Chapter 31. Cancer Chemotherapy

Cancer is a disease of cells characterized by a shift in the control mechanisms that govern cell proliferation and differentiation. Cells that have undergone neoplastic transformation often express normal fetal cell surface antigens or display other signs of apparent immaturity. Cancer cells may also exhibit qualitative or quantitative chromosomal abnormalities, including translocations and amplified gene sequences. Cancer cells proliferate excessively and form local tumors that can compress or invade adjacent normal structures. Within local tumors, a small subpopulation of cells can be described as tumor stem cells. These cells retain the ability to undergo repeated cycles of proliferation and can migrate to distant sites in the body to colonize various organs in the process called metastasis. Thus, tumor stem cells can express clonogenic (colony-forming) capabilities. Chromosomal abnormalities in tumor stem cells reflect their genetic instability, which leads to progressive selection of subclones that can survive more readily in the host’s multicellular environment. Abnormalities in various metabolic pathways and cellular components (e.g., expression of cell-surface drug transporters) accompany neoplastic progression. The invasive and metastatic processes, as well as metabolic abnormalities resulting from the cancer, cause illness and eventual death unless the neoplasm can be eradicated with treatment.

A classification of anticancer drugs is presented in Figure 31–1. Initial division is based on whether the drugs affect DNA (action on DNA and action on mitotic spindle) or modulate hormonal activity (hormonal agents). Drugs affecting DNA may inhibit synthesis or directly damage DNA. As a group, anticancer drugs are more toxic than any other drugs because they act not only on neoplastic cells but also on normal cells that are in dividing or resting states. Therefore, the benefits of anticancer drugs must be carefully weighed against their risks.

The incidence, geographic distribution, and behavior of specific types of cancer are related to multiple factors, including gender, age, genetic make-up, and exposure to environmental carcinogens. Of these, environmental exposure is the only modifiable risk factor. Chemical carcinogens, particularly those in tobacco smoke, as well as azo dyes, aflatoxins, asbestos, and benzene have been clearly implicated in cancer induction in humans and animals. In the laboratory, potential environmental carcinogens can be identified by microbial mutagenesis and animal testing.

Certain deoxyribonucleic acid (DNA) viruses and type C ribonucleic acid (RNA) viruses have been implicated as cancer-causing (oncogenic) agents in animals and humans. Oncogenic RNA viruses contain a reverse transcriptase that transcribes the RNA of the tumor virus into the DNA code of the infected host cell. In this way, the information governing transformation becomes a stable part of the host cell genome. Expression of virus-induced neoplasia also depends on additional host and environmental factors that modulate the transformation process. Certain cellular genes, known as oncogenes, are homologous to the transforming genes of retroviruses and induce neoplastic transformation. Oncogenes code for specific growth factors and their receptors, and may be amplified (increased number of gene copies) or modified by a single nucleotide polymorphism in malignant cells. Another class of genes, tumor suppressor genes, plays an important role in suppressing neoplastic transformation. If a tumor suppressor gene is mutated, deleted, or damaged, neoplastic change is likely to occur. Such changes may be inherited, occur spontaneously, or may be acquired through exposure to exogenous chemicals or radiation.

Cancer is the second most common cause of death in the United States, causing over 500,000 fatalities annually. Currently, one-third of cancer patients are cured with local modalities (surgery or radiation therapy), which are quite effective when the tumor has not metastasized by the time of treatment. In the remaining cases, when early micrometastasis is a characteristic feature of the neoplasm, a systemic approach such as chemotherapy is required (often in conjunction with surgery or radiation) for effective cancer management. At present, about 50% of patients with cancer can be cured, with chemotherapy contributing to the cure in 10 to 15% of patients.

Cancer cell cycle kinetics and population kinetics explain, in part, the limited effectiveness of most available anticancer drugs. Figure 31–2 presents a schematic summary of cell cycle kinetics and stages at which particular anticancer drug classes act. This information is relevant to the mode of action, indications, and scheduling of cell cycle–specific drugs (CCS, drugs that are most effective in a particular phase of the cycle) and cell cycle–nonspecific (CCNS, insensitive to the phase of the cell cycle) drugs. Examples of drugs falling into these two major classes are summarized in Table 31–1.

In general, CCSdrugs are most effective in hematologic malignancies and in solid tumors in which a relatively large proportion of the cells are proliferating or are in the growth fraction. The growth fraction represents the number of cells within the malignant tumor that are at some stage of division (i.e., other than G0) compared to the total number of malignant cells (i.e., those in division plus those in G0) (Figure 31–2). For the growth fraction, the first value is placed in the numerator and the latter value in the denominator. The fraction is then represented as a percentage. The CCNS drugs (many of which bind to and damage cellular DNA) are useful for treating solid tumors with both low and high growth fractions. In all instances, effective agents sterilize (i.e., inactivate) tumor stem cells, which are often only a small fraction of the cells within a tumor. Non–stem cells (i.e., those that have irreversibly differentiated) are considered sterile and are not a significant component of the cancer problem.

Drug resistance is a major problem in cancer chemotherapy. Mechanisms of resistance include, but are not limited to, the following six examples.

• 1. Cancer cells may increase their rate of DNA repair. This mechanism is particularly important in the case of resistance to alkylating agents.
• 2. Some tumor cells increase their production of thiol-trapping agents (e.g., glutathione), which inactivate certain anticancer drugs. This mechanism of resistance is seen with several of the alkylating agents and antibiotics.
• 3. Cancer cells may alter target enzymes. For example, increased synthesis of dihydrofolate reductase and changes in this enzyme are mechanisms of resistance of tumor cells to methotrexate.
• 4. Cancer cells may decrease conversion of a prodrug into the active form of the drug. Resistance to the purine antimetabolites (mercaptopurine, thioguanine) and the pyrimidine antimetabolites (cytarabine, fluorouracil) can result from decreased activity of tumor cell enzymes required to convert these prodrugs to their cytotoxic metabolites.
• 5. Cancer cells may increase the inactivation of certain cancer drugs. Increased activity of enzymes capable of inactivating anticancer drugs is a mechanism of tumor cell resistance to most of the purine and pyrimidine antimetabolites.
• 6. Cancer cells may decrease intracellular drug concentration by increased efflux pump activity. This form of multidrug resistance involves increased expression of a normal gene. For example, MDR1 is a gene that codes for a cell surface P-glycoprotein. As discussed in Chapter 3, this transport protein is normally present in various cells throughout the body. In intestinal cells, the protein is involved in transport of drugs back into the lumen. In some multidrug-resistant malignancies, the activity of this transporter is increased, and the accelerated efflux of many anticancer drugs provides resistance for these cells.

Alkylating Agents

The alkylating agents include nitrogen mustards (cyclophosphamide, mechlorethamine), nitrosoureas (carmustine, lomustine), and alkylsulfonates (busulfan). Other drugs that act in part as alkylating agents include cisplatin, dacarbazine, and procarbazine. The alkylating agents are CCNS drugs. Some are active as given, whereas others are prodrugs that are converted to active metabolites in the body. The reactive molecules covalently bind with one of the four nucleotides in DNA. This binding (alkylation) usually follows intramolecular cyclization in the drug, which creates an intermediate that forms a covalent bond with DNA. When two nucleotides in the double helix DNA are alkylated by the same drug molecule, the two DNA strands are cross-linked. The resulting cross-linked DNA cannot be separated and replicated in mitosis, halting cell division. Alkylating agents may also exert cytotoxic effects by forming covalent bonds with other cellular constituents such as proteins. Alkylation of DNA also results in abnormal base pairing and DNA strand breakage. Several alkylating agents and their acute and delayed toxicities are listed in Table 31–2. DNA alkylation probably represents the major interaction that leads to cell death. Some of the more commonly used alkylating drugs are discussed below.

Cyclophosphamide

Cyclophosphamide is a prodrug that is converted to one or more highly reactive metabolites by hepatic cytochrome P450 enzymes. Clinical uses of cyclophosphamide include non-Hodgkin’s lymphoma, breast and ovarian cancers, and neuroblastoma. One advantage of the drug is that it can be taken orally. Toxicities observed with cyclophosphamide include cardiac dysfunction, pulmonary toxicity, and a syndrome of inappropriate antidiuretic hormone release.

Cisplatin, Carboplatin, and Oxaliplatin

These drugs are rarely used alone in cancer chemotherapy, but are included as part of a larger drug treatment regimen. Their mechanism of action is not completely understood, but they are thought to act like alkylating agents. These drugs are used intravenously. They distribute to most tissues and are cleared in unchanged form by the kidney. Cisplatin is commonly used as a component of regimens for cancers of the testicle, bladder, lung, and ovary. Carboplatin has similar uses. Oxaliplatin has activity against colorectal cancer. Their toxicities are listed in Table 31–2. In the case of cisplatin, drug-induced renal damage may be reduced by the use of mannitol (an osmotic diuretic) and forced hydration. Carboplatin and oxaliplatin are less nephrotoxic than cisplatin, but they are more neurotoxic and have greater myelosuppressant actions.

Procarbazine

Procarbazine is orally active and penetrates into most tissues, including the cerebrospinal fluid. The drug is eliminated via hepatic metabolism. Procarbazine forms hydrogen peroxide, which generates free radicals that cause DNA strand scission (breaks). The drug is used as a component of regimens for Hodgkin’s disease and non-Hodgkin’s lymphomas (common cancers of lymphatic tissue) and for some brain tumors. Procarbazine has multiple toxicities, including peripheral neuropathy and skin reactions. Procarbazine also inhibits many enzymes, including monoamine oxidase and those involved in hepatic drug metabolism. Disulfiram-like reactions have occurred with ethanol.

Other Alkylating Agents

Busulfan is sometimes used in chronic myelogenous leukemia. Carmustine and lomustine are highly lipid-soluble drugs used as adjuncts in the management of brain tumors. Dacarbazine is used in regimens for Hodgkin’s disease. Additional toxicities include skin rash, phototoxicity, and a flu-like syndrome.

Antimetabolites

Antimetabolites used in cancer are structurally similar to endogenous compounds that are important in rapidly dividing cells. They include antagonists of folic acid (methotrexate), purines (mercaptopurine, thioguanine), and pyrimidines (fluorouracil, cytarabine). Antimetabolites are CCSdrugs that act primarily in the S phase of the cell cycle (Figure 31–2). Their sites of action on DNA synthetic pathways are shown in Figure 31–3. In addition to cytotoxic effects on neoplastic cells, the antimetabolites also have immunosuppressant effects (Chapter 32). Commonly used antimetabolites and delayed toxicities of these drugs are presented in Table 31–3.

Methotrexate

Both oral and intravenous administration of methotrexate afford good tissue distribution except to the CNS. Methotrexate is not metabolized, and its clearance is dependent on renal function. Adequate hydration is needed to prevent crystallization in renal tubules. Methotrexate acts as an inhibitor of dihydrofolate reductase. This action decreases synthesis of thymidylate, purine nucleotides, and several amino acids, thus interfering with nucleic acid and protein metabolism. The formation of polyglutamate derivatives of methotrexate appears to be important for cytotoxic actions. Tumor cell resistance mechanisms include decreased drug accumulation, changes in the activity of dihydrofolate reductase or its drug sensitivity, and decreased formation of polyglutamates. Clinically, methotrexate is effective in choriocarcinoma, acute leukemias, non-Hodgkin’s and cutaneous T-cell lymphomas, and breast cancer. Methotrexate is also used as an immune suppressant in rheumatoid arthritis, psoriasis, and transplant rejection. In combination with mifepristone, it is an effective abortifacient. The most common toxicities are listed in Table 31–3. Long-term use of methotrexate has caused hepatotoxicity and pulmonary infiltrates and fibrosis. Salicylates, nonsteroidal anti-inflammatory drugs, sulfonamides, and sulfonylureas enhance the toxicity of methotrexate.

Mercaptopurine and Thioguanine

Both mercaptopurine (6-MP) and thioguanine (6-TG) have low oral bioavailability because of first-pass metabolism. Mercaptopurine and thioguanine act as purine antimetabolites. Both drugs are activated by hypoxanthine-guanine phosphoribosyltransferases (HGPRTases) to toxic nucleotides that inhibit several enzymes involved in purine metabolism. Resistant tumor cells may have decreased HGPRTase activity, or they may have increased production of alkaline phosphatases that inactivate the toxic nucleotides. Clinical uses of these purine antimetabolites are mainly in the acute leukemias and chronic myelocytic leukemia. Bone marrow suppression is the dose-limiting toxicity. Hepatic dysfunction includes cholestasis, jaundice, and necrosis. The metabolism of 6-MP by xanthine oxidase is inhibited by allopurinol, a drug used in the treatment of gout (Chapter 34).

Fluorouracil

When given intravenously, fluorouracil (5-FU) is widely distributed, including into the cerebrospinal fluid. Elimination is mainly by metabolism. Fluorouracil is converted in cells to 5-fluoro-2′-deoxyuridine-5′-monophosphate, which inhibits thymidylate synthase and leads to “thymineless death” of cells. Resistance mechanisms include decreased activation of 5-FU, increased thymidylate synthase activity, and reduced drug sensitivity of this enzyme. Fluorouracil is used clinically in bladder, breast, colon, head and neck, liver, and ovarian cancers. The drug is also used topically for keratoses and superficial basal cell carcinoma. In addition to the toxicities listed in Table 31–3, alopecia may occur.

Cytarabine

Cytabarine (cytosine arabinoside, ARA-C) is used parenterally and (with slow intravenous infusion) may reach appreciable levels in the cerebrospinal fluid. Cytarabine is eliminated via hepatic metabolism. Cytarabine acts as a pyrimidine antimetabolite; it is activated by kinases to ara-cytidine triphosphate (AraCTP), an inhibitor of DNA polymerases. Of all the antimetabolites, cytarabine is the most specific for the S phase of the tumor cell cycle. Resistance to cytarabine can occur as a result of decreased uptake or decreased conversion to AraCTP. Clinically, cytarabine is a major drug for the treatment of acute myelogenous leukemia. Neurotoxicity is associated with high doses and includes cerebellar dysfunction and peripheral neuritis.

Plant Alkaloids

These important CCSdrugs include vinca alkaloids (vinblastine, vincristine), podophyllotoxins (etoposide, teniposide), camptothecins (topotecan, irinotecan), and taxanes (paclitaxel, docetaxel). These drugs act in S, G2, and M phases of the cell cycle (Figure 31–2). The acute and delayed toxicities associated with these anticancer drugs are presented in Table 31–4.

Vinblastine, Vincristine, and Vinorelbine

Vinblastine and vincristine are natural alkaloids, whereas vinorelbine is semisynthetic. These drugs are given parenterally. They penetrate most tissues, but not the cerebrospinal fluid, and are cleared mainly via biliary excretion. These agents block mitotic spindle formation by preventing the assembly of tubulin dimers into microtubules. They act primarily in the M phase of the cell cycle. Resistance can occur from increased drug efflux from tumor cells via overexpression of membrane drug transporters. Clinically, vincristine is used in acute leukemias, lymphomas, Wilms’ tumor, and choriocarcinoma. Vinblastine is used for lymphomas, neuroblastoma, testicular carcinoma, and Kaposi’s sarcoma. Vinorelbine is used mainly in lung and breast cancers.

Etoposide and Teniposide

Etoposide and teniposide are extracted from the root of the May apple plant. They are usually used parenterally, but etoposide is also well absorbed after oral administration and distributes to most tissues. Elimination is mainly via the kidneys, and dose reductions should be made in patients with renal impairment. Their mechanisms of action are similar: they increase DNA degradation (possibly via interaction with topoisomerase II) and inhibit mitochondrial electron transport. The drugs are most active in the late S and early G2 phases of the cell cycle. Clinically, these drugs are used in combination drug regimens for therapy of lung (small cell), prostate, and testicular carcinomas. The toxicities of etoposide and teniposide are similar.

Topotecan and Irinotecan

Topotecan inhibits the activity of topoisomerase I, the key enzyme responsible for cutting and religating (i.e., joining) single DNA strands, processes that are essential for normal DNA replication and repair. Inhibition of topoisomerase I results in DNA damage. Topotecan is indicated in the treatment of patients with advanced ovarian cancer and small cell lung cancer. The main route of elimination is renal excretion, and dosage reduction is required in patients with abnormal renal function. Irinotecan is a prodrug converted by the liver into an active metabolite that is also a potent inhibitor of topoisomerase I. Irinotecan is indicated in metastatic colorectal cancer. Diarrhea associated with irinotecan therapy can be severe, leading to significant electrolyte imbalance and dehydration.

Paclitaxel and Docetaxel

Although paclitaxel and docetaxel were originally extracted from the bark of the yew tree, these taxanes are now produced synthetically. Paclitaxel and docetaxel are given intravenously. The mechanism of action is interference with the mitotic spindle. In contrast to vinca alkaloids, taxanes prevent microtubule disassembly into tubulin monomers. Clinical uses include treatment for several solid tumors, including advanced breast and ovarian cancers. The toxicities of these drugs are not identical to each other (Table 31–4).

Antibiotics

This category of antineoplastic drugs comprises several structurally dissimilar agents, including doxorubicin,daunorubicin, bleomycin, dactinomycin, and mitomycin. A major mechanism of action of these antibiotics is binding to DNA through intercalation between specific bases. This results in blocking synthesis of RNA, DNA, or both and DNA strand scission, thus interfering with cell replication. Acute and delayed toxicities associated with these anticancer drugs are listed in Table 31–5.

Bleomycin

Bleomycin is a mixture of glycopeptides that must be given parenterally. The drug is inactivated by tissue aminopeptidases, but some renal clearance of intact drug also occurs. Bleomycin generates free radicals that bind to DNA, causing strand breaks and inhibiting DNA replication. Bleomycin is a CCS drug active in the G2 phase of the tumor cell cycle (Figure 31–2). Clinically, bleomycin is an important component of drug regimens for Hodgkin’s disease and testicular cancer. The drug is also used for treatment of non-Hodgkin’s lymphomas and for squamous cell carcinomas. Pulmonary fibrosis develops slowly, but is the dose-limiting toxicity. Hypersensitivity manifestations are common and include chills, fever, and anaphylaxis. Mucocutaneous reactions are also common and include alopecia, blister formation, and hyperkeratosis.

Doxorubicin, Daunorubicin, and Idarubicin

Doxorubicin and daunorubicin must be given intravenously. They are metabolized in the liver, and the products are excreted in the bile and urine. These anthracyclines have multiple mechanisms of action, including intercalation between base pairs in DNA, inhibition of topoisomerase II, and generation of free radicals. As a result, they block DNA and RNA synthesis and cause DNA strand scission. Membrane disruption also occurs. The anthracyclines are CCNSdrugs. Clinically, doxorubicin is used in Hodgkin’s disease, myelomas, sarcomas, and breast, endometrial, lung, ovarian, and thyroid cancers. The main use of daunorubicin is in the treatment of acute leukemias. Idarubicin, a newer anthracycline, is approved for use in acute myelogenous leukemia. These drugs demonstrate similar toxicities, including gastrointestinal distress and severe alopecia. Cardiotoxicity includes initial electrocardiographic abnormalities, with the possibility of arrhythmias, and a cumulative dose-dependent, slowly developing cardiomyopathy and congestive heart failure. Dexrazoxane, an inhibitor of iron-mediated free radical generation, may protect against cardiotoxicity. Liposomal formulations of doxorubicin may be less cardiotoxic.

Dactinomycin

Dactinomycin must be given parenterally. Intact drug and metabolites are excreted in the bile. Dactinomycin is a CCNS drug that binds to double-stranded DNA and inhibits DNA-dependent RNA synthesis. Clinically, dactinomycin is used in melanoma and Wilms’ tumor.

Mitomycin

Mitomycin is given intravenously and is rapidly cleared via hepatic metabolism. The drug is a CCNS agent that is converted by liver enzymes to an alkylating agent that cross-links DNA. Mitomycin is used occasionally in combination regimens for adenocarcinomas of the cervix, stomach, pancreas, and lung. Myelosuppression is severe, and the drug is toxic to the heart, liver, lung, and kidney.

Hormonal Anticancer Agents

Many of these drugs are discussed in other chapters and are mentioned here only in relation to their clinical application in cancer chemotherapy. The toxicities associated with the hormonally active anticancer drugs are presented in Table 31–6.

Gonadal Hormone Antagonists

Breast cancer and prostate cancer, two common neoplasms, are usually present in a hormone dependent form. Agents that inhibit estrogen or progesterone synthesis or the receptors for these ligands are extremely useful in many patients with breast cancer. Similarly, antiandrogenic drugs have proven to be useful in men with advanced prostate cancer.

Tamoxifen, a selective estrogen receptor modulator (Chapter 22), acts as an estrogen antagonist in estrogen-sensitive breast cancer cells. It is used in estrogen receptor–positive breast carcinoma. Women with a strong family history of breast cancer are at high risk for breast cancer. Because tamoxifen appears to have a preventive effect in women at high risk for breast cancer, it is now approved as a chemopreventive agent in this population. Toremifene is a newer estrogen receptor antagonist that is used in advanced breast cancer.

Flutamide is an androgenreceptor antagonist used in prostatic carcinoma. Bicalutamide and nilutamide are similar in mechanism and application. These drugs are often used in combination with the gonadotropin-releasing hormone (GnRH) analogs (see below) to prevent the initial tumor flare (i.e., short-lived increase in tumor growth and symptoms) caused by GnRH, and to prevent the action of androgens produced by extragonadal tissues. For additional information, see Chapter 22.

Gonadotropin-Releasing Hormone Analogs

Leuprolide, goserelin, andnafarelin are GnRH agonists (Chapter 22) that are effective in advanced prostatic carcinoma. When administered in constant doses to maintain stable blood levels, they inhibit release from the pituitary of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). As a result, androgen production drops to castration levels and tumor growth may be slowed.

Synthesis Inhibitors

Aminoglutethimide, anastrozole, exemestane, and letrozole inhibit steroid synthesis. Whereas aminoglutethimide inhibits synthesis of all steroid hormones, the other agents inhibit aromatase, the enzyme that converts precursor steroids into estrogens. Aromatase inhibitors are used commonly now in the treatment of estrogen receptor-positive breast cancer. Aminoglutethimide is used for some cases of metastatic breast cancer or advanced prostate cancer.

Glucocorticoids

Glucocorticoids are useful in the treatment of acute leukemia, lymphoma, multiple myeloma, and other hematologic malignancies as well as in advanced breast cancer. Anticancer actions probably involve multiple mechanisms. In addition, they are effective as supportive therapy in the management of cancer-related hypercalcemia. Prednisone is the most commonly used glucocorticoid in cancer chemotherapy. For additional information, see Chapter 23.

Miscellaneous Anticancer Agents

Additional anticancer drugs not associated with the previous drug classes are presented below, and their acute and delayed toxicities are listed in Table 31–7.

Asparaginase

Asparaginase is an enzyme that depletes serum asparagine by hydrolyzing circulating l-asparagine to aspartic acid and ammonia. The drug is used in the treatment of T-cell auxotrophic cancers (certain pediatric leukemias and lymphomas) that require exogenous asparagine for growth. Asparaginase is given intravenously.

Imatinib

Imatinib is an example of a selective anticancer drug whose development was guided by knowledge of a specific oncogene. Imatinib inhibits tyrosine kinase activity of the protein product of the BCR-ABL oncogene that is commonly expressed in chronic myelogenous leukemia (CML). Durable remissions and apparent cures have occurred in patients treated with this drug. Resistance may occur because of mutation of the BCR-ABL gene. Imatinib is also effective for treatment of gastrointestinal stromal tumors that express the c-kit tyrosine kinase.

Monoclonal Antibodies

Trastuzumab is a monoclonal antibody that binds to a surface growth factorreceptor protein on cells that overexpress the human epidermal growth factor receptor-2 (HER2) gene in advanced breast cancers. Binding of trastuzumab to the HER2 receptor causes receptor uptake into the cell, thereby preventing receptors from being activated by the circulating ligand. Acute toxicity includes nausea and vomiting, chills, fevers, and headache. Rituximab is a monoclonal antibody with high affinity for a surface protein in non-Hodgkin’s lymphoma cells. The drug is currently used with conventional anticancer drugs (e.g., cyclophosphamide plus vincristine plus prednisone) in some types of lymphomas. Use of rituximab is associated with hypersensitivity reactions and myelosuppression.

Interferons

The interferons are endogenous glycoproteins with antineoplastic, immunosuppressive, and antiviral actions. Alpha interferons (Chapter 32) are effective against a number of neoplasms, including hairy cell leukemia, early-stage CML, and T-cell lymphomas. Toxic effects of the interferons include myelosuppression and neurologic dysfunction.

The Log-Kill Hypothesis

Patients with widespread cancer may have up to 1012 tumor cells throughout the body at the time of diagnosis (Figure 31–4). If an effective anticancer drug kills 103-fold (99.9%) of these tumor cells, treatment would induce a clinical remission associated with major symptomatic improvement and the number of tumor cells would be reduced 1,000-fold from 1012 to 109. Cytotoxic drugs act with first-order kinetics. That is, a given dose kills a constant proportion of a cell population rather than a constant number of cells. The log-kill hypothesis proposes that the magnitude of tumor cells killed by anticancer drugs is a logarithmic function. In the previous example, a 3-log-kill dose of an effective drug reduced the cancer cell population from 1012 cells to 109. This resulted from a total kill of 999 × 109 cells. The same dose would reduce a starting population of 106 cells to 103 cells. This would represent a kill of 999 × 103 cells. In both cases, the dose reduces the numbers of cells by 3 orders of magnitude, or “3 logs.” The remaining cells might be inherently resistant to the drug, may reside in a pharmacologic sanctuary such as the central nervous system, or may have been in an insensitive stage of the cell cycle.

The relationship of the number of tumor cells to the time of diagnosis, symptoms, treatment, and death is presented in Figure 31–4. The value of repeated courses of anticancer treatment at intervals shorter than the time for tumor regrowth is indicated by comparing the middle treatment regimen to the upper treatment regimen. The middle treatment regimen also documents the value of earlier diagnosis, when there are fewer cancer cells. Finally, the lower treatment regimen illustrates the value of combining various therapeutic modalities such as surgery and anticancer drug regimens to decrease the number of neoplastic cells.

Principles of Combination Therapy

Anticancer drugs found to be effective in various neoplasms are summarized in Table 31–8. Clinically, combinations of different anticancer drugs are often used. Chemotherapy with combinations of anticancer drugs usually increases log-kill markedly, and in some cases synergistic effects are achieved. Synergyoccurs when the effect of two different anticancer drugs is greater than the sum of the effects of each drug individually. Drug combinations are often cytotoxic to a heterogeneous population of cancer cells, and may prevent development of resistant clones. Drug combinations that include CCS and CCNS drugs may be cytotoxic to both dividing and resting cancer cells. Four principles are important for selecting appropriate drugs to use in combination chemotherapy. First, each drug should be active when used alone against the particular cancer. Second, the drugs should have different mechanisms of action. Third, cross-resistance between drugs should be minimal. Finally, the drugs should have different toxic effects.

Additional Strategies for Cancer Chemotherapy

Pulse Therapy

Pulse therapy involves intermittent treatment with high doses of an anticancer drug—doses that are too toxic to be used continuously. Intensive pulse therapy every 3 to 4 weeks allows for maximum effects on neoplastic cells, with hematologic and immunologic recovery between courses. This type of regimen is used successfully in therapy of acute leukemias, testicular carcinomas, and Wilms’ tumor.

Recruitment and Synchrony

The strategy of recruitment involves initial use of a CCNSdrug to achieve a significant log-kill, which results in recruitment into cell division of cells previously resting in the G0 phase of the cell cycle. Subsequent administration of a CCS drug that is active against dividing cells may then achieve maximal cell kill. A similar approach involves synchrony. One example is the use of vinca alkaloids to hold cancer cells in the M phase. Subsequent treatment with another CCS drug, such as the S phase–specific agent cytarabine, may result in a greater killing effect on the neoplastic cell population.

Rescue Therapy

Toxic effects of anticancer drugs can sometimes be alleviated by a rescue strategy. This involves the administration of essential metabolites to counteract the effects of anticancer drugs on normal (nonneoplastic) cells. For example, high doses of methotrexate may be given for 36 to 48 hours and terminated before severe toxicity occurs in cells of the gastrointestinal tract and bone marrow. Leucovorin (formyl tetrahydrofolate), which is accumulated more readily by normal than by neoplastic cells, is then administered. This results in rescue (“leucovorin rescue”) of the normal cells because leucovorin bypasses the dihydrofolate reductase step in folic acid synthesis. Mercaptoethanesulfonate (mesna) “traps” acrolein released from cyclophosphamide and thus reduces the incidence of hemorrhagic cystitis. Dexrazoxane inhibits free radical formation and affords protection against the cardiac toxicity of anthracyclines (e.g., doxorubicin).

The role of physical therapy and conditioning in patients undergoing chemotherapy has increased in importance in recent years. Rehabilitation programs are an integral component in the overall treatment regimen in this patient population. Research has documented that all patient populations benefit from these programs regardless of the type of cancer, gender, or age of the patients.

If possible, the rehabilitation program should begin prior to initiating cancer treatment. A reduced intensity program should occur during the “on phase” of cancer treatment. The on phase is when the patient is receiving chemotherapy, radiation, or surgical procedures. This phase of the program may occur in the hospital, outpatient clinic, or at home. During the “off phase” of the cancer treatment regimen, goals for increasing muscle force and aerobic capacity should be set to counteract the deterioration that often occurs during the on phase.

Although these rehabilitation programs require individualization, certain components should be included for optimal outcomes. First, the program should have both aerobic and resistive exercise components. Maintaining flexibility through active and passive range of motion and stretching is also critical. Range of motion is especially important when edema is a problem, such as in surgical or radiologic procedures for breast cancer. These programs should be conducted every day or every other day during both on and off phases. They should be continued for 6 to 8 weeks following the last on phase of the regimen.

Rehabilitation programs have multiple benefits for cancer patients. They assist in maintaining cardiovascular and pulmonary function, as well as general aerobic capacity. Research indicates that moderate fatigue associated with rehabilitation programs improves patients’ capacity to withstand pain, fatigue, and other adverse effects of anticancer regimens.

Patients participating in rehabilitation also receive psychologic benefits, as documented by improvements in various quality of life (QOL) surveys. In these patients, improvement in depression is proportional to improvement in QOL assessments and functional capacity.

Finally, careful evaluation of all patients should be conducted as pain and dysfunction associated with cancer may have musculoskeletal manifestations. For example, lung cancer with metastases to the lower thoracic or lumbar spine may present similarly to musculoskeletal low back pain.

Adverse Drug Reactions

• • Nausea and vomiting
• • Fatigue
• • Decreased blood cell components (may include any or all of the following):
  • • White blood cells (leukopenia)
  • • Red blood cells (anemia)
  • • Platelets (thrombocytopenia)

Effects Interfering with Rehabilitation

• • Decreased wound healing
• • Increased risk of infection
• • Decreased exercise endurance

Possible Therapy Solutions

• • Develop exercise regimen to increase endurance

Brief History: The patient is a 42-year-old male with chronic myelogenous leukemia. He was referred to a major research hospital for full myeloablative (bone marrow–destroying) therapy and fractionated total body irradiation plus intravenous melphalan, followed by autologous hematopoietic cell transplantation. The on phase of the treatment was performed while the patient stayed at the hospital in an apartment provided onsite. The hospital has an established rehabilitation program to assist in maintaining function and overall health during this treatment regimen.

Current Medical Status and Drug Therapy: The patient completed the myeloablative therapy prior to receiving the autologous hematopoietic cells and cytokines to stimulate myelopoietic, erythrocyte, and platelet formation. Rehabilitation activities began at this time.

Rehabilitation Setting: The patient is complaining of nausea and vomiting and is receiving prednisolone for these adverse effects of the cancer regimen. He is also complaining of arthralgia and myalgia resulting from stimulation of hematopoietic activity. Owing to his decreased immunocompetence, the patient is treated individually. As immunocompetence improves, the patient will be allowed to interact with other individuals in the hospital.

Problem/Clinical Options: A rehabilitation program that incorporates maintaining functional capacity while relieving pain associated with the oncology treatment regimen is developed. Because of the patient’s immunocompromised state, initial rehabilitation activities are conducted individually in the onsite apartment. Aerobic activities are limited to bed to chair and other transfers with limited ambulation on level surfaces with an ambulation device when required. The patient’s hematocrit is also low, so he has minimal aerobic capacity. Active and passive range of motion (ROM) and stretching are conducted to maintain ROM. Modalities are incorporated to relieve pain. As immunocompetence and hematocrit improve, rehabilitation activities are continued in a common room where other patients undergoing cancer treatment are participating in conditioning programs. The rehabilitation program now includes active stretching to warm up, light weights for resistive training, followed by aerobic activity on a recumbent bicycle. At discharge, the patient is referred to a hospital-based outpatient clinic for supervision and progression of the rehabilitation program during the off phase of the cancer treatment regimen.

The reader is referred to the manufacturers’ literature for the most recent information.