Information on cell and population kinetics of cancer cells explains, in part, the limited effectiveness of most available anticancer drugs. A schematic summary of cell cycle kinetics is presented in Figure 54–2. This information is relevant to the mode of action, indications, and scheduling of cell cycle– specific (CCS) and cell cycle–nonspecific (CCNS) drugs. Agents falling into these two major classes are summarized in Table 54–1.
The Role of Drug Combinations
With rare exceptions (eg, choriocarcinoma and Burkitt’s lymphoma), single drugs are unable to cure cancers when they are in an advanced stage. In the 1960s and early 1970s, drug
Synthesis of cellular components needed for DNA synthesis
Replication of DNA genome
FIGURE 54–2 Cell cycle and cancer. A conceptual depiction of the cell cycle phases that all cells—normal and neoplastic—must traverse before and during cell division. The percentages given represent the approximate percentage of time spent in each phase by a typical malignant cell; the duration of G1, however, can vary markedly. Many of the effective anti-cancer drugs exert their action on cells traversing the cell cycle and are called cell cycle-specific (CCS) drugs (see Table 54–1). A second group of agents called cell cycle-nonspecific (CCNS) drugs can sterilize tumor cells whether they are cycling or resting in the G0 compartment. CCNS drugs can kill both G0 and cycling cells (although cycling cells are more sensitive).
TABLE 54–1 Cell cycle effects of major classes of anti-cancer drugs.
combination regimens were developed based on the known biochemical actions of available anti-cancer drugs rather than on their clinical efficacy. Such regimens were, however, largely ineffective. The era of effective combination chemotherapy began when a number of active drugs from different classes became available for use in combination in the treatment of the acute leukemias and lymphomas. Following this initial success with hematologic malignancies, combination chemotherapy was extended to the treatment of solid tumors.
The use of combination chemotherapy is important for several reasons. First, it provides maximal cell kill within the range of toxicity tolerated by the host for each drug as long as dosing is not compromised. Second, it provides a broader range of interaction between drugs and tumor cells with different genetic abnormalities in a heterogeneous tumor population. Finally, it may prevent and/or slow the subsequent development of cellular drug resistance. Of note, these same concepts apply to the therapy of chronic infections, such as HIV and tuberculosis.
Certain principles have guided the selection of drugs in the most effective drug combinations, and they provide a paradigm for the development of new drug therapeutic programs.
1.
Efficacy: Only drugs known to have some level of clinical efficacy when used alone against a given tumor should be selected for use in combination. If available, drugs that produce complete remission in some fraction of patients are preferred to those that produce only partial responses.
2.
Toxicity: When several drugs of a given class are available and are equally effective, a drug should be selected on the basis of toxicity that does not overlap with the toxicity of other drugs in the combination. Although such selection leads to a wider range of adverse effects, it minimizes the risk of a lethal effect caused by multiple insults to the same organ system by different drugs and allows dose intensity to be maximized.
3.
Optimum scheduling: Drugs should be used in their optimal dose and schedule, and drug combinations should be given at consistent intervals. Because long intervals between cycles negatively affect dose intensity, the treatment-free interval between cycles should be the shortest time necessary for recovery of the most sensitive normal target tissue, which is usually the bone marrow.
4.
Mechanism of interaction: There should be a clear understanding of the biochemical, molecular, and pharmacokinetic mechanisms of interaction between the individual drugs in a given combination, to allow for maximal antitumor effect. Omission of a drug from a combination may allow overgrowth by a tumor clone sensitive to that drug alone and resistant to other drugs in the combination.
5.