The American Cancer Society defines cancer as a group of diseases characterized by uncontrolled growth, and the spread of abnormal cells that left untreated may lead to death. Related to this definition is the term neoplasia, which is the uncontrolled growth of new tissue, the product of which is known as a tumor, and these tumors may be either malignant or benign. Malignant tumors have the capability of invading surrounding tissues and moving to distant locations in the body in a process known as metastasis; characteristics that benign tumors do not possess. Treatment of malignant tumors or cancer has generally involved initially surgical removal followed by radiation and/or chemotherapy, if necessary. In those cases where complete surgical removal is not feasible, radiation and chemotherapy become the only available options. The term chemotherapy, in the strictest sense, refers to drugs that are used to kill cells and includes both antibiotics and agents used in the treatment of cancer, but it is often used to refer exclusively to anticancer agents also known as antineoplastics. Traditional chemotherapy has been based on the principle of selective toxicity; however, this has been difficult to achieve in the case of cancer cells because these cells utilize the biochemical pathways used by normal cells. In many cases, the agents have attempted to exploit the increased proliferative rates of cancer cells compared with normal cells. This has been difficult to achieve even in a relative sense because, in part, of the fact that not all normal tissue is slowly proliferative and, conversely, not all cancer cells are highly proliferative.
Increased knowledge of intercellular and intracellular communication has led to the development of several newer agents that have shown some effectiveness in treating several cancers, especially when used in combination with more traditional agents. These have included several monoclonal antibodies that target the overproduction of growth factor receptors and TK inhibitors that target the transduc-tion process involved in growth factor stimulation.
Progress against neoplastic disease has also been greatly aided by early detection resulting from increased public awareness and improved diagnostics. As a result, neoplasms are often detected before they have a chance to metastasize and become more difficult to treat. Surgery followed by chemotherapy is often effective in accomplishing a 5-year survival in cancers that are discovered early and have not metastasized. The approach to treatment depends on the extent of the disease and the so-called stage. There are several methods of staging including the commonly used TNM system, where T—tumor, N—lymph node involvement, and M—metastasis. In this system, T and N are followed by numbers (1, 2, 3, etc.) to indicate the size of the tumor and the extent of lymph node involvement, respectively, where higher numbers are associated with more advanced disease. M is followed by either "0" to indicate metastasis has not occurred or "1" to indicate that it has. An alternative system utilizes stage 0 through stage IV designations, with higher numbers indicating progression of the disease. In this system, stage IV indicates that the primary tumor has metastasized.
Even with all the advancements, progress in many cases has been very slow. In comparing 5-year survival rates for patients with pancreatic cancer diagnosed between 1975 and 1977, with those diagnosed between 1996 and 2003, the rate increased from 2% to only 5%. Five-year survival rates for lung cancer patients increased from 13% to 16% during the same interval. It is obvious that these results do not represent tremendous progress in these types of cancer, and some of the increase may be ascribed to increased public awareness and better diagnostic methods that have allowed for earlier detection. This is important because the starting date in calculating a 5-year survival rate is the day of initial detection. This lack of progress in lung cancer is especially ominous since the American Cancer Society estimates that lung cancer will account for the greatest percentage of cancer deaths in 2008.1
As part of the definition, cancer is a group of diseases and these have been traditionally grouped together based on the organ in which the cancer originated. Even this grouping is somewhat misleading, because all cancers of a particular organ may not be caused by the same genetic alterations. This has important consequences for therapy, because the ability to respond to a chemotherapeutic agent is partly dependent on the genetic abnormality occurring in the cell.
The primary risk factor for most cancers is age. There are certainly other risk factors such as exposure to environmental toxins, but generally, as aging occurs, the chance of developing cancer increases. This is related to the genetic component of cancer so that every time a cell divides, there is a small chance that an aberrant cancer cell may arise as a result of mutation or translocation of DNA. This is cumulative so that the chances increase with an increasing number of cell divisions and, hence, age.
Normal cellular growth and proliferation are generally driven by factors external to the cell. Mitogenic signals such as hormones and growth factors direct the cell to undergo mitosis and are generally released from other tissues setting up a system of checks and balances where any one cell type is not allowed to proliferate in an uncontrolled manner. In cancer cells, this system may become disrupted in several ways. For example, some cells may acquire the ability to synthesize their own growth factors in a process known as autocrine signaling. It is also possible for cells to lose the requirements for growth factors altogether and still be capable of proliferating. There are numerous ways in which this may come about. For example, the signal trans-duction processes in which the interaction of a growth factor and its receptor is translated into cellular division may become permanently activated at any one point along the chain or at multiple points. Central to this idea is the concept of oncogenes or cancer-producing genes, the products of which may be responsible for these types of alterations. Oncogenes themselves are not normally present in the genome; however, precursors known as proto-oncogenes are commonly seen. Alterations in these proto-oncogenes by mutation or translocation may result in their transformation to an oncogene and the development of cancer. Several of these are listed in Table 10.1, but it should be kept in mind that although conversion of any particular proto-oncogene to an oncogene may be associated with a particular cancer, it is not seen in all patients that develop this type of cancer.
The process of cell division occurs through a series of phases that collectively are known as the cell cycle. Starting in the G1 for gap 1 or growth 1 phase, the enzymes necessary for the replication of DNA are synthesized (Fig. 10.1). Alternatively, cells may enter the G0 phase in which they do not prepare for cell division but carry on normal metabolic processes. Entry into G0 (sometimes referred to as senescence) is not an irreversible process; however, some
TABLE 10.1 Selected Oncogenes and the Associated Human Cancer
Associated Human Cancer
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