Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 53 Principles of Antineoplastic Drug Use

One of the fundamental advances made in oncology in the last few decades is the recognition that cancer is a genetic disease. This does not mean that all cancers are inherited (although numerous genetic diseases are associated with a predisposition to cancer), but rather that neoplastic cells have an altered genetic content. This was first recognized in leukemias, which were all found to be associated with an abnormal karyotype. Eventually it was noted that most malignant cells have chromosomal rearrangements, and even cells with apparently normal karyotypes can almost always be found to have definable abnormalities (e.g., translocations, deletions).

By definition, neoplastic cells and tissues are characterized by uncontrolled growth, usually accompanied by a loss of cellular differentiation (anaplasia). The diseased cells and tissues are described as tumors, neoplasms, or cancers and occur in benign (nonvirulent) or malignant (virulent) states. Malignant neoplastic cells typically invade surrounding tissues, violating the basement membrane of the tissue of origin and eventually undergoing metastasis. More than 100 types of malignant neoplasms affect humans and are classified primarily according to their anatomical location and the type of cell involved. The advent of molecular diagnostic methods will almost certainly modify this number.

In the United States, malignant neoplasms are responsible for causing approximately 500,000 deaths per year (20% to 25% of total mortality), with approximately 1,000,000 new cases developing each year. Lung, large intestine, breast, and prostate neoplasms account for approximately 55% of both new cases and cancer deaths in the United States. Solid tumors arising from epithelial cells are termedcarcinomas, whereas those originating from connective or mesenchymal tissue are termed sarcomas. Malignancies that arise from the hematopoietic system include the leukemias and lymphomas.

The mechanisms by which malignant neoplasms originate in humans are still not clear. Carcinogenesis (i.e., the creation of malignant neoplastic cells) appears to result from the activation of specific dominant growth genes, called oncogenes, or a loss of functional negative effectors, called tumor suppressor genes. On the basis of the findings in the best-studied tumors, it is now believed that both kinds of genetic changes are essential for development of a full malignant phenotype. Protooncogenes, when activated, become oncogenes, which encode modified proteins that cause cellular dedifferentiation and proliferation characteristics of the neoplastic state. Activation of protooncogenes can occur by means of several pathways that often involve exposure of cells to chemicals, radiation, or viruses. Activation can result from a single point mutation. The most common oncogenes found thus far in human tumors belong to the RAS gene family, which codes for guanosine triphosphate-binding proteins. When RAS is converted to the activated form, it fails to dephosphorylate guanosine triphosphate and cells are transformed to a neoplastic phenotype. More than 100 protooncogenes are known to exist. Clearly, most if not all products of these variously dominantly acting oncogenes are components of cellular signaling pathways. Other genes, known as tumor-suppressing genes, also are present in human cells and function to suppress excessive cellular growth. Retinoblastoma (tumor of the eye) is a prototype of a malignancy caused by a genetic loss of the tumor-suppressor gene RB. A second common tumor suppressor gene is P53, which has recently been shown to possess the important function of protecting genomic stability. Because cancer can be defined by a loss of genomic stability, it is not surprising that mutations in P53 are the single most prevalent lesion in human cancer.

Tumor growth represents a balance between cell division and cell death. Recently it has become clear that, in addition to cells dying from necrosis, cells can exit the cell cycle by way of apoptosis, which is a form of programmed cell death. Apoptosis is not only important developmentally (e.g., thymic involution), but the apoptotic pathway is also an important pathway in the cellular response to DNA-damaging agents such as chemotherapy. It is now believed that all chemotherapeutic agents act via apoptosis. Indeed, the apoptotic pathway is now being targeted in the development of drugs. Interestingly, some oncogenes, namely BCL2, act by blocking apoptosis.

From the clinical standpoint, the primary difficulty in the successful control and treatment of malignant neoplasms is that by the time cancers are detected, they are relatively large (a 1-cm3 volume of tumor usually contains 109 cells) and frequently have metastasized. The chances of curing metastatic disease are small, because effective local treatments such as surgery and radiotherapy cannot remove or destroy all the malignant cells.

The generally accepted approach in the therapy of neoplastic diseases (Fig. 53-1) remains the removal or destruction of the neoplastic cells while minimizing toxic effects on non-neoplastic cells. It has been a long-standing question whether drugs effective against one type of neoplasm should be effective against all types. Clinical experience, however, has shown a wide range of drug activities among different types of tumors (sarcoma, carcinoma, leukemia, and lymphoma) and among tumors in different anatomical locations (breast, colon, and lung). Therefore interest has focused on treating each of the more than 100 clinically important forms of cancer as distinct diseases. Some of the therapeutic approaches listed in Figure 53-1 are not available for clinical use but represent experimental approaches that are under study. For example, drugs that function specifically to return neoplastic cells to normal differentiating cells and drugs that prevent metastases are not available or are highly experimental.

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FIGURE 53–1 Major approaches to therapy of cancers. Tumor cells are shown in red and non-tumor cells in green. *In clinical use. Others are experimental.

These chapters on antineoplastic agents address the principles in using chemotherapy and the mechanisms of action and the problems associated with the clinical use of antineoplastic drugs in humans.

A growing number of tumor types now respond to treatment with antineoplastic drugs. The types of clinical response to chemotherapy in patients of various ages with advanced-stage tumors are listed in the Therapeutic Overview Box.

Chemotherapy has been very effective in the management of leukemias and lymphomas, both in children and adults, such that most cases of leukemia in children are now curable. The success of treatment for adult leukemias is somewhat less, but complete remission in response to induction therapy is often achievable. On the other hand, only a small number of solid tumors respond completely to chemotherapy. Choriocarcinoma, Ewing’s sarcoma, and testicular carcinoma are examples of solid tumors that can be cured with chemotherapy, even if they have metastasized.

It is of interest to compare the tumor types in which therapy has been aided greatly by antineoplastic drugs with the leading causes of cancer mortality (Fig. 53-2). Unfortunately, chemotherapy is only minimally effective in management of the most common forms of neoplastic diseases. Overall, carcinoma of the lung accounts for the greatest number of cancer deaths in men and women, and although chemotherapy can produce objective responses, it is not curative in this setting. Thus, despite progress, there is still a great need for more effective chemotherapy for the major neoplastic diseases.

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FIGURE 53–2 Estimated cancer deaths in the United States in 2004—percentage distribution of sites by sex. (Excludes basal and squamous cell skin cancers and carcinoma in situ, except bladder).

Modified from American Cancer Society: Cancer statistics, 2004. CA Cancer J Clin 2004; 54:1.

DRUG SELECTION AND PROBLEMS

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.

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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:

• Curative, to obtain complete remission (e.g., Hodgkin’s disease).

• Palliative, to alleviate symptoms but with little expectation of complete remission (e.g., carcinoma of the esophagus, with chemotherapy performed to ease the dysphagia).

• Adjuvant, to improve the chances for a cure or prolong the period of disease-free survival when no detectable cancer is present but subclinical numbers of neoplastic cells are suspected (e.g., chemotherapy for breast cancer after surgical resection of all known tumor).

Therapeutic Overview

Cancers in which complete remissions to chemotherapy are common and cures are seen even in advanced disease*

Acute lymphocytic leukemia (adults and children)

Acute myelogenous leukemia

Hodgkin’s disease (lymphoma)

Non-Hodgkin’s lymphoma

Choriocarcinoma

Testicular cancer

Burkitt’s lymphoma

Ewing’s sarcoma

Wilms’ tumor

Small-cell lung cancer

Ovarian cancer

Hairy cell leukemia

Cancers in which objective responses are seen but chemotherapy does not have curative potential in advanced disease

Multiple myeloma

Breast cancer

Head and neck cancer

Colorectal carcinomas

Chronic lymphocytic leukemia

Chronic myelogenous leukemia

Transitional cell carcinoma of bladder

Gastric adenocarcinomas

Cervical carcinomas

Medulloblastoma soft-tissue sarcoma

Neuroblastoma

Endometrial carcinomas

Insulinoma

Osteogenic sarcoma

Non-small cell lung cancer

Cancers in which only occasional objective responses to chemotherapy are seen

Melanoma

Renal tumor

Pancreatic carcinomas

Hepatocellular carcinoma

Prostate carcinomas (hormone nonresponsive)

* 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.

• Use drugs that show activity against the type of tumor being treated. The rationale is that only rarely will a compound that shows no activity alone have an effect when used in combination. Agents used should also not be cross-resistant, thus expanding their anti-tumor activity.

• Use drugs that have minimal or no overlapping toxicities. Although this may broaden the range of undesirable side effects of the drug combination, the goal is to reduce the possibility of life-threatening side effects that act in concert. For this reason the side effects of the drugs selected should be diverse and not centered on the same organ system.

• The dosing schedule for each drug should be optimal, and doses should be given at consistent times. In establishing the frequency of a dosing regimen, it is usual to allow sufficient time between dosage sequences to permit the most-sensitive tissues (often bone marrow) to recover.

• Whenever possible, use drug combinations that result in synergistic activity, thus optimizing the therapeutic benefit and reducing the risk and severity of adverse effects.

• Use drugs that have different mechanisms of action, or that affect tumor cells at different stages of the cell cycle. Because not all cells are in the same stage simultaneously, this allows more cells to be targeted at each administration.

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 Go 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 Go 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

Terminology

Cancer

Drugs

MOPP

Hodgkin’s

Mechlorethamine, vincristine, procarbazine, prednisone

ABVD

Hodgkin’s

Doxorubicin, bleomycin, vinblastine, dacarbazine

CMF

Breast

Cyclophosphamide, methotrexate, 5-fluorouracil

CAF

Breast

Cyclophosphamide, doxorubicin, 5-fluorouracil

 

Acute lymphocytic leukemia

Vincristine, prednisone, asparaginase, daunorubicin

 

Acute myelogenous leukemia

Cytarabine, plus mitoxantrone or idarubicin or daunorubicin

 

Chronic myelogenous leukemia

Hydroxyurea, interferon

 

Wilms’

Actinomycin D, vincristine, doxorubicin

 

Small cell (lung)

Etoposide-cisplatin

 

Non-small cell (lung)

Cisplatin, etoposide

PVC

Anaplastic oligodendrogliomas

Procarbazine, vincristine, CCNU

BEP

Germ cell cancers

Bleomycin, etoposide, cisplatin

 

Ovary

Paclitaxel, carboplatin

CHOP

Lymphoma

Cyclophosphamide, doxorubicin, vincristine, prednisone

 

Head and neck

5-fluorouracil, cisplatin

 

Colon/rectum

5-fluorouracil, leucovorin

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.

BOX 53–1 Tendency of Antineoplastic Drugs to Induce Nausea or Vomiting

Strong Tendency

Cisplatin, dacarbazine, mechlorethamine, cyclophosphamide, doxorubicin, lomustine, carmustine

Moderate Tendency

Daunorubicin, actinomycin D, cytarabine, procarbazine, methotrexate, mitomycin, etoposide

Low Tendency

Chlorambucil, vincristine, tamoxifen, bleomycin, hydroxyurea, fluorouracil

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).

New Horizons

Although significant advances have been made in the treatment of the hematological neoplastic diseases over the past several decades, less progress has been made in the treatment of most solid tumors. During this same time there has been an explosion in our understanding of the basic science of cancer. For example, the past few decades have witnessed the description of RNA and deoxyribonucleic acid tumor viruses, oncogenes, and anti-oncogenes (tumor suppressor genes) as well as dramatic advances in our understanding of cell-cycle regulation, apoptosis, and the signaling pathways in deoxyribonucleic acid damage responses. Many gene products involved in these pathways are new targets in the treatment of malignancies (see Chapter 54). Over the next several years many cancer treatments are certain to be devised based on our increased understanding of these basic molecular mechanisms, thereby narrowing the chasm between the molecular biology of cancer and clinical oncology.

Pharmacogenomics is making significant advances in determining risks of recurrence, mortality, and response to adjuvant chemotherapy. The United States Food and Drug Administration has approved the use of pharmacogenetic testing, Oncotype DX, and is carrying out long-term studies for verification of predictive value. This test analyzes a 21-gene panel to determine the risk of recurrence for a breast cancer patient treated in the early stages, and what benefit, if any, is provided by chemotherapy. In combination with other clinical information such as tumor size and lymph node involvement, this pharmacogenomic screening may help patients avoid unnecessary chemotherapy and guide more appropriate clinical decisions.

FURTHER READING

Mina etal 2007 Mina L, Soule SE, Badve S, et al. Predicting response to primary chemotherapy: Gene expression profiling of paraffin-embedded core biopsy tissue. Breast Cancer Res Treat. 2007;103:197-208.

Tiseo M, Loprevite M, Ardizzoni A. Epidermal growth factor receptor inhibitors: A new prospective in the treatment of lung cancer. Curr Med Chem Anti-Canc Agents. 2004;4:139-148.

Workman P. Strategies for treating cancers caused by multiple genome abnormalities: From concepts to cures? Curr Opin Investig Drugs. 2003;4:1410-1415.

SELF-ASSESSMENT QUESTIONS

1. Which of the following diseases is potentially curable with combination chemotherapy even when both the liver and lung are involved by metastatic disease?

A. Breast cancer

B. Colon cancer

C. Hodgkin’s disease

D. Non-small-cell carcinoma of the lung

E. Stomach cancer

2. Which of the following statements best describes why patients who fail to respond to first-line chemotherapy have a decreased likelihood of a response to a second-line regimen?

A. Decreased performance status of patient

B. Increased tumor burden

C. Tumor cell resistance caused by multidrug resistance gene

D. Tumor cell resistance caused by selection of resistant clones

E. All of the above

3. Although many anticancer drugs can induce nausea and vomiting, some have a stronger tendency than others. Which of the following drugs has the greatest tendency to induce vomiting?

A. Bleomycin

B. Chlorambucil

C. Cisplatin

D. Hydroxyurea

E. Vincristine

4. There are several goals for the administration of chemotherapeutic agents in the treatment of cancer. Which of the following terms describes chemotherapy that is administered after surgery, radiation, or both?

A. Adjuvant

B. Curative

C. Elective

D. Palliative