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Although most new drugs for cancer are agents that target molecular changes that occur in tumors (described in Chap. 19), chemotherapy still provides the backbone of drug therapy for most types of cancer. Chemotherapy is used commonly to treat people with metastatic cancer, and for many common types of adult cancer can provide palliation—either by prolonging survival and/or by improving quality of life. Only for relatively rare tumors such as childhood leukemia and some other cancers affecting children, and testicular cancer in men, can chemotherapy cure metastatic disease. Chemotherapy (and other systemic treatments) are also used either before (neoadjuvant) or after (adjuvant) surgery (and sometimes before, with, or after radiotherapy) in people without overt spread of disease, and can then improve the probability of cure by eliminating undetectable micrometastases.
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Principles of pharmacokinetics and pharmacodynamics of anticancer drugs are discussed in Section 18.2 of this chapter; the same principles apply also to targeted agents (described in Chap. 19). Properties of chemotherapy drugs in common clinical use are discussed in Section 18.3. The major limitation with all types of systemic treatment of cancers is the innate presence or acquired development of drug resistance of the tumor: common mechanisms of drug resistance are discussed in Section 18.4.
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18.2 GENERAL PRINCIPLES OF PHARMACOLOGY
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18.2.1 Pharmacokinetics and Pharmacodynamics
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Pharmacokinetics is the study of the time course of drug and metabolite levels in different body fluids and tissues, including absorption, distribution, metabolism, and elimination. The study of the relationship between drug effect and its concentration is known as pharmacodynamics. Alterations in pharmacokinetic properties of a drug may result in different drug concentrations over time in different tissues. Understanding the pharmacodynamics of a drug can explain subsequent differences in drug effect or response.
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Although most chemotherapy drugs are given by intravenous injection at discrete intervals and drug absorption is not a therapeutic concern, many newer targeted agents are given continuously by mouth. Oral drug administration is convenient for patients, but it requires patient compliance and depends on efficient absorption from the gastrointestinal tract. Only a proportion of an orally administered drug may be delivered to the systemic circulation and become available for therapeutic effects. Absolute bioavailability refers to the amount of a drug that is available after oral administration compared to that after intravenous administration, whereas relative bioavailability is the amount of a drug that is available from one formulation relative to that from another nonintravenous formulation. Factors influencing the bioavailability of a drug include patient compliance, disintegration of a capsule or a tablet and dissolution of the drug into gastrointestinal fluid, stability of the drug in the gastrointestinal tract, absorption through the gastrointestinal mucosa, and first-pass metabolism in the liver. Problems seen in cancer patients, such as changes in gastrointestinal motility, mucosal damage from cancer therapy, and the use of other medications ...