Porth's Essentials of Pathophysiology, 4e

151

Neoplasia

C h a p t e r 7

used. Drugs used in combinations are individually effective against the tumor and synergistic with each other. The maximum possible drug doses usually are used to ensure the maximum cell kill within the range of toxicity tolerated by the host for each drug. Routes of administration and dosage schedules are carefully designed to ensure optimal delivery of the active forms of the drugs to the tumor during the sensitive phase of the cell cycle. Chemotherapy Side Effects. Unfortunately, chemo- therapeutic drugs affect both cancer cells and the rapidly proliferating cells of normal tissue, producing undesir- able side effects. Some side effects appear immediately or after a few days (acute), some within a few weeks (intermediate), and others months to years after chemo- therapy administration (long term). Most chemotherapeutic drugs suppress bone marrow function and formation of blood cells, leading to anemia, neutropenia, and thrombocytopenia. With neutropenia, there is risk for developing serious infections, whereas thrombocytopenia increases the risk for bleeding. The availability of hematopoietic growth factors (e.g., gran- ulocyte colony-stimulating factor [G-CSF]); erythropoi- etin, which stimulates red blood production; and IL-11, which stimulates platelet production) has shortened the period of myelosuppression, thereby reducing the need for hospitalizations due to infection and decreasing the need for blood products. Anorexia, nausea, and vomiting are common prob- lems associated with cancer chemotherapy. 58 The severity of the vomiting is related to the emetic potential of the particular drug. These symptoms can occur within min- utes or hours of drug administration and are thought to be due to stimulation of the chemoreceptor trigger zone in the medulla that stimulates vomiting (see Chapter 28). The chemoreceptor trigger zone responds to the level of chemicals circulating in the blood. The acute symp- toms usually subside within 24 to 48 hours and often can be relieved by antiemetic drugs. The pharmacologic approaches to prevent chemotherapy-induced nausea and vomiting have greatly improved over several decades. The development of serotonin (5-HT 3 ) receptor antagonists has facilitated the use of highly emetic chemotherapy drugs by more effectively reducing the nausea and vomit- ing induced by these drugs. Alopecia or hair loss results from impaired prolifera- tion of the hair follicles and is a side effect of a number of cancer drugs; it usually is temporary, and the hair tends to regrow when treatment is stopped. The rap- idly proliferating structures of the reproductive system are particularly sensitive to the action of cancer drugs. Women may experience changes in menstrual flow or have amenorrhea. Men may have a decreased sperm count (i.e., oligospermia) or absence of sperm (i.e., azo- ospermia). Many chemotherapeutic agents also may have teratogenic or mutagenic effects leading to fetal abnormalities. 58 Chemotherapy drugs are toxic to all cells. Because they are potentially mutagenic, carcinogenic, and teratogenic, special care is required when handling or administering

the drugs. Drugs, drug containers, and administration equipment require special disposal as hazardous waste. 60 Hormone and AntihormoneTherapy Hormonal therapy consists of administration of drugs designed to deprive the cancer cells of the hormonal sig- nals that otherwise would stimulate them to divide. It is used for cancers that are responsive to or dependent on hormones for growth and have specific hormone recep- tors. 61 Among the tumors that are known to be respon- sive to hormonal manipulation are those of the breast, prostate, and endometrium. Other cancers, such as Kaposi sarcoma and renal, liver, ovarian, and pancreatic cancer, are also responsive to hormonal manipulation, but to a lesser degree. The therapeutic options for altering the hormonal environment in the woman with breast cancer or the man with prostate cancer include surgical and phar- macologic measures. Surgery involves the removal of the organ responsible for the hormone produc- tion that is stimulating the target tissue (e.g., ovaries in women or testes in men). Pharmacologic methods focus largely on reducing circulating hormone levels or changing the hormone receptors so that they no longer respond to the hormone. Pharmacologic sup- pression of circulating hormone levels can be effected through pituitary desensitization, as with the admin- istration of androgens, or through the administration of gonadotropin-releasing hormone (GnRH) analogs that act at the level of the hypothalamus to inhibit gonadotropin production and release. Another class of drugs, the aromatase inhibitors , is used to treat breast cancer; these drugs act by interrupting the biochemi- cal processes that convert the adrenal androgen andro- stenedione to estrone. 62 Hormone receptor function can be altered by the administration of pharmacologic doses of exogenous hormones that act by producing a decrease in hormone receptors or by antihormone drugs (antiestrogens and antiandrogens) that bind to hormone receptors, mak- ing them inaccessible to hormone stimulation. Initially, patients often respond favorably to hormonal treat- ments, but eventually the cancer becomes resistant to hormonal manipulation, and other approaches must be sought to control the disease. Biotherapy Biotherapy involves the use of immunotherapy and biologic response modifiers as a means of changing a person’s immune response and modifying tumor cell biology. It involves the use of monoclonal antibodies, cytokines, and adjuvants. 63 Monoclonal Antibodies. Recent advances in the ability to manipulate the genes of immunoglobulins have resulted in the development of a wide array of monoclonal antibod- ies directed against tumor-specific antigens as well as sig- naling molecules. 64 These include chimeric human-murine (mouse) antibodies with human constant region and murine-variable regions (see Chapter 15, Figure 15-10),