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ChemotherapyBiotherapy &Targeted Therapies

MiKaela Olsen RN, MS, OCN

Oncology and BMT Clinical Nurse Specialist

Objectives

State the dose limiting toxicity of chemotherapy

Describe the mechanism of action of 2Describe the mechanism of action of 2 different biotherapy drugs

State the theory behind targeted therapies

Why Use Chemotherapy?

Characteristics of malignant cells Uncontrolled growth

Decreased ability to repair DNA damage Decreased ability to repair DNA damage

Need for systemic treatment Metastatic tumors

Cancers that are systemic by nature

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Goals of Chemotherapy

Cure = No evidence of disease: Normal life span

Control = Increase in survival and quality of life

Palliation = Increase in comfort

Affect of Chemotherapy on Dividing Cells

Interferes with alldividing cells

Cell division cycleCell division cycle

Cell cycle specificity Specific

Non-specific

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Alkylating AgentsCell cycle non-specific

Destroys DNA by causing cross-linking of strands during replication

Examples: Mechlorethamine (Nitrogen Mustard)

Cyclophosphamide

Cisplatin

Dacarbazine

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Anti-tumor Antibiotics

Cell cycle non-specific

Interferes with DNA and RNA synthesis

Examples:Examples: Doxorubicin

Daunorubicin

Bleomycin

Mitomycin

Antimetabolites

Cell cycle specific (S phase)Block DNA synthesis by substituting for normal enzymes or other cellular ycomponentsExamples: Fluourouracil Methotrexate Cytarabine

Nitrosureas

Cell cycle non-specific

Cross the BBB

SterilitySterility

Second malignancies

Examples: BCNU, CCNU

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Plant AlkaloidsCell cycle specific (M phase)

Block mitosis by interfering with the integrity of the mitotic apparatusintegrity of the mitotic apparatus

Examples: Vincristine

Etoposide

Paclitaxel

Hormones and Hormone Antagonists

Cell cycle non-specificInterfere with cellular division by altering the intracellular environmentExamples: Corticosteroids Megestrol acetate Tamoxifen Luprolide

Chemotherapy Side Effects

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Chemotherapy Adverse Effects: Myelosuppression

Mechanism of OccurrencePotential problems Leukopenia: Infection Thrombocytopenia: Bleedingy p g Anemia: Fatigue

At risk populations Myelosuppressive chemotherapy regimens Previous/concurrent myelosuppressive therapies Hematologic malignancies Source of infection Cardiopulmonary compromise

ABSOLUTE NEUTROPHIL COUNT (ANC)

Polys + Bands X WBC = ANC100

Example: WBC = 4.5, Polys = 77, Bands = 3

77 + 3 X 4.5 = 10080% X 4.5 = 3600 normal count

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ANC AND RISK OF INFECTION

1,000 - 1,500 Minimal Risk

500 - 1,000

< 500

Moderate Risk

Severe Risk

CLINICAL MANIFESTATION

Fever > 38oC (100.4o F)

Reliable & often only sign of infectionReliable & often only sign of infection

If extremely neutropenic, they may not be able to manifest the usual sign

Chemotherapy Adverse Effects: Nausea and Vomiting

Mechanism of occurrence

P ttPatterns Acute

Delayed

Anticipatory

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Chemotherapy Adverse Effects: Nausea and Vomiting

Potential Problems Dehydration Inadequate nutritional intake

F ti Fatigue

At Risk Populations Emetogenic chemotherapy drugs History of nausea/vomiting Gastrointestinal/pelvic tumors Other medications (e.g. opioids, antibiotics)

Emetogenic Potential of Select Chemotherapy Drugs

HighestCisplatinDacarbazineMechlorethamineCyclophosphamideDoxorubicin/Daunorubicin

Lowest

Doxorubicin/DaunorubicinCytarabinePaclitaxelEtoposideMethotrexateBleomycinVincristineFluorouracilHormones

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Chemotherapy Adverse Effects: Mucositis/Stomatitis

Mechanism of Occurrence

Potential Problems Pain

Decreased food and fluid intake

Increased risk for infection

At risk populations Causative agents

Intensive treatment regimens

History alcohol/tobacco use

Poor oral hygiene

Head and neck tumors

Chemotherapy Adverse Effects: Peripheral Neuropathies

Mechanism of occurrence

Potential problems Discomfort (pain hyperesthesias) Discomfort (pain, hyperesthesias)

Increased risk of injury

At risk populations Causative agents

History of alcoholism or diabetes

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Chemotherapy Adverse Effects: Renal Toxicity

Mechanism of occurrencePotential problems Electrolyte wastingy g Decreased ability to clear

toxins/drugs

At risk populations Causative agents

(chemotherapy, antibiotics)

Dehydration Preexisting renal disease

Chemotherapy Adverse Effects: Cardiac Toxicity

Mechanism of OccurrencePotential problems

A ti it i t l Activity intolerance Congestive heart failure

At risk populations Causative agents Children and elderly Pre-existing heart disease

Chemotherapy Adverse Effects: Pulmonary Toxicity

Mechanism of occurrencePotential problems Shortness of breath/DOE Activity intolerancey Oxygen dependence

At risk populations Causative agents Concurrent radiation therapy Pre-existing lung disease

Primary or metastatic cancer History of smoking

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Chemotherapy Adverse Effects: Fatigue

Mechanism of occurrence

Potential problems Activity tolerance

Decreased treatment tolerance

At risk populations Intensive treatment

regimens

Impaired activity tolerance prior to treatment

Chemotherapy Adverse Effects: Alopecia

Mechanism of occurrence

Potential Problems Alteration in self concept Alteration in self concept

At risk populations Causative agents

Intensive treatment regimens

Safe Handling of Hazardous Drugs

What is a hazardous drug? Any drug which poses a significant risk to

healthcare workers because of a potentialt t t i t ito cause teratogenic, mutagenic, carcinogenic or reproductive toxicity as well as other serious organ damage.

Includes antineoplastic agents, as well as some biologic, anti-viral and anti-infective agents.

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Safe Handling of Hazardous Drugs

How might I be exposed to hazardous drugs? Healthcare workers can be exposed toHealthcare workers can be exposed to

hazardous drugs during preparation, transportation, administration, disposal of administration equipment, or disposal of body excreta from patients who have received hazardous drugs.

Decreasing Risk of Exposure to Hazardous Drugs

Wear protective gown and gloves when handling hazardous drugs or contaminated body fluids/excreta.Change gloves and wash hands before and after working withbefore and after working with hazardous drugs.Wear goggles or facial splash guard when there is risk of splashing of drug or body fluids.Avoid hand to mouth or eye contact while working with hazardous drugs or contaminated body fluids.

Chemotherapy Pretreatment AssessmentPatient knowledge of: Disease and treatment plan

Reason for using chemotherapy

Specific agents to be administered

Laboratory data Complete blood count with WBC differential

Liver function test

Renal function test

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Chemotherapy Pretreatment AssessmentHistory and Physical Assessment Side effects of previous treatments

Signs/symptoms of infection

Nutritional status

Integrity of skin and mucosal barriers

Cardiopulmonary status

Energy level

Emotional response to disease and treatment

Social support

BiotherapyBiological therapy is the therapeutic use of agents derived from biologic sources and/or affecting biologic responses.

Also called “immunotherapy” and “biotherapy.”

Modifies the body’s biologic/immune response resulting in therapeutic effects.

Types

Interferons

InterleukinsInterleukins

Hematopoietic Growth Factors

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Immune System ReviewComplex system of cells and creation of antibodies Retains memory of previous encounters with immunogens and mounts responses on new challenges Differentiates between “self” and “foreign”In many cancers, may not recognize the cancer as “foreign” and/or the immune system does not act against it Some biological therapies stimulate the immune system to attack cancer.

Hematopoietic Growth Factors

Hematopoietic Growth Factors (HGFs) – proteins that interact with specific receptors to regulate the production, maturation, and function of blood cells.maturation, and function of blood cells.

Usually used to ameliorate side effects of chemotherapy, although some are under investigation for anti-tumor properties.

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Hematopoietic Growth Factors

Agent Function Indication

G-CSF

Filgrastim (Neupogen®), Amgen

Stimulates production, differentiation, and maturation of neutrophils

Neutropenia

Pegfilgrastim

(Neulasta®), Amgen

Stimulates production, differentiation, and maturation of neutrophils

Neutropenia

GM-CSF

Sargramostim (Leukine®), Berlex

Stimulates production of both granulocytes and macrophages

Neutropenia

Erythropoietin alpha

(Procrit®), OrthoBiotech; (Epogen ®), Amgen

Stimulates red blood cell production Anemia

Interleukin-11

Oprevelkin

(Neumega®), Wyeth-Ayerst

Stimulates platelet production Thrombo-cytopenia

Darbepoetin alfa

(Aranesp®), Amgen

Stimulates erythropoiesis Anemia

Interferons: Biological Activities

Antiviral action

Inhibition of oncogenes

Regulation of tumor cell growth; limitation of proliferation

Immunomodulation

Interferons: Cancer Therapy

Name & manufacturer FDA-Approved Uses

Intron® A Malignant melanoma

Hairy cell leukemia(IFN-2b, recombinant) [Schering]

Hairy cell leukemia

AIDS-related Kaposi’s sarcoma

Lymphoma

Roferon®-A

(IFN- 2a, recombinant) [Roche Laboratories]

Hairy cell leukemia

AIDS-related Kaposi’s sarcoma

Chronic myelogenous leukemia

Intron® A, Schering; Roferon®-A, Roche Laboratories

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Interleukins: Biological Activities

•Autocrine action (T helper cells)•Monocyte/macrophage activation•Promotion of cell division and release of mediators (T cells)•Activation and promotion of cell division (B cells)•Activation of Natural Killer (NK) cells

Interleukin-2: Indications/ Administration

Interleukin-2

[Aldeskeukin]

Proleukin® (Chiron)

Renal cell cancer

Metastatic melanoma Subcutaneous

Because of the possible severity of high-dose side effects, administration of high-dose therapy should take place in the hospital setting and not in out-patient clinics.

Standard regimen, Interleukin-2: 600,000 IU/kg (0.037 mg/kg) administered every 8 hours by a 15-minute IV infusion for a maximum of 14 doses. Following 9 days of rest, schedule is repeated for another 14 doses, for maximum of 28 doses per course, as tolerated. During clinical trials, doses were frequently withheld for toxicity.

Proleukin®, Chiron

Molecular Targeted Therapies

Tyrosine Kinase Inhibitors

Proteasome InhibitorsProteasome Inhibitors

Monoclonal antibodies (MoAbs)

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Tyrosine Kinase Inhibitors (TKI)

Imatinib Mesylate (Gleevec®), Novartis

Gefitinib (Iressa®), AstraZeneca

TKIs are enzymes within the cell that block the ability y yof the protein tyrosine kinase to function, limiting cancerous cell growth.

Certain leukemias, as well as cancer of the breast, prostate, ovary, bladder, liver, and lung may be successfully treated with tyrosine kinase inhibitors.

Proteasome InhibitorsBlock activity of proteasomes, enzymes that help regulate cell function and growth

Proteasomes are involved in the cell cycle, growth of new blood vessels (angiogenesis), cellgrowth of new blood vessels (angiogenesis), cell adhesion, cytokine production, and apoptosis.

Blockade can lead to cell death in cancers.

Bortezomib (Velcade™)Indications and Dosing

Indicated for patients with Multiple Myeloma (MM) who have received 2 prior therapies and have shown disease progression since the last therapy

IV injection: 1.3 mg/m2 twice weekly for 2 weeks

Administered on days 1,4, 8, and 11, with a 10 day rest period before the next cycle.

Velcade™ (Millennium Pharmaceuticals, Inc.)

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Monoclonal Antibodies

MoAbs are artificially produced in the laboratory and are designed to bind to the antigens expressed on the surface of malignant cells

Block the growth of the tumor and/or recruit theBlock the growth of the tumor and/or recruit the body’s immune system to attack the cancer cells

Can be given as a monotherapy, in combination with chemotherapy, and with other targeted therapies under clinical trial

Differences Between Chemotherapy and Monoclonal Antibody Therapy

Traditional Chemotherapy

Injury to cancer cells and normal cellsSid ff t /t i it

Monoclonal AntibodiesSpecifically target tumor cellsFewer side effects to

l llSide effects/toxicity can be cumulative and may lead to long term sequelae

Multi-drug resistance

normal cellsLess chance of drug resistance Fewer cumulative side effectsFew dose-limiting side effects

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Immunotherapy Targets on B Cellsslg

DR

CD19 CD20

CD22 Surface proteins targeted by immunotherapy

B lymphocyte

py naked monoclonal

antibodies (MAbs)

conjugated MAbs radioisotopes

drugs

toxins

Adapted from Press O, et al. Cancer J Sci Am. 1998:4(suppl 2):s19–s26.

Monoclonal Antibodies: Unconjugated

Monoclonal Antibodies: Conjugated

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Efficacy of Unlabeled Tositumomab Enhanced Through the Crossfire

Effect of Iodine-131

Unlabeled “cold” Antibody Radiolabeled Antibody

Courtesy of Andrew Zelenetz, MD.

MoAbs FDA-Approved for Cancer Therapy

Monoclonal Antibody Function Indication

Alemtuzumab

(Campath®), Berlex

Targets 21-28 kD cell surface glycoprotein, CD52

B-cell lymphocytic leukemia

Bevacizumab

(Avastin™) Genentech

Targets VEGF, prevents

Metastatic colorectal cancer, first line(Avastin ), Genentech prevents

angiogenesiscancer, first line

Cetuximab

(Erbitux™), Imclone/Bristol-Meyers Squibb

Targets EGFR receptor

Metastatic colorectal cancer, relapsed

Gemtuzumab ozogamicin (Mylotarg®), Wyeth-Ayerst

Targets the CD33 antigen; conjugated with calicheamicin (antibiotic)

Acute myeloid leukemia, relapsed

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FDA-Approved Moabs (cont.)

Monoclonal Antibody Function Indication

Ibritumomab tiuxetan

(Zevalin®), IDEC

Targets CD20 antigen; conjugated with Y-90

Relapsed lymphoma

Trastuzumab Targets HER2 Metastatic breastTrastuzumab

(Herceptin™), Genentech

Targets HER2 receptor

Metastatic breast cancer

Rituximab

(Rituxan™), IDEC

Targets CD20 B cells; induces apoptosis

B-cell non-Hodgkin’s lymphoma (NHL)

Tositumomab

(Bexxar®), Corixa

Targets CD20 B cells; conjugated with Iodine I 131

B-cell non-Hodgkin’s lymphoma (NHL)

Resources for Information about Cancer Care

American Cancer Society: www.cancer.org

National Cancer Institute:National Cancer Institute: www.nci.nih.gov

Oncology Nursing Society: www.ons.org

Association of Pediatric Oncology Nurses: www.apon.org