal

Antibody

Cancer Cell

Cell Death

Breslin, 2007

Immune effector cells

Compliment

Cytokines release into blood stream

Cytokines Release can cause…

• Fever• Chills • Rigors• Nausea• Vomiting • Dyspnea• Hypotension

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.

True or False, CYTOKINES:

True!

True!

True!

Time out…let’s reflect!

Clinical Symptoms of CRS

Cytokine-Release Syndrome can present almost the same as type one (IgE) 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 promptlyto 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

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.

Three StagesAlarm: 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

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 releasesEpinephrine and Norepinephrine

Increased Heart Rate

Increased Blood

pressure

Results in

Increased pressure can damage artery

lining

Glucose, fat, cholesterol in blood clump together

and create plaque

Blood vessels increase muscle tissue to

control increased blood flow

All can lead to stroke/ MI

Incorrect

Correct! Increase in BP

Decreased in HR

Correct! Increase in HR

Decrease in BPincorrect!

What effect does the release of norepinephrine and epinephrine cause? Select all that apply:

Time out…let’s reflect…

Management and the Role of the Oncology Nurse

Nursing Interventions

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?

Are you ready to administer the

Chemotherapy or Biotherapy infusion?

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 H1 and H2 receptors and act competitively to antagonize many effects of the inflammatory response.

It may be necessary to give H1 and H2 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 mmHg

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 O2 if needed)

-Monitor vital signs Q2 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 familyPolovich 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

• 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?Vogel, 2010

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 20mg IV, diphenhydramine, 25mg IV, famotidine, 20 mg IV, and zofran 8 mg, IV. The following chemotherapy was ordered: paclitaxel 175mg/m2 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? Continue to monitor the patient Slow the infusion down Assure the patient she will feel better in no time Stop the infusion

Myers, 2000

Incorrect

Correct!

Incorrect

Incorrect

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 v4.03

(CTAE). Published date June 14, 2010. Available at http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Accessed March 9, 2011.

• Polovich, M., Whitford, J. M., & Olsen, M. 2009. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. 3rd edition. Oncology Nursing Society.

• Porth, C.M., 2009. Pathophysiology, 7th edition. Lippincott.• Scripture, C.D., Sparreboom, A., & Figg, W. (2005). Modulation of cytochrome p450

activity: implications for cancer therapy. The Lancet. 6;780-789.

• Timoney, J., P., Eagan, M., 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.