Chemotherapy of Neoplastic Diseases

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.

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:

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.

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.