Unraveling the Paclitaxel Mystery Pathophysiology of Type I

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 Unraveling the Paclitaxel Mystery Pathophysiology of Type I Hypersensitivity Reactions Carrie Bilicki, RN,

Unraveling the Paclitaxel Mystery Pathophysiology of Type I Hypersensitivity Reactions Carrie Bilicki, RN, BSN, OCN Carrie. bilicki@aurora. org MSN 621 Spring Alverno College, Milwaukee Wisconsin

Learning Objectives • Explain the pathophysiology of a Type I hypersensitivity reaction • Relate

Learning Objectives • Explain the pathophysiology of a Type I hypersensitivity reaction • Relate humoral immunity to the body’s response during a hypersensitivity reaction to paclitaxel • Identify and prevent adverse events to improve patient outcomes • Describe the rationale for rechallenging patients with paclitaxel 9/25/2020 2

Overall Tutorial Outcome The primary goal of this tutorial is to educate nurses who

Overall Tutorial Outcome The primary goal of this tutorial is to educate nurses who administer Paclitaxel on the pathophysiology of a type I reaction to this chemotherapy. Additionally, learners will be able to verbalize the principles in preventing a reaction, understanding an evidenced based approach in the management of an anaphylactic reaction. 9/25/2020 3

Directions for Using the Tutorial • When you see a link, click on it

Directions for Using the Tutorial • When you see a link, click on it for more information on that topic, or to be directed back to a definition of that term • Use the Navigation buttons on the bottom of each page to move to the next page or previous page – Clicking on will move you ahead one slide – Clicking on will move you back one slide – Clicking on will take you to the main menu 9/25/2020 4

You can proceed on with the tutorial by moving forward or come to the

You can proceed on with the tutorial by moving forward or come to the main menu to review a Specific section! Main Menu • Definitions • Pathophysiology of Type I reaction • Relating Type I reaction to Paclitaxel • Genetics • Nursing Sensitive outcomes 9/25/2020 5

In order to break this down and understand the pathophysiology of what is happening

In order to break this down and understand the pathophysiology of what is happening to the body with a hypersensitivity/anaphylaxis reaction we need to first understand the language used. These Next Slides will review & define common terms In describing hypersensitivity 9/25/2020 Microsoft Image Clip Art, 2007 6

Normal Immune Response Our Immune system is the body’s natural defense against infections and

Normal Immune Response Our Immune system is the body’s natural defense against infections and diseases. Antibodies are produced and part of a healthy immune system. Adaptive (acquired) immunity is the antigen-specific defense mechanisms, taking days to become effective and developed though out the life span. Humoral 9/25/2020 Cell Mediated Microsoft Image Clip Art, 2007 7

B-LYMPHOCYTE B-lymphocytes are white blood cells that play a large role in humoral immunity.

B-LYMPHOCYTE B-lymphocytes are white blood cells that play a large role in humoral immunity. Lymphocytes manufacture antibodies, proteins which possess Grabs the ability to recognize and bind to foreign and holds substances. The antibodies may be either secreted or bound to the lymphocyte membrane. onto Ig. E Plasma cells are differentiated lymphocytes which are specialized to manufacture and secrete relatively large amounts of antibody. Their principal function is to make antibodies against antigens. They recognize antigens via B-cell I’ll remember receptors (BCRs). you antigen! 9/25/2020 8

ANTIGEN A substance that reacts with antibody molecules and antigen receptors on lymphocytes. An

ANTIGEN A substance that reacts with antibody molecules and antigen receptors on lymphocytes. An immunogen is an antigen that is recognized by the body as nonself and stimulates an adaptive immune response. 9/25/2020 10

Mast Cells Secretory alarm cells in our tissue 9/25/2020 Cells, which synthesize and store

Mast Cells Secretory alarm cells in our tissue 9/25/2020 Cells, which synthesize and store histamines, found in most body tissues, particularly just below the epithelial surfaces, serous cavities, and around blood vessels. In an allergic response, an allergen stimulates the release of Ig. E antibodies, which attach themselves to mast cells. Microsoft Image Clip Art, 2007 Trigger the process of inflammation Ig. E binds to the mast cell 11

BASOPHILS In the blood 9/25/2020 Leukocytes that promote inflammation by releasing or synthesizing such

BASOPHILS In the blood 9/25/2020 Leukocytes that promote inflammation by releasing or synthesizing such inflammatory mediators as histamine, leukotrienes, and prostaglandins. 13

HISTAMINE A chemical naturally produced in cells of the body. Overproduction in response to

HISTAMINE A chemical naturally produced in cells of the body. Overproduction in response to allergens is released by basophils, mast cells, and platelets which promotes inflammation by causing vasodilatation and increased capillary permeability. An allergic reaction indicates an excessive release of histamines. 9/25/2020 Microsoft Image Clip Art, 2007 14

INFLAMMATION A process in which blood vessels dilate and become more permeable, thus enabling

INFLAMMATION A process in which blood vessels dilate and become more permeable, thus enabling body defense cells and defense chemicals to leave the blood and enter the tissues. Acute inflammation is usually a localized, protective response to tissue injury. Excessive or chronic inflammation, however, may lead to tissue destruction. 9/25/2020 17

Paclitaxel ALLERGEN: An antigen causing an allergic reaction. 9/25/2020 19

Paclitaxel ALLERGEN: An antigen causing an allergic reaction. 9/25/2020 19

Antibodies or Immunoglobulins Specific proteins produced by Blymphocytes and plasma cells in response to

Antibodies or Immunoglobulins Specific proteins produced by Blymphocytes and plasma cells in response to a specific antigen and capable of reacting with that antigen. For this tutorial we are focusing on the antibody Ig. E. 9/25/2020 20

Antibody Structure Constantly circulating in our system these antibodies are shaped like the letter

Antibody Structure Constantly circulating in our system these antibodies are shaped like the letter Y. These antibodies bind to antigens triggering a cascade of events causing the hypersensitivity 9/25/2020 There are 5 classes of human antibodies: immunoglobulin G (Ig. G), immunoglobulin M (Ig. M), immunoglobulin A (Ig. A), immunoglobulin D (Ig. D), immunoglobulin E (Ig. E). Microsoft Image Clip Art, 2007 Hypersensitivity Reaction 21

Normal Immune Response The difference between a normal immune response and a type I

Normal Immune Response The difference between a normal immune response and a type I hypersensitive response is that plasma cells secrete Ig. E, resulting in a systemic inflammatory response that can result in symptoms as benign as a runny nose, to lifethreatening anaphylactic shock and death. 22

Humoral Immunity Immediate Hypersensitivities Humoral immunity involves the production of antibody molecules in response

Humoral Immunity Immediate Hypersensitivities Humoral immunity involves the production of antibody molecules in response to an antigen and is mediated by B-lymphocytes. 9/25/2020 24

Cell-Mediated Immunity Delayed Hypersensitivites Type IV Production of cytotoxic T-ymphocytes, activated macrophages, activated Natural

Cell-Mediated Immunity Delayed Hypersensitivites Type IV Production of cytotoxic T-ymphocytes, activated macrophages, activated Natural Killer (NK) cells, and cytokines in response to an antigen. Mediated by T-Lymphocytes 26

Review of Hematopoiesis & Pluripotent Immunity Stem Cell Myeloid stem cell CFU-GEMM BFU-E CFU-Meg

Review of Hematopoiesis & Pluripotent Immunity Stem Cell Myeloid stem cell CFU-GEMM BFU-E CFU-Meg CFU-GM CFUEO Monoblast Megakaryocyte Reticulocyte Lymphoid stem cell CFUMast Neutrophil Platelets NK precursor CFU-G monocyte RBC Pre- Pre. Bcell TCell Eosinophil Macrophage Tissue Mast Cell B T Natural killer cell Plasma Cell 27

Review of Hematopoiesis & Immunity CFUMast Humoral Immunity Pre. Bcell Cell Mediated Immunity Pre.

Review of Hematopoiesis & Immunity CFUMast Humoral Immunity Pre. Bcell Cell Mediated Immunity Pre. TCell lymphocytes B Tissue Mast Cell NK precursor T Natural killer cell Plasma Cell 28

Role of Lymphocytes in the Immune System Lymphocytes are responsible for specific immune recognition

Role of Lymphocytes in the Immune System Lymphocytes are responsible for specific immune recognition of pathogens. They circulate freely throughout the body moving from blood stream to tissue and back. There role is to act as scouts & destroy pathogens entering the body B-Cells are genetically programmed to encode a surface receptor specific for a particular antigen. Once the B cell recognizes an antigen, the B cell multiplies and differentiates into antibody producing Plasma Cells T-cells release cytokines and have direct cell-cell interactions T-helper cells interact with B cells and phagocytes Cytotoxic T cells destroy host cells infected by viruses or other Intracellular pathogens 29

Lets check our understanding! These concepts can be confusing! Humoral immunity can cause harm

Lets check our understanding! These concepts can be confusing! Humoral immunity can cause harm to the body by antigen/antibody interactions and our body’s systemic reaction is termed a hypersensitivity. True or False Microsoft Image Clip Art, 2007 30

TYPE I HYPERSENSITIVITY Humoral Immunity Most common type of hypersensitivity due to excessive production

TYPE I HYPERSENSITIVITY Humoral Immunity Most common type of hypersensitivity due to excessive production of the class of antibody known as Ig. E is made in response to an allergen. For this tutorial we are focusing on the allergen Paclitaxel and the Type I hypersensitivity that is seen. 9/25/2020 33

 Here is a visual of what is happening. Lets break down these concepts!

Here is a visual of what is happening. Lets break down these concepts! Ig. E mediated Reaction=Type I Second exposure! Allergen specific Ig. E antibody to attach to Ig. E receptors on Mast & Bashophils Immediate and delayed Release of Mast Cells or Basophil Mediators Histamine Prostaglandins Cascade of leukotrienes Cellular events Eosinophil’s called upon, more cellular inflammation & injury Neutrophils come too! Microsoft Image Clip Art, 2007 9/25/2020 Chinen, Fleisher, Shearer, 2008 34

Anaphylaxis “Anaphylaxis is caused by the interaction of a foreign antigen with specific immunoglobulin

Anaphylaxis “Anaphylaxis is caused by the interaction of a foreign antigen with specific immunoglobulin E (Ig. E) antibodies found on the tissue of mast cells and peripheral blood basophils. The subsequent release of bioactive mediators from these cellular components results in smooth muscle spasm, mucosal edema and inflammation, and increased capillary permeability. ” 9/25/2020 Timoney, J. P et al 2003 35

Anaphylaxis is the most severe form of an Ig. E mediated hypersensitivity and may

Anaphylaxis is the most severe form of an Ig. E mediated hypersensitivity and may occur within minutes of an exposure. Acute & life-threating characterized by respiratory distress, laryngeal edema, severe bronchospasm and usually is accompanied by cutaneous (pruritus, flush, urticaria, angioedema) and GI symptoms. **Anaphylaxis is directly related to the release of Ig. E, whereas an Anaphylactoid reaction is not caused by Ig. E. Clinical presentations are the same. The jury is still out…is a Paclitaxel reaction from Ig. E release or not? (Timoney, et. al 2003) (Lieberman et. al 2005) 36

Really? In English Please Anaphylaxis is a severe, lifethreatening, generalized or systematic hypersensitivity reaction.

Really? In English Please Anaphylaxis is a severe, lifethreatening, generalized or systematic hypersensitivity reaction. Characterized by breathing and circulatory problems, usually associated with skin and mucosal changes. Ig. E 9/25/2020 Ig. E is made in response to the allergen! Microsoft Image Clip Art, 2007 37

Hypersensitivity vs. Anaphylaxis! With Taxol Same word? Different meaning? Infusion related side effects General

Hypersensitivity vs. Anaphylaxis! With Taxol Same word? Different meaning? Infusion related side effects General term for allergic reaction Anaphylaxis is the severity of the hypersensitivity Magnified immune response Local tissue injury or change t. o. body in response to antigen or foreign substance Non immune mediated vs. immune? Release of histamine Release of cytokines Same outcome regardless of mechanism Adverse Event Carrie Bilicki, 2009 “There is no universally accepted clinical definition of anaphylaxis”. Lieberman et. al, 2005, p. 500 38

Genetic Link to Allergies? Studies have looked at the receptor site for IL 4.

Genetic Link to Allergies? Studies have looked at the receptor site for IL 4. Variation’s in the genes were found in patients who had a history of various allergies, this variant occurred at a Genetic low frequency with alteration patients with no at the end of the IL 4 allergies. receptor 9/25/2020 Interleuki n 4 (IL 4) is a protein that induces immune cells to make Ig. E Patient outcome: With this genetic mutation patients have an exaggerated response to allergens 39

Pre-disposed to Allergies? Children of allergic parents are more likely to develop allergies 9/25/2020

Pre-disposed to Allergies? Children of allergic parents are more likely to develop allergies 9/25/2020 Chinen, Fleisher, Shearer , 2008 40

CYTOCHROMES P 450 (CYP) (big fancy word for enzymes that work in the liver

CYTOCHROMES P 450 (CYP) (big fancy word for enzymes that work in the liver to break down the drug) CYP = DNA Codes our proteins RNA DNA missing parts=altered metabolism What’s in your Genes! Detoxification & elimination of drug & Activation of prodrug We all metabolize differently! Ever wonder why some patients have every side effect and others experience few or none? Think P 450! TAXOL METABOLIZED BY CYP pathway CYP 2 C 8 CYP 3 A 4 Poor metabolizers have trouble breaking down the drug, increased side effects! Also effects the transport of the drug Marsh, et. al, 2007 41

Let’s Review! Answer the following questions True or False to the following questions 1.

Let’s Review! Answer the following questions True or False to the following questions 1. 2. 3. 9/25/2020 True or False - The main cause of a hypersensitivity is plasma cells secreting Ig. G. True or False – An Allergen is an antigen causing an allergic reaction True or False – Histamine release causes vessels to constrict and blood pressure to rise Microsoft Image Clip Art, 2007 42

What are the effects of a Type I hypersensitivity, and how are they linked

What are the effects of a Type I hypersensitivity, and how are they linked to Paclitaxel? Let’s Find Out! 9/25/2020 Microsoft Image Clip Art, 2007 43

What are Taxanes? • Taxanes are a category of highly effective chemotherapeutic agents, and

What are Taxanes? • Taxanes are a category of highly effective chemotherapeutic agents, and standard of care for numerous cancer diseases • Taxanes are in the class of microtubule stabilizing agents, to review these medications, indications, and side effects click on the links below ü Paclitaxel (Taxol) FDA approved in 1994 revolutionalized how we treat patients. ü Docetaxel (Taxotere) FDA approved 1996 the “cousin” to Paclitaxel. Lost some of the anaphylactic properties, gained bone marrow suppression ü Nab-paclitaxel (Abraxane) Bound to protein, nanoparticle formulation of paclitaxel 9/25/2020 44

Immune System Type I reaction related to Paclitaxel First exposure Sensitizes the Mast cells

Immune System Type I reaction related to Paclitaxel First exposure Sensitizes the Mast cells Cutaneous What does this really mean? & mucosal surfaces Circulating basophils The allergen (the chemotherapy or drug formulation in our case) enters the body and is recognized by the surface immunoglobulin (the Ig. E) on a B-lymphocyte. The B-lymphocyte then proliferates and differentiates into plasma cells. 9/25/2020 Copyright © Gary E. Kaiser The Grapes of Staph http: //student. ccbcmd. edu/~gkaiser/goshp. html Used with permission. 45

Immune System The plasma cells produce and secrete Ig. E which binds to receptors

Immune System The plasma cells produce and secrete Ig. E which binds to receptors on mast cells and basophils. Initial exposure does not trigger symptoms! 9/25/2020 Copyright © Gary E. Kaiser The Grapes of Staph http: //student. ccbcmd. edu/~gkaiser/goshp. html Used with permission. 46

An antigen causing an allergic reaction Immune System Ig. E antibody produced in response

An antigen causing an allergic reaction Immune System Ig. E antibody produced in response to the allergen Mast cell synthesizes and stores histamine Basophils. Leukocytes Allergen cross reacting with Ig. E on mast cell. Ig. E also promotes inflammation to recruit phagocytes. 9/25/2020 Copyright © Gary E. Kaiser The Grapes of Staph http: //student. ccbcmd. edu/~gkaiser/goshp. html Used with permission. 47

HYPERSENSITIVITY Histamine! Immune System Proinflammatory mediators also released with histamine! Leukotrienes Prostaglandins • Uticaria

HYPERSENSITIVITY Histamine! Immune System Proinflammatory mediators also released with histamine! Leukotrienes Prostaglandins • Uticaria • Rash • Angioedema • Bronchospasm • hypotention The next time the allergen enters the body, it cross-links to the Ig. E bound to the mast cells. This triggers the mast cell to release its histamine and other inflammatory mediators. The inflammatory mediators are now able to bind to receptors on target cells which leads to smooth muscle contraction, vascular permeability , dilation of blood vessels, constriction of bronchioles, excessive mucus secretion. 9/25/2020 Copyright © Gary E. Kaiser The Grapes of Staph http: //student. ccbcmd. edu/~gkaiser/goshp. html Used with permission. 48

Adverse Effects of Taxanes • • • 9/25/2020 Common Peripheral neuropathies Alopecia Asthenia Diarrhea

Adverse Effects of Taxanes • • • 9/25/2020 Common Peripheral neuropathies Alopecia Asthenia Diarrhea Hypersensitivity Reaction Hypotension Anemia Mucositis Myalgias Nausea/Vomiting Neutropenia Rare • • • Cardiopyopathy Dysrhytmias Thrombocytopenia Interstitial pneumonitis Edema 51

Quick Check! • To make sure we are understanding! Microsoft Image Clip Art, 2007

Quick Check! • To make sure we are understanding! Microsoft Image Clip Art, 2007 9/25/2020 If a patient has known allergies the levels of Ig. E may be thousands of times higher than those without allergies? True or False 54

What does this really mean? Allergen! Paclitaxel given Body says wowzers!! Histamine B-lymphocytes say

What does this really mean? Allergen! Paclitaxel given Body says wowzers!! Histamine B-lymphocytes say never fear “B-lymphs here!” The plasma cells differentiated from the Blymphocytes secreting Ig. E which binds to the mast cells thoughout our body tissue So now what… 9/25/2020 (Carrie Bilicki, 2009) Microsoft Image Clip Art, 2007 60

What’s the body doing!? Remember histamine promotes inflammation causing vasodilation and increased capillary permeability

What’s the body doing!? Remember histamine promotes inflammation causing vasodilation and increased capillary permeability Resulting in Dilatation of Blood Vessels, flushing to skin, drop in blood pressure, worst case scenario shock “So what” you say? ? How do we stop this! Increased capillary permeability causing swelling of tissues (edema), if severe untreated reaction decreased blood volume, shock Constricted bronchial airways, wheezing & difficulty breathing, stimulation of mucous secretion causing congestion Stimulation of nerve endings, causing itching & pain to skin 9/25/2020 61

If we think about preventing reactions in Paclitaxel this all starts to make sense!

If we think about preventing reactions in Paclitaxel this all starts to make sense! Minimize Can you guess what “H” stands for? the risk please! Histamine! H 2 antagonist Antihistamine H 1 receptor antagonist steroids Routinely given by intravenous route, however studies have shown safe protection against hypersensitivity reactions when given orally 9/25/2020 (Zidan et. al, 2008) Microsoft Image Clip Art, 2007 62

Steroids, not only to build muscles! Decadron is given as a premedication to stabilize

Steroids, not only to build muscles! Decadron is given as a premedication to stabilize mast cell membranes and prevent mast cell degranulation. 9/25/2020 Microsoft Image Clip Art, 2007 63

Antagonist is an agent which serves to inhibit the release or action • Antihistamines

Antagonist is an agent which serves to inhibit the release or action • Antihistamines are reversible competitive antagonists of histamine at H 1 receptor sites. They do not prevent histamine release or bind to the histamine that has already been released. The H 1 receptor blockade results in decreased vascular permeability, reduction of pruritus and relaxation of smooth muscle in the respiratory and gastrointestinal tracts. • H 2 Antagonist Inhibits histamine action at parietal cell H 2 receptors 9/25/2020 65

H 1 antagonist Diphenhydramine 50 mg IV 30 minutes prior to hanging Paclitaxel Blocks

H 1 antagonist Diphenhydramine 50 mg IV 30 minutes prior to hanging Paclitaxel Blocks the binding of histamine to H 1 receptors on target cells 9/25/2020 Microsoft Image Clip Art, 2007 66

H 2 Antagonist üCimetidine 300 mg IV üFamotidine 20 mg IV üRanitidine 150 mg

H 2 Antagonist üCimetidine 300 mg IV üFamotidine 20 mg IV üRanitidine 150 mg IV One of these agents to be used as a premedication Reducing mucus secretion and vascular smooth relaxation 9/25/2020 (Greenberger, 2002) Microsoft Image Clip Art, 2007 67

How does the H 2 antagonist work? Histamine is a chemical naturally produced by

How does the H 2 antagonist work? Histamine is a chemical naturally produced by certain cells in the body including cells in the lining of the stomach called the enterochromaffinlike cells (ECL cells). Histamine released from ECL cells then stimulate the acid making cells (parietal cells) in the lining of the stomach to release acid. What H 2 blockers do is stop the acid making cells in the stomach lining from responding to histamine. This reduces the amount of acid produced by your stomach. 9/25/2020 Diagram copyright EMIS and Pi. P 2009, as distributed on http: //www. patient. co. uk 68

What is the incidence of a hypersensivity to Paclitaxel? Despite premedication there is estimated

What is the incidence of a hypersensivity to Paclitaxel? Despite premedication there is estimated 44% minor reactions occuring in patients and approximately 1. 5 -3% of patients experiencing major anaphylactic reactions 9/25/2020 (Zuylen, Verweij, Sparreboom, 2001) Microsoft Image Clip. Art, 2007 69

Allergic Drug Reaction (ADR) (Hypersensitivity) These reactions are mediated by our immune system that

Allergic Drug Reaction (ADR) (Hypersensitivity) These reactions are mediated by our immune system that share similar characteristics Involve previous exposure to this drug or a similar agent Small number of patients Clinical presentation 9/25/2020 (Timoney, Eagan, sklarin, 2003) Reaction develops rapidly with reexposure 70

Poor Reporting of ADR is voluntary by health care professionals. True statistics on the

Poor Reporting of ADR is voluntary by health care professionals. True statistics on the frequency of a hypersensitivity are not available. Do you know your institution’s guidelines? Are you reporting ADRs? When would you need to report a reaction to the Us Food and Drug Administration (FDA)? 9/25/2020 Microsoft Image Clip Art, 2007 71

Keys to successful outcomes! • Premedication's! Critical, critical! • Patients prior allergic reaction •

Keys to successful outcomes! • Premedication's! Critical, critical! • Patients prior allergic reaction • Educate patient and family on potential and actual side effects 9/25/2020 Microsoft Image Clip Art, 2007 72

What’s the deal with Paclitaxel? Ovarian Breast Endometrial Less common tumors/off label Taxol saving

What’s the deal with Paclitaxel? Ovarian Breast Endometrial Less common tumors/off label Taxol saving lives Bladder Esophageal Testicular Lung 9/25/2020 Head & Neck Presently one of the most widely used chemotherapeutic agents today due to its potent tumor cytotoxcity in numerous cancer diagnoses (Price, Mariana, Castells, 2002) Microsoft Image Clip Art, 2007 73

What’s the deal with Paclitaxel? The Great Mystery…Is it the drug or the solution?

What’s the deal with Paclitaxel? The Great Mystery…Is it the drug or the solution? Countless studies have evaluated what causes the hypersensitivity and anaphylaxis in patients. Remember an anaphylaxis reaction is the release of histamine in response to the allergen, an anaphylactoid reaction is unrelated to histamine release but the same clinical presentation. Paclitaxel (Taxol) was developed from the bark of the Pacific yew tree (Taxus brevifolia) How creative in picking the name! In early phase I studies in the late 1980’s this chemotherapy agent it almost never made it to be one of the most standard chemotherapy agents to date! This was due to severe hypersensitivity reactions in patients and many deaths. Over the years it is a known reaction potential and hence the guidelines for pre-medications and slow titration to reduce the reaction potential of our patients. 9/25/2020 74

What’s the deal with Paclitaxel and Cremophor EL (Cr. EL)? Made from castor oil

What’s the deal with Paclitaxel and Cremophor EL (Cr. EL)? Made from castor oil So needs Poorly soluble in water Axonal degeneration & demyelination Cr. EL linked to the main cause of neurotoxicity Why we need special tubing! 50% Cr. EL& 50% dehydrated ethanol Known to leach plasticizers from standard IV bags and tubing sets Otherwise toxins could cause hepatic toxicity Approximately 25% of patients with neuropathies Flu like symptoms, loss of circulation, imbalance, memory problems Damage occurs to the brain and/or peripheral nervous system Careful assessment of your patients is needed with each cycle In order for this chemotherapy to be administered it needs this “vehicle” Paclitaxel alone is insoluble in water. Think of it like oil and water, without the Cremophor EL the paclitaxel would remain in suspension unable to be delivered. (Zuylen, Verweij, Sparreboom, 2001) Carrie Bilicki, 2009 75

The great mystery continues… But wait? How can this be? From what we know

The great mystery continues… But wait? How can this be? From what we know about a type I reaction it is the first exposure that “primes” the Ig. E. Then the next time the allergen enters the body, it triggers the mast cell to release its histamine and other inflammatory mediators. Patients usually react on the first exposure to paclitaxel! 76

 Reaction mystery Continues…. Ig. E or not! Is the Cremophor EL a direct

Reaction mystery Continues…. Ig. E or not! Is the Cremophor EL a direct NON Ig. E histamine releaser? And other studies have reported it’s the paclitaxel alone that caused histamine release There a few theories on what is occurring. No clinical studies have measured serum tryptase after reactions Cremophor EL is used in anesthetics, vitamins, sedatives and found in cosmetics, perfumes, creams This could be the “priming” Ig. E exposure! Are we not mixing the Paclitaxel and Cremophor well enough prior to administration? Tryptase is a mediator along with histamine that is released from mast cells into circulation when an allergic reaction or inflammation occurs. This level can be measured in the blood serum of patients to determine if an anaphylactic reaction had occurred. Histamine metabolites can be measured in urine studies. Cremophor EL is 50% alcohol, animal studies have shown a possible link of the histamine release to the components of Cremophor EL “The mechanism(s) underlying paclitaxel hypersensitivity-like reactions is skill unknown, and clinical data on probable complement and mast cell activation are lacking” (Price et. al, 2002, p. 205) (Zuylen, Verweij, Sparreboom, (2001) (Price, Castells, 2002) 77

Cremophor EL Microsoft Image Clip To give you an idea the concentration Art, 2007

Cremophor EL Microsoft Image Clip To give you an idea the concentration Art, 2007 used in Paclitaxel it is 25. 8 ml administered (in an average adult) compared to 1. 5 ml in a dose of diazepam or 3. 5 ml in Cyclosporin A. This may help you understand slowing the infusion will lessen the volume of concentration delivered & the importance to ensure your infusion bag is gently mixed prior to hanging Paclitaxel. Gelderblom, et. al. 2001 78

Known Risk… whatever the cause In the early days of administering Paclitaxel it was

Known Risk… whatever the cause In the early days of administering Paclitaxel it was given in the Intensive Care Unit because of the high incidence of reactions. We now know a lot more on the management of hypersensitivity to this chemotherapy. A hypersensitivity reaction will most likely occur within minutes of administration or shortly after you increase the rate. This is why it is so important to follow all the steps when administering Paclitaxel. Missing one step in premedication, length of time between premedication's, and titration of paclitaxel can be detrimental to your patient. We never know who is going to react. Being prepared is key! 9/25/2020 Microsoft Image Clip Art, 2007 79

Know your patient The number one preventative measure you can do to stop a

Know your patient The number one preventative measure you can do to stop a reaction is to know your patient and their history! Assess your patient for previous Type I (Ig. E mediated) allergic reactions. Genetic predisposition for sensitization to antigens. seminal fluid food vaccines antibiotics exercise induced other medications idiopathic anesthesia blood transfusions latex Lieberman et. al, 2005 bee stings 80

Did you know? Microsoft Image Clip Art, 2007 v. The more rapidly anaphylaxis occurs

Did you know? Microsoft Image Clip Art, 2007 v. The more rapidly anaphylaxis occurs during an infusion the more likely it is to be severe and potentially life threatening v. Most reactions will occur within minutes, but some patients may have a delayed reaction such as 30 minutes into the infusion v. Some patients may have a delayed reaction called “Late Phase” or “Biphasic reactions, which may occur 8 -12 hours after the patient is home v. Once a patient is reacting despite the best interventions and aggressive treatment patients may experience protracted and severe anaphylaxis up to 32 hours Lieberman et. al, 2005 81

Did you Know? Microsoft Image Clip Art, 2007 “Increased vascular permeability, a characteristic feature

Did you Know? Microsoft Image Clip Art, 2007 “Increased vascular permeability, a characteristic feature of anaphylaxis, allows transfer of as much as 50% of the intravascular fluid into the extravascular space within 10 minutes. As a result, hemodynamic collapse might occur rapidly with little or no cutaneous or respiratory manifestations”. That means our patients may not complain of any shortness of breath, itching, or any forewarning! Good to Know! Lieberman et. al, 2005 82

Ready, Set, Go! Microsoft Image Clip Art, 2007 9/25/2020 üEstablished protocol to deal with

Ready, Set, Go! Microsoft Image Clip Art, 2007 9/25/2020 üEstablished protocol to deal with any event, equipment and emergent medication readily available üPatient teaching completed üPatient history obtained üPremedication's administered as ordered üYou follow your established clinical guidelines for the administration of Paclitaxel üStay with your patient for the first 15 minutes, monitoring vital signs 83

Let’s review! Mrs. Smith is in for her first infusion of Paclitaxel, 10 minutes

Let’s review! Mrs. Smith is in for her first infusion of Paclitaxel, 10 minutes into her infusion she complains of itchy hands. What do you do? A. Assure her this is a common side effect, to be expected and continue on with the titration of Paclitaxel B. Call a code, rushing to the patient asking if she would like “last rights” C. Remain calm, assess all symptoms and (1) stop the infusion, infuse Normal Saline and continue to monitor the patient, or (2) slow the infusion an monitor for symptoms to alleviate. D. Offer the patient hand lotion and tell her this may help her dry, itchy hands. 84

Keys to successful management You know the risks! What’s your patient’s baseline? Know what

Keys to successful management You know the risks! What’s your patient’s baseline? Know what you should monitor for! PROACTIVE Ongoing monitoring and early interventions are the key to safe administration & intervention if needed to a anaphylaxis reaction Level of consciousness, acute confusion or gazed appearance may indicate decreased oxygen saturation Monitor airway, watch for shortness of breath, cough, wheezing Cardiovascular system, ongoing evaluation of blood pressure and pulse Skin changes, flushing to face, itching, facial edema GI symptoms, nausea, vomiting, diarrhea Neurological changes, lightheadedness, headaches, feeling of impending doom Lieberman et. al, 2005 89

Slow and steady wins the race Reactions are very frightening for you, the patient

Slow and steady wins the race Reactions are very frightening for you, the patient and their family! We know how beneficial Paclitaxel is for our patients learn why it is important to go slow, monitor for reactions, and understand the process of safely rechallenging patients. Microsoft Image Clip Art, 2007 90

Slow Down! What’s the rush? Keep your Patient safe Concentration & Rate Dependant Microsoft

Slow Down! What’s the rush? Keep your Patient safe Concentration & Rate Dependant Microsoft Image Clip Art, 2007 • Theory behind binding of anti-cholesterol antibodies to the oil rich Cremophor El causes heightened hypersensitivity • We now realize that histamine is released in response to the antigen, give the body time to recognize and process, slower concentration, less callout of the immune response • For patients showing EARLY clinical signs, slowing the infusion rate can alleviate hypersensitivity symptoms. STAY with your patient and monitor closely for the first 15 minutes. Safe delivery by a knowledgeable nurse! Tije, Verweij, Loos, Sparreboom, 2003 Improved Patient outcomes! 91

Slow Down! What’s the rush? Keep your Patient safe Concentration & Rate Dependant Microsoft

Slow Down! What’s the rush? Keep your Patient safe Concentration & Rate Dependant Microsoft Image Clip Art, 2007 Up to 44% of patients receiving Paclitaxel will still react with minor symptoms of itching hands or skin flushing, despite adequate premedications. Important to start slow, and reduce the rate if your patient starts to complain of symptoms. Stay close to your patient, and monitor. Your strong assessment skills will allow patients to complete their infusions without experiencing a “full blown” reaction! Safe delivery by a knowledgeable nurse! Tije, Verweij, Loos, Sparreboom, 2003 Improved Patient outcomes! 92

Your patient reacts! Now what? First Step--Stay in CONTROL v. Stop Infusion v. Recline

Your patient reacts! Now what? First Step--Stay in CONTROL v. Stop Infusion v. Recline your patient, elevating legs to slow progression of hemodynamic compromise, prevent hypotension, & encourage blood flow to the head, heart, and kidneys I’m in control? ? !! Microsoft Image Clip Art, 2007 **Some physicians may administer corticosteroids to block late allergic symptoms (no effect on initial reaction) v. Maintain Airway, monitor pulse oximetry, administer oxygen to patient v. Bolus Normal Saline to replace fluids, goal to keep systolic blood pressure greater than 90 mm v. Possible re-dosing of diphenhydramine, and antihistamines v. Give Epinephrine to control symptoms and increase Blood Pressure v. If patients fails to show response to the above interventions, transport patient to an emergency room for further interventions and monitoring (Albanell, Baselga, 2000), Lieberman et. al, 2005 93

Did you Know? ? “ “Lactated Ringers solution might potentially contribute to metabolic acidosis,

Did you Know? ? “ “Lactated Ringers solution might potentially contribute to metabolic acidosis, and dextrose is rapidly extravased from the intravascular circulation to the interstitial tissues”. Lieberman, et al p. 493 Main message! Use Normal Saline, and up to 7 liters might be needed! One to two liters at a rate of 5 -10 ml/kg in the first 5 minutes! Who Knew! Microsoft Image Clip Art, 2007 Lieberman et. al, 2005 94

Knowledge is POWER! Desensitization Protocols… used to scare you…not anymore! When patients are given

Knowledge is POWER! Desensitization Protocols… used to scare you…not anymore! When patients are given a desensitization protocol, the goal is to give small dilute amounts of Paclitaxel over an extended period of time. What is believed to happen is stimulation of the production of Ig. G and Ig. A. These antibodies, then, act as blocking antibodies to bind to and neutralize as much of the allergen BEFORE it can bind to the deeper cell-bound Ig. E on the mast cells and connective tissue. Remember Ig. E is the culprit in producing histamine release. So, No histamine, No allergic reaction! Most Up to 90% of patients Can successfully be rechallenged patients can tolerate retreatment 95

Knowledge is POWER! Desensitization Protocols… used to scare you…not anymore! Most institutions have established

Knowledge is POWER! Desensitization Protocols… used to scare you…not anymore! Most institutions have established rechallenge protocols Some institutions have found benefit in using the model of a rechallenge protocol on ALL patients starting with cycle 1 of Paclitaxel to minimize reactions. The next slide is an example used by an outpatient infusion center in York, Pennsylvania. This change in practice was due to NURSES questioning infusion reactions (27% of patients) and collaborating with physicians piloting their established rechallenge protocol on all Paclitaxel patients. Outcome=less than 1% of patients show infusion reactions, virtually eliminating any reactions in their clinic. 96

Knowledge is POWER! Apple Hill Infusion Center York, Pennsylvania Paclitaxel Rechallenge Protocol 1. 2.

Knowledge is POWER! Apple Hill Infusion Center York, Pennsylvania Paclitaxel Rechallenge Protocol 1. 2. 3. 4. 5. 6. Premedications: Decadron 20 mg po, Cimetidine 300 mg IV & Benadryl 50 mg IV 40 ml/hr for 15 minutes 60 ml/hr for 30 minutes 80 ml/hr for 30 minutes 90 ml/hr for 30 minutes 100 ml/hr until completed Based on 135 mg/m² dose in 205 ml of D 5 W, given every 3 weeks Vital signs are taken every 15 minutes for the first hour, including apical pulse then hourly for the remainder of the infusion (Huddleston et. al, 2005) 97

Knowledge is POWER! The decision to rechallenge is evaluated individually with each patient after

Knowledge is POWER! The decision to rechallenge is evaluated individually with each patient after careful consideration by the treating physician and patient. Nursing Sensitive Outcomes 1. Safety (preventable adverse events) 2. Psychological distress related to anxiety of the patient 3. Physiological outcomes related to interventions to control systemic response to Taxane therapy Your role is to be knowledgeable, supportive, and manage your patient with nursing sensitive outcomes! 98

Case Study! Lets Apply this! Mrs. Smith, new ovarian cancer diagnosis arrives to your

Case Study! Lets Apply this! Mrs. Smith, new ovarian cancer diagnosis arrives to your clinic for her first time Carboplatin/Taxol regimen. She is anxious, already has had chemotherapy/side effect teaching. You reassure her you will be by her side and will monitor her closely over the next hour, and through the duration of the infusion. . You know how important it is to monitor her closely especially for the first 15 minutes. 1. Pre-medicaitons hung as ordered and given 30 minutes prior to the initiation of Taxol. 2. 5 minutes into the infusion she complains of being SOB, her blood pressure has dropped to 82/50 and her pulse ox is reading at 88%. Her pulse is at 102 and respirations are 20 a minute. Your keen assessment skills and knowledge that Taxol can cause a hypersensitivity reaction you are aware these are signs of a systemic reaction caused by Ig. E antibodies reacting with the infusion; subsequent release of histamine is causing these cascade of events and you need to act fast! 99

Case Study! Lets Apply this! Swiftly you stop the infusion and place O 2

Case Study! Lets Apply this! Swiftly you stop the infusion and place O 2 on your patient monitoring her response to oxygen, titrating the oxygen to maintain a saturation above 92%. Normal Saline is now infusing while you are consistently assessing her vital signs, with the goal to maintain her systolic blood pressure above 90 mm. You have already reclined your patient, elevating legs to slow progression of hemodynamic compromise, prevent hypotension, & encourage blood flow to the head, heart, and kidneys You were so prepared and in control prior to hanging the Taxol you have your standard hypersensitivity reaction orders next to the patient “just in case” and have all necessary rescue medications available. 100

Case Study! Lets Apply this! Great news! She responds to your interventions within minutes

Case Study! Lets Apply this! Great news! She responds to your interventions within minutes of removing the Taxol. Seems the Taxol was the allergen reacting with the antibodies Ig. E. These antibodies attached to mast cells and basophils to release histamine. That dang histamine caused the blood pressure to drop; constricted bronchial airways, wheezing & difficulty breathing, stimulation of mucous secretion causing congestion and drop in pulse ox. Your skills as an informed, knowledgeable oncology nurse enabled this patient to have a potentially severe outcome, be manageable and safe! Your patient also was spared unnecessary frantic response because you remained in control & you were aware this was a potential. NICE JOB! 101

You did it! Conclusions! Did we unravel the Mystery a little? Microsoft Image Clip

You did it! Conclusions! Did we unravel the Mystery a little? Microsoft Image Clip Art, 2007 • Pathophysiology: of humoral immunity- Type I hypersensitivity reactions (antibody Ig. E) related to the immune system response • Evaluating other possible reasoning behind Paclitaxel hypersensitivity reactions • Anaphylaxis vs. anaphylactoid reactions • Developing strategies for preventing and managing hypersensitivity reactions • Understand the rationale for rechallenging patients 102

References • • Albanell, J. , Basselga, J. , (2000) Systemic Therapy Emergencies. Seminars

References • • Albanell, J. , Basselga, J. , (2000) Systemic Therapy Emergencies. Seminars In Oncology, 27(3) 347 -361. Bristol-Myers Squibb Company. (2007). Taxol® (paclitaxell) injection [Package insert]. Princeton, NJ: Author. Chinen, J. , Fleiser, T. A. , Shearer, W. T. , (2008). The immune system: An overview. In Adkinson: Middleton’s Allergy: Principles and Practice. Retrieved February 27, 2009 from Ovid database. Chung, C. (2008). Managing Premedicaitons and the risk for reactions to infusional monoclonal antibody therapy. The Oncologist, 13(6) 725 -732. Gelderblom, H. , Verweij, J. , Nooter, K. , Spareboom, A. (2001) Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. European Journal of Cancer, 37, 15901598. ’ Greenberger, P. A. , (2002). Anaphylaxis. In Manual of Allergy & Immunology (10). Retrieved February 27, 2009 from Ovid database. Heinz-Josef, L. , (2007) Management and preparedness for infusion and hypersensitivity reactions. The Oncologist, 12, 601 -609. Retrieved February 20 t, 2009 at www. The. Oncologistcom. Huddleston, R. , Berkheimer, C. , Landis, S. , Houck, D. , Proctor, A. , & Whiteford, J. (2005). Improving patient outcomes in an ambulatory infusion setting decreasing infusion reactions of patients receiving paclitaxel and carboplatin. Journal of Infusion Nursing, 28(3), 170 -172. 9/25/2020 103

References cont. • • • Lieberman, P. , Kemp, S. F. , Oppenheimer, J.

References cont. • • • Lieberman, P. , Kemp, S. F. , Oppenheimer, J. , Lang, D. M. , Berstein, I. L. , & Nicklas, R. A. , (2005). The Diagnosis and management of anaphylaxis: An updated practice parameter. The Journal of Allergy and Clinical Immunology, 115(3), 483 -523. Markman, M. , Kennedy, A. , Webster, K. , Kulp, B. , Peterson, G. , Belinson, Jerome. (2000). Paclitaxel-associated hypersensitivity reactions: Experience of the Gynecologic Oncology Program of the Cleveland Clinic Cancer Center. Journal of Clinical Oncology, 18(1) 102 -105. Retrieved February 20, 2009, from Ovid database. Marsh, S. , Somlo, G. , Frankel, Pl, King, C. R. , Shannon, W. D. , Mc. Leod, H. , L. et al. (2007). Pharmacogenetic analysis of paclitaxel transport and metabolism genes in breast cancer. The Pharmacogenics Journal, 7, 362 -365. doi: 10. 1038/sj. spj. 65 oo 434. Microsoft. (2007). Clipart. Retrieved April 15, 2009 from http: //office. microsoft. com/enus/clipart/default. Myers, J. S. , (2000). Hypersensitivity reactions to paclitaxel: Nursing interventions. Clinical Journal of Oncology Nursing, 4(4), 161 -163. Myers, J. S. , (2000). Emergency: Chemotherapy-induced hypersensitivity reaction. American of Nursing, 10(4), 53 -54. 9/25/2020 104

References cont. • • • Price, K. , S. , & Castells, M. C.

References cont. • • • Price, K. , S. , & Castells, M. C. (2002). Taxol reactions. Allergy and Asthma Proc, 43(3), 205 -208. Tije, A. , J. , Verweij, J. , Loos, W. , Sparreboom, A. (2003) Pharmacological effects of formulation vehicles implications for cancer chemotherapy. Clin Pharmocokinet, 42(7), 665 -680. 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. Slater J. , W. , Zechnich AD, Haxby DG. Second-generation antihistamines. A comparative review. Drugs 1999; 57(1): 31 -47. Zidan, J. , Hussein, O. , Abzah, A. , Tamam, Sl, & Farraj, Z. (2008). Oral premedication for the prevention of hypersensitivity reactions to paclitaxel. Med Oncology, 25, 274 -278. Zuylen, L, . V. , Verweij, J. , Sparreboom, A. (2001) Role of formulation vehicles in taxane pharmacology. Investigational New Drugs, (19) , 125 -141. 9/25/2020 105

Thank YOU! Thank you for taking the time to view this tutorial. My hopes

Thank YOU! Thank you for taking the time to view this tutorial. My hopes are patient outcomes are improved through increased nursing knowledge in understanding the great reaction mystery’s of Paclitaxel! If you would like to contact me with questions or comments I can be reached at: Carrie. bilicki@aurora. org 414 -587 -1860 9/25/2020 Template copyright 2005 www. brainybetty. com 106