The Nature of the Problem

One of the difficulties in treating neoplastic diseases is that the tumor burden often is excessive by the time the diagnosis is made. This is shown in Figure 53-3, where the number of cells in a typical solid tumor is shown versus time, with 10⁹ cells roughly equivalent to a volume of 1 cubic centimeter, and representing the minimum size tumor that can usually be detected. It takes approximately 30 doublings for a single cell to reach 10⁹ cells. On the other hand, it takes only 10 additional doublings for 10⁹ cells to reach a population of 10¹² cells, which is no longer compatible with life. The significance of a large number of cells already established at the time of detection becomes readily evident, with 10¹² to 10¹³ tumor cells leading to death. Thus by the time a tumor is detected, only a small number of doublings are required before it is fatal. Of course, not all tumor cells are cycling, so no meaningful predictions about longevity can be made purely on the basis of doubling times. Also, doubling times of human tumors vary greatly. For acute lymphocytic leukemia, the doubling time during log-phase (first-order) growth is 3 to 4 days, whereas the doubling time for lung squamous cell carcinoma is approximately 90 days. Thus in roughly 100 days, two lymphocytic leukemia cells in theory could keep doubling and reach 10⁹ cells. Such a situation is extremely difficult to treat only with drugs and is cited here to emphasize the difficulty of the therapeutic task using currently available diagnostic timetables. In addition, by the time a tumor is clinically detectable, it already has a well-developed vascular supply and most probably has already metastasized. Mathematical models suggest that it also has a high likelihood of being resistant to cytotoxic agents that function through the same pathways.

FIGURE 53–3 Typical tumor growth curve showing that roughly 10⁹ cells are needed for a diagnosis.

Primary versus Adjuvant Therapy

The objective of chemotherapy in any given individual patient may be:

* Depending on tumor type, complete remission may result in cure.

Selection of Drug Regimen

Although choriocarcinoma (gestational trophoblastic disease) and hairy cell leukemia are treated by using single drugs, nearly all other neoplasms are treated with combinations of drugs.

The choice of drugs and dosing schedule for multiple-drug therapy has been and remains largely empirical. There are continuing efforts to try to understand why some combinations are more effective than others for the management of certain tumor types. Despite this empirical approach, several guidelines are generally applicable when selecting drug combinations. Of noteworthy interest, many of these guidelines are similar to the guidelines for treating infectious organisms.

Many sophisticated approaches have been used for selecting drugs and dosing schedules for combination chemotherapy, but the results have been disappointing. Some approaches have included drugs that have different mechanisms of action, in the hope that one mechanism would succeed where the others fail. Another goal of the multiple-mechanism approach has been the discovery of synergistic combinations. Several combinations, including sequential methotrexate-5-fluorouracil, doxorubicin-cyclophosphamide, and cisplatin-etoposide, have been found to be synergistic when tested against tumor cells cultured in vitro. A major problem of this approach, however, is that the observed in vivo clinical results often do not correlate with the in vitro data.

The relative sequence of drugs and the timing of drug administration may also play a significant role. As noted in Chapter 54, most drugs are more effective against tumor cells that are cycling rather than cells resting in the G_o phase, but cells may be present in any part of the cycle in vivo. The effectiveness of some drug combinations may be in part attributable to their activation of cells in the G_o phase to start cycling or to cycle more rapidly (see Fig. 54-1). A greater number of cells are then positioned in portions of the cell cycle where antineoplastic drugs can exert their cytotoxic actions.

Antineoplastic drugs are used as the primary mode of therapy when the tumor is known to be sensitive, or when surgical removal or radiation destruction of the main tumor mass is not particularly feasible. A more difficult situation is posed by a patient who presents with metastatic disease of a tumor type that is not responsive to chemotherapy. In this situation the best option is treatment with a newer experimental agent. An easier situation is the patient in whom drugs can be used as an adjuvant therapy after surgical or radiation removal of the primary tumor. Adjuvant therapy is commonly used in management of completely resected breast cancer and colorectal cancer. Significant improvement in survival is seen in patients with either of these tumors who receive adjuvant chemotherapy. Some examples of common combination drug regimens are given in Table 53-1.

TABLE 53–1 Common Combination Drug Regimens

There is a growing trend toward the use of high-dose protocols in an effort to push higher concentrations of drug into the tumor cells. This is also true for drugs that are rapidly degraded in plasma such as cytarabine. The emergence of granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor as agents that can reduce chemotherapy-induced neutropenia and infections have accelerated this trend toward high-dose therapy.

Special Clinical Problems

Because chemotherapy is a systemic treatment, it is impossible to deliver drug to the tumor without injuring normal tissue. In fact, normal tissue toxicity is the dose-limiting factor for all antineoplastic agents. Normal tissue toxicity can either be acute (with or shortly after chemotherapy) or delayed (months to years after chemotherapy). Most acute side effects (nausea, vomiting, alopecia, bone marrow suppression) are reversible.

Delayed side effects of chemotherapy are quite diverse and include pulmonary fibrosis, sterility, neuropathy, and nephropathy, but the most important are leukemia and cardiotoxicity. Chemotherapy-induced leukemias are associated mainly with the alkylating agents. Cardiotoxicity is associated with the anthracyclines. Recently dexrazoxane, a bisdioxopiperazine compound, has been shown to reduce the risk of anthracycline-induced cardiomyopathy. It is thought to act by preventing free radical damage by the iron-doxorubicin complex.

Nausea and vomiting can be expected in a high fraction of patients receiving antineoplastic drugs. Some of the drugs most and least likely to trigger emesis are listed in Box 53-1. Although the clinical management of nausea and vomiting can become a serious problem, many drugs now exist to successfully control these symptoms.

Targeted Therapies and Biological Response Modifiers

Targeted therapies are becoming increasingly important in treatment of cancer. Examples include bevacizumab, which targets vascular endothelial growth factor; I¹³¹ tositumomab and Y-90-ibritumomab tiuxetan, which target CD20 and are used for treatment of chemotherapy-refractory non-Hodgkin’s lymphoma; and gefitinib and the antibody cetuximab, which target the epidermal growth factor receptor pathway. Biological response modifiers comprise a class of agents that stimulate the human immune system to destroy tumor cells. The α and β human interferons are efficacious in hairy cell leukemia and in certain skin cancers and may become aids for treating chronic myelogenous leukemia and non-Hodgkin’s lymphoma. Interleukin-2 is another endogenous compound that may prove beneficial in treating lung, renal, colorectal, and several other tumor types. Still other compounds include tumor necrosis factor, human growth factors, and monoclonal antibodies (see Chapter 6).