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Chemotherapy of Neoplastic Diseases

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Chemotherapy of Neoplastic Diseases

Introduction

Among the subspecialties of internal medicine, medical oncology may have had the greatest impact in changing the practice of medicine in the past four decades, as curative treatments have been identified for a number of previously fatal malignancies such as testicular cancer, lymphomas, and leukemia. New drugs have entered clinical use for disease presentations previously either untreatable or amenable to only local means of therapy, such as surgery and irradiation. At present, adjuvant chemotherapy routinely follows local treatment of breast cancer, colon cancer, and rectal cancer, and chemotherapy is employed as part of a multimodality approach to the initial treatment of many other tumors, including locally advanced stages of head and neck, lung, cervical, and esophageal cancer, soft tissue sarcomas, and pediatric solid tumors. The basic approaches to cancer treatment are constantly changing. Clinical protocols are now exploring genetic therapies, manipulations of the immune system, stimulation of normal hematopoietic elements, induction of differentiation in tumor tissues, and inhibition of angiogenesis. Research in each of these new areas has led to experimental or, in some cases, routine applications for both malignant and nonmalignant disease. The same drugs used for cytotoxic antitumor therapy have become important components of immunosuppressive regimens for rheumatoid arthritis (methotrexate and cyclophosphamide), organ transplantation (methotrexate and azathioprine), sickle cell anemia (hydroxyurea), antiinfective chemotherapy (trimetrexate and leucovorin), and psoriasis (methotrexate). Thus, a broad spectrum of medical, surgical, and pediatric specialists employ these drugs for both neoplastic and nonneoplastic disease.



At the same time, few categories of medication in common use have a narrower therapeutic index and a greater potential for causing harmful side effects than do the antineoplastic drugs. A thorough understanding of their pharmacology, drug interactions, and clinical pharmacokinetics is essential for safe and effective use in human beings.

Traditionally, cancer drugs were discovered through large-scale screening of synthetic chemicals and natural products against animal tumor systems, primarily murine leukemias. The agents discovered in the first two decades of cancer chemotherapy (1950 to 1970) largely interacted with DNA or its precursors, inhibiting the synthesis of new genetic material or causing irreparable damage to DNA itself. An overview of such agents is given in Figure IX1. In recent years, the discovery of new agents has extended from the more conventional natural products such as paclitaxel and semisynthetic agents such as etoposide, both of which target the proliferative process, to entirely new fields of investigation that represent the harvest of new knowledge about cancer biology. The first successful applications of this knowledge include diverse drugs. One agent, interleukin-2, regulates the proliferation of tumor-killing T lymphocytes and so-called natural killer cells; this agent has proven able to induce remissions in a fraction of patients with malignant melanoma and renal cell carcinoma, diseases unresponsive to conventional drugs. Another agent, all-trans-retinoic acid, elicits differentiation and can be used to promote remission in acute promyelocytic leukemia, even after failure of standard chemotherapy. The related compound 13-cis-retinoic acid prevents occurrence of second primary tumors in patients with head and neck cancer. Initial success in characterizing unique tumor antigens and oncogenes has introduced new possible therapeutic opportunities based on an understanding of tumor biology. Thus the bcr-abl translocation in chronic myelocytic leukemia codes for a tyrosine kinase essential to cell proliferation and survival. Inhibition of the kinase by imatinib (STI-571), a new molecularly targeted drug, has produced a high response rate in chronic-phase patients resistant to standard therapy. In a similar, though immunological, approach tumor-associated antigens, such as the her-2/neu receptor in breast cancer cells, have become the target for monoclonal antibody therapy that has shown activity in patients. These examples emphasize that the care of cancer patients is likely to undergo revolutionary changes as entirely new treatment approaches are identified, based on new knowledge of cancer biology (Kaelin, 1999). The diversity of agents useful in treatment of neoplastic disease is summarized in Table IX1. The classification used in Chapter 52: Antineoplastic Agents, which follows, is a convenient framework for describing various types of agents.

Figure IX1. Summary of the Mechanisms and Sites of Action of Chemotherapeutic Agents Useful in Neoplastic Disease. PALA =N-phosphonoacetyl-L-aspartate; TMP = thymidine monophosphate.

It is unlikely that new therapies will totally replace existing drugs, as these drugs have become increasingly effective and their toxicities have become more manageable and predictable in recent years. Improvements in their use are the result of a number of factors, including the following:

1. Drugs now are routinely used earlier in the course of the patient's management, often in conjunction with radiation or surgery, to treat malignancy when it is most curable and when the patient is best able to tolerate treatment. Thus, adjuvant therapy and neoadjuvant chemotherapy are used in conjunction with irradiation and surgery in the treatment of head and neck, esophageal, lung, and breast cancer patients.



2. The availability of granulocyte colony-stimulating factor (G-CSF; see Chapter 54: Hematopoietic Agents: Growth Factors, Minerals, and Vitamins) has shortened the period of leukopenia after high-dose chemotherapy, increasing the safety of bone marrowablative regimens and decreasing the incidence of life-threatening infection. A similar megakaryocyte growth and development factor has been cloned but has not yet achieved a useful place as an adjunct to chemotherapy.

3. A greater insight into the mechanisms of tumor cell resistance to chemotherapy has led to the more rational construction of drug regimens and the earlier use of intensive therapies.

Drug-resistant cells may be selected from the larger tumor population by exposure to low-dose, single-agent chemotherapy. The resistance that arises may be specific for the selecting agent, such as the deletion of a necessary activating enzyme (deoxycytidine kinase for cytosine arabinoside), or more general, such as the overexpression of a general drug-efflux pump such as the P-glycoprotein, a product of the MDR gene. This membrane protein is one of several ATP-dependent transporters that confer resistance to a broad range of natural products used in cancer treatment. More recently, it has become appreciated that mutations underlying malignant transformation, such as the loss of the p53 suppressor oncogene, may lead to drug resistance. (A suppressor gene is essential for normal control of cell proliferation; its loss or mutation allows cells to undergo malignant transformation.) Mutation of p53, or its loss, or the overexpression of the bcl-2 gene that is translocated in nodular non-Hodgkin's lymphomas, inactivates a key pathway of programmed cell death (apoptosis) and leads to survival of highly mutated tumor cells that have the capacity to survive DNA damage. Drug discovery efforts are now directed toward restoring apoptosis in tumor cells, as this process, or its absence, seems to have profound influence on tumor cell sensitivity to drugs. Each of these topics concerning drug resistance is covered in greater detail in Chapter 52: Antineoplastic Agents.

In designing specific regimens for clinical use, a number of factors must be taken into account. Drugs are generally more effective in combination and may be synergistic through biochemical interactions. These interactions are useful in designing new regimens. It is more effective to use drugs that do not share common mechanisms of resistance and that do not overlap in their major toxicities. Drugs should be used as close as possible to their maximum individual doses and should be given as frequently as possible to discourage tumor regrowth and to maximize dose intensity (the dose given per unit time, a key parameter in the success of chemotherapy). Since the tumor cell population in patients with visible disease exceeds 1 g, or 109 cells, and since each cycle of therapy kills less than 99% of the cells, it is necessary to repeat treatments in multiple cycles to kill all the tumor cells.

The Cell Cycle

An understanding of cell-cycle kinetics is essential for the proper use of the current generation of antineoplastic agents. Many of the most potent cytotoxic agents act by damaging DNA. Their toxicity is greater during the S, or DNA synthetic, phase of the cell cycle, while others, such as the vinca alkaloids and taxanes, block the formation of the mitotic spindle in M phase. These agents have activity only against cells that are in the process of division. Accordingly, human neoplasms that are currently most susceptible to chemotherapeutic measures are those with a high percentage of cells undergoing division. Similarly, normal tissues that proliferate rapidly (bone marrow, hair follicles, and intestinal epithelium) are subject to damage by most antineoplastic drugs, and such toxicity often limits the usefulness of drugs. On the other hand, slowly growing tumors with a small growth fraction (for example, carcinomas of the colon or lung) often are unresponsive to cytotoxic drugs. Although differences in the duration of the cell cycle occur between cells of various types, all cells display a similar pattern during the division process. This cell cycle may be characterized as follows (see Figure IX2): (1) There is a presynthetic phase (G1); (2) the synthesis of DNA occurs (S); (3) an interval follows the termination of DNA synthesis, the postsynthetic phase (G2); and (4) mitosis (M) ensuesthe G2 cell, containing a double complement of DNA, divides into two daughter G1 cells. Each of these cells may immediately reenter the cell cycle or pass into a nonproliferative stage, referred to as G0. The G0 cells of certain specialized tissues may differentiate into functional cells that no longer are capable of division. On the other hand, many cells, especially those in slow-growing tumors, may remain in the G0 state for prolonged periods, only to reenter the division cycle at a later time. Damaged cells that reach the G1/S boundary undergo apoptosis, or programmed cell death, if the p53 gene is intact and if it exerts its normal checkpoint function. If the p53 gene is mutated and the checkpoint function fails, damaged cells will not be diverted to the apoptotic pathway. These cells will proceed through S phase and some will emerge as a drug-resistant population. Thus, an understanding of cell-cycle kinetics and the controls of normal and malignant cell growth is crucial to the design of current therapy regimens and the search for new drugs.



Figure IX2. The Cell Cycle and the Relationship of Antitumor Drug Action to the Cycle. G1 is the period between mitosis and the beginning of DNA synthesis. Resting cells (cells that are not preparing for cell division) are said to be in a subphase of G1, G0. S is the period of DNA synthesis; G2 the premitotic interval; and M the period of mitosis. Examples of cell-cycledependent anticancer drugs are listed in blue below the phase in which they act. Drugs that are cytotoxic for cells at any point in the cycle are called cycle-phase-nonspecific drugs. (Modified from Pratt et al., 1994 with permission.)

Achieving Therapeutic Balance and Efficacy

While not the subject of this chapter, it must be emphasized that the treatment of most cancer patients requires a skillful interdigitation of multiple modalities of treatment, including surgery, irradiation, and drugs. Each of these forms of treatment carries its own risks and benefits. It is obvious that not all drugs and not all regimens are safe or appropriate for all patients. Numerous factors must be considered, such as renal and hepatic function, bone marrow reserve, and the status of general performance and accessory medical problems. Beyond those considerations, however, are less quantifiable factors such as the likely natural history of the tumor being treated, the patient's willingness to undergo harsh treatments, the patient's physical and emotional tolerance for side effects, and the likely long-term gains and risks involved.

The emphasis in Chapter 52: Antineoplastic Agents is placed upon the drugs, but it is essential to point out the importance of the role played by the patient. It is generally agreed that patients in good nutritional state and without severe metabolic disturbances, infections, or other complications have better tolerance for chemotherapy and have a better chance for significant improvement than do severely debilitated individuals. Ideally, the patient should have adequate renal, hepatic, and bone marrow function, the latter uncompromised by tumor invasion, previous chemotherapy, or irradiation (particularly of the spine or pelvis). Nevertheless, even patients with advanced disease have improved dramatically with chemotherapy. Although methods that would enable accurate prediction of the responsiveness of a particular tumor to a given agent are still investigational, in the future, molecular studies of tumor specimens may allow prediction of response and the rational selection of patients for specific drugs. Despite efforts to anticipate the development of complications, anticancer agents have variable pharmacokinetics and toxicity in individual patients. The causes of this variability are not always clear and often may be related to interindividual differences in drug metabolism, drug interactions, or bone marrow reserves. In dealing with toxicity, the physician must provide vigorous supportive care, including, where indicated, platelet transfusions, antibiotics, and hematopoietic growth factors (see Chapter 54: Hematopoietic Agents: Growth Factors, Minerals, and Vitamins). Other delayed toxicities affecting the heart, lungs, or kidneys may not be reversible and may lead to permanent organ damage or death. Fortunately, such toxicities will be uncommon if the physician adheres to standard protocols and respects the guidelines for drug usage detailed in the following discussion.





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