Principles of Cancer Therapy

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Chapter 37 Principles of Cancer Therapy

Neville F. Hacker

The standard modalities for the management of gynecologic cancer are surgery, chemotherapy, radiation therapy, and hormonal therapy. In this chapter, the principles of chemotherapy, radiation therapy, and hormonal manipulation are discussed, together with the principles of pain management and end-of-life issues. Targeted therapies and hyperthermia are at present experimental modalities and are not included.

Cellular Biology

The characteristic feature of malignant tumor growth is its uncontrolled cellular proliferation, which requires replication of DNA. There are two distinct phases in the life cycle of all cells: mitosis (M phase), during which cellular division occurs; and interphase, the interval between successive mitoses.

Interphase is subdivided into three separate phases (Figure 37-1). Immediately following mitosis is the G₁ phase, which is of variable duration and is characterized by a diploid content of DNA. DNA synthesis is absent, but RNA and protein synthesis occur. During the shorter S phase, the entire DNA content is duplicated. This is followed by the G₂ phase, which is characterized by a tetraploid DNA content and by continuing RNA and protein synthesis in preparation for cell division. When mitosis occurs, a duplicate set of chromosomal DNA is inherited by each daughter cell, thus restoring the diploid DNA content. Following mitosis, some cells leave the cycle temporarily or permanently and enter the G₀ or resting phase.

FIGURE 37-1 Phases of the cell cycle and sites of action of cell cycle–specific drugs.

The growth fraction of the tumor is the proportion of actively dividing cells. The higher the growth fraction, the fewer the number of cells in the G₀ phase and the faster the tumor-doubling time.

Chemotherapeutic agents and radiation kill cells by first-order kinetics, which means that a constant proportion of cells is killed for a given dosage, regardless of the number of cells present. Both therapeutic modalities are most effective against actively dividing cells because cells in the resting (G₀) phase are better able to repair sublethal damage. Unfortunately, both therapeutic modalities also suppress rapidly dividing normal cells, such as those in the gastrointestinal mucosa, bone marrow, and hair follicles.

Chemotherapy

One of the major advances in medicine since the 1950s has been the successful treatment of certain disseminated malignancies, including choriocarcinoma and germ cell ovarian tumors, with chemotherapy.

CLASSIFICATION OF CHEMOTHERAPEUTIC AGENTS

Chemotherapeutic agents act primarily by disrupting nuclear DNA, thus inhibiting cellular division. They may be subdivided into two categories according to their mode of action relative to the cell cycle:

1. Cell cycle–nonspecific agents, such as alkylating agents, cisplatin, and paclitaxel, exert their damage at any phase of the cell cycle. They may damage resting as well as cycling cells, but the latter are much more sensitive.

2. Cell cycle–specific agents exert their lethal effects exclusively or primarily during one phase of the cell cycle. Examples include hydroxyurea and methotrexate, which act primarily during the S phase; bleomycin, which acts in the G₂ phase; and the vinca alkaloids, which act in the M phase.

PRINCIPLES OF CHEMOTHERAPY

Chemotherapeutic agents are selected on the basis of previous experience with particular agents for a given tumor. The drugs are usually given systemically so that the tumor can be treated regardless of its anatomic location. To increase the local concentration, certain drugs may occasionally be administered topically, by intraarterial infusion, or by intrathecal or intracavitary instillation (e.g., intraperitoneal therapy for ovarian cancer).

Chemotherapy is generally not administered if the neutrophil count is less than 1500 cells/mm³ or if the platelet count is less than 100,000 cells/mm³. Nadir blood counts are obtained 7 to 14 days after treatment, and subsequent doses may need to be reduced if there is significant myelosuppression or if the patient develops febrile neutropenia. Dosage reduction may also be necessary because of toxicity to other organs, such as the gastrointestinal tract, liver, or kidneys.

Resistance to chemotherapeutic agents may be temporary or permanent. Temporary resistance is mainly related to the poor vascularity of bulky tumors, which results in poor tissue concentrations of the drugs and an increasing proportion of cells in the relatively resistant G₀ phase of the cell cycle. Permanent resistance mainly results from spontaneous mutation to phenotypic resistance and occurs most commonly in bulky tumors. Permanent resistance may also be acquired by frequent exposure to chemotherapeutic agents.

CHEMOTHERAPEUTIC AGENTS

The common agents used in the management of gynecologic malignancies may be classified as shown in Table 37-1. This table also contains a summary of the main indications for and side effects of these drugs.

TABLE 37-1 INDICATIONS, SIDE EFFECTS, AND PRECAUTIONS FOR COMMONLY USED CHEMOTHERAPEUTIC AGENTS

Alkylating Agents

The cytotoxicity of alkylating agents results from their ability to cause alkylation to DNA, resulting in cross-linkage between DNA strands and prevention of DNA replication. There is cross-resistance among the various alkylating agents.

Antimetabolites

Antimetabolites are compounds that closely resemble normal intermediaries, for which they may substitute in biochemical reactions, and thereby produce a metabolic block; for example, methotrexate competitively inhibits the enzyme dihydrofolate reductase, thus preventing the conversion of dihydrofolate to tetrahydrofolate. The latter is required for the methylation reaction necessary for the synthesis of purine and pyrimidine subunits of nucleic acid.

Antibiotics

Antibiotics are naturally occurring antitumor agents elaborated by certain species of Streptomyces. They have no single, clearly defined mechanism of action, but many agents in this group intercalate between strands of the DNA double helix, thereby inhibiting both DNA and RNA synthesis and causing oxygen-dependent strand breaks.

Plant Alkaloids

The most common plant alkaloids are the vinca alkaloids, which are derived from the periwinkle plant. These include vincristine and vinblastine. They are spindle toxins that interfere with cellular microtubules and cause metaphase arrest.

Other plant alkaloids include the epipodophyllotoxins such as etoposide (VP16), which are extracts from the mandrake plant, and paclitaxel (Taxol), an extract from the bark of the Pacific yew tree. Docetaxel (Taxotere) is the first semisynthetic analogue of paclitaxel. Etoposide appears to act by causing single-strand DNA breaks. Paclitaxel binds preferentially to microtubules, which results in their polymerization and stabilization.

Other Drugs

Cisplatin, one of the more important drugs in gynecologic oncology, causes inhibition of DNA synthesis by forming interstrand and intrastrand linkages. Carboplatin is an analogue of cisplatin with a similar mechanism of action and efficacy, but with less gastrointestinal and renal toxicity.

Radiation Therapy

Radiation may be defined as the propagation of energy through space or matter.

TYPES OF RADIATION

There are two main types of radiation: electromagnetic and particulate.

Electromagnetic Radiation

Examples of electromagnetic radiation include the following:

• Visible light

• Infrared light

• Ultraviolet light

• X-rays (photons)

• Gamma rays (photons)

X-rays and gamma rays are identical electromagnetic radiations, differing only in their mode of production. X-rays are produced by bombardment of an anode by a high-speed electron beam; gamma rays result from the decay of radioactive isotopes, such as cobalt-60 (⁶⁰Co).

X-rays and gamma rays (photons) are differentiated from electromagnetic radiation of longer wavelength by their greater energy, which allows them to penetrate tissues and cause ionization.

Particulate Radiation

Particulate radiation consists of moving particles of matter. Their energy consists of the kinetic energy of the moving particles.

The particles vary greatly in size and include the following:

• Neutrons (no charge)

• Protons (positive charge)

• Electrons (negative charge)

The most commonly used particles are electrons. They may be derived from a linear accelerator, the beam of electrons being directed into the patient without first striking a metal target and producing x-rays. Alternatively, high-energy electrons (called β particles) may be derived from the radiodecay of an unstable isotope, such as phosphorus-32 (³²P). Particulate radiation penetrates tissues less than photons but also produces ionization.

UNIT OF RADIATION MEASUREMENT

The Gray (Gy) is equivalent to an absorbed energy of 1 joule per kilogram of absorbing material.

INVERSE SQUARE LAW

The intensity of electromagnetic radiation is inversely proportional to the square of the distance from the source. Thus, the dose of radiation 2 cm from a point source will be 25% of the dose at 1 cm.

BIOLOGIC CONSIDERATIONS

Ionization of Molecules

Radiation damage is caused by the ionization of molecules in the cell, with the production of free radicals.

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