2© paradigm publishing, inc. chapter 21 cancer and chemotherapy

© Paradigm Publishing, Inc. 2

Chapter 21

Cancer and Chemotherapy


Chapter 21

Topics

• Pathophysiology of Cancer Malignancy • Drugs for Cancer • Preparing and Handling Cytotoxic Drugs • Preventing Chemotherapy-Related Medication Errors


Pathophysiology of Cancer and Malignancy

About Cancer and Chemotherapy Agents• Cancer is the second leading cause of death in the U.S.• About 1.5 million people diagnosed with cancer each year• 1 out of every 2 people in the U.S. will develop cancer • Medications to treat cancer (chemotherapy) are complex

Narrow window between safe use and toxicity Chemotherapy administered in a hospital or outpatient

chemotherapy infusion center by IVTechnicians prepare most of these drugs

Oral chemotherapy is expanding patient care into community practice



About Cancer• Cancer is a group of diseases characterized by the

uncontrolled growth of dysfunctional cells• Two major classes of the genes in the cancer process:

oncogenes and tumor-suppressor genes Oncogenes promote cancer formation Tumor-suppressor genes turn off or downregulate the

proliferation of cancer cells• All cells, including oncogenes, develop from proto-

oncogenes (code for growth factors or their receptors)



About Cancer (continued)• Alterations of proto-oncogenes can activate the oncogenes

that promote abnormal cell growth Activation can occur via exposure to chemicals, viruses,

radiation, or hereditary factors Example: erb-B2 (or HER-2neu); codes for a growth

factor receptor found in some breast cancers• Mutations or deletions of tumor-suppressor genes can also

result in uncontrolled cell growth Example: The normal gene product of p53 induces

apoptosis (cell death) in abnormal or aging cells



Cell Proliferation and Gompertzian Kinetics • Mathematical model to show an approximation of tumor

cell proliferation• Early cancer growth is exponential

Takes about 30 divisions of cells to make 1 gram (about 1 cm3) of tumor mass

This is the smallest clinically detectable tumor At this stage, tumor is most sensitive to chemotherapy

agents that attack and destroy rapidly dividing cells



Cell Proliferation and Gompertzian Kinetics (continued)• A lethal tumor burden (size) is 1 kg mass (about 1012 cells)

Tumor burden relates to chemotherapy response The smaller the tumor burden, the more effective

chemotherapy will be• Cell-kill hypothesis: each cycle of chemotherapy kills a

certain percentage of cancer cells Tumor cell count never reaches zero from treatment When number of cancer cells is low enough, normal

defense mechanisms take over and kill remaining cells



Tumor Cell Growth• A tumor must

reach a certain size before it can be detected

• Chemotherapy drugs can kill only a percentage of cancer cells after this point


Drugs for Cancer

About Chemotherapy• Chemotherapy is the use of drugs to treat disease; the

term most often refers to drugs used to treat cancer• Chemotherapy drugs are cytotoxic drugs (toxic to cells),

hormonal therapies, or targeted therapies for cancer• Multiple factors affect tumor response to chemotherapy

Tumor size (tumor burden), cell resistance to the drug, amount of chemotherapy given, condition of patient

• Chemotherapy is usually given in combination regimens Combination chemotherapy maximizes effectiveness of

regimen while minimizing toxicity and resistance


Drugs for Cancer

The Cell Cycle and Use of Multiple Drugs

Multiple agents are often used to act on phases of the cell cycle to increase effectiveness and kill more cancer cells


Drugs for Cancer

The Cell Cycle• The process of division of normal and cancer cells • Cancer cells most sensitive to drugs that affect cell cycle• Cell cycle–specific chemotherapy regimens administered

as continuous infusions or in repeated bolus doses These drugs are schedule-dependent Examples: continuous infusion of fluorouracil or

cytarabine; repeated bolus doses of weekly bleomycin• Cell cycle–nonspecific drugs work at any point in the cell

cycle; these drugs are more dose-dependent Example: cyclophosphamide (alkylating agent)


Drugs for Cancer

Types of ChemotherapyPrimary Chemotherapy

Initial cancer treatment with curative intent; used for Hodgkin’s disease, lymphoma, leukemias, testicular cancer

Adjuvant Chemotherapy

Treatment of residual cells after surgical removal or tumor reduction (e.g., after mastectomy for breast cancer). Neoadjuvant chemotherapy shrinks large tumor for surgical removal. Both curative if tumor is removed.

Palliative Chemotherapy

For incurable cancer: prolongs and improves quality of life; reduces tumor size, symptoms


Drugs for Cancer

Traditional Chemotherapy and Cytotoxic Drugs• Cytotoxic drugs interfere with some normal process of cell

function or proliferation• Four categories: alkylating agents (oldest), antimetabolites,

topoisomerase inhibitors, antimicrotubule agents See Table 21.1 for a list of cytotoxic drugs in each

category and their major side effects• Cytotoxic drugs do not target tumor cells specifically; can

cause many side effects to normal cell function See Table 21.2 for toxicities of specific chemotherapy

drugs and preventive measures to avoid these toxicities


Drugs for Cancer

Common Side Effects of Chemotherapy Drugs

• Bone marrow suppression (decreased production of blood cells, increased risks of infections and bleeding)

• Hair loss (alopecia)

• Nausea and vomiting

• Mucosal damage to the lining of the mouth and intestinal tract (mucositis)


Your Turn

Question 1: What is the purpose of giving chemotherapy in combination regimens?

Answer: Combination chemotherapy maximizes effectiveness of the regimen while minimizing toxicity and resistance.

Question 2: What is the reason traditional chemotherapy drugs cause a lot of side effects related to normal cell function?

Answer: These cytotoxic drugs exert the majority of their effects on cancer cells, but they do not target tumor cells specifically.


Drugs for Cancer

Alkylating Agents• Mechanism of Action: bind to and damage DNA during the

cell division process, preventing cell replication• Indication: treat a wide variety of cancer types• Side Effects (common): bone marrow suppression,

infertility, nausea, vomiting, hair loss• Side Effects (rare, severe): secondary cancers (mutagenic)• Cautions (cisplatin): renal damage, depletion of potassium

and magnesium, peripheral neuropathy, ototoxicity• Cautions (ifosfamide): hemorrhagic cystitis; can be

prevented if co-administered with mesna


Drugs for Cancer

Antimetabolites• Mechanism of Action: work in the synthesis phase of the

cell cycle by a variety of different mechanisms Some inhibit enzyme activity needed for DNA/RNA

synthesis; others interfere with enzymes needed for tumor proliferation; still others act as false nucleotides

• Indication: variety of tumors (see Tables 21.3 and 21.4)• Side Effects (common): bone marrow suppression,

immune system suppression, mucositis• Side Effects (capecitabine): hand-foot syndrome• Side Effects (cytarabine): conjunctivitis


Drugs for Cancer

Antimetabolites (continued)• Methotrexate

Indication: leukemias, bone cancer, breast cancer, lymphomas

Complicated to administer; very wide range of doses Can cause serious toxicities such as kidney damage IV fluids are given to alkalinize (increase pH of) urine to

avoid formation of damaging crystals in kidneys Can cause severe bone marrow suppression, mucosal

injury in the intestinal tract Prevent by administering leucovorin (folinic acid)


Drugs for Cancer

Topoisomerase Inhibitors • Mechanism of Action: interfere with DNA repair function

of topoisomerases and disrupt the cell replication process• Indications: very important in the treatment of many

different types of cancer (see Tables 21.3 and 21.4)• Side Effects (common): bone marrow suppression,

mucositis, nausea and vomiting, alopecia• Topoisomerase I inhibitors include topotecan (ovarian and

lung cancers) and irinotecan (lung and colon cancers) Side Effect (irinotecan): severe diarrhea; managed with

injectable atropine (an anticholinergic)


Drugs for Cancer

Topoisomerase Inhibitors: Anthracyclines• Mechanism of Action: inhibit topoisomerase activity by

inserting themselves (or intercalating) into DNA strands• Indication (doxorubicin): breast cancer and lymphomas• Indication (epirubicin): breast, stomach, esophageal cancer• Indication (daunorubicin and idarubicin): leukemia• Side Effect (most serious, all): cardiac toxicity; typically

occurs many years after patients have received drug• Caution (all): extravasation (drugs are called vesicants)

Some anthracyclines are in liposomal products to decrease toxicity


Drugs for Cancer

Chemotherapy Vesicant Drugs

• Daunorubicin

• Doxorubicin

• Epirubicin

• Idarubicin

• Mechlorethamine

• Mitomycin

• Vinblastine

• Vincristine

• Vinorelbine


Drugs for Cancer

Antimicrotubule Agents• Mechanism of Action: interfere with the formation and

function of microtubules; prevent cell growth and division• Most antimicrotubules are derived from plant sources

The vinca alkaloids are derived from periwinkle plants The taxanes are derived from yew trees

• Indications: lung, breast, ovarian, prostate, and testicular cancers; leukemia; lymphoma

• Side Effects (paclitaxel, docetaxel): allergic reactions during administration (can premedicate to avoid)

• Side Effects (all): peripheral neuropathy


Drugs for Cancer

Miscellaneous Cytotoxic Drugs: Bleomycin• Mechanism of Action: causes cuts or breaks in DNA

strands, preventing the process of cell proliferation• Indications: testicular cancer, Hodgkin’s disease • Side Effect: pulmonary fibrosis (deadly lung toxicity);

however, does not cause bone marrow suppression

Miscellaneous Cytotoxic Drugs: Asparaginase• Indication: acute lymphocytic leukemia in children• Mechanism of Action: breaks down asparagine, depriving

leukemia cells of this essential amino acid• Side Effect: possible allergic reaction; can switch types


Drugs for Cancer

Hormonal Drug Therapies• Some types of cancer depend on naturally occurring

hormones for growth Estrogen and progesterone often stimulate breast

tumors Prostate cancer often depends on testosterone for

growth• Antiestrogens are often used to treat breast cancer

Tamoxifen, anastrazole, letrozole, exemestane• Antiandrogens, such as bicalutamide and flutamide, are

used to treat prostate cancer


Drugs for Cancer

Hormonal Drug Therapies (continued)• LHRH stimulates the production of both male and female

reproductive hormones Over time, continuous exposure to LHRH shuts down

production of sex hormones• Leuprolide (Lupron) and goserelin (Zoladex) are analogs of

naturally occurring LHRH Indication: hormone-sensitive tumors, such as breast

and prostate cancers Mechanism of Action: eliminates source of endogenous

estrogen, progesterone, and testosterone production


Drugs for Cancer

Targeted Drug Therapies • Therapies are directed at specific molecular entities

required for tumor cell development, proliferation, growth• They exert fewer effects on normal cells; usually much

better tolerated than traditional cytotoxic drugs• Many signal transduction inhibitors affect the molecular

abnormalities associated with specific tumor types Indication (imatinib and dasatinib): CML

• Monoclonal antibodies target markers on tumor cells Indication (trastuzumab): breast cancer Indication (rituximab): non-Hodgkin’s lymphoma


Drugs for Cancer

Targeted Anticancer Therapy

Category Anticancer Effect Examples

Signal transduction inhibitors

Prevent transmission of intracellular signals that stimulate cell proliferation

• Dasatinib (Sprycel)• Erlotinib (Tarceva)• Imatinib (Gleevec)• Sunitinib (Sutent)

Angiogenesis inhibitors

Prevent formation of blood vessels that allow tumor growth and invasion of tissue

• Bevacizumab (Avastin)

• Thalidomide (Thalomid)


Drugs for Cancer

Targeted Anticancer Therapy (continued)

Category Anticancer Effect Examples

Monoclonal antibodies

Directed at a specific marker or receptor on the surface of tumor cells, leading to destruction of those cells

• Cetuximab (Erbitux)

• Panitumumab (Vectibix)

• Rituximab (Rituxan)• Trastuzumab

(Herceptin)


Drugs for Cancer

Targeted Drug Therapies (continued)• Some targeted therapies have narrow therapeutic

application; many agents target a wider variety of cancers• Bevacizumab, an angiogenesis inhibitor, treats breast,

lung, colon, and brain cancers Also enhances the effects of cytotoxic drugs when co-

administered• Cetuximab, a monoclonal antibody, treats head, neck,

colon, lung, and pancreatic cancers


Drugs for Cancer

Targeted Drug Therapies: Side Effects• Targeted therapies are usually much better tolerated than

are traditional cytotoxic drugs• They can cause acne-like skin reactions

Sometimes, the rash is a sign that treatment is working Rash managed with topical creams and antibiotic gels

• Monoclonal antibodies can cause allergic reactions Premedicating with acetaminophen, diphenhydramine,

corticosteroids can prevent infusion reactions• Severe: bevacizumab can interfere with blood vessel

formation, preventing wound healing


Drugs for Cancer

Targeted Drug Therapies: Side Effects (continued)• Severe: bevacizumab can cause bleeding, high blood

pressure, and kidney damage

Targeted Drug Therapies: The Future• Typically provide much more direct treatment for cancer• Fewer side effects than traditional cytotoxic drugs


Your Turn

Question 1: What has caused drug companies to manufacture some anthracycline drugs in lipid formulations?

Answer: Anthracyclines can cause severe tissue damage if extravasation occurs (the infusion leaks under the skin during administration). Liposomal products help decrease toxicity.

Question 2: Targeted drug therapies offer newer and smarter approaches for chemotherapy treatment. How is this done?

Answer: These agents target specific molecular entities required for tumor cell development, proliferation, and growth. By targeting specific features of tumor cells, these therapies exert fewer effects on normal cells and are usually much better tolerated than traditional cytotoxic drugs.


Preparing and Handling Cytotoxic Drugs

Required Precautions• Long-term exposure to cytotoxic drugs require precautions

in handling, preparation, and administration• Compounding of oral or injectable hazardous drugs must

be done in either a Class II BSC or a CACI• It is crucial to adhere to strict aseptic and negative

pressure techniques as well as wearing PPE• The CSTD vial-transfer system allows no venting or

exposure of hazardous substances to the environment It is used inside a BSC or a CACI



Required Precautions (continued)• Dispose of all unused hazardous drugs as bulk

chemotherapy waste; requires special handling• See the ASHP Web site for Guidelines on Handling

Hazardous Drugs

Personal Protective Equipment (PPE)• Always use PPE when handling oral and injectable

hazardous drugs• Includes: gloves, gowns, shoe and hair covers, respirator,

safety goggles or glasses



Personal Protective Equipment (PPE) (continued)• Use PPE when

Performing inventory control measures, such as unpacking a drug order

Assembling hazardous drugs for compounding Compounding or cleaning up hazardous drugs Cleaning up spills inside or outside a BSC or a CACI

• Discard all PPE as chemotherapy waste



Aseptic and Negative Pressure Techniques• Use proper aseptic technique when compounding any IV

preparation• Use a BSC or a CACI with a vertical airflow hood when

compounding hazardous preparations• Use a slight negative pressure (vacuum inside the vial) to

prevent spraying or leaking



Handling Spills/Exposures • Clean up small accidental spills to reduce exposure to

hazardous drugs• Accidental exposure to hazardous drugs inhalation,

ingestion, injection, topical absorption (skin, eyes)• Spill kits should be available in all areas where hazardous

drugs are prepared, administered, or transported• MSDS best source for information about hazardous drugs

Available from manufacturers; keep in pharmacies



Special Preparations • Many hazardous drugs require special handling during

preparation or administration Have sensitivity to light (cisplatin, doxorubicin) Need refrigeration to maintain stability (busulfan,

dacarbazine) Require special equipment due to issues with plastic

(etoposide, paclitaxel, carmustine) Require filters in the infusion tubing (paclitaxel)

• Follow procedures for compatibility and precipitation of drugs (etoposide, fluorouracil)



Special Preparations (continued) • Use correct diluent for reconstitution and final dilution• Follow the same rules for PPE that apply to IV product

compounding that apply to oral product compounding• Follow special precautions for preparations of IT hazardous

drugs via lumbar puncture into Ommaya reservoir Delivers chemotherapy directly into CSF Includes: methotrexate, cytarabine, hydrocortisone Do not use preservatives in drug or diluent

• Use special precautions so drugs for IV administration are not confused with drugs for IT administration


Preventing Chemotherapy-Related Medication Errors

Role of Pharmacy Technicians• Are responsible for drug inventory and medication storage• Should implement measures to prevent drug and product

mix-ups, especially in SALAD Do not store SALADs next to each other Apply sound-alike/look-alike stickers (e.g., for

doxorubicin and liposomal doxorubicin [Doxil]) Use colored and/or lidded storage bins Notice tall-man lettering on labels (CISplatin vs.

CARBOplatin, vinCRIStine vs. vinBLAStine)Differing parts of two similar words in capital letters



Role of Pharmacy Technicians (continued)• Prevent errors in calculations: double-check every

calculation and verify the correct drug concentration• Prevent errors in pharmacist order entry: compare final

product label to the original physician order Verify drug, dose, administration schedule, route, and

duration of therapy• Prevent errors in dosing: ensure adherence to specific

manufacturer-provided drug warnings



Role of Pharmacy Technicians (continued)• Prevent errors in administration route

Use syringe overwrap from manufacturer for vincristine and vinblastine to indicate that giving these drugs by the IT route is lethal

• Maintain a clean and organized work environment to avoid chemotherapy medication errors and contamination

• Ensure that there is no confusion about what is being mixed and which drug and concentration are being used

• Complete compounding so products meet acceptable standards and are safe


Summary• Treating cancer involves multiple modalities, such as

surgery, radiation, and drug therapy• Traditional cytotoxic agents are potent cancer-fighting

drugs, but cause a lot of toxicities to normal tissue• Targeted therapies are generally safer and better

tolerated, but still pose risks for serious side effects• Oral cancer treatment expanding into community settings• Technicians must follow special precautions in handling,

preparation, and administration of cytotoxic drugs

2© paradigm publishing, inc. chapter 21 cancer and chemotherapy

Documents

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cancer chemotherapy

proliferation of cancer

chemotherapy agents

cancer process

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number of cancer cells

chemotherapy slide