Basic principles of cancer chemotherapy

CHAPTER 101


Basic principles of cancer chemotherapy


As mortality from infectious diseases has declined, thanks to antimicrobial drugs and public health measures, cancer has emerged as the second leading cause of death. The American Cancer Society estimated that 571,950 Americans died from cancer in the year 2011. Only heart disease kills more people. Among women ages 30 to 74, neoplastic diseases lead all other causes of mortality. Among children ages 1 to 14 years, cancer is the leading nonaccidental cause of death. As shown in Table 101–1, among women, the most common cancers are cancers of the breast, lung, colon, and rectum. Among men, the most common cancers are cancers of the prostate, lung, colon, and rectum.



We have three major modalities for treating cancer: surgery, radiation therapy, and drug therapy. Surgery is the most common treatment for solid cancers. In contrast, drug therapy is the treatment of choice for disseminated cancers (leukemias, disseminated lymphomas, and metastases) along with several localized cancers (eg, choriocarcinoma, testicular carcinoma). Drug therapy also plays an important role as an adjunct to surgery and irradiation: By suppressing or killing malignant cells that surgery and irradiation leave behind, adjuvant drug therapy can reduce recurrence and improve survival.


Anticancer drugs fall into four major classes: cytotoxic agents (ie, drugs that kill cells directly), hormones and hormone antagonists, biologic response modifiers (eg, immunomodulating agents), and targeted drugs (ie, drugs that bind with specific molecules [targets] that promote cancer growth). Of the four classes, the cytotoxic agents are used most often. You should note that the term cancer chemotherapy applies only to the cytotoxic drugs—it does not apply to the use of hormones, biologic response modifiers, or targeted drugs. In this chapter, our discussion of anticancer drugs pertains almost exclusively to the cytotoxic agents.


The modern era of cancer chemotherapy dates from 1942, the year in which “nitrogen mustards” were first used for cancer. Since the introduction of nitrogen mustards, chemotherapy has made significant advances. For patients with some forms of cancer (Table 101–2), drugs can often be curative. Cancers with a high cure rate include Hodgkin’s disease, testicular cancer, and acute lymphocytic leukemia. For many patients whose cancer is not yet curable, chemotherapy can still be of value, offering realistic hopes of palliation and prolonged life. However, although progress in chemotherapy has been encouraging, the ability to cure most cancers with drugs alone remains elusive. At this time, the major impediment to successful chemotherapy is toxicity of anticancer drugs to normal tissues.



TABLE 101–2 


Some Cancers for Which Drugs May Be Curative*








































Type of Cancer Drug Therapy†
Hodgkin’s lymphoma Doxorubicin + bleomycin + vinblastine + dacarbazine
Burkitt’s lymphoma Cyclophosphamide + vincristine + methotrexate + doxorubicin + prednisone
Choriocarcinoma Methotrexate ± leucovorin
Small cell cancer of lung Etoposide + either cisplatin or carboplatin
Testicular cancer Cisplatin + etoposide ± bleomycin
Wilms’ tumor‡ Dactinomycin + vincristine ± doxorubicin ± cyclophosphamide
Ewing’s sarcoma‡ Cyclophosphamide + doxorubicin + vincristine alternating with etoposide + ifosfamide (with mesna)
Acute myeloid leukemia Daunorubicin + cytarabine + etoposide
Breast cancer‡ Fluorouracil + doxorubicin + cyclophosphamide
Colorectal cancer‡ Fluorouracil + leucovorin + oxaliplatin
Acute lymphocytic leukemia Vincristine + prednisone + asparaginase + daunorubicin or doxorubicin ± cyclophosphamide

*“Cure” is defined as a 5-year disease-free interval following treatment.


†These are representative regimens. Other regimens may also be highly effective.


‡Chemotherapy is combined with surgery and/or radiotherapy in these cancers.


Our principal objectives in this chapter are to examine the major obstacles confronting successful chemotherapy, the strategies being employed to overcome those obstacles, the major toxicities of the chemotherapeutic drugs, and steps that can be taken to minimize drug-induced harm and discomfort. As background for addressing these issues, we begin by discussing (1) the nature of cancer itself and (2) the tissue growth fraction and its relationship to cancer chemotherapy.




What is cancer?


In the discussion below, we consider properties shared by neoplastic cells as a group. However, although the discussion addresses cancers in general, be aware that the term cancer refers to a large group of disorders and not to a single disease: There are more than 100 different types of cancer, most of which have multiple subtypes. These various forms of cancer differ in clinical presentation, aggressiveness, drug sensitivity, and prognosis. Because of this diversity, treatment must be individualized, based on the specific biology of the cells involved.




Characteristics of neoplastic cells


Persistent proliferation.

Unlike normal cells, whose proliferation is carefully controlled, cancer cells undergo unrestrained growth and division. This capacity for persistent proliferation is the most distinguishing property of malignant cells. In the absence of intervention, cancerous tissues will continue to grow until they cause death.


It was once believed that cancer cells divided more rapidly than normal cells and that this excessive rate of division was responsible for the abnormal growth patterns of cancerous tissues. We now know that this concept is not correct. Division of neoplastic cells is not necessarily rapid: Although some cancers are composed of cells that divide rapidly, others are composed of cells that divide slowly. The correct explanation for the relentless growth of tumors is that malignant cells are unresponsive to the feedback mechanisms that regulate cellular proliferation in healthy tissue. Hence, cancer cells are able to continue multiplying under conditions that would suppress further growth and division of normal cells.






Etiology of cancer

The abnormal behavior of cancer cells results from alterations in their DNA. Specifically, malignant transformation results from a combination of activating oncogenes (cancer-causing genes) and inactivating tumor suppressor genes (genes that prevent replication of cells that have become cancerous). These genetic alterations are caused by chemical carcinogens, viruses, and radiation (x-rays, ultraviolet light, radioisotopes). Malignant transformation occurs in three major stages, called initiation, promotion, and progression. These stages suggest that DNA in cancer cells undergoes a series of small modifications, rather than a single large change. This accumulated genetic damage leads to dysregulation of cell division and protection against cell death.


It is important to appreciate that the changes in cellular function caused by malignant transformation are primarily quantitative (rather than qualitative). That is, malignant transformation simply results in the overexpression or underexpression of the same gene products made by normal cells. As a result, cancer cells employ the same metabolic machinery as normal cells, use the same signaling pathways as normal cells, and express the same surface antigens as normal cells. Nonetheless, even though these changes are only quantitative, they are still sufficient to allow unrestrained growth and avoidance of cell death.



The growth fraction and its relationship to chemotherapy


The growth fraction of a tissue is a major determinant of its responsiveness to chemotherapy. Consequently, before we discuss the anticancer drugs, we must first understand the growth fraction. In order to define the growth fraction, we need to review the cell cycle.




The cell cycle

The cell cycle is the sequence of events that a cell goes through from one mitotic division to the next. As shown in Figure 101–1, the cell cycle consists of four major phases, named G1, S, G2, and M. (The length of the arrows in the figure is proportional to the time spent in each phase.) For our purpose, we can imagine the cycle as beginning with G1, the phase in which the cell prepares to make DNA. Following G1, the cell enters S phase, the phase in which DNA synthesis actually takes place. After synthesis of DNA is complete, the cell enters G2 and prepares for mitosis (cell division). Mitosis occurs next during M phase. Upon completing mitosis, the resulting daughter cells have two options: they can enter G1 and repeat the cycle, or they can enter the phase known as G0. Cells that enter G0 become mitotically dormant; they do not replicate and are not active participants in the cycle. Cells may remain in G0 for days, weeks, or even years. Under appropriate conditions, resting cells may leave G0 and resume active participation in the cycle.


image
Figure 101–1  The cell cycle.



Impact of tissue growth fraction on responsiveness to chemotherapy

As a rule, chemotherapeutic drugs are much more toxic to tissues that have a high growth fraction than to tissues that have a low growth fraction. Why? Because most cytotoxic agents are more active against proliferating cells than against cells in G0. Proliferating cells are especially sensitive to chemotherapy because cytotoxic drugs usually act by disrupting either DNA synthesis or mitosis—activities that only proliferating cells carry out. Unfortunately, toxicity of anticancer drugs is not restricted to cancers: These drugs are also toxic to normal tissues that have a high growth fraction (eg, bone marrow, GI epithelium, hair follicles, sperm-forming cells).


Having established the relationship between growth fraction and drug sensitivity, we can apply this knowledge to predict how specific cancers will respond to chemotherapy. As a rule, the most common cancers—solid tumors of the breast, lung, prostate, colon, and rectum—have a low growth fraction, and hence respond poorly to cytotoxic drugs. In contrast, only some rarer cancers—such as acute lymphocytic leukemia, Hodgkin’s disease, and certain testicular cancers—have a high growth fraction, and hence tend to respond well to cytotoxic drugs. In practical terms, this means that the most common cancers, which don’t respond well to drugs, must be managed primarily with surgery. Only a few cancers can be managed primarily with drugs.



Obstacles to successful chemotherapy


In this section we consider the major factors that limit success in chemotherapy. Foremost among these is the serious and unavoidable toxicity to normal cells caused by cytotoxic drugs. Other important factors include resistance to chemotherapy and high tumor load (owing to late diagnosis).



Toxicity to normal cells


Toxicity to normal cells is a major barrier to successful chemotherapy. Injury to normal cells occurs primarily in tissues where the growth fraction is high: bone marrow, GI epithelium, hair follicles, and germinal epithelium of the testes. Drug-induced injury to each of these tissues is discussed in detail below. For now, let’s consider injury to normal cells as a group.


Toxicity to normal cells is dose limiting. That is, dosage cannot exceed an amount that produces the maximally tolerated injury to normal cells. Hence, although very large doses of cytotoxic drugs might be able to produce cure, these doses cannot be given because they are likely to kill the patient.


Why are cytotoxic anticancer drugs so harmful to normal tissues? Because these drugs lack selective toxicity. That is, they cannot kill target cells without also killing other cells with which the target cells are in intimate contact. We first encountered this concept in Chapter 83 (Basic Principles of Antimicrobial Therapy). As noted there, successful antimicrobial therapy is possible because antimicrobial drugs are highly selective in their toxicity. Penicillin, for example, can readily kill invading bacteria while being virtually harmless to cells of the host. This high degree of selective toxicity stands in sharp contrast to the lack of selectivity displayed by cytotoxic anticancer drugs.


Why have we been unable to develop drugs that selectively kill neoplastic cells? Because neoplastic cells and normal cells are very similar: Differences between them are quantitative rather than qualitative. To make a cytotoxic drug that is truly selective, the target cell must have a biochemical feature that normal cells lack. By way of illustration, let’s consider penicillin, which kills bacteria by disrupting the bacterial cell wall. Because our cells don’t have a cell wall, penicillin can’t hurt us. Unfortunately, we have yet to identify unique biochemical features that would render cancer cells vulnerable to selective attack. Nonetheless, as discussed below under Looking Ahead, there is reason for hope: Our expanding knowledge of cancer biology is revealing potential new targets for anticancer drugs. Exploiting these targets may lead to anticancer drugs that are more selective than the drugs we have now.



Cure requires 100% cell kill


To cure a patient of cancer, we must eliminate virtually every malignant cell. Why? Because just one remaining cell can proliferate and cause relapse. For most patients, 100% cell kill cannot be achieved. Factors that make it difficult to achieve complete cell kill include (1) the kinetics of drug-induced cell kill, (2) minimal participation of the immune system in eliminating malignant cells, and (3) disappearance of symptoms before all cancer cells are gone.






When should treatment stop?

We have no way of knowing when 100% cell kill has been achieved. As a result, there is no definitive method for deciding just when chemotherapy should stop. As indicated in Figure 101–2, symptoms disappear long before the last malignant cell has been eliminated. Once a cancer has been reduced to less than 1 billion cells, it becomes undetectable by usual clinical methods; all signs of disease are absent, and the patient is considered in complete remission. It is obvious, however, that a patient harboring a billion malignant cells is by no means cured. It is also obvious that further chemotherapy is indicated. However, what is not so obvious is just how long therapy should last: Because the patient is already asymptomatic, we have no objective means of determining when to stop treatment. The clinical dilemma is this: If therapy continues too long, the patient will be needlessly exposed to serious toxicity; conversely, if drugs are discontinued prematurely, relapse will occur.


image
Figure 101–2  Gompertzian tumor growth curve showing the relationship between tumor size and clinical status.


Absence of truly early detection


Early detection of cancer is rare. Cancer of the cervix, which can be diagnosed with a Papanicolaou (Pap) test, is the primary exception. All other forms of cancer are significantly advanced by the time they have grown large enough for discovery. The smallest detectable cancers are about 1 cm in diameter, have a mass of 1 gm, and consist of about 1 billion cells (see Fig. 101–2). Detection at this stage cannot be considered early.


Late detection has three important consequences. First, by the time the primary tumor is discovered, metastases may have formed. Second, the tumor will be less responsive to drugs than it would have been at an earlier stage (see below). Third, if the cancer has been present for a long time, the patient may be debilitated by the disease, and therefore less able to tolerate treatment.


Even though truly early detection is largely impossible, every effort at relatively early detection should be made. Why? Because the smaller a cancer is when treatment begins, the better the chances of long-term survival. Hence, even if a cancer has 1 billion cells when it’s detected, that’s still far better than a gazillion. Accordingly, the American Cancer Society recommends routine testing for several cancers, including cancers of the prostate, breast, uterus, rectum, and colon. Table 101–3 indicates who should be tested, how often, and what test or procedure should be performed. With breast cancer, a yearly mammogram can detect disease before it becomes widely invasive, thereby greatly increasing survival—even though more than a billion cells may be present at the time of discovery. Along with routine testing, patients should be counseled about ways to reduce cancer risk, especially avoiding tobacco and excessive exposure to ultraviolet radiation, and receiving a human papillomavirus (HPV) vaccination to protect against cervical cancer (see Chapter 68).



TABLE 101–3 


American Cancer Society Recommendations for the Early Detection of Breast, Colorectal, Prostate, and Cervical Cancers, 2011














Type of Cancer Recommendation
Breast Women age 40 and older should have an annual mammogram and an annual clinical breast examination (CBE) by a healthcare professional. Ideally, the CBE should be conducted before the scheduled mammogram. Women ages 20–39 should have a CBE at least every 3 years. Beginning in their early 20s, women may perform periodic breast self-examinations, in addition to receiving recommended CBEs.
Colon and rectum Beginning at age 50, men and women should follow one of the 7 examination schedules below:

Related posts:

  1. Orientation to pharmacology
  2. Drug therapy of infertility
  3. Drugs for the ear
  4. Pharmacodynamics

Stay updated, free articles. Join our Telegram channel
Tags:
Jul 24, 2016 | Posted by in NURSING | Comments Off on Basic principles of cancer chemotherapy

Full access? Get Clinical Tree

 Get Clinical Tree app for offline access