Overview of Chemotherapy
Chemotherapy is the use of cytotoxic agents to destroy cancer cells. Chemotherapy dates back to the 1500s, when heavy metals were used systemically to treat cancers, and severe toxicity and limited cure were reported. Since then, a vast spectrum of antineoplastic drugs has been discovered to achieve cure, control, and palliation of many cancers. The new and improved changes in the drug approval process of the Food and Drug Administration have speeded the entry of novel drugs that have made chemotherapy a vital part of the cancer armamentarium. Chemotherapy remains the primary treatment for some malignancies and an adjunct to other treatment modalities (surgery, radiation, and immunotherapy). Unlike surgery and radiation, chemotherapy is distinguished by its systemic effects. Most of the drugs are transported by the bloodstream; most do not cross the blood-brain barrier and therefore cannot reach the central nervous system.
To achieve the above goals, chemotherapeutic drugs (as single agents or in combination) may be used in the following strategies:
Adjuvant: A short course of high-dose, usually combination drugs is given after radiation or surgery to destroy residual tumor cells.
Consolidation: Chemotherapy is given after induction therapy has achieved a complete remission; the regimen is repeated to increase the cure rate or to prolong patient survival.
Induction: This term is commonly used in the treatment of hematologic malignancies. It refers to the use of usually
a combination of high-dose drugs to induce a complete response when initiating a curative regimen.
a combination of high-dose drugs to induce a complete response when initiating a curative regimen.
Intensification: After complete remission is achieved, the same agents used for induction are given at higher doses, or different agents are given at high doses to effect a better cure rate or a longer remission.
Maintenance: Single or combination, low-dose cytotoxic drugs are used on a long-term basis in patients who are in complete remission to delay regrowth of residual cancer cells.
Neoadjuvant: Adjuvant chemotherapeutic drugs are used during the pre- or perioperative period.
Palliative: Chemotherapy is given to control symptoms, provide comfort, and improve quality of life if cure is impossible.
Salvage: A potentially curative high-dose regimen is given to a patient whose symptoms have recurred or whose treatment has failed with another regimen.
The human body is composed of an intricate network of nondividing and dividing cells organized into various tissues that perform specific functions. Nondividing cells, such as striated muscle cells and neurons, are highly differentiated and do not need to replicate to maintain their function. Dividing cells, such as germ, epithelial, and bone marrow stem cells, must replicate to maintain their function.
The body regulates all replication of dividing cells by maintaining a balance between the birth and death of cells. The body’s maintenance of this homeostasis depends on the synthesis of trigger proteins, or signals, in response to cell death. This synthesis stimulates the entry and movement of dividing cells through the process of cell division.
The Cell CycleThe cell cycle is the cornerstone of cell division and proliferation. Both normal and malignant cells undergo this process, which may last for approximately 25 to 30 hours (Fig. 1-1). There are five phases to the process. In the first phase, Gap 0 (G0), a cell can stay in a dormant or latent state for months or even years until stimulated to move forward in the cycle. Because certain cells divide more rapidly than others, some rest in the G0 phase for a brief period, whereas others bypass
the G0 phase and enter the second phase, the Gap 1 (G1) phase, directly if the body needs the immediate production of a certain cell. The G1 phase occurs after mitosis, the birth of two daughter cells. During this phase, the cell synthesizes RNA and the proteins needed for DNA synthesis. The time a cell spends in this phase varies and can last from hours to days, depending on the cell type. After RNA and protein syn-theses occur, the cell then enters the third phase, the synthesis (S) phase, when RNA, protein, and DNA syntheses occur and DNA replicates.
the G0 phase and enter the second phase, the Gap 1 (G1) phase, directly if the body needs the immediate production of a certain cell. The G1 phase occurs after mitosis, the birth of two daughter cells. During this phase, the cell synthesizes RNA and the proteins needed for DNA synthesis. The time a cell spends in this phase varies and can last from hours to days, depending on the cell type. After RNA and protein syn-theses occur, the cell then enters the third phase, the synthesis (S) phase, when RNA, protein, and DNA syntheses occur and DNA replicates.
 Fig. 1-1. The cell life cycle. |
DNA is an essential nucleic acid composed of deoxyribose, a phosphate, and four nitrogenous bases: adenine, guanine, cytosine, and thymine. Adenine and guanine are the purines, and cytosine and thymine are the pyrimidines. Chemical reactions occur between the two purines and also between the two pyrimidines, leading to the formation of the double-stranded DNA helix, which serves as the genetic template of the cell.
Generally, the S phase lasts 8 to 12 hours. The cell then enters the fourth phase, Gap 2 (G2), when more RNA and protein syntheses take place in preparation for mitosis. This phase tends to last 2 to 4 hours; then the cell enters the fifth or mitosis (M) phase. The M phase consists of the following orchestrated subphases: prophase, metaphase, anaphase,
and telophase (see Fig. 1-1). As the cell progresses through these subphases, the cytoplasm and nucleus divide so that replication of the cell results in the birth of two daughter cells.
and telophase (see Fig. 1-1). As the cell progresses through these subphases, the cytoplasm and nucleus divide so that replication of the cell results in the birth of two daughter cells.
It is not clearly understood how the body maintains normal cellular homeostasis. What has been postulated is that the body possesses a feedback system that signals a cell to enter the G1 phase of the cell life cycle in response to cell death. In patients with cancer, this feedback system is dysfunctional, and the cancer cell enters the cell cycle independently of the body’s feedback system.
Cancer Cell CharacteristicsEvery cell in the body has a genetically programmed clock that directs the timing of its reproductive activity. Cancer is a disease in which the cells fail to respond to the homeostatic mechanism that controls the cellular birth and death processes. Although the growth of cancer cells is dysfunctional and uncontrolled, the cancer cells undergo the different phases of the cell cycle that normal cells do.
Four basic features differentiate the cancer cell from the normal cell:
Uncontrolled cell proliferation
Decreased cellular differentiation
Inappropriate ability to invade surrounding tissue
Ability to establish new growth at ectopic sites
Cancer cells have the same chemical structures as normal cells; the critical change appears to be in growth and differentiation. Cell production in cancer is not proportional to cell loss; production of new cells occurs at a faster rate than is needed to compensate for the loss of cells.
CELLULAR KINETICS
Most chemotherapeutic drugs exert cytotoxic activity primarily on macromolecular synthesis or function. This means that they interfere either with the synthesis of DNA, RNA, or proteins or with the appropriate functioning of the preformed mol-ecule. When this interference happens, a proportion of the cells die. Chemotherapy works on the principle of first-order kinetics, which postulates that the number of tumor cells killed by an antineoplastic agent is proportional
to the dose used. This is a constant percentage of the total number of malignant cells present. Figure 1-2 is a visual representation of the cell kill theory. For example, if a tumor containing 1 million cells is exposed to a drug that has a 90% cell kill rate, the first chemotherapy dose will destroy 90%, or 900,000, of the cancer cells. The second dose will kill another 90% of the remaining cells (90,000), and 10,000 cells will survive. Because only a portion of the cells die, expected
doses of chemotherapy must be repeated to reduce the population of cancer cells until just one cell remains. It is hoped that the body’s immune response will kill the final cell.
to the dose used. This is a constant percentage of the total number of malignant cells present. Figure 1-2 is a visual representation of the cell kill theory. For example, if a tumor containing 1 million cells is exposed to a drug that has a 90% cell kill rate, the first chemotherapy dose will destroy 90%, or 900,000, of the cancer cells. The second dose will kill another 90% of the remaining cells (90,000), and 10,000 cells will survive. Because only a portion of the cells die, expected
doses of chemotherapy must be repeated to reduce the population of cancer cells until just one cell remains. It is hoped that the body’s immune response will kill the final cell.
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