Chemotherapy Biotherapy & 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 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 Need for systemic treatment  Metastatic tumors  Cancers that are systemic by nature

1 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 all dividing cells Cell division cycle Cell cycle specificity  Specific  Non-specific

2 Alkylating Agents Cell cycle non-specific Destroys DNA by causing cross-linking of strands during replication Examples:  Mechlorethamine (Nitrogen Mustard)  Cyclophosphamide  Cisplatin  Dacarbazine

3 Anti-tumor Antibiotics

Cell cycle non-specific Interferes with DNA and RNA synthesis Examples:  Doxorubicin  Daunorubicin  Bleomycin  Mitomycin

Antimetabolites

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

Nitrosureas

Cell cycle non-specific Cross the BBB Sterility Second malignancies Examples:  BCNU, CCNU

4 Plant Alkaloids

Cell cycle specific (M phase) Block mitosis by interfering with the integrity of the mitotic apparatus Examples:  Vincristine  Etoposide  Paclitaxel

Hormones and Hormone Antagonists Cell cycle non-specific Interfere with cellular division by altering the intracellular environment Examples:  Corticosteroids  Megestrol acetate  Tamoxifen  Luprolide

Chemotherapy Side Effects

5 Chemotherapy Adverse Effects: Myelosuppression Mechanism of Occurrence Potential problems  Leukopenia: Infection  Thrombocyyptopenia: Bleedin 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 = ANC 100

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

77 + 3 X 4.5 = 100 80% X 4.5 = 3600 normal count

6 ANC AND RISK OF INFECTION

1,000 - 1,500 Minimal Risk

500 - 1,000 Moderate Risk

< 500 Severe Risk

CLINICAL MANIFESTATION Fever > 38oC (100.4o F)

Reliable & 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 PttPatterns  Acute  Delayed  Anticipatory

7 Chemotherapy Adverse Effects: Nausea and Vomiting Potential Problems  Dehydration  Inadequate nutritional intake  FtiFatigue 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 Cisplatin Highest Dacarbazine Mechlorethamine Cyclophosphamide Doxorubicin/Daunorubicin Cytarabine Paclitaxel Etoposide Methotrexate Bleomycin Vincristine Lowest Fluorouracil Hormones

8 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)  Increased risk of injury At risk populations  Causative agents  History of alcoholism or diabetes

9 Chemotherapy Adverse Effects: Renal Toxicity Mechanism of occurrence Potential problems  Electrolyygte wasting  Decreased ability to clear toxins/drugs At risk populations  Causative agents (chemotherapy, antibiotics)  Dehydration  Preexisting renal disease

Chemotherapy Adverse Effects: Cardiac Toxicity

Mechanism of Occurrence Potential problems  AtiititlActivity intolerance  Congestive heart failure At risk populations  Causative agents  Children and elderly  Pre-existing heart disease

Chemotherapy Adverse Effects: Pulmonary Toxicity Mechanism of occurrence Potential problems  Shortness of breath/DOE  Activity intolerance  Oxygen dependence At risk populations  Causative agents  Concurrent radiation therapy  Pre-existing lung disease  Primary or metastatic cancer  History of smoking

10 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 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 potential to cause t ttitieratogenic, 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.

11 Safe Handling of Hazardous Drugs How might I be exposed to hazardous drugs?  Healthcare 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 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 Assessment Patient 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

12 Chemotherapy Pretreatment Assessment History 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

Biotherapy

Biological 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

Interleukins

Hematopoietic Growth Factors

13 Immune System Review

Complex 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.

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

14 Hematopoietic Growth Factors Agent Function Indication G-CSF Stimulates production, differentiation, Neutropenia Filgrastim (Neupogen®), Amgen and maturation of neutrophils

Pegfilgrastim Stimulates production, differentiation, Neutropenia (Neulasta®), Amgen and maturation of neutrophils

GM-CSF Stimulates production of both Neutropenia Sargramostim (Leukine®), Berlex granulocytes and macrophages

Erythropoietin alpha Stimulates red blood cell production Anemia (Procrit®), OrthoBiotech; (Epogen ®), Amgen Interleukin-11 Stimulates platelet production Thrombo- Oprevelkin cytopenia (Neumega®), Wyeth-Ayerst Darbepoetin alfa Stimulates erythropoiesis Anemia (Aranesp®), Amgen

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) AIDS-related Kaposi’s sarcoma [Schering] Lymphoma Roferon®-A Hairy cell leukemia AIDS-related Kaposi’s sarcoma (IFN- 2a, recombinant) Chronic myelogenous leukemia [Roche Laboratories]

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

15 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 Renal cell cancer [Aldeskeukin] Metastatic melanoma Subcutaneous Proleukin® (Chiron)

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.

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.

Proleukin®, Chiron

Molecular Targeted Therapies

Tyrosine Kinase Inhibitors

Proteasome Inhibitors

Monoclonal antibodies (MoAbs)

16 Tyrosine Kinase Inhibitors (TKI) Imatinib Mesylate (Gleevec®), Novartis

Gefitinib (Iressa®), AstraZeneca

TKIs are enzyyymes within the cell that block the ability of 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 Inhibitors

Block activity of proteasomes, enzymes that help regulate cell function and growth

Proteasomes are involved in the cell cycle, growth 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.)

17 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 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 Monoclonal Antibodies Chemotherapy Specifically target tumor Injury to cancer cells cells and normal cells Fewer side effects to Side e ffec ts /toxi c ity normallll cells can be cumulative Less chance of drug and may lead to long resistance term sequelae Fewer cumulative side Multi-drug resistance effects Few dose-limiting side effects

18 Immunotherapy Targets

slg on B Cells CD19 CD20

DR CD22 Surface proteins targeted by immunotherapy B lymphocyte  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

19 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 Targets 21-28 kD cell B-cell lymphocytic (Campath®), Berlex surface glycoprotein, leukemia CD52 Bevacizumab Targets VEGF, Metastatic colorectal (Avastin™), Genentech prevents cancer, first line angiogenesis Cetuximab Targets EGFR Metastatic colorectal (Erbitux™), receptor cancer, relapsed Imclone/Bristol-Meyers Squibb Gemtuzumab Targets the CD33 Acute myeloid ozogamicin (Mylotarg®), antigen; conjugated leukemia, relapsed Wyeth-Ayerst with calicheamicin (antibiotic)

20 FDA-Approved Moabs (cont.)

Monoclonal Antibody Function Indication

Ibritumomab tiuxetan Targets CD20 Relapsed lymphoma (Zevalin®), IDEC antigen; conjugated with Y-90 Trastuzumab Targets HER2 Metastatic breast (Herceptin™), receptor cancer Genentech Rituximab Targets CD20 B B-cell non-Hodgkin’s (Rituxan™), IDEC cells; induces lymphoma (NHL) apoptosis Tositumomab Targets CD20 B B-cell non-Hodgkin’s (Bexxar®), Corixa cells; conjugated with lymphoma (NHL) Iodine I 131

Resources for Information about Cancer Care American Cancer Society: www.cancer.org National Cancer Institute: www.nci.nih.gov Oncology Nursing Society: www.ons.org Association of Pediatric Oncology Nurses: www.apon.org

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