Chemotherapy

Chemotherapy, or the use of chemical agents to destroy cancer cells, is a mainstay in the treatment of malignancies. The possible role in treating illness was discovered when the bone marrow suppressive effect of nitrogen mustard was noted in the early 1900's. Since that time, the search for drugs with anticancer activity has continued, and the goal of treatment with chemotherapy has evolved from relief of symptoms to cure. A major advantage of chemotherapy is its ability to treat widespread or metastatic cancer, whereas surgery and radiation therapies are limited to treating cancers that are confined to specific areas.

Principles of Treatment

An understanding of the normal cell cycle and the behavior of malignant or cancerous cells is necessary in order to comprehend how chemotherapy destroys cancer cells. Below is an example of the cell cycle.

Chemotherapeutic Agents

Almost all chemotherapy agents currently available kill cancer cells by affecting DNA synthesis or function, a process that occurs through the cell cycle. Each drug varies in the way this occurs within the cell cycle.

The major categories of chemotherapy agents are alkylating agents, antimetabolites, plant alkaloids, antitumor antibiotics, and steroid hormones. Each drug is categorized according to their effect on the cell cycle and cell chemistry.

• Alkylating agents kill cells by directly attacking DNA. Alkylating agents may be used in the treatment of chronic leukemias, Hodgkin's disease, lymphomas, and certain carcinomas of the lung, breast, prostate and ovary. Cyclophosphamide is an example of a commonly used alkylating agent.
• Nitrosoureas act similarly to akylating agents and also inhibit changes necessary for DNA repair. These agents cross the blood-brain barrier and are therefore used to treat brain tumors, lymphomas, multiple myeloma, and malignant melanoma. Carmustine (BCNU) and lomustine (CCNU) are the major drugs in this category.
• Antimetabolites are that drugs block cell growth by interfering with certain activities, usually DNA synthesis. Once ingested into the cell they halt normal development and reproduction. All drugs in this category affect the cell during the "S" phase of the cell cycle. Antimetabolites may be used in the treatment of acute and chronic leukemias, choriocarcinoma, and some tumors of the gastrointestinal tract, breast and ovary. . Examples of commonly used antimetabolites are 6-mercaptopurine and 5-fluorouracil (5FU).
• Antitumor antibiotics are a diverse group of compounds. In general, they act by binding with DNA and preventing RNA synthesis. These agents are widely used in the treatment of a variety of cancers. The most commonly used drugs in this group are doxorubicin (Adriamycin), mitomycin-C, and bleomycin.
• Plant (vinca) alkaloids are anti-tumor agents derived from plants. These drugs act specifically by blocking cell division during mitosisThey are commonly used in the treatment of acute lymphoblastic leukemia, Hodgkin's and non-Hodgkin's lymphomas, neuroblastomas, Wilms' tumor, and cancers of the lung, breast and testes. Vincristine and vinblastine are commonly used agents in this group.
• Steroid hormones are useful in treating some types of tumors. This class includes adrenocorticosteroids, estrogens, antiestrogens, progesterones, and androgens. Although their specific mechanism of action is not clear, steroid hormones modify the growth of certain hormone-dependent cancers. Tamoxifen is an example, which is used for estrogen dependent breast cancer.

In addition, other miscellaneous antineoplastic drugs exist whose mechanisms of action do not permit broad categorization

Chemotherapy Administration

The most common routes of administration for chemotherapy are by mouth, through a vein, and into a muscle. More recently, other methods have been used to increase the local concentration of chemotherapy at the tumor site. Chemotherapy can be administered directly into a specific cavity (intracavitary), the abdomen (intraperitoneal), the lung (intrapleural), the central nervous system (intra-thecal), or applied directly to the skin (topical).

Because many chemotherapeutic agents also effect healthy cells and organs, the patient's laboratory data should be checked before chemotherapy administration, including white blood cell count, hemoglobin/hematocrit, platelet count, renal function tests, liver function tests. In addition, assessment for organ specific drug effects will be performed on a periodic basis. Abnormalities in any of these values may require dose adjustments or the delay of therapy. Additionally, pretreatment actions, such as increased fluids or administration of anti-nausea medicines may be needed to decrease side effects.

Several strategies may be used to maximize the toxic effect of chemotherapy. Chemotherapy is generally spaced out over an extended period of time to gradually lower the number of tumor cells to the point where the body's own immune responses can control further tumor growth. Many patients receive their chemotherapy over a 4 to 12 month period of time. Additionally, the interval between doses of chemotherapy is based on achieving the greatest effect on the cancer cells, while also allowing the healing of the normal healthy cells. Most often, patients receive their chemotherapy every 3 to 4 weeks.

Strategies of Chemotherapy Administration

Combination Chemotherapy combines agents that differ in both the way they act and their side effects. This is done to achieve maximum tumor effect with minimal side effects. Because tumor cells have different biological characteristics (heterogeneity), combining drugs may effectively eliminate cancer cells' resistance to a single agent.

Adjuvant Chemotherapy may be given when no clear evidence of cancer can be found, but certain factors (e.g. metastasis to the lymph nodes) predict an increased risk of cancer recurrence. Use of chemotherapy at an earlier stage of tumor growth may hinder the development of resistance to chemotherapy often observed in large or metastatic cancers.

Combined Modality Chemotherapy may also be used in combination with other treatment modalities, such as radiation or surgery. Therapies are combined to obtain a greater response rate than could be achieved with a single treatment modality. Today, using more than one treatment modality effectively treats most cancers.

Hormonal Manipulation does not directly kill cells and, therefore, is not curative. Their purpose is to prevent cell division and further growth of hormone-dependent tumors. Their use is frequently reserved for the management of patients with locally advanced or metastatic cancer.

Investigational Therapy

The identification and development of effective new anticancer drugs is an on-going process. Following rigorous testing in laboratory animals and experimental model systems, chemotherapy agents with demonstrated antitumor activity are evaluated in clinical trials. In Phase I trials, the initial phase of clinical investigation, a new treatment is evaluated in cancer patients for the first time. The purpose of these studies is to determine the associated side effects, the highest dose safely tolerated, and the optimal schedule or mode of delivery of a new therapy. Phase II trials test a new therapy (using the dose, method of administration, and schedule defined in Phase I) in patients with a variety of tumors to determine whether there is identifiable antitumor activity. In Phase III trials, new therapies that exhibited activity in Phase II are compared to the standard or best available therapy for each type of tumor tested.

Participation in a clinical trial is one treatment option, which may be offered to patients at some point during therapy. The continuing progress of cancer treatment depends upon the participation of adequate numbers of patients in such studies.