A carcinogen is any substance that can cause cancer. In the nucleus of every cell are found molecules of nucleic acids, so named because of their location in the cell nucleus. The two types of nucleic acids are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). DNA molecules are the master molecules of genetic material within cells and contain the approximately 30,000 genes of the human genome. Genes are transcribed into messenger RNA molecules, which in turn are translated into protein molecules necessary for cellular structure and function. This process is discussed further in the section on alkylating drugs in Chapter 46. A mutagen is any substance or physical agent (e.g., radiation) that induces changes in DNA molecules. Mutations often transform normal cells into cancer cells. Thus, mutagenicity is associated with and often (but not always) leads to carcinogenicity. The U.S. Food and Drug Administration (FDA) mandates that carcinogenic studies be performed before any new drug is approved for use. However, no amount of clinical testing can fully reveal all of a drug’s possible carcinogenic effects. Carcinogenic effects may not be observed in the laboratory animals on which the drug has been tested but may be reported when the drugs are used in human subjects. Given the relatively small numbers of patients tested in clinical research trials, the carcinogenic potential of a given drug may not be observed until after the drug is marketed for use in the general population. If patterns of carcinogenicity begin to emerge during this period of postmarketing surveillance (or postmarketing studies), the drug may be recalled from the market.

The immune system plays an important role in the body in terms of cancer surveillance and the elimination of neoplastic cells. Neoplastic cells are believed to develop in everyone; however, a healthy person’s immune system recognizes them as abnormal and eliminates them by means of cell-mediated immunity (cytotoxic T lymphocytes; see Chapter 47). It has also been shown that the incidence of cancer is much higher in immunocompromised individuals. The relationship between cancer and a suppressed immune system has also been noted in cancer patients being treated with immunosuppressive drugs after organ transplantation. The higher rates of cancers such as skin cancer and lymphoma in transplant patients is a result of this aggressive use of drugs to prevent organ rejection.

The cell growth characteristics of normal and neoplastic cells are similar. Both types of cells pass through five distinct gap phases: G₀, the resting phase, in which the cell is considered out of the cell cycle; G₁, the first gap phase; S, the synthesis phase; G₂, the second gap phase; and M, the mitosis phase (Figure 45-2). During mitosis, one cell divides into two identical daughter cells. Mitosis is further subdivided into four distinct subphases related to the time periods before and during the alignment and separation of the chromosomes (DNA strands): prophase, metaphase, anaphase, and telophase. A complete cell cycle from one mitosis to the next is called the generation time. It is different for all tumors, ranging from hours to days. The cell growth cycle and the events that occur in the various phases are summarized in Table 45-5. Figure 45-3 shows where in the general phases of the cell cycle the various cell cycle–specific chemotherapeutic drugs show their greatest activity.

Recall from Chapter 2 that medications have a chemical name, a generic name, and a trade name. This section introduces yet another name for medications, especially cancer drugs: the investigational or protocol name. A drug’s chemical name is used by the chemists who first discover and work with the drug. The generic name is frequently first assigned to a chemical compound after a pharmaceutical manufacturer has determined that it is worthy of continued clinical research. It is often at this point that the chemical compound becomes an investigational drug. The trade name is a marketing name used by the manufacturer of a given drug primarily to market the drug. During the time before marketing and while a given medication is undergoing clinical research, it is frequently referred to by its protocol name. The protocol name is often a code name that consists of a combination of letters and numbers separated by one or more dashes. Although investigational drugs for all disease classes usually have some kind of protocol name, protocol names tend to be used more commonly in patient care settings for cancer drugs than for other drug classes. Here are two typical examples that illustrate these concepts:

Normal cells in the body divide (proliferate) in a controlled and organized fashion, and this growth is regulated by means of various mechanisms. In contrast, cancer cells lack regulatory mechanisms, and they proliferate uncontrollably. Figure 45-4 shows how various combinations of cancer treatment may succeed, or fail, over time.

Cancer chemotherapy drugs can be subdivided into two main groups based on where in the cell cycle they have their effects. Antineoplastic drugs that are cytotoxic (cell killing) in any phase of the cycle are called cell cycle–nonspecific drugs. Those drugs that are cytotoxic during a specific cell cycle phase are called cell cycle–specific drugs. These are broad categories that describe the activity of a drug with regard to cell cycle. Individual drugs may have actions that fall into both of these categories. Regardless of the cell cycle characteristics of a drug, it is more effective on rapidly growing tumors. This chapter discusses the cell cycle–specific drugs. Chapter 46 focuses on cell cycle–nonspecific drugs as well as various miscellaneous antineoplastic drugs.

The ultimate goal of any anticancer regimen is to kill every neoplastic cell and produce a cure, but this goal is not achieved in most cases. Fortunately, some patients’ immune systems may be able to clear the remaining tumor. Factors that affect the chances of cure and the length of patient survival include the cancer stage at time of diagnosis, the type of cancer and its doubling time, the efficacy of the cancer treatment, the development of drug resistance, and the general health of the patient. When total cure is not possible, the primary goal of therapy is to control the growth of the cancer while maintaining the best quality of life for the patient with the least possible level of discomfort and fewest treatment adverse effects.

It must be emphasized that cancer care and treatment involve many rapidly evolving medical sciences. Cancer is an intensively researched area, with the ultimate goals being to prevent cancer and to prevent premature death. Chemotherapy medications are often dosed as part of complex, specific treatment protocols that are subject to frequent revision by oncology clinicians and researchers. For these reasons, you must recognize that the drug dosing information provided in this chapter is intended only to be representative of current cancer treatment and is not absolute or comprehensive. Furthermore, the indications that are listed for each specific drug are the primary FDA-approved indications that are current at the time of this writing. These, too, may change unpredictably with time as a given drug is determined to be more (or less) effective for treating certain types of cancer. Also, in clinical practice, patients are often treated with one or more antineoplastic medications in “off-label” uses; that is, the drug is not currently approved for those particular uses by the FDA.

No antineoplastic drug is effective against all types of cancer. Most cancer drugs have a low therapeutic index, which means that a fine line exists between therapeutic and toxic levels. Clinical experience has shown that a combination of drugs is usually more effective than single-drug therapy. Because drug-resistant cells often develop, exposure to multiple drugs with multiple mechanisms and sites of action will destroy more subpopulations of cells. The delayed onset of resistance to a particular antineoplastic drug is one benefit of combination drug therapy. To be most effective, however, the drugs used in such a combination regimen would ideally possess the following characteristics:

Hair follicle cells are rapidly dividing cells. Cancer drugs that affect these cells often cause the adverse effect known as alopecia, or hair loss. Many patients, especially women, choose to wear wigs, hats, or scarves to disguise this adverse effect. Some antineoplastic drugs are more harmful to the epithelial cells of the stomach and intestinal tract, which often leads to diarrhea and mucositis, and may also increase the risk of nausea and vomiting. The likelihood that a given drug will produce vomiting is known as its emetic potential. Anticancer drugs cause nausea and vomiting by stimulating the cells of the chemoreceptor trigger zone. Several antiemetic drugs are used to prevent these symptoms and are described in Chapter 52. Box 45-1 lists the relative emetic potential of selected chemotherapy drugs.

Myelosuppression, also known as bone marrow suppression or bone marrow depression, is another unwanted adverse effect of certain antineoplastics. It commonly results from drug- or radiation-induced destruction of certain rapidly dividing cells in the bone marrow, primarily the cellular precursors of WBCs, red blood cells (RBCs), and platelets. This can also occur due to the disease processes of the cancer itself. Myelosuppression, in turn, leads to leukopenia, anemia, and thrombocytopenia. The cancer patient is often at greater risk for infection because of leukopenia (reduced WBC count) secondary to chemotherapy. Patients often need antibiotics intravenously (IV), either to prevent or to treat bacterial infections. Such patients are referred to as being neutropenic. Drug-induced anemia (reduced RBC count) often leads to hypoxia and fatigue, whereas thrombocytopenia (reduced platelet count) makes the patient more susceptible to bleeding. The lowest level of WBCs in the blood following chemotherapy (or radiation) treatment is called the nadir. The time until the nadir is reached in a given patient may become shorter and the recovery time for the bone marrow may become longer with multiple courses of antineoplastic treatment. The nadir normally occurs roughly 10 to 28 days after dosing, depending on the particular cancer drug or combination of drugs that is used to treat the patient. Anticipation of this nadir based on known cancer drug data can be used to guide the timing of prophylactic (preventative) administration of antibiotics and blood stimulants known as hematopoietic growth factors (see Chapter 47).

Common indications for various antineoplastic drugs are listed in the Dosages tables. Also provided in various locations in this chapter and in Chapter 46 are tables and boxes (Tables 45-8 and 46-2 and Boxes 46-1 and 46-2) containing drug-specific guidelines for the treatment of extravasation—unintended leakage of a chemotherapy drug (with vesicant potential) into the surrounding tissues outside of the IV line.

Because of the often severe toxicity of cancer medications, a current major focus of cancer drug research is the development of targeted drug therapy. Targeted drug therapy utilizes drugs that recognize a specific molecule involved in the growth of cancer cells, while mostly sparing healthy cells. One example of such targeted therapy is the newer class of cancer drugs known as monoclonal antibodies (see Chapter 47).

Pharmacokinetic data for antineoplastic medications is seldom used to guide dosing. Assay complexity coupled with a poor correlation between blood concentration and toxicity and efficacy limits its value. Only a handful of anticancer drugs benefit from therapeutic drug monitoring. For these reasons, pharmacokinetic data are not included with the drug profiles in this chapter.

In spite of their notorious toxicity, given the often fatal outcome of neoplastic diseases, most cancer drugs are only rarely considered to be absolutely contraindicated. Even if a patient has a known allergic reaction to an antineoplastic medication, the urgency of treating the patient’s cancer necessitates administering the medication and treating any allergic symptoms with premedications such as antihistamines, corticosteroids, and acetaminophen. For these reasons, no specific contraindications are listed for any of the drugs in this chapter.

Common relative contraindications for cancer drugs include weakened status of the patient as manifested by indicators such as very low WBC count, ongoing infectious process, severe compromise in nutritional and hydration status, reduced kidney or liver function, or a decline in organ function in any system that may be further affected by the toxic effect of the drug being administered. These are situations in which chemotherapy treatment is commonly delayed until the patient’s status improves. In general, most chemotherapy is held when the patient’s absolute neutrophil count (ANC) is less than 500 cells/mm³ (severe neutropenia) (see Chapter 46). Alternatively, dosages are often reduced for frail elderly patients or others with significantly compromised organ system function, depending on the drugs used.

Reduction in fertility is a major concern in postpubertal patients. Cancer also complicates 1 in 1000 pregnancies. All chemotherapy drugs are classified as pregnancy category D. The choice to use chemotherapy in a pregnant woman is based on risk versus benefit. Both radiation and chemotherapy treatments can cause significant permanent fetal harm or death. The greatest risk is during the first trimester. Chemotherapy treatment during the second or third trimester is more likely to improve maternal outcome without significant fetal risk. However, radiation treatment poses great risk to the fetus throughout pregnancy and is reserved for the postpartum period if possible. Prepubertal patients are more resilient, however, and can have normal puberty and fertility.

In the elderly, frailty refers to loss of most of the patient’s functional reserve and limited ability to tolerate even minimal physiologic stress (e.g., chemotherapy treatment). More robust elderly patients are certainly better candidates for cancer treatment, although frail patients often benefit as well, especially in terms of palliative (noncurative) symptom control.

Antineoplastic antimetabolites are cell cycle–specific analogues that work by antagonizing the actions of key cellular metabolites. More specifically, antimetabolites inhibit cellular growth by interfering with the synthesis or actions of compounds critical to cellular reproduction: the vitamin folic acid, purines, and pyrimidines. Purines and pyrimidines make up the bases contained in nucleic acid molecules (DNA and RNA). Antimetabolites work via two mechanisms: (1) by falsely substituting for purines, pyrimidines, or folic acid; and (2) by inhibiting critical enzymes involved in the synthesis or function of these compounds. Thus, they ultimately inhibit the synthesis of DNA, RNA, and proteins, all of which are necessary for cell survival. Antimetabolites work primarily in the S phase of the cell cycle, during which DNA synthesis is most active. The available antimetabolites and the metabolites they antagonize are as follows:

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