2. Cancer and Chemotherapy
Chapter 21
Cancer and Chemotherapy
© Paradigm Publishing, Inc.

3. © Paradigm Publishing, Inc.
Topics
Pathophysiology of Cancer Malignancy
Drugs for Cancer
Preparing and Handling Cytotoxic Drugs
Preventing Chemotherapy-Related Medication Errors
© Paradigm Publishing, Inc.

4. 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 IV
Technicians prepare most of these drugs
Oral chemotherapy is expanding patient care into community practice
United States (U.S.)
intravenous (IV)
© Paradigm Publishing, Inc.

5. Pathophysiology of Cancer and Malignancy
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)
© Paradigm Publishing, Inc.

6. Pathophysiology of Cancer and Malignancy
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
© Paradigm Publishing, Inc.

7. Pathophysiology of Cancer and Malignancy
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
centimeter (cm)
© Paradigm Publishing, Inc.

8. Pathophysiology of Cancer and Malignancy
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
© Paradigm Publishing, Inc.

9. Pathophysiology of Cancer and Malignancy
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
Chart adapted from Schorge et al., Williams Gynecology,
© Paradigm Publishing, Inc.

10. © Paradigm Publishing, Inc.
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
© Paradigm Publishing, Inc.

11. © Paradigm Publishing, Inc.
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
© Paradigm Publishing, Inc.

12. © Paradigm Publishing, Inc.
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)
© Paradigm Publishing, Inc.

13. © Paradigm Publishing, Inc.
Drugs for Cancer
Types of Chemotherapy
Primary 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
© Paradigm Publishing, Inc.

14. © Paradigm Publishing, Inc.
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
© Paradigm Publishing, Inc.

15. © Paradigm Publishing, Inc.
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)
© Paradigm Publishing, Inc.

16. © Paradigm Publishing, Inc.
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.
© Paradigm Publishing, Inc.

17. © Paradigm Publishing, Inc.
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
© Paradigm Publishing, Inc.

18. © Paradigm Publishing, Inc.
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
© Paradigm Publishing, Inc.

19. © Paradigm Publishing, Inc.
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)
© Paradigm Publishing, Inc.

20. © Paradigm Publishing, Inc.
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)
© Paradigm Publishing, Inc.

21. © Paradigm Publishing, Inc.
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
© Paradigm Publishing, Inc.

22. © Paradigm Publishing, Inc.
Drugs for Cancer
Chemotherapy Vesicant Drugs
Daunorubicin
Mitomycin
Doxorubicin
Vinblastine
Epirubicin
Vincristine
Idarubicin
Vinorelbine
Mechlorethamine
© Paradigm Publishing, Inc.

23. © Paradigm Publishing, Inc.
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
© Paradigm Publishing, Inc.

24. © Paradigm Publishing, Inc.
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
© Paradigm Publishing, Inc.

25. © Paradigm Publishing, Inc.
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
© Paradigm Publishing, Inc.

26. © Paradigm Publishing, Inc.
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
luteinizing hormone releasing hormone (LHRH)
© Paradigm Publishing, Inc.

27. © Paradigm Publishing, Inc.
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
chronic myelogenous leukemia (CML)
© Paradigm Publishing, Inc.

28. © Paradigm Publishing, Inc.
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)
© Paradigm Publishing, Inc.

29. © Paradigm Publishing, Inc.
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)
© Paradigm Publishing, Inc.

30. © Paradigm Publishing, Inc.
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
© Paradigm Publishing, Inc.

31. © Paradigm Publishing, Inc.
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
© Paradigm Publishing, Inc.

32. © Paradigm Publishing, Inc.
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
© Paradigm Publishing, Inc.

33. © Paradigm Publishing, Inc.
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.
© Paradigm Publishing, Inc.

34. 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
Biological Safety Cabinet (BSC)
Compounding Aseptic Containment Isolator (CACI or glove box)
personal protective equipment (PPE)
Closed System Transfer Device (CSTD)
© Paradigm Publishing, Inc.

35. Preparing and Handling Cytotoxic Drugs
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
American Society of Health-System Pharmacists (ASHP)
© Paradigm Publishing, Inc.

36. Preparing and Handling Cytotoxic Drugs
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
© Paradigm Publishing, Inc.

37. Preparing and Handling Cytotoxic Drugs
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
© Paradigm Publishing, Inc.

38. Preparing and Handling Cytotoxic Drugs
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
Material Safety Data Sheet (MSDS)
© Paradigm Publishing, Inc.

39. Preparing and Handling Cytotoxic Drugs
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)
© Paradigm Publishing, Inc.

40. Preparing and Handling Cytotoxic Drugs
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
intrathecally (IT)
cerebrospinal fluid (CSF)
© Paradigm Publishing, Inc.

41. 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
sound-alike, look-alike drugs (SALAD)
© Paradigm Publishing, Inc.

42. Preventing Chemotherapy-Related Medication Errors
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
© Paradigm Publishing, Inc.

43. Preventing Chemotherapy-Related Medication Errors
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
© Paradigm Publishing, Inc.

44. © Paradigm Publishing, Inc.
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
© Paradigm Publishing, Inc.