Chemotherapy

This chapter provides basic concepts and principles related to chemotherapy and the primary mechanisms of action in the treatment goals of oncology patients. In addition, standards related to safe handling, administration, patient/family education, and specific specialty populations are reviewed.

BIOLOGIC AND PHARMACOLOGICAL BASES FOR CANCER CHEMOTHERAPY

Cancer is characterized by uncontrolled abnormal cell growth, often with invasion of healthy tissues locally or throughout the body (metastasis) (Vedes & Biderman, 2001). Chemotherapy is used to prevent cancer cells from multiplying, invading, or metastasizing. Cancer spreads primarily by direct extension through the lymph nodes or the bloodstream. Unlike other cancer treatment modalities (surgery and/or radiation), chemotherapy is a systemic treatment that enables the therapy to combat primary disease sites, areas of known metastasis, and possibly microscopic spread of disease.

The biological basis of cancer chemotherapy is grounded in the understanding of cell division or the cell cycle, which is reviewed in Section One: Cancer Pathophysiology. Briefly, the cell cycle is the mechanism by which all cells divide and replicate both normal and neoplastic cells. See the figure on right for phases of the cell cycle. Generally, the cell is most vulnerable during active division. The cell cycle is the process in which the cell replicates and passes all information needed to make an identical replica of itself. Most chemotherapeutic agents are classified according to where they affect cell cycle activity and how they affect cellular function.

The goals of chemotherapy are targeted at three areas; cure, control, or palliation. Cure is the desired outcome for all patients, but the likelihood depends on several factors at the time of diagnosis and other factors throughout the planned treatment course. The extent of disease at diagnosis, functional status of the patient, physiological presentation at diagnosis, and other socioeconomic influences determine the goal of cancer treatment for each patient. Cure may be further defined as a prolonged absence of disease. The term remission, which is an absence of detectable disease, may be used instead of cure because of the likelihood of recurrence that may be seen in some cancers, such as leukemia and lymphoma. Control is the goal of most therapy when a cure is unrealistic, given disease state or type. Control is also a cautious approach to treatment outcomes. Control focuses on maintaining or improving functional status in the presence of known disease without complete elimination of disease. Chemotherapy for palliation is therapy used when cure or control is not possible because of the extent of disease. Quality of life, disease symptom management, and end of life issues/hospice are a primary focus of control as a goal.

Phases of the cell cycle.

(From McKance, K., & Huether, S. [1998]. Pathophysiology: the biologic basis for disease in adults and children [3rd ed..]. St. Louis: Mosby.)

The timing of chemotherapy in the treatment of cancer is another decision that must be made before therapy initiation. Chemotherapy may be given as adjuvant, neoadjuvant, chemopreventive, and myeloablative.

• Adjuvant therapy is given after a primary treatment (surgery, radiation); the goal is to reduce chance of recurrence by targeting remaining disease after primary treatment.

• Neoadjuvant therapy is given before another treatment with the goal of shrinking tumor before removal or decrease the likelihood of micrometastasis.

• Chemoprevention is the use of selected agents to prevent cancer from occurring in identified high-risk individuals (e.g., tamoxifen).

Myeloablation is the obliteration of bone marrow as preparation for stem cell or bone marrow transplantation (Kelleher, Polovich, & White, 2005). Chemotherapy is also used as a primary treatment to treat a tumor usually seen with minimal disease. It is very important that patient and family members are informed of treatment goals before the initiation of therapy to allow them to set realistic goals in their personal lives. The information needs to be repeated throughout the course of planned treatments.

Chemotherapy is usually given as combination therapy using two or more agents together. The combinations of different agents affect the cell at different points in the cell cycle, allowing for maximum cell kill while minimizing toxicities. Principles for selection of chemotherapeutic agents for combination therapy include (1) choose drugs with single-agent activity, (2) avoid drugs with overlapping dose-limiting toxicities, (3) administer drugs at optimal dose and schedule as determined by clinical trials, (4) give chemotherapy at regular intervals, and (5) minimize the time between cycles (Tortorice, 2000). Combination therapy may also increase the range of drug activity resistance of tumor cell to single agents. In addition, combination chemotherapy may prevent or slow the development of resistance by the cancer cells and have a synergistic effect in combination with other agents (Brescia, 2003).

Tumor cells exposed to chemotherapy sometimes develop mechanisms to protect themselves against the drugs effect. Resistance is the term used to describe the process. Resistance may result from alteration in chemotherapeutic agent metabolism, alteration in cytotoxic targets, biochemical cofactor presence or absence, ability of cell to repair deoxyribonucleic acid (DNA) lesions, or decreased intracellular drug concentration. The most significant explanation of drug resistance is the P-glycoprotein efflux pump associated with overexpression of the MDR-1 gene (multidrug resistance) (Tortorice, 2000). Drug resistance may have many factors that affect response to therapy. Resistance may be inherent or acquired, single agent or multidrug, temporary or permanent. Prevention of drug resistance is another justification for combination chemotherapy (See the box below).

Biochemical Mechanisms Involved in Drug Resistance

• Impaired transport of the chemotherapeutic drug across the cell membrane

• Decreased intracellular activation of the chemotherapeutic drug

• Altered or increased amounts of the intracellular target for the chemotherapeutic drug

• Increased intracellular detoxification of the chemotherapeutic drug

• Increased efficiency of DNA repair of cellular damage caused by the chemotherapeutic drug

• The development of the multidrug resistant phenotype

From Miaskowski, C. & Viele, C. (1999). Cancer chemotherapy. In C. Miaskowski & P. Buchsel (Eds): Oncology nursing: Assessment and clinical care. Mosby: St. Louis, MO.

CELL CYCLE SPECIFICITY AND CHEMOTHERAPY

Chemotherapy uses knowledge of the cell cycle in the attempt to destroy or disrupt the abnormal growth of cancer cells. Most chemotherapeutic agents are classified according to where effects are produced in the cell cycle. Cell cycle–specific agents exert effect when the cell is actively dividing (G1, S, G2, or M phases). Agents that are cell cycle specific tend to be schedule dependent because the greatest tumor kill is obtained when given in frequent divided doses or in continuous infusions to capture the cell in a specific phase. Cell cycle–nonspecific agents are effective in all cell cycle phases, including the resting phase (G0). Cell cycle–nonspecific agents also exhibit a steep dose-response curve that allows increased dosing and frequency (dose-dense/intense) with increased cell kill without extending duration of the cell exposure to the agent.

CHEMOTHERAPY CLASSIFICATIONS

Chemotherapeutic agents are classified by mechanism of action and specificity. The major classifications are listed in the box below. See the figure on page 185 for a diagram of chemotherapeutic agent mechanism of actions. Each classification contains agents that have similar characteristics and side effect profiles. Although the agents are similar, each agent must be addressed on an individual basis or in combination with finalization of a treatment plan.

Major Classification of Chemotherapeutic Drugs

Alkylating agents

Nitrosoureas

Antimetabolites

Antitumor antibiotics

Plant alkaloids

Miscellaneous agents

Hormones

From Miaskowski, C. & Viele, C. (1999). Cancer chemotherapy. In C. Miaskowski & P. Buchsel (Eds): Oncology nursing: Assessment and clinical care. Mosby: St. Louis, MO.

Alkylating Agents

Alkylating agents are cell cycle–nonspecific agents that bind with the DNA and protein molecules, which result in DNA strand breakage. Common toxicities include myelosuppression, hypersensitivity, renal impairment, gastrointestinal (GI) toxicities (nausea/vomiting, diarrhea, etc.), and cutaneous toxicities (alopecia, skin rashes). Side effects are dose dependent and may be cumulative. Alkylating agents are also strongly associated with secondary malignancies, which are usually different malignancies from the original disease that can occur months to years after treatment for a primary cancer. Routes of administration may include oral, intravenous, or topical, depending on the agent and treatment plan. Common alkylating agents include altretamine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, mechlorethamine, oxiliplatin, temozolomide, and thiotepa.

Mechanism of action of chemotherapeutic agents.

(From Krakoff I. [1991]. Cancer chemotherapeutic and biologic agents. CA: A Cancer Journal for Clinicians, 41, 264-278.)

Nitrosoureas

Nitrosoureas are cell cycle–nonspecific agents that have the same mechanism of action and toxicities as alkylating agents with the inclusion of gonadal toxicities. They also have the ability to cross the blood-brain barrier. Nitrosoureas have a high lipid solubility that enables them free passage across membranes; therefore, they rapidly penetrate the blood-brain barrier, whereas most other agents are unable to do so (Calvo & Takimoto, 2005). Blood-brain barrier penetration allows nitrosoureas to be prominently used in the treatment of brain tumor and other central nervous system diseases. Common nitrosourea agents include carmustine, lomustine, and streptozocin.

Antimetabolites

Antimetabolites are cell cycle–specific agents that act in the S-phase of the cell cycle. Antimetabolites interfere with DNA synthesis by imitating the chemical structure of essential enzymes needed for DNA replication or by becoming incorporated into the structure of the DNA molecule. These agents are most effective against cancers that have a high growth fraction or rapidly dividing cells. Common toxicities include myelosuppression, GI toxicities (nausea/vomiting, mucositis, diarrhea), and cutaneous (rash, alopecia, photosensitivity, hyperpigmentation) toxicities. Routes of administration are based on agent and treatment plan and may include topical, oral, intravenous, intrathecal, and intramuscular. Common antimetabolites include capecitabine, cladribine, cytarabine, cytarabine liposomal, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, pentostatin, raltitrexed, thioguanine, trimetrexate, and uracil.

Antitumor Antibiotics

Antitumor antibiotics are cell cycle–nonspecific agents with variable sites of effect dependent on the agent used. Antitumor antibiotics are also referred to as natural products because they occur naturally or are synthesized from microorganisms and have both antimicrobial and cytotoxic activity. Antitumor antibiotics have two primary mechanisms of cell kill: free radical formation and the inhibition of topoisomerase II enzyme that results in DNA disruption and eventually cell death. Antitumor antibiotics are also known as anthracyclines. Cardiac tissues, because of a complex drug-iron complex, are especially vulnerable to anthracyclines (Tortorice, 2000). Common toxicities include myelosuppression and GI, cutaneous, and primary organ toxicities (cardiac, pulmonary). Routes of administration include intravenous, intra-arterial, or intravesical (bladder instillation). Common antitumor antibiotics include bleomycin, dactinomycin, daunorubicin, daunorubicin citrate liposomal, doxorubicin, doxorubicin liposomal, epirubicin, idarubicin, mitomycin, mitoxantrone, and valrubicin.

Plant Alkaloids

Plant alkaloids are cell cycle–specific agents that act by binding to specific cell proteins that cause mitotic arrest, causing a depletion of amino acids necessary for cell replication and apoptosis (programmed cell death). Plant alkaloids are naturally occurring alkaloids isolated from plant material or the result of synthetic and semisynthetic compounds originally extracted from plants. Common side effects include myelosuppression, GI toxicities (constipation, diarrhea), hypersensitivity reactions, and cutaneous (alopecia) and autonomic and peripheral neurological toxicities. Routes of administration are based on agent and treatment plan and include oral, intravenous, and intrathecal. Plant alkaloids include four different categories:

1. Camptothecins (irinotecan, topotecan)

2. Epipodophyllotoxins (etoposide)

3. Taxanes (paclitaxel, docetaxel)

4. Vinca alkaloids (vinblastine, vincristine, vinorelbine)

Microtubular Stabilizing Agents

A number of agents are in clinical development that target microtubules. Intact microtubules are needed for the formation of mitotic spindles in the process of cell division. This new class of chemotherapy drugs is called epothilones (Goodin, Kane, & Rubin, 2004; Petrylak & Kelly, 2004). The agents have been isolated from the mycobacterium, Sporangium cellulosum. The drugs work in the G2/M phase of the cell cycle to initiate apoptosis. Epothilones provide an advantage over taxanes by binding to a different site. Therefore, epothilones provide activity in cancers that have developed taxane resistance.

Epothilones have shown activity in several cancers, including breast, lymphoma, renal, prostate, and ovarian. Side effects are similar to those of taxanes. Hypersensitivity reactions have been reported in cremophor-based epothilone agents. Other side effects to monitor for are neutropenia, peripheral neuropathy, fatigue, arthralgia, myalgia, nausea/vomiting, diarrhea, and stomatitis. Several of the current agents in development are ixabepilone and patupilone (Goodin, Kane, & Rubin, 2004; Petrylak & Kelly, 2004).

Miscellaneous Agents

Miscellaneous agents are cell cycle nonspecific. They act by inhibiting protein synthesis, blocking DNA replication, or triggering mechanisms that mediate cell death. Common side effects include myelosuppression, GI toxicity, and hepatotoxicity. Routes of administration include intravenous and oral. Common miscellaneous agents include arsenic trioxide, asparaginase, bortezomib, mesylate, mitotane, pegaspargase, and procarbazine.

See the table on page 187 for classification of chemotherapeutic agents.

PATIENT AND FAMILY PREPARATION FOR CHEMOTHERAPY ADMINISTRATION

Patient and family interactions are an important dynamic and must be used to prepare for the initiation of cancer treatment. Preparation before the treatment is vital to the overall success or lack thereof to prescribed therapy. Patient and family assessment and education are critical and must be geared toward the individual needs of the patient.

Patient and Family Assessment

The nurse administrating the chemotherapy should conduct a pretreatment assessment of the patient according to the guidelines listed in the box on page 187. Along with these guidelines, the nurse should keep in mind that patients will come with a lifetime of influences that affect the response to all of the changes involved with a diagnosis of cancer and required treatment. Past experiences affect their current physical presentation at diagnosis and how they will perceive current interactions with the health care team. Preconceived ideas of cancer, cultural and ethnic background, adult learning style, educational background, socioeconomic status, past coping mechanisms, and numerous other influences will affect the needed preparation for chemotherapy. Inclusion of family, significant others, or existing support systems is critical in preparation for chemotherapy initiation.

Patient and Family Education

The education of patients and family is a continuous process that should begin at the time of diagnosis with additional teaching before the administration of chemotherapy. Principles of adult learning should be incorporated in all teaching sessions. Strongly encourage patients to bring someone with them to all sessions. This will allow patients to have needed support during a stressful and physically demanding process. The presence of a trusted individual will help to ensure understanding of information given.

Formulation of a teaching plan should incorporate knowledge of the patient’s and family’s primary language and level of understanding, ability to read, readiness to learn, anxiety levels, and any other potential barriers to learning (Miaskowski, 1997; Powell, 1996). The nurse should review the topics outlined in the boxes on p. 187 and provide written material to reinforce all verbal instructions.

SAFE HANDLING

One of the most prevailing issues for staff is the inherent potential for harm in the delivery of care to cancer patients. Chemotherapy agents are hazardous drugs. The term “hazardous drugs” leads one to proceed with caution in the administration of these agents. Hazardous drug handling guidelines have been available for 20 years. According to the American Society of Health System Pharmacists (ASHP), any drug that requires special handling is referred to as a hazardous drug (ASHP, 2005). Recommendations for practice have been established by the Oncology Nursing Society (ONS), the Occupational Safety and Health Administration (OSHA), and the National Institute for Occupational Safety and Health (NIOSH) for safe handling of chemotherapy. The four major goals for safe handling of chemotherapy are listed in the table below.

Chemotherapy Classifications

Drug Class	Mechanism of Action	Drug Name
Alkylating agents	Cell cycle nonspecific	Altretamine Busulfan
Alkylating agents	Binds with DNA and protein molecules	Carboplatin Chlorambucil Cisplatin Cyclophosphamide Dacarbazine Ifosfamide mechlorethamine Oxiliplatin Temozolomide Thiotepa
Antitumor antibiotic	Cell cycle nonspecific	Bleomycin Dactinomycin Daunorubicin Daunorubicin citrate liposomal Doxorubicin Doxorubicin liposomal Epirubicin Idarubicin Mitomycin Mitoxantrone Valrubicin
Plant alkaloid Camptothecins Epipodophyllotoxins Taxanes Vinca alkaloids	Cell cycle specific Bind to certain cell proteins to initiate mitotic arrest	Camptothecins Irinotecan Topotecan Epipodophyllotoxins Etoposide Taxanes Paclitaxel Docetaxel Vinca alkaloids Vinblastine Vincristine Vinorelbine
Antimetabolites	Cell cycle specific Acts in the S-phase	Cepecitabine Cladribine Cytarabine Cytarabine liposomal Decitabine Floxuridine Flidarabine Fluorouracil Gemcitabine mercaptopurine Methotrexate Pentostatin Raltitrexed Thioguanine Trimetrexate Uracil
Nitrosoureas	Cell cycle nonspecific Binds with DNA and protein molecules Crosses blood-brain barrier	Carmustine Lomustine Streptozocin
Microtubular stabilizer Epothilones	Cell cycle specific Acts in the G2/M-phase of the cell cycle	Epothilones Ixabepilone Patupilone
Miscellaneous	Cell cycle non-specific	Arsenic trioxide Asparaginase Bortezomib mesylate Mitotane Pegaspargase Procarbazine