62 CANCER CHEMOTHERAPY
Harrison’s Manual of Medicine
Biology of Tumor Growth
Development of Drug Resistance
Categories of Chemotherapeutic Agents and Major Toxicities
Complications of Therapy
BIOLOGY OF TUMOR GROWTH
Two essential features of cancer cells are uncontrolled growth and the ability to metastasize. The malignant phenotype of a cell is the end result of a series of genetic changes that remove safeguards restricting cell growth and induce new features that enable the cell to metastasize, including surface receptors for binding to basement membranes, enzymes to poke holes in anatomic barriers, cytokines to facilitate mobility, and angiogenic factors to develop a new vascular lifeline for nutrients and oxygen. These genetic changes usually involve increased or abnormal expression or activity of certain genes known as proto- oncogenes (often growth factors or their receptors, enzymes in growth pathways, or transcription factors), deletion or inactivation of tumor suppressor genes, and defects in DNA repair enzymes. These genetic changes may occur by point mutation, gene amplification, gene rearrangement, or epigenetic changes such as altered gene methylation.
Once cells are malignant, their growth kinetics are similar to those of normal cells but lack regulation. For unclear reasons, tumor growth kinetics follow a Gompertzian curve: as the tumor mass increases, the fraction of dividing cells declines. Thus, by the time a cancer is large enough to be detected clinically, its growth fraction is often small. Unfortunately, tumor growth usually does not stop altogether before the tumor reaches a lethal tumor burden. Cancer cells proceed through the same cell-cycle stages as normal cycling cells: G1 (period of preparation for DNA synthesis), S (DNA synthesis), G2 (tetraploid phase preceding mitosis in which integrity of DNA replication is assessed), and M (mitosis). Some noncycling cells may remain in a Go, or resting, phase for long periods. Certain chemotherapeutic agents are specific for cells in certain phases of the cell cycle, a fact that is important in designing effective chemotherapeutic regimens.
DEVELOPMENT OF DRUG RESISTANCE
Drug resistance can be divided into de novo resistance or acquired resistance. De novo resistance refers to the tendency of many of the most common solid tumors to be unresponsive to chemotherapeutic agents. In acquired resistance, tumors initially responsive to chemotherapy develop resistance during treatment, usually because resistant clones appear within tumor cell populations. (Table 62-1).
Table 62-1 Response of Tumors to Chemotherapy
Resistance can be specific to single drugs, because of defective transport of the drug, decreased activating enzymes, increased drug inactivation, increases in target enzyme levels, or alterations in target molecules. Multiple drug resistance occurs in cells overexpressing the P glycoprotein, a membrane glycoprotein responsible for enhanced efflux of drugs from cells, but there are other mechanisms as well.
CATEGORIES OF CHEMOTHERAPEUTIC AGENTS AND MAJOR TOXICITIES
A partial list of toxicities is shown in Table 62-2; some toxicities may apply only to certain members of a group of drugs.
Table 62-2 List of Toxicities
COMPLICATIONS OF THERAPY
While the effects of cancer chemotherapeutic agents may be exerted primarily on the malignant cell population, virtually all currently employed regimens have profound effects on normal tissues as well. Every side effect of treatment must be balanced against potential benefits expected, and pts must always be fully apprised of the toxicities they may encounter. While the duration of certain adverse effects may be short-lived, others, such as sterility and the risk of secondary malignancy, have long-term implications; consideration of these effects is of importance in the use of regimens as adjuvant therapy. The combined toxicity of regimens involving radiotherapy and chemotherapy is greater than that seen with each modality alone. Teratogenesis is a special concern in treating women of childbearing years with radiation or chemotherapy. The most serious late toxicities are sterility (common; from alkylating agents), secondary acute leukemia (rare; from alkylating agents and topoisomerase inhibitors), secondary solid tumors (0.5–1%/year risk for at least 25 years after treatment; from radiation therapy), premature atherosclerosis (3-fold increased risk of fatal MI; from radiation therapy), heart failure (rare; from anthracyclines), and pulmonary fibrosis (rare; from bleomycin).
For a more detailed discussion, see Sausville EA and Longo DL: Principles of Cancer Treatment, Chap. 84, p. 530, in HPIM-15.