Acronyms

ABVD Doxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazine

CHOP Cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), prednisone

CMF Cyclophosphamide, methotrexate, fluorouracil

COP Cyclophosphamide, vincristine (Oncovin), prednisone

FAC Fluorouracil, doxorubicin (Adriamycin), cyclophosphamide

FEC Fluorouracil, epirubicin, cyclophosphamide

5-FU 5-Fluorouracil

FOLFIRI Fluorouracil, leucovorin, irinotecan

FOLFOX Fluorouracil, leucovorin, oxaliplatin

MP Melphalan, prednisone

6-MP 6-Mercaptopurine

MOPP Mechlorethamine, vincristine (Oncovin), procarbazine, prednisone

MTX Methotrexate

PCV Procarbazine, lomustine, vincristine

PEB Cisplatin (platinum), etoposide, bleomycin

6-TG 6-Thioguanine

VAD Vincristine, doxorubicin (Adriamycin), dexamethasone

XELOX Capecitabine, oxaliplatin

Case Study 1

A 55-year-old man presents with increasing fatigue, 15-pound weight loss, and a microcytic anemia. Colonoscopy identifies a mass in the ascending part of the colon, and biopsy reveals well-differentiated colon cancer. He is found to have stage III colon cancer and he undergoes surgical resection. What is this patient's prognosis? Should he receive adjuvant chemotherapy? The patient receives a combination of 5-fluorouracil, leucovorin, and oxaliplatin for his adjuvant therapy. One week after receiving his first cycle of therapy, he experiences significant toxicity in the form of myelosuppression, diarrhea, and altered mental status. What is the most likely explanation for this increased level of toxicity?

Case Study 2

A 28-year-old woman presents with a 1-cm mass in the right supraclavicular fossa. Biopsy reveals nodular sclerosing Hodgkin's disease, and careful staging suggests stage III disease. What drugs are useful in Hodgkin's lymphoma? What is her prognosis with optimal chemotherapy? What are some of the potential long-term consequences of chemotherapy and how might this affect treatment decisions?

Cancer Chemotherapy: Introduction

In 2008, cancer was the second leading cause of mortality from disease in the USA, causing over 500,000 deaths. Cancer is a disease characterized by a loss in the normal control mechanisms that govern cell survival, proliferation, and differentiation. Cells that have undergone neoplastic transformation usually express cell surface antigens that may be of normal fetal type, may display other signs of apparent immaturity, and may exhibit qualitative or quantitative chromosomal abnormalities, including various translocations and the appearance of amplified gene sequences. It is now well-established that a small subpopulation of cells, referred to as tumor stem cells, reside within a tumor mass. They retain the ability to undergo repeated cycles of proliferation as well as to migrate to distant sites in the body to colonize various organs in the process called metastasis. Such tumor stem cells thus can express clonogenic (colony-forming) capability, and they are characterized by chromosome abnormalities reflecting their genetic instability, which leads to progressive selection of subclones that can survive more readily in the multicellular environment of the host. This genetic instability also allows them to become resistant to chemotherapy and radiotherapy. The invasive and metastatic processes as well as a series of metabolic abnormalities associated with the cancer result in tumor-related symptoms and eventual death of the patient unless the neoplasm can be eradicated with treatment.

Causes of Cancer

The incidence, geographic distribution, and behavior of specific types of cancer are related to multiple factors, including sex, age, race, genetic predisposition, and exposure to environmental carcinogens. Of these factors, environmental exposure is probably most important. Exposure to ionizing radiation has been well documented as a significant risk factor for a number of cancers, including acute leukemias, thyroid cancer, breast cancer, lung cancer, soft tissue sarcoma, and basal cell skin cancers. Chemical carcinogens (particularly those in tobacco smoke) as well as azo dyes, aflatoxins, asbestos, benzene, and radon have all been well documented as leading to cancer in animals and humans.

Several viruses  have been implicated in the etiology of various human cancers. For example, hepatitis B and hepatitis C are associated with the development of hepatocellular cancer; HIV is associated with Hodgkin's and non-Hodgkin's lymphomas; human papillomavirus is associated with cervical cancer; and Ebstein-Barr virus is associated with nasopharyngeal cancer. Expression of virus-induced neoplasia may also depend on additional host and environmental factors that modulate the transformation process. Cellular genes are known that are homologous to the transforming genes of the retroviruses, a family of RNA viruses, and induce oncogenic transformation. These mammalian cellular genes, known as oncogenes,  have been shown to code for specific growth factors and their corresponding receptors. These genes may be amplified (increased number of gene copies) or mutated, both of which can lead to constitutive overexpression in malignant cells. The bcl-2 oncogene may be a generalized pro-survival gene that directly inhibits apoptosis, a key pathway of programmed cell death.

Another class of genes, known as tumor suppressor genes,  may be deleted or mutated, which gives rise to the neoplastic phenotype. The p53 gene is the best-established tumor suppressor gene identified to date, and the normal wild-type gene appears to play an important role in suppressing neoplastic transformation. Of note, p53 is mutated in up to 50% of all human solid tumors, including liver, breast, colon, lung, cervix, bladder, prostate, and skin.

Cancer Treatment Modalities

With present methods of treatment, about one third of patients are cured with local treatment strategies, such as surgery or radiotherapy, when the tumor remains localized at the time of diagnosis. Earlier diagnosis might lead to increased cure rates with such local treatment; however, in the remaining cases, early micrometastasis is a characteristic feature of these neoplasms, indicating that a systemic approach with chemotherapy is required for effective cancer management. In patients with locally advanced disease, chemotherapy is often combined with radiotherapy to allow for surgical resection to take place, and such a combined modality approach has led to improved clinical outcomes. At present, about 50% of patients who are initially diagnosed with cancer can be cured. In contrast, chemotherapy alone is able to cure only about 10–15% of all cancer patients.

Chemotherapy is presently used in three main clinical settings: (1) primary induction treatment for advanced disease or for cancers for which there are no other effective treatment approaches, (2) neoadjuvant treatment for patients who present with localized disease, for whom local forms of therapy such as surgery or radiation, or both, are inadequate by themselves, (3) adjuvant treatment to local methods of treatment, including surgery or radiation therapy, or both.

Primary induction chemotherapy refers to drug therapy administered as the primary treatment in patients who present with advanced cancer for which no alternative treatment exists. This has been the mainstay approach in treating patients with advanced metastatic disease, and in most cases, the goals of therapy are to palliate tumor-related symptoms, improve overall quality of life, and prolong time to tumor progression. Studies in a wide range of solid tumors have shown that chemotherapy in patients with advanced disease confers survival benefit when compared with supportive care, providing sound rationale for the early initiation of drug treatment. However, cancer chemotherapy can be curative in a small subset of patients who present with advanced disease. In adults, these curable cancers include Hodgkin's and non-Hodgkin's lymphoma, acute myelogenous leukemia, germ cell cancer, and choriocarcinoma, while the curable childhood cancers include acute lymphoblastic leukemia, Burkitt's lymphoma, Wilms' tumor, and embryonal rhabdomyosarcoma.

Neoadjuvant chemotherapy refers to the use of chemotherapy in patients who present with localized cancer for which alternative local therapies, such as surgery, exist but for which they are less than completely effective. At present, neoadjuvant therapy is most often administered in the treatment of anal cancer, bladder cancer, breast cancer, esophageal cancer, laryngeal cancer, locally advanced non-small cell lung cancer, and osteogenic sarcoma. For some of these diseases, such as anal cancer, gastroesophageal cancer, laryngeal cancer, and non-small cell lung cancer, optimal clinical benefit is derived when chemotherapy is administered with radiation therapy either concurrently or sequentially.

One of the most important roles for cancer chemotherapy is as an adjuvant to local treatment modalities such as surgery or radiation therapy, and this has been termed adjuvant chemotherapy. The goal of chemotherapy in this situation is to reduce the incidence of both local and systemic recurrence and to improve the overall survival of patients. In general, chemotherapy regimens with clinical activity against advanced disease may have curative potential following surgical resection of the primary tumor, provided the appropriate dose and schedule are administered. Adjuvant chemotherapy is effective in prolonging both disease-free survival (DFS) and overall survival (OS) in patients with breast cancer, colon cancer, gastric cancer, non-small cell lung cancer, Wilms' tumor, anaplastic astrocytoma, and osteogenic sarcoma. Patients with primary malignant melanoma at high risk of metastases derive clinical benefit from adjuvant treatment with the biologic agent -interferon, although this treatment must be given for 1 year's duration for maximal clinical efficacy. Finally, the antihormonal agents tamoxifen, anastrozole, and letrozole are effective in the adjuvant therapy of postmenopausal women with early-stage breast cancer whose breast tumors express the estrogen receptor (see Chapter 40 for additional detail). However, because these agents are cytostatic rather than cytocidal, they must be administered on a long-term basis, with the standard recommendation being 5 years' duration.

Role of Cell Cycle Kinetics & Anticancer Effect

The key principles of cell cycle kinetics were initially developed using the murine L1210 leukemia as the experimental model system (Figure 54–1). However, drug treatment of human cancers requires a clear understanding of the differences between the characteristics of this rodent leukemia and of human cancers, as well as an understanding of the differences in growth rates of normal target tissues between mice and humans. For example, L1210 is a rapidly growing leukemia with a high percentage of cells synthesizing DNA, as measured by the uptake of tritiated thymidine (the labeling index). Because L1210 leukemia has a growth fraction of 100% (ie, all its cells are actively progressing through the cell cycle), its life cycle is consistent and predictable. Based on the murine L1210 model, the cytotoxic effects of anticancer drugs follow log cell kill kinetics. In general, a given agent would be predicted to kill a constant fraction of cells as opposed to a constant number. Thus, if an individual drug leads to a 3 log kill of cancer cells and reduces the tumor burden from 10¹⁰ to 10⁷ cells, the same dose used at a tumor burden of 10⁵ cells reduces the tumor mass to 10² cells. Cell kill is, therefore, proportional, regardless of tumor burden. The cardinal rule of chemotherapy—the invariable inverse relation between cell number and curability—was established with this model, and this relationship is applicable to other hematologicmalignancies.

Although growth of murine leukemias simulates exponential cell kinetics, mathematical modeling data suggest that most human solid tumors do not grow in such an exponential manner. Taken together, the experimental data in human solid cancers support a Gompertzian model of tumor growth and regression. The critical distinction between Gompertzian and exponential growth is that in Gompertzian kinetics, the growth fraction of the tumor is not constant but decreases exponentially with time (exponential growth is matched by exponential retardation of growth, due to blood supply limitations and other factors). The growth fraction peaks when the tumor is approximately 37% of its maximum size. Under the Gompertzian model, when a patient with advanced cancer is treated, the tumor mass is larger, its growth fraction is low, and the fraction of cells killed is, therefore, small. An important feature of Gompertzian growth is that response to chemotherapy in drug-sensitive tumors depends, in large measure, on where the tumor is in its particular growth curve.

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.

With rare exceptions (eg, choriocarcinoma and Burkitt's lymphoma), single drugs at clinically tolerable doses have been unable to cure cancer. In the 1960s and early 1970s, drug combination regimens were developed based on the known biochemical actions of available anticancer 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 hematologicmalignancies, combination chemotherapy was extended to the treatment of solid tumors.

The Role of Drug Combinations

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 or slow the subsequent development of cellular drug resistance. The same principles apply to the therapy of several chronic infections, eg, 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 be somewhat effective against the same tumor when used alone 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: In addition, 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 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.      Avoidance of arbitrary dose changes: An arbitrary reduction in the dose of an effective drug in order to add other less effective drugs may reduce the dose of the most effective agent below the threshold of effectiveness and destroy the ability of the combination to cure disease in a given patient.

Dosage Factors

One of the main factors limiting the ability of chemotherapy or radiation therapy to achieve cure is the problem of effective dosing. The dose-response curve in biologic systems is usually sigmoidal in shape, with a threshold, a linear phase, and a plateau phase. For chemotherapy, therapeutic selectivity is dependent on the difference between the dose-response curves of normal and tumor tissues. In experimental animal models, the dose-response curve is usually steep in the linear phase, and a reduction in dose when the tumor is in the linear phase of the dose-response curve almost always results in a loss in the capacity to cure the tumor effectively before a reduction in the antitumor activity is observed. Although complete remissions continue to be observed with dose reduction as low as 20%, residual tumor cells may not be entirely eliminated, thereby allowing for eventual relapse. Because anticancer drugs are associated with toxicity, it is often appealing for clinicians to avoid acute toxicity by simply reducing the dose or by increasing the time interval between each cycle of treatment. However, such empiric modifications in dose represent a major cause of treatment failure in patients with drug-sensitive tumors.

A positive relationship between dose intensity and clinical efficacy has been documented in several solid tumors, including advanced ovarian, breast, lung, and colon cancers, as well as in hematologic malignancies, including the lymphomas. At present, there are three main approaches to dose-intense delivery of chemotherapy. The first approach is by dose escalation whereby the doses of the anticancer agents are increased. The second strategy is to administer anticancer agents in a dose-intense manner by reducing the interval between treatment cycles, while the third approach involves sequential scheduling of either single agents or of combination regimens. Each of these strategies is presently being applied to a wide range of cancers, and in general, such dose-intense regimens have significantly improved clinical outcomes.

Drug Resistance

A fundamental issue in cancer chemotherapy is the development of cellular drug resistance. Some tumor types, eg, malignant melanoma, renal cell cancer, and brain cancer, exhibit primary resistance, ie, absence of response on the first exposure, to currently available agents. The presence of inherent drug resistance is thought to be tightly associated with the genomic instability associated with the development of most cancers. For example, mutations in the p53 tumor suppressor gene occur in at least 50% of all human tumors. Preclinical and clinical studies have shown that loss of p53 function leads to resistance to radiation therapy as well as to resistance to a wide range of anticancer agents. Defects in the mismatch repair enzyme family, which are tightly linked to the development of familial and sporadic colorectal cancer, gives rise to resistance to unrelated anticancer agents, including the fluoropyrimidines, the thiopurines, and cisplatin/carboplatin. In contrast to primary resistance, acquired resistance develops in response to exposure to a given anticancer agent. Experimentally, drug resistance can be highly specific to a single drug and is usually based on a specific change in the genetic machinery of a given tumor cell with amplification or increased expression of one or more genes. In other instances, a multidrug-resistant phenotype occurs, associated with increased expression of the MDR1 gene, which encodes a cell surface transporter glycoprotein (P-glycoprotein, see Chapter 1). This form of drug resistance leads to enhanced drug efflux and reduced intracellular accumulation of a broad range of structurally unrelated anticancer agents, including the anthracyclines, vinca alkaloids, taxanes, camptothecins, epipodophyllotoxins, and even small molecule inhibitors, such as imatinib.

Basic Pharmacology of Cancer Chemotherapeutic Drugs

Alkylating Agents

The major clinically useful alkylating agents (Figure 54–3) have a structure containing a bis(chloroethyl)amine, ethyleneimine, or nitrosourea moiety. Among the bis(chloroethyl)amines, cyclophosphamide, mechlorethamine, melphalan, and chlorambucil are the most useful. Ifosfamide is closely related to cyclophosphamide but has a somewhat different spectrum of activity and toxicity. Thiotepa and busulfan are used to treat breast and ovarian cancer, and chronic myeloid leukemia, respectively. The major nitrosoureas are carmustine (BCNU), lomustine (CCNU), and semustine (methyl-CCNU). A variety of investigational alkylating agents have been synthesized that link various carrier molecules such as amino acids, nucleic acid bases, hormones, or sugar moieties to a group capable of alkylation; however, site-directed alkylation has not been successful to date.

Mechanism of Action

As a class, the alkylating agents exert their cytotoxic effects via transfer of their alkyl groups to various cellular constituents. Alkylations of DNA within the nucleus probably represent the major interactions that lead to cell death. However, these drugs react chemically with sulfhydryl, amino, hydroxyl, carboxyl, and phosphate groups of other cellular nucleophiles as well. The general mechanism of action of these drugs involves intramolecular cyclization to form an ethyleneimonium ion that may directly or through formation of a carbonium ion transfer an alkyl group to a cellular constituent (Figure 54–4). In addition to alkylation, a secondary mechanism that occurs with nitrosoureas involves carbamoylation of lysine residues of proteins through formation of isocyanates.

The major site of alkylation within DNA is the N7 position of guanine; however, other bases are also alkylated to lesser degrees, including N1 and N3 of adenine, N3 of cytosine, and O6 of guanine, as well as phosphate atoms and proteins associated with DNA. These interactions can occur on a single strand or on both strands of DNA through cross-linking, as most major alkylating agents are bifunctional, with two reactive groups. Alkylation of guanine can result in miscoding through abnormal base pairing with thymine or in depurination by excision of guanine residues. The latter effect leads to DNA strand breakage through scission of the sugar-phosphate backbone of DNA. Cross-linking of DNA appears to be of major importance to the cytotoxic action of alkylating agents, and replicating cells are most susceptible to these drugs. Thus, although alkylating agents are not cell cycle specific, cells are most susceptible to alkylation in late G₁ and S phases of the cell cycle and express blockage in G₂.

Resistance

The mechanism of acquired resistance to alkylating agents may involve increased capability to repair DNA lesions, decreased transport of the alkylating drug into the cell, and increased production of glutathione and glutathione-associated proteins, which are needed to conjugate the alkylating agent, or increased glutathione S-transferase activity, which catalyzes the conjugation.

Pharmacologic Effects

The adverse effects usually associated with alkylating agents are generally dose-related and occur primarily in rapidly growing tissues such as bone marrow, the gastrointestinal tract, and the reproductive system. Nausea and vomiting can be a serious issue with a number of these agents. In addition, they have direct vesicant effects and can damage tissues at the site of injection as well as produce systemic toxicity. As a class, alkylating agents are carcinogenic in nature, and there is an increased risk of secondary malignancies, especially acute myelogenous leukemia.

Cyclophosphamide is a widely used alkylating agent, and one of the advantages of this compound is that it has high oral bioavailability. As a result, it can be administered via the oral and intravenous routes with equal clinical efficacy. It is inactive in its parent form, and must be activated to cytotoxic forms by liver microsomal enzymes (Figure 54–5). The cytochrome P450 mixed-function oxidase system converts cyclophosphamide to 4-hydroxycyclophosphamide, which is in equilibrium with aldophosphamide. These active metabolites are delivered to both tumor and normal tissue, where nonenzymatic cleavage of aldophosphamide to the cytotoxic forms—phosphoramide mustard and acrolein—occurs. The liver appears to be protected through the enzymatic formation of the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide.

The major toxicities of the individual alkylating agents are outlined in Table 54–2 and discussed below.

Nitrosoureas

These drugs appear to be non-cross-resistant with other alkylating agents; all require biotransformation, which occurs by nonenzymatic decomposition, to metabolites with both alkylating and carbamoylating activities. The nitrosoureas are highly lipid-soluble and are able to cross the blood-brain barrier, making them effective in the treatment of brain tumors. Although the majority of alkylations by the nitrosoureas are on the N7 position of guanine in DNA, the critical alkylation responsible for cytotoxicity is on the O6 of guanine, which leads to G-C crosslinks in DNA. After oral administration of lomustine, peak plasma levels of metabolites appear within 1–4 hours; central nervous system concentrations reach 30–40% of the activity present in the plasma. Urinary excretion appears to be the major route of elimination from the body. One naturally occurring sugar-containing nitrosourea, streptozocin, is interesting because it has minimal bone marrow toxicity. This agent has activity in the treatment of insulin-secreting islet cell carcinoma of the pancreas.

Nonclassic Alkylating Agents

Several other compounds have mechanisms of action that involve DNA alkylation as their cytotoxic mechanism of action. These agents include procarbazine, dacarbazine, and bendamustine. Their clinical activity and associated toxicities are listed in Table 54–2.

Procarbazine

The oral agent procarbazine is a methylhydrazine derivative, and it is commonly used in combination regimens for Hodgkin's and non-Hodgkin's lymphoma and brain tumors.

The precise mechanism of action of procarbazine is uncertain; however, the drug inhibits DNA, RNA, and protein biosynthesis; prolongs interphase; and produces chromosome breaks. Oxidative metabolism of this drug by microsomal enzymes generates azoprocarbazine and H₂O₂, which may be responsible for DNA strand scission. A variety of other drug metabolites are formed that may be cytotoxic. One metabolite is a weak monoamine oxidase (MAO) inhibitor, and adverse events can occur when procarbazine is given with other MAO inhibitors as well as with sympathomimetic agents, tricyclic antidepressants, antihistamines, central nervous system depressants, antidiabetic agents, alcohol, and tyramine-containing foods.

There is an increased risk of secondary cancers in the form of acute leukemia, and the carcinogenic potential of procarbazine is thought to be higher than that of most other alkylating agents.

Dacarbazine

Dacarbazine is a synthetic compound that functions as an alkylating agent following metabolic activation in the liver by oxidative N-demethylation to the monomethyl derivative. This metabolite spontaneously decomposes to diazomethane, which generates a methyl carbonium ion that is believed to be the key cytotoxic species. Dacarbazine is administered parenterally and is used in the treatment of malignant melanoma, Hodgkin's lymphoma, soft tissue sarcomas, and neuroblastoma. In terms of safety profile, the main dose-limiting toxicity is myelosuppression, but nausea and vomiting can be severe in some cases. This agent is a potent vesicant, and care must be taken to avoid extravasation.

Bendamustine

Bendamustine is a bifunctional alkylating agent consisting of a purine benzimidazole ring and a nitrogen mustard moiety. As with other alkylating agents, it forms cross-links with DNA resulting in single- and double-stranded breaks, leading to inhibition of DNA synthesis and function. This molecule also inhibits mitotic checkpoints and induces mitotic catastrophe, which leads to cell death. Of note, the cross-resistance between bendamustine and other alkylating agents is only partial. This agent is approved for use in patients with chronic lymphocytic leukemia, and activity has also been observed in Hodgkin's and non-Hodgkin's lymphoma, multiple myeloma, and breast cancer. The main dose-limiting toxicities include myelosuppression and mild nausea and vomiting. Hypersensitivity infusion reactions, skin rash, and other skin reactions occur rarely.

Platinum Analogs

Three platinum analogs are currently used in clinical practice: cisplatin,  carboplatin,  and oxaliplatin.  Cisplatin (cis-diamminedichloroplatinum [II]) is an inorganic metal complex that was initially discovered through a serendipitous observation that neutral platinum complexes inhibited division and induced filamentous growth of Escherichia coli. Several platinum analogs were subsequently synthesized. Although the precise mechanism of action of the platinum analogs is unclear, they are thought to exert their cytotoxic effects in the same manner as alkylating agents. As such, they kill tumor cells in all stages of the cell cycle and bind DNA through the formation of intrastrand and interstrand cross-links, thereby leading to inhibition of DNA synthesis and function. The primary binding site is the N7 position of guanine, but covalent interaction with the N3 position of adenine and O6 position of cytosine can also occur. In addition to targeting DNA, the platinum analogs have also been shown to bind to both cytoplasmic and nuclear proteins, which may also contribute to their cytotoxic and antitumor effects. The platinum complexes appear to synergize with certain other anticancer drugs, including alkylating agents, fluoropyrimidines, and taxanes.

Cisplatin has major antitumor activity in a broad range of solid tumors, including non-small cell and small cell lung cancer, esophageal and gastric cancer, head and neck cancer, and genitourinary cancers, particularly testicular, ovarian, and bladder cancer. When used in combination regimens, cisplatin-based therapy has led to the cure of nonseminomatous testicular cancer. In terms of clinical pharmacology, cisplatin and the other platinum analogs are extensively cleared by the kidneys and excreted in the urine. As a result, dose modification is required in the setting of renal dysfunction.

Carboplatin is a second-generation platinum analog whose mechanisms of cytotoxic action, mechanisms of resistance, and clinical pharmacology are identical to that described for cisplatin. As with cisplatin, carboplatin has broad-spectrum activity against a wide range of solid tumors. However, in contrast to cisplatin, it exhibits significantly less renal toxicity and gastrointestinal toxicity. Its main dose-limiting toxicity is myelosuppression. It has therefore been widely used in transplant regimens to treat refractory hematologicmalignancies. Moreover, since vigorous intravenous hydration is not required for carboplatin therapy, carboplatin is viewed as an easier agent to administer to patients, and as such, it has widely replaced cisplatin in various combination chemotherapy regimens.

Oxaliplatin is a third-generation diaminocyclohexane platinum analog. Its mechanism of action and clinical pharmacology are identical to those of cisplatin and carboplatin. However, tumors that are resistant to cisplatin or carboplatin on the basis of mismatch repair defects are not cross-resistant to oxaliplatin, and this finding may explain the activity of this platinum compound in colorectal cancer. Oxaliplatin was originally approved for use as second-line therapy in combination with the fluoropyrimidine 5-fluorouracil (5-FU) and leucovorin, termed the FOLFOX regimen, for metastatic colorectal cancer. In 2005, the same FOLFOX regimen was approved for the first-line treatment of advanced colorectal cancer. Oxaliplatin-based chemotherapy is also approved in the adjuvant therapy of high-risk stage II and stage III colon cancer, and activity has been observed in other gastrointestinal cancers, such as pancreatic, gastroesophageal, and hepatocellular cancers. Neurotoxicity is the main dose-limiting toxicity and is manifested by a peripheral sensory neuropathy. There are two forms of neurotoxicity, an acute form that is often triggered and worsened by exposure to cold, and a chronic form that is dose-dependent. Although this chronic form is cumulative in nature, it tends to be reversible, in sharp contrast to cisplatin-induced neurotoxicity.

The major toxicities of the individual platinum analogs are outlined in Table 54–2.

Antimetabolites

The development of drugs with actions on intermediary metabolism of proliferating cells has been important both conceptually and clinically. While biochemical properties unique to all cancer cells have yet to be discovered, there are a number of quantitative differences in metabolism between cancer cells and normal cells that render cancer cells more sensitive to the antimetabolites. Many of these agents have been rationally designed and synthesized based on knowledge of critical cellular processes involved in DNA biosynthesis.

The individual antimetabolites and their respective clinical spectrum and toxicities are presented in Table 54–3. The principal drugs are discussed below.

Antifolates

Methotrexate

Methotrexate (MTX) is a folic acid analog that binds with high affinity to the active catalytic site of dihydrofolate reductase (DHFR), interfering with the synthesis of tetrahydrofolate (THF), which serves as the key one-carbon carrier for enzymatic processes involved in de novo synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine. Inhibition of these various metabolic processes thereby interferes with the formation of DNA, RNA, and key cellular proteins. Intracellular formation of polyglutamate metabolites, with the addition of up to 5–7 glutamate residues, is critically important for the therapeutic action of MTX, and this process is catalyzed by the enzyme folylpolyglutamate synthase (FPGS). MTX polyglutamates are selectively retained within cancer cells, and they display increased inhibitory effects on enzymes involved in de novo purine nucleotide and thymidylate biosynthesis, making them important determinants of MTX's cytotoxic action.

Resistance to MTX has been attributed to (1) decreased drug transport via the reduced folate carrier or folate receptor protein, (2) decreased formation of cytotoxic MTX polyglutamates, (3) increased levels of the target enzyme DHFR through gene amplification and other genetic mechanisms, and (4) altered DHFR protein with reduced affinity for MTX. Recent studies have suggested that decreased accumulation of drug through activation of the multidrug resistance transporter P170 glycoprotein may also result in drug resistance.

MTX is administered by the intravenous, intrathecal, or oral route. However, oral bioavailability is saturable and erratic at doses greater than 25 mg/m². Renal excretion is the main route of elimination and is mediated by glomerular filtration and tubular secretion. As a result, dose modification is required in the setting of renal dysfunction. Care must also be taken when MTX is used in the presence of drugs such as aspirin, penicillin, cephalosporins, and nonsteroidal anti-inflammatory agents, as they inhibit the renal excretion of MTX. The biologic effects of MTX can be reversed by administration of the reduced folate leucovorin (5-formyltetrahydrofolate) or by L-leucovorin, which is the active enantiomer. Leucovorin rescue is used in conjunction with high-dose MTX therapy to rescue normal cells from undue toxicity, and it has also been used in cases of accidental drug overdose. The main adverse effects are listed in Table 54–3.

Pemetrexed

Pemetrexed is a pyrrolopyrimidine antifolate analog with activity in the S phase of the cell cycle. As in the case of MTX, it is transported into the cell via the reduced folate carrier and requires activation by FPGS to yield higher polyglutamate forms. While this agent targets DHFR and enzymes involved in de novo purine nucleotide biosynthesis, its main mechanism of action is inhibition of thymidylate synthase. At present, this antifolate is approved for use in combination with cisplatin in the treatment of mesothelioma, as a single agent in the second-line therapy of non-small cell lung cancer, and in combination with cisplatin for the first-line treatment of non-small cell lung cancer. As with MTX, pemetrexed is mainly excreted in the urine, and dose modification is required in the setting of renal dysfunction. The main adverse effects include myelosuppression, skin rash, mucositis, diarrhea, and fatigue. Of note, vitamin supplementation with folic acid and vitamin B12 appear to reduce the toxicities associated with pemetrexed, while not interfering with clinical efficacy. With respect to the hand-foot syndrome (recurrent painful swelling of the hands and feet), dexamethasone treatment has been shown to be effective in reducing the incidence and severity of this toxicity.

Fluoropyrimidines

5-Fluorouracil

5-Fluorouracil (5-FU) is inactive in its parent form and requires activation via a complex series of enzymatic reactions to ribosyl and deoxyribosyl nucleotide metabolites. One of these metabolites, 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), forms a covalently ternary complex with the enzyme thymidylate synthase and the reduced folate 5,10-methylenetetrahydrofolate, a reaction critical for the de novo synthesis of thymidylate. This results in inhibition of DNA synthesis through "thymineless death." 5-FU is converted to 5-fluorouridine-5'-triphosphate (FUTP), which is then incorporated into RNA, where it interferes with RNA processing and mRNA translation. 5-FU is also converted to 5-fluorodeoxyuridine-5'-triphosphate (FdUTP), which can be incorporated into cellular DNA, resulting in inhibition of DNA synthesis and function. Thus, the cytotoxicity of 5-FU is thought to be the result of combined effects on both DNA- and RNA-mediated events.

5-FU is normally administered intravenously with a half-life of 10–15 minutes. The clinical activity of this drug is highly schedule-dependent and because of its extremely short half-life, standard schedules of administration should be followed. Up to 80–85% of an administered dose of 5-FU is catabolized by the enzyme dihydropyrimidine dehydrogenase. Of note, there is a pharmacogenetic syndrome that involves partial or complete deficiency of the DPD enzyme, and in this setting, which is seen in up to 5% of all cancer patients, severe toxicity in the form of myelosuppression, diarrhea, nausea and vomiting, and neurotoxicity, has been observed.

5-FU remains the most widely used agent in the treatment of colorectal cancer, both as adjuvant therapy and for advanced disease. It also has activity against a wide variety of solid tumors, including cancers of the breast, stomach, pancreas, esophagus, liver, head and neck, and anus. Major toxicities include myelosuppression, gastrointestinal toxicity in the form of mucositis and diarrhea, skin toxicity manifested by the hand-foot syndrome, and neurotoxicity.

Capecitabine

Capecitabine is a fluoropyrimidine carbamate prodrug with 70–80% oral bioavailability. It undergoes extensive metabolism in the liver by the enzyme carboxylesterase to an intermediate, 5'-deoxy-5-fluorocytidine. This is converted to 5'-deoxy-5-fluorouridine by the enzyme cytidine deaminase. These two initial steps occur mainly in the liver. The 5'-deoxy-5-fluorouridine metabolite is then hydrolyzed by thymidine phosphorylase to 5-FU directly in the tumor. The expression of thymidine phosphorylase has been shown to be significantly higher in a broad range of solid tumors than in corresponding normal tissue, particularly in breast cancer and colorectal cancer.

This oral fluoropyrimidine is used in the treatment of metastatic breast cancer either as a single agent or in combination with other anticancer agents, including docetaxel, paclitaxel, lapatinib, ixabepilone, and trastuzumab. It is also approved for use in the adjuvant therapy of stage III and high-risk stage II colon cancer as well as for treatment of metastatic colorectal cancer as monotherapy. At this time, significant efforts are directed at combining this agent with other active cytotoxic agents, including irinotecan and oxaliplatin. In Europe, the capecitabine/oxaliplatin (XELOX) regimen is already approved for the first-line treatment of metastatic colorectal cancer. The main toxicities of capecitabine include diarrhea and the hand-foot syndrome. While myelosuppression, nausea and vomiting, and mucositis are also observed with this agent, the incidence is significantly less than that seen with intravenous 5-FU.

Deoxycytidine Analogs

Cytarabine

Cytarabine (ara-C) is an S phase-specific antimetabolite that is converted by deoxycytidine kinase to the 5'-mononucleotide (ara-CMP). Ara-CMP is further metabolized to the diphosphate and triphosphate metabolites, and the ara-CTP triphosphate is felt to be the main cytotoxic metabolite. Ara-CTP competitively inhibits DNA polymerase- and DNA polymerase-, thereby resulting in blockade of DNA synthesis and DNA repair, respectively. This metabolite is also incorporated into RNA and DNA. Incorporation into DNA leads to interference with chain elongation and defective ligation of fragments of newly synthesized DNA. The cellular retention of ara-CTP appears to correlate with its lethality to malignant cells.

After intravenous administration, the drug is cleared rapidly, with most of an administered dose being deaminated to inactive forms. The stoichiometric balance between the level of activation and catabolism of cytarabine is important in determining its eventual cytotoxicity.

The clinical activity of this drug is highly schedule-dependent and because of its rapid degradation, it must be given by continuous infusion over a 5–7 day period. Its activity is limited exclusively to hematologicmalignancies, including acute myelogenous leukemia and non-Hodgkin's lymphoma. This agent has absolutely no activity in solid tumors. The main adverse effects associated with cytarabine therapy include myelosuppression, mucositis, nausea and vomiting, and neurotoxicity when high-dose therapy is administered.

Gemcitabine

Gemcitabine is a fluorine-substituted deoxycytidine analog that is phosphorylated initially by the enzyme deoxycytidine kinase to the monophosphate form and then by other nucleoside kinases to the diphosphate and triphosphate nucleotide forms. The antitumor effect is considered to result from several mechanisms: inhibition of ribonucleotide reductase by gemcitabine diphosphate, which reduces the level of deoxyribonucleoside triphosphates required for DNA synthesis; inhibition by gemcitabine triphosphate of DNA polymerase- and DNA polymerase-, thereby resulting in blockade of DNA synthesis and DNA repair; and incorporation of gemcitabine triphosphate into DNA, leading to inhibition of DNA synthesis and function. Following incorporation of gemcitabine nucleotide, only one additional nucleotide can be added to the growing DNA strand, resulting in chain termination.

This nucleoside analog was initially approved for use in advanced pancreatic cancer but is now widely used to treat a broad range of malignancies, including non-small cell lung cancer, bladder cancer, ovarian cancer, soft tissue sarcoma, and non-Hodgkin's lymphoma. Myelosuppression in the form of neutropenia is the principal dose-limiting toxicity. Nausea and vomiting occur in 70% of patients and a flu-like syndrome has also been observed. In rare cases, renal microangiopathy syndromes, including hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura have been reported.

Purine Antagonists

6-Thiopurines

6-Mercaptopurine (6-MP) was the first of the thiopurine analogs found to be effective in cancer therapy. This agent is used primarily in the treatment of childhood acute leukemia, and a closely related analog, azathioprine, is used as an immunosuppressive agent (see Chapter 55). As with other thiopurines, 6-MP is inactive in its parent form and must be metabolized by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) to form the monophosphate nucleotide 6-thioinosinic acid, which in turn inhibits several enzymes of de novo purine nucleotide synthesis. The monophosphate form is eventually metabolized to the triphosphate form, which can then get incorporated into both RNA and DNA. Significant levels of thioguanylic acid and 6-methylmercaptopurine ribotide (MMPR) are also formed from 6-MP. These metabolites may contribute to its cytotoxic action.

6-Thioguanine (6-TG) also inhibits several enzymes in the de novo purine nucleotide biosynthetic pathway. Various metabolic lesions result, including inhibition of purine nucleotide interconversion; decrease in intracellular levels of guanine nucleotides, which leads to inhibition of glycoprotein synthesis; interference with the formation of DNA and RNA; and incorporation of thiopurine nucleotides into both DNA and RNA. 6-TG has a synergistic action when used together with cytarabine in the treatment of adult acute leukemia.

6-MP is converted to an inactive metabolite (6-thiouric acid) by an oxidation reaction catalyzed by xanthine oxidase, whereas 6-TG undergoes deamination. This is an important issue because the purine analog allopurinol, a potent xanthine oxidase inhibitor, is frequently used as a supportive care measure in the treatment of acute leukemias to prevent the development of hyperuricemia that often occurs with tumor cell lysis. Because allopurinol inhibits xanthine oxidase, simultaneous therapy with allopurinol and 6-MP would result in increased levels of 6-MP, thereby leading to excessive toxicity. In this setting, the dose of mercaptopurine must be reduced by 50–75%. In contrast, such an interaction does not occur with 6-TG, which can be used in full doses with allopurinol.

The thiopurines are also metabolized by the enzyme thiopurine methyltransferase (TPMT), in which a methyl group is attached to the thiopurine ring. There is a pharmacogenetic syndrome in which there is partial or complete deficiency of this enzyme. Patients with this genotype are at increased risk for developing severe toxicities in the form of myelosuppression and gastrointestinal toxicity with mucositis and diarrhea.

Fludarabine

Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-arabinofuranosyladenosine and then phosphorylated intracellularly by deoxycytidine kinase to the triphosphate. The triphosphate metabolite interferes with the processes of DNA synthesis and DNA repair through inhibition of DNA polymerase- and DNA polymerase-. The triphosphate form can also be directly incorporated into DNA, resulting in inhibition of DNA synthesis and function. The diphosphate metabolite of fludarabine inhibits ribonucleotide reductase, leading to inhibition of essential deoxyribonucleotide triphosphates. Finally, fludarabine induces apoptosis in susceptible cells through as yet undetermined mechanisms. This purine nucleotide analog is used mainly in the treatment of low-grade non-Hodgkin's lymphoma and chronic lymphocytic leukemia (CLL). It is given parenterally and up to 25–30% of parent drug is excreted in the urine. The main dose-limiting toxicity is myelosuppression. This agent is a potent immunosuppressant with inhibitory effects on CD4 and CD8 T cells. Patients are at increased risk for opportunistic infections, including fungi, herpes, and Pneumocystis jiroveci pneumonia (PCP). Patients should receive PCP prophylaxis with trimethoprim-sulfamethoxazole (double strength) at least three times a week, and this should continue for up to 1 year after stopping fludarabine therapy.

Cladribine

Cladribine (2-chlorodeoxyadenosine) is a purine nucleoside analog with high specificity for lymphoid cells. Inactive in its parent form, it is initially phosphorylated by deoxycytidine kinase to the monophosphate form and eventually metabolized to the triphosphate form, which can then be incorporated into DNA. The triphosphate metabolite can also interfere with DNA synthesis and DNA repair by inhibiting DNA polymerase- and DNA polymerase-, respectively. Cladribine is indicated for the treatment of hairy cell leukemia, and it also has activity in CLL and low-grade non-Hodgkin's lymphoma. It is normally administered as a single continuous 7-day infusion; under these conditions, it has a very manageable safety profile with the main toxicity consisting of transient myelosuppression. As with other purine nucleoside analogs, it has immunosuppressive effects, and a decrease in CD4 and CD8 T cells, lasting for over 1 year, is observed in patients.

Natural Product Cancer Chemotherapy Drugs

Vinca Alkaloids

Vinblastine

Vinblastine is an alkaloid derived from the periwinkle plant Vinca rosea. Its mechanism of action involves inhibition of tubulin polymerization, which disrupts assembly of microtubules, an important part of the cytoskeleton and the mitotic spindle. This inhibitory effect results in mitotic arrest in metaphase, bringing cell division to a halt, which then leads to cell death. Vinblastine and other vinca alkaloids are metabolized by the liver P450 system, and the majority of the drug is excreted in feces via the biliary system. As such, dose modification is required in the setting of liver dysfunction. The main adverse effects are outlined in Table 54–4, and they include nausea and vomiting, bone marrow suppression, and alopecia. This agent is also a potent vesicant, and care must be taken in its administration. It has clinical activity in the treatment of Hodgkin's and non-Hodgkin's lymphomas, breast cancer, and germ cell cancer.

Vincristine

Vincristine is an alkaloid derivative of Vinca rosea and is closely related in structure to vinblastine. Its mechanism of action, mechanism of resistance, and clinical pharmacology are identical to those of vinblastine. Despite these similarities to vinblastine, vincristine has a strikingly different spectrum of clinical activity and safety profile.

Vincristine has been effectively combined with prednisone for remission induction in acute lymphoblastic leukemia in children. It is also active in various hematologicmalignancies such as Hodgkin's and non-Hodgkin's lymphomas, and multiple myeloma, and in several pediatric tumors including rhabdomyosarcoma, neuroblastoma, Ewing's sarcoma, and Wilms' tumor.

The main dose-limiting toxicity is neurotoxicity, usually expressed as a peripheral sensory neuropathy, although autonomic nervous system dysfunction with orthostatic hypotension, urinary retention, paralytic ileus, or constipation, cranial nerve palsies, ataxia, seizures, and coma have been observed. While myelosuppression occurs, it is generally milder and much less significant than with vinblastine. The other potential adverse effect that can develop is the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

Vinorelbine

Vinorelbine is a semisynthetic derivative of vinblastine whose mechanism of action is identical to that of vinblastine and vincristine, ie, inhibition of mitosis of cells in the M phase through inhibition of tubulin polymerization. This agent has activity in non-small cell lung cancer, breast cancer, and ovarian cancer. Myelosuppression with neutropenia is the dose-limiting toxicity, but other adverse effects include nausea and vomiting, transient elevations in liver function tests, neurotoxicity, and SIADH.

Taxanes & Related Drugs

Paclitaxel  is an alkaloid ester derived from the Pacific yew (Taxus brevifolia) and the European yew (Taxus baccata). The drug functions as a mitotic spindle poison through high-affinity binding to microtubules with enhancement of tubulin polymerization. This promotion of microtubule assembly by paclitaxel occurs in the absence of microtubule-associated proteins and guanosine triphosphate and results in inhibition of mitosis and cell division.

Paclitaxel has significant activity in a broad range of solid tumors, including ovarian, advanced breast, non-small cell and small cell lung, head and neck, esophageal, prostate, and bladder cancers and AIDS-related Kaposi's sarcoma. It is metabolized extensively by the liver P450 system, and nearly 80% of the drug is excreted in feces via the hepatobiliary route. Dose reduction is required in the setting of liver dysfunction. The primary dose-limiting toxicities are listed in Table 54–4. Hypersensitivity reactions may be observed in up to 5% of patients, but the incidence is significantly reduced by premedication with dexamethasone, diphenhydramine, and an H₂ blocker.

A novel albumin-bound paclitaxel formulation (Abraxane) is approved for use in metastatic breast cancer. In contrast to paclitaxel, this formulation is not associated with hypersensitivity reactions, and premedication to prevent such reactions is not required. Moreover, this agent has significantly reduced myelosuppressive effects compared with paclitaxel, and the neurotoxicity that results appears to be more readily reversible than is typically observed with paclitaxel.

Docetaxel is a semisynthetic taxane derived from the European yew tree. Its mechanism of action, metabolism, and elimination are identical to those of paclitaxel. It is approved for use as second-line therapy in advanced breast cancer and non-small cell lung cancer, and it also has major activity in head and neck cancer, small cell lung cancer, gastric cancer, advanced platinum-refractory ovarian cancer, and bladder cancer. Its major toxicities are listed in Table 54–4.

Although not a taxane, ixabepilone is a novel microtubule inhibitor that was recently approved for metastatic breast cancer in combination with the oral fluoropyrimidine capecitabine or as monotherapy. It is a semisynthetic analog of epothilone B, and is active in the M phase of the cell cycle. This agent binds directly to -tubulin subunits on microtubules, leading to inhibition of normal microtubule dynamics. Of note, this agent continues to have activity in drug-resistant tumors that overexpress P-glycoprotein or tubulin mutations. The main adverse effects include myelosuppression, hypersensitivity reactions, and neurotoxicity in the form of peripheral sensory neuropathy.

Epipodophyllotoxins

Etoposide  is a semisynthetic derivative of podophyllotoxin, which is extracted from the mayapple root (Podophyllum peltatum).  Intravenous and oral formulations of etoposide are approved for clinical use in the USA. The oral bioavailability is about 50%, requiring the oral dose to be twice that of an intravenous dose. Teniposide is a related drug used outside the USA. The primary mode of action involves inhibition of topoisomerase II, which results in DNA damage through strand breakage induced by the formation of a ternary complex of drug, DNA, and enzyme. Up to 30–50% of drug is excreted in the urine, and dose reduction is required in the setting of renal dysfunction. Etoposide has clinical activity in germ cell cancer, small cell and non-small cell lung cancer, Hodgkin's and non-Hodgkin's lymphomas, and gastric cancer. In addition, it is effective in high-dose regimens in the transplant setting for breast cancer and lymphomas.

Camptothecins

The camptothecins are natural products derived from the Camptotheca acuminata  tree originally found in China; they inhibit the activity of topoisomerase I, the key enzyme responsible for cutting and religating single DNA strands. Inhibition of this enzyme results in DNA damage. Topotecan and irinotecan are the two camptothecin compounds used in clinical practice in the USA. Topotecan is indicated in the treatment of advanced ovarian cancer as second-line therapy following initial treatment with platinum-based chemotherapy. It is also approved as second-line therapy of small cell lung cancer. The main route of elimination is renal excretion, and dosage must be adjusted in patients with renal impairment.

Irinotecan is a prodrug that is converted mainly in the liver by the carboxylesterase enzyme to the SN-38 metabolite, which is 1000-fold more potent as an inhibitor of topoisomerase I than the parent compound. In contrast to topotecan, irinotecan and SN-38 are mainly eliminated in bile and feces, and dose reduction is required in the setting of liver dysfunction. Irinotecan was originally approved as second-line monotherapy in patients with metastatic colorectal cancer who had failed fluorouracil-based therapy. It is now approved as first-line therapy when used in combination with 5-FU and leucovorin. Myelosuppression and diarrhea are the two most common adverse events. There are two forms of diarrhea: an early form that occurs within 24 hours after administration and is thought to be a cholinergic event effectively treated with atropine, and a late form that usually occurs 2–10 days after treatment. The late diarrhea can be severe, leading to significant electrolyte imbalance and dehydration in some cases.

Antitumor Antibiotics

Screening of microbial products has led to the discovery of a number of growth-inhibiting compounds that have proved to be clinically useful in cancer chemotherapy. Many of these antibiotics bind to DNA through intercalation between specific bases and block the synthesis of RNA, DNA, or both; cause DNA strand scission; and interfere with cell replication. All of the anticancer antibiotics now being used in clinical practice are products of various strains of the soil microbe Streptomyces. These include the anthracyclines, bleomycin, and mitomycin.

Anthracyclines

The anthracycline antibiotics, isolated from Streptomyces peucetius  var caesius,  are among the most widely used cytotoxic anticancer drugs. The structures of two congeners, doxorubicin and daunorubicin, are shown below. Several other anthracycline analogs have entered clinical practice, including idarubicin, epirubicin, and mitoxantrone. The anthracyclines exert their cytotoxic action through four major mechanisms: (1) inhibition of topoisomerase II; (2) high-affinity binding to DNA through intercalation, with consequent blockade of the synthesis of DNA and RNA, and DNA strand scission; (3) generation of semiquinone free radicals and oxygen free radicals through an iron-dependent, enzyme-mediated reductive process; and (4) binding to cellular membranes to alter fluidity and ion transport. While the precise mechanisms by which the anthracyclines exert their cytotoxic effects remain to be defined (and may depend upon the specific tumor type), it is now well-established that the free radical mechanism is the cause of the cardiotoxicity associated with the anthracyclines (Table 54–4).

In the clinical setting, anthracyclines are administered via the intravenous route. The anthracyclines are metabolized extensively in the liver, with reduction and hydrolysis of the ring substituents. The hydroxylated metabolite is an active species, whereas the aglycone is inactive. Up to 50% of drug is eliminated in the feces via biliary excretion, and dose reduction is required in the setting of liver dysfunction. Although anthracyclines are usually administered on an every-3-week schedule, alternative schedules such as low-dose weekly or 72–96 hour continuous infusions have been shown to yield equivalent clinical efficacy with reduced toxicity.

Doxorubicin is one of the most important anticancer drugs in clinical practice, with major clinical activity in cancers of the breast, endometrium, ovary, testicle, thyroid, stomach, bladder, liver, and lung; in soft tissue sarcomas; and in several childhood cancers, including neuroblastoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma. It also has clinical activity in hematologic malignancies, including acute lymphoblastic leukemia, multiple myeloma, and Hodgkin's and non-Hodgkin's lymphomas. It is generally used in combination with other anticancer agents (eg, cyclophosphamide, cisplatin, and 5-FU), and clinical activity is improved with combination regimens as opposed to single-agent therapy.

Daunorubicin was the first agent in this class to be isolated, and it is still used in the treatment of acute myeloid leukemia. Its efficacy in solid tumors appears to be limited.

Idarubicin is a semisynthetic anthracycline glycoside analog of daunorubicin, and it is approved for use in combination with cytarabine for induction therapy of acute myeloid leukemia. When combined with cytarabine, idarubicin appears to be more active than daunorubicin in producing complete remissions and in improving survival in patients with acute myelogenous leukemia.

Epirubicin is an anthracycline analog whose mechanism of action and clinical pharmacology are identical to those of all other anthracyclines. It was initially approved for use as a component of adjuvant therapy in early-stage, node-positive breast cancer but is also used in the treatment of metastatic breast cancer and gastroesophageal cancer.

Mitoxantrone (dihydroxyanthracenedione) is an anthracene compound whose structure resembles the anthracycline ring. It binds to DNA to produce strand breakage and inhibits both DNA and RNA synthesis. It is currently used in the treatment of advanced, hormone-refractory prostate cancer and low-grade non-Hodgkin's lymphoma. It is also indicated in breast cancer and in pediatric and adult acute myeloid leukemias. Myelosuppression with leukopenia is the dose-limiting toxicity, and mild nausea and vomiting, mucositis, and alopecia also occur. Although the drug is thought to be less cardiotoxic than doxorubicin, both acute and chronic cardiac toxicity are reported. A blue discoloration of the fingernails, sclera, and urine is observed 1–2 days after drug administration.

The main dose-limiting toxicity of all anthracyclines is myelosuppression, with neutropenia more commonly observed than thrombocytopenia. In some cases, mucositis is dose-limiting. Two forms of cardiotoxicity are observed. The acute form occurs within the first 2–3 days and presents as arrhythmias and conduction abnormalities, other electrocardiographic changes, pericarditis, and myocarditis. This form is usually transient and in most cases is asymptomatic. The chronic form results in a dose-dependent, dilated cardiomyopathy associated with heart failure. The chronic cardiac toxicity appears to result from increased production of free radicals within the myocardium. This effect is rarely seen at total doxorubicin dosages below 500–550 mg/m². Use of lower weekly doses or continuous infusions of doxorubicin appear to reduce the incidence of cardiac toxicity. In addition, treatment with the iron-chelating agent dexrazoxane (ICRF-187) is currently approved to prevent or reduce anthracycline-induced cardiotoxicity in women with metastatic breast cancer who have received a total cumulative dose of doxorubicin of 300 mg/m². The anthracyclines can also produce a "radiation recall reaction," with erythema and desquamation of the skin observed at sites of prior radiation therapy.

Mitomycin

Mitomycin (mitomycin C) is an antibiotic isolated from Streptomyces caespitosus. It undergoes metabolic activation through an enzyme-mediated reduction to generate an alkylating agent that cross-links DNA. Hypoxic tumor stem cells of solid tumors exist in an environment conducive to reductive reactions and are more sensitive to the cytotoxic actions of mitomycin than normal cells and oxygenated tumor cells. It is active in all phases of the cell cycle, and is the best available drug for use in combination with radiation therapy to attack hypoxic tumor cells. Its main clinical use is in the treatment of squamous cell cancer of the anus in combination with 5-FU and radiation therapy. In addition, it is used in combination chemotherapy for squamous cell carcinoma of the cervix and for breast, gastric, and pancreatic cancer. One special application of mitomycin has been in the intravesical treatment of superficial bladder cancer. Because virtually none of the agent is absorbed systemically, there is little to no systemic toxicity when used in this setting.

The common toxicities of mitomycin are outlined in Table 54–4. Hemolytic-uremic syndrome, manifested as microangiopathic hemolytic anemia, thrombocytopenia, and renal failure, as well as occasional instances of interstitial pneumonitis have been reported.

Bleomycin

Bleomycin is a small peptide that contains a DNA-binding region and an iron-binding domain at opposite ends of the molecule. It acts by binding to DNA, which results in single-strand and double-strand breaks following free radical formation, and inhibition of DNA biosynthesis. The fragmentation of DNA is due to oxidation of a DNA-bleomycin-Fe(II) complex and leads to chromosomal aberrations. Bleomycin is a cell cycle-specific drug that causes accumulation of cells in the G₂ phase of the cell cycle.

Bleomycin is indicated for the treatment of Hodgkin's and non-Hodgkin's lymphomas, germ cell tumor, head and neck cancer, and squamous cell cancer of the skin, cervix, and vulva. One advantage of this agent is that it can be given subcutaneously, intramuscularly, or intravenously. Elimination of bleomycin is mainly via renal excretion; dose modification is recommended in patients with renal dysfunction.

Pulmonary toxicity is dose-limiting for bleomycin and usually presents as pneumonitis with cough, dyspnea, dry inspiratory crackles on physical examination, and infiltrates on chest x-ray. The incidence of pulmonary toxicity is increased in patients older than 70 years of age, in those who receive cumulative doses greater than 400 units, in those with underlying pulmonary disease, and in those who have received prior mediastinal or chest irradiation. In rare cases, pulmonary toxicity can be fatal. Other toxicities are listed in Table 54–4.

Miscellaneous Anticancer Drugs

A large number of newer anticancer drugs that do not fit traditional categories have become available; they are listed in Table 54–5.

Imatinib, Dasatinib, & Nilotinib

Imatinib is an inhibitor of the tyrosine kinase domain of the Bcr-Abl oncoprotein and prevents phosphorylation of the kinase substrate by ATP. It is indicated for the treatment of chronic myelogenous leukemia (CML), a pluripotent hematopoietic stem cell disorder characterized by the t(9:22) Philadelphia chromosomal translocation. This translocation results in the Bcr-Abl fusion protein, the causative agent in CML, and is present in up to 95% of patients with this disease. This agent also inhibits other receptor tyrosine kinases for platelet-derived growth factor receptor (PDGFR), stem cell factor, and c-kit.

Imatinib is well absorbed orally, and it is metabolized in the liver, with elimination of metabolites occurring mainly in feces via biliary excretion. This agent is approved for use as first-line therapy in chronic phase CML, in blast crisis, and as second-line therapy for chronic phase CML that has progressed on prior interferon-alfa therapy. Imatinib is effective also for treatment of gastrointestinal stromal tumors expressing the c-kit tyrosine kinase. The main adverse effects are listed in Table 54–5.

Dasatinib is an oral inhibitor of several kinases, including Bcr-Abl, Src, c-kit, and PDGFR-. It differs from imatinib in that it binds to the active and inactive conformations of the Abl kinase domain and overcomes imatinib resistance resulting from mutations in the Bcr-Abl kinase. It is approved for use in CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) with resistance or intolerance to imatinib therapy.

Nilotinib is a second generation phenylamino-pyrimidine molecule that inhibits Bcr-Abl, c-kit, and PDGFR- tyrosine kinases. It has a higher binding affinity (up to 20- to 50-fold) for the Abl kinase when compared with imatinib, and it overcomes imatinib resistance resulting from Bcr-Abl mutations. It is approved for chronic phase and accelerated phase CML with resistance or intolerance to prior therapy that included imatinib.

Imatinib, dasatinib, and nilotinib are all metabolized in the liver, mainly by the CYP3A4 liver microsomal enzyme. A large fraction of each drug is eliminated in feces via the hepatobiliary route. It is important to review the patient's current list of prescription and nonprescription drugs because these agents have potential drug-drug interactions, especially with those that are also metabolized by the CYP3A4 system. In addition, patients should avoid grapefruit products and the use of St. John's wort, as they may alter the clinical activity of these small molecule inhibitors (see Chapter 4).

Growth Factor Receptor Inhibitors

Cetuximab & Panitumumab

The epidermal growth factor receptor (EGFR) is a member of the erb-B family of growth factor receptors, and it is overexpressed in a number of solid tumors, including colorectal cancer, head and neck cancer, non-small cell lung cancer, and pancreatic cancer. Activation of the EGFR signaling pathway results in downstream activation of several key cellular events involved in cellular growth and proliferation, invasion and metastasis, and angiogenesis. In addition, this pathway inhibits the cytotoxic activity of various anticancer agents and radiation therapy, presumably through suppression of key apoptotic mechanisms, thereby leading to the development of cellular drug resistance.

Cetuximab is a chimeric monoclonal antibody directed against the extracellular domain of the EGFR, and it is presently approved for use in combination with irinotecan for metastatic colon cancer in the refractory setting or as monotherapy in patients who are deemed to be irinotecan-refractory. Because cetuximab is of the G₁ isotype, its antitumor activity may be mediated in part by immunologic-mediated mechanisms. There is growing evidence that cetuximab can be effectively and safely combined with irinotecan- and oxaliplatin-based chemotherapy in the first-line treatment of metastatic colorectal cancer as well. Regimens combining cetuximab with cytotoxic chemotherapy may be of particular benefit in the neoadjuvant therapy of patients with liver-limited disease. Although this antibody was initially approved to be administered on a weekly schedule, pharmacokinetic studies have shown that an every-2-week schedule provides the same level of clinical activity as the weekly schedule. This agent is also approved for use in combination with radiation therapy in patients with locally advanced head and neck cancer. Cetuximab is well tolerated, with the main adverse effects being an acneiform skin rash, hypersensitivity infusion reaction, and hypomagnesemia.

Panitumumab is a fully human monoclonal antibody directed against the EGFR and works through inhibition of the EGFR signaling pathway. In contrast to cetuximab, this antibody is of the G₂ isotype, and as such, it would not be expected to exert any immunologic-mediated effects. Presently, panitumumab is approved for patients with refractory metastatic colorectal cancer who have been treated with all other active agents. As this is a fully human antibody, infusion-related reactions are seen only rarely, and acneiform skin rash and hypomagnesemia are the two main adverse effects associated with this agent.

Gefitinib & Erlotinib

Gefitinib and erlotinib are small molecule inhibitors of the tyrosine kinase domain associated with the EGFR, and both are used in the treatment of non-small cell lung cancer that is refractory to at least one prior chemotherapy regimen. Patients who are nonsmokers and who have a bronchoalveolar histologic subtype appear to be more responsive to these agents. In addition, erlotinib has been approved for use in combination with gemcitabine for the treatment of advanced pancreatic cancer. Both agents are metabolized in the liver by the CYP3A4 enzyme system, and elimination is mainly hepatic with excretion in feces. Caution must be taken when using these agents with drugs that are also metabolized by the liver CYP3A4 system, such as phenytoin and warfarin, and the use of grapefruit products should be avoided. An acneiform skin rash, diarrhea, and anorexia and fatigue are the most common adverse effects observed with these small molecules (Table 54-5).

Bevacizumab, Sorafenib, & Sunitinib

The vascular endothelial growth factor (VEGF) is one of the most important angiogenic growth factors. The growth of both primary and metastatic tumors requires an intact vasculature. As a result, the VEGF-signaling pathway represents an attractive target for chemotherapy. Several approaches have been taken to inhibit VEGF signaling; they include inhibition of VEGF interactions with its receptor by targeting either the VEGF ligand with antibodies or soluble chimeric decoy receptors, or by direct inhibition of the VEGF receptor–associated tyrosine kinase activity by small molecule inhibitors.

Bevacizumab is a recombinant humanized monoclonal antibody that targets all forms of VEGF-A. This antibody binds to and prevents VEGF-A from interacting with the target VEGF receptors. Bevacizumab can be safely and effectively combined with 5-FU-, irinotecan-, and oxaliplatin-based chemotherapy in the treatment of metastatic colorectal cancer. Bevacizumab is FDA approved as a first-line treatment for metastatic colorectal cancer in combination with any intravenous fluoropyrimidine-containing regimen and is now also approved in combination with chemotherapy for metastatic non-small lung cancer and breast cancer. One potential advantage of this antibody is that it does not appear to exacerbate the toxicities typically observed with cytotoxic chemotherapy. The main safety concerns associated with bevacizumab include hypertension, an increased incidence of arterial thromboembolic events (transient ischemic attack, stroke, angina, and myocardial infarction), wound healing complications and gastrointestinal perforations, and proteinuria.

Sorafenib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs), especially VEGF-R2 and VEGF-R3, platelet-derived growth factor- (PDGFR-), and raf kinase. It was initially approved for advanced renal cell cancer, and recently was approved for advanced hepatocellular cancer.

Sunitinib is similar to sorafenib in that it inhibits multiple RTKs, although the specific types are somewhat different. They include PDGFR- and PDGFR-, VEGFR-R1, VEGF-R2, VEGF-R3, and c-kit. It is approved for the treatment of advanced renal cell cancer and for the treatment of gastrointestinal stromal tumors (GIST) after disease progression on or with intolerance to imatinib.

Both sorafenib and sunitinib are metabolized in the liver by the CYP3A4 system, and elimination is primarily hepatic with excretion in feces. Each of these agents has potential interactions with drugs that are also metabolized by the CYP3A4 system, especially warfarin. In addition, patients should avoid grapefruit products and the use of St. John's wort, as they may alter the clinical activity of these agents. Hypertension, bleeding complications, and fatigue are the most common adverse effects seen with both agents. With respect to sorafenib, skin rash and the hand-foot syndrome are observed in up to 30–50% of patients. For sunitinib, there is also an increased risk of cardiac dysfunction, which, in some cases, can lead to congestive heart failure

Asparaginase

Asparaginase (L -asparagine amidohydrolase) is an enzyme used to treat childhood ALL. The drug is isolated and purified from Escherichi coli  or Erwinia chrysanthemi  for clinical use. It hydrolyzes circulating L-asparagine to aspartic acid and ammonia. Because tumor cells in ALL lack asparagine synthetase, they require an exogenous source of L-asparagine. Thus, depletion of L-asparagine results in effective inhibition of protein synthesis. In contrast, normal cells can synthesize L-asparagine and thus are less susceptible to the cytotoxic action of asparaginase. The main adverse effect of this agent is a hypersensitivity reaction manifested by fever, chills, nausea and vomiting, skin rash, and urticaria. Severe cases can present with bronchospasm, respiratory failure, and hypotension. Other adverse effects include an increased risk of both clotting and bleeding as a result of alterations in various clotting factors, pancreatitis, and neurologic toxicity with lethargy, confusion, hallucinations, and in severe cases, coma.

Retinoic Acid Derivatives

Tretinoin (all-trans-retinoic acid) is active in patients with acute promyelocytic leukemia (APL) through the induction of terminal differentiation, in which the leukemic promyelocytes lose their ability to proliferate. APL is associated with a t(15:17) chromosomal translocation, which disrupts the gene for the nuclear receptor- for retinoic acid and fuses it to a gene called PML. This chimeric gene, which expresses aberrant forms of the retinoic acid receptor- (RAR-), is present in virtually all patients with promyelocytic leukemia and appears to be responsible for sensitivity to all-trans-retinoic acid. This agent is approved for use in APL following progression or relapse with anthracycline-based chemotherapy and for patients in whom anthracycline-based chemotherapy is contraindicated. However, a number of serious adverse events have been observed, which include vitamin A toxicity manifesting as headache, fever, dry skin and mucous membranes, skin rash, pruritus, and conjunctivitis; retinoic acid syndrome (fever, leukocytosis, dyspnea, weight gain, diffuse pulmonary infiltrates, and pleural or pericardial effusions); increased serum cholesterol and triglyceride levels; central nervous system toxicity in the form of dizziness, anxiety, depression, confusion, and agitation; abdominal pain and diarrhea; and transient elevations in liver function tests.

Arsenic Trioxide

Arsenic trioxide (As2O3) is used for induction of remission in patients with APL with the (15:17) chromosomal translocation refractory to or relapsed following first-line therapy with all-trans-retinoic acid- and anthracycline-based chemotherapy. It functions by inducing differentiation through degradation of the chimeric PML/RAR- protein. In addition, it induces apoptosis through a mitochondrion-dependent process, resulting in subsequent release of cytochrome C with caspase activation. This drug is administered via the intravenous route, and it is widely distributed in the body. The main toxicities are fatigue, electrocardiographic changes with QT prolongation, arrhythmias, and a syndrome characterized by fever, dyspnea, skin rash, fluid retention, and weight gain.

Clinical Pharmacology of Cancer Chemotherapeutic Drugs

A thorough knowledge of the kinetics of tumor cell proliferation along with an understanding of the pharmacology and mechanism of action of cancer chemotherapeutic agents is important in designing optimal regimens for patients with cancer. The strategy for developing drug regimens also requires a knowledge of the specific characteristics of individual tumors. For example, is there a high growth fraction? Is there a high spontaneous cell death rate? Are most of the cells in G₀? Is a significant fraction of the tumor composed of hypoxic stem cells? Are their normal counterparts under hormonal control? Similarly, an understanding of the pharmacology of specific drugs is important. Are the tumor cells sensitive to the drug? Is the drug cell cycle specific? Does the drug require activation in certain normal tissue such as the liver (cyclophosphamide), or is it activated in the tumor tissue itself (capecitabine)? Knowledge of specific pathway abnormalities (eg, EGFR pathway) for intracellular signaling may prove important for the next generation of anticancer drugs.

For some tumor types, especially those of gonadal tissues, knowledge of receptor expression is important. For example, in patients with breast cancer, analysis of the tumor for expression of estrogen or progesterone receptors is important in guiding therapy with selective estrogen receptor modulators. In the case of prostate cancer, chemical suppression of androgen secretion with gonadotropin-releasing hormone agonists or antagonists is important. The basic pharmacology of hormonal therapy is discussed in Chapter 40. The use of specific cytotoxic and biologic agents for each of the main cancers is discussed in this section.

The Leukemias

Acute Leukemia

Childhood Leukemia

Acute lymphoblastic leukemia (ALL) is the main form of leukemia in childhood, and it is the most common form of cancer in children. Children with this disease have a relatively good prognosis. A subset of patients with neoplastic lymphocytes expressing surface antigenic features of T lymphocytes has a poor prognosis (see Chapter 55). A cytoplasmic enzyme expressed by normal thymocytes, terminal deoxycytidyl transferase (terminal transferase), is also expressed in many cases of ALL. T-cell ALL also expresses high levels of the enzyme adenosine deaminase (ADA). This led to interest in the use of the ADA inhibitor pentostatin (deoxycoformycin) for treatment of such T-cell cases. Until 1948, the median length of survival in ALL was 3 months. With the advent of methotrexate, the length of survival was greatly increased. Subsequently, corticosteroids, 6-mercaptopurine, cyclophosphamide, vincristine, daunorubicin, and asparaginase have all been found to be active against this disease. A combination of vincristine and prednisone plus other agents is currently used to induce remission. Over 90% of children enter complete remission with this therapy with only minimal toxicity. However, circulating leukemic cells often migrate to sanctuary sites located in the brain and testes. The value of prophylactic intrathecal methotrexate therapy for prevention of central nervous system leukemia (a major mechanism of relapse) has been clearly demonstrated. Intrathecal therapy with methotrexate should therefore be considered as a standard component of the induction regimen for children with ALL.

Adult Leukemia

Acute myelogenous leukemia (AML) is the most common leukemia in adults. The single most active agent for AML is cytarabine; however, it is best used in combination with an anthracycline, in which case complete remissions occur in about 70% of patients. While there are several anthracyclines that can be effectively combined with cytarabine, idarubicin is considered to be the preferred anthracycline.

Patients often require intensive supportive care during the period of induction chemotherapy. Such care includes platelet transfusions to prevent bleeding, the granulocyte colony-stimulating factor filgrastim to shorten periods of neutropenia, and antibiotics to combat infections. Younger patients (eg, < age 55) who are in complete remission and have an HLA-matched donor are candidates for allogeneic bone marrow transplantation. The transplant procedure is preceded by high-dose chemotherapy and total body irradiation followed by immunosuppression. This approach may cure up to 35–40% of eligible patients. Patients over age 60 respond less well to chemotherapy, primarily because their tolerance for aggressive therapy and resistance to infection are lower.

Once remission of AML is achieved, consolidation chemotherapy is required to maintain a durable remission and to induce cure.

Chronic Myelogenous Leukemia

Chronic myelogenous leukemia (CML) arises from a chromosomally abnormal hematopoietic stem cell in which a balanced translocation between the long arms of chromosomes 9 and 22, t(9:22), is observed in 90–95% of cases. This translocation results in constitutive expression of the Bcr-Abl fusion oncoprotein with a molecular weight of 210 kDa. The clinical symptoms and course are related to the white blood cell count and its rate of increase. Most patients with white cell counts over 50,000/L should be treated. The goals of treatment are to reduce the granulocytes to normal levels, to raise the hemoglobin concentration to normal, and to relieve disease-related symptoms. The signal transduction inhibitor imatinib is considered as standard first-line therapy in previously untreated patients with chronic phase CML. Nearly all patients treated with imatinib exhibit a complete hematologic response, and up to 40–50% of patients show a complete cytogenetic response. As described previously, this drug is generally well tolerated and is associated with relatively minor adverse effects. For patients who are intolerant or become resistant to imatinib, dasatinib and nilotinib each show clinical activity. Other treatment options include interferon-, busulfan, other oral alkylating agents, and hydroxyurea.

Chronic Lymphocytic Leukemia

Patients with early-stage chronic lymphocytic leukemia (CLL) have a relatively good prognosis, and therapy has not changed the course of the disease. However, in the setting of high-risk disease or in the presence of disease-related symptoms, treatment is indicated.

Chlorambucil and cyclophosphamide are the two most widely used alkylating agents for this disease. Chlorambucil is frequently combined with prednisone, although there is no clear evidence that the combination yields better response rates or survival compared with chlorambucil alone. In most cases, cyclophosphamide is combined with vincristine and prednisone (COP), or it can also be given with these same drugs along with doxorubicin (CHOP). Bendamustine is the newest alkylating agent to be approved for use in this disease either as monotherapy or in combination with prednisone. The purine nucleoside analog fludarabine is also effective in treating CLL. This agent can be given alone, in combination with cyclophosphamide and with mitoxantrone and dexamethasone, or combined with the anti-CD20 antibody rituximab.

Monoclonal antibody-targeted therapies are being widely used in CLL, especially in relapsed or refractory disease. Rituximab is an anti-CD20 antibody that has documented clinical activity in this setting. This chimeric antibody appears to enhance the antitumor effects of cytotoxic chemotherapy, and is also effective in settings in which resistance to chemotherapy has developed. Alemtuzumab is a humanized monoclonal antibody directed against the CD52 antigen and is approved for use in CLL that is refractory to alkylating agent or fludarabine therapy. Response rates up to 30–35% are observed, with disease stabilization in another 30% of patients.

Hodgkin's & Non-Hodgkin's Lymphomas

Hodgkin's Lymphoma

The treatment of Hodgkin's lymphoma has undergone dramatic evolution over the last 30 years. This particular lymphoma is now widely recognized as a B-cell neoplasm in which the malignant Reed-Sternberg cells have rearranged VH genes. In addition, the Epstein-Barr virus genome has been identified in up to 80% of tumor specimens.

Complete staging evaluation is required before a definitive treatment plan can be made. For patients with stage I and stage IIA disease, there has been a significant change in the treatment approach. Initially, these patients were treated with extended-field radiation therapy. However, given the late effects of radiation therapy, which include hypothyroidism and an increased risk of secondary cancers and coronary artery disease, combined-modality therapy with a brief course of combination chemotherapy and involved field radiation therapy is now the recommended approach. The main advance for patients with advanced stage III and IV Hodgkin's lymphoma came with the development of MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) chemotherapy in the 1960s. This regimen resulted initially in high complete response rates—on the order of 80–90%, with cures in up to 60% of patients. More recently, the anthracycline-containing regimen termed ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) has been shown to be more effective and less toxic than MOPP, especially with regard to the incidence of sterility and secondary malignancies. In general, four cycles of ABVD are given to patients. An alternative regimen, termed Stanford V, utilizes a 12-week course of combination chemotherapy (doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone), followed by involved radiation therapy.

With all of these regimens, over 80% of previously untreated patients with advanced Hodgkin's lymphoma (stages III and IV) are expected to go into complete remission, with disappearance of all disease-related symptoms and objective evidence of disease. In general, approximately 50–60% of all patients with Hodgkin's lymphoma are cured of their disease.

Non-Hodgkin's Lymphoma

Non-Hodgkin's lymphoma is a heterogeneous disease, and the clinical characteristics of non-Hodgkin's lymphoma subsets are related to the underlying histopathologic features and the extent of disease involvement. In general, the nodular (or follicular) lymphomas have a far better prognosis, with a median survival up to 7 years, compared with the diffuse lymphomas, which have a median survival of about 1–2 years.

Combination chemotherapy is the treatment standard for patients with diffuse non-Hodgkin's lymphoma. The anthracycline-containing regimen CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) has been considered the best treatment in terms of initial therapy. Randomized phase III clinical studies have now shown that the combination of CHOP with the anti-CD20 monoclonal antibody rituximab results in improved response rates, disease-free survival, and overall survival compared with CHOP chemotherapy alone.

The nodular follicular lymphomas are low-grade, relatively slow-growing tumors that tend to present in an advanced stage and are usually confined to lymph nodes, bone marrow, and spleen. This form of non-Hodgkin's lymphomas, when presenting at an advanced stage, is considered incurable, and treatment is generally palliative. To date, there is no evidence that immediate treatment with combination chemotherapy offers clinical benefit over close observation and "watchful waiting" with initiation of chemotherapy at the onset of disease symptoms.

Multiple Myeloma

This plasma cell malignancy is one of the models of neoplastic disease in humans as it arises from a single tumor stem cell. Moreover, the tumor cells produce a marker protein (myeloma immunoglobulin) that allows the total body burden of tumor cells to be quantified. Multiple myeloma principally involves the bone marrow and bone, causing bone pain, lytic lesions, bone fractures, and anemia as well as an increased susceptibility to infection.

Most patients with multiple myeloma are symptomatic at the time of initial diagnosis and require treatment with cytotoxic chemotherapy. Treatment with the combination of the alkylating agent melphalan and prednisone (MP protocol) has been a standard regimen for nearly 30 years. About 40% of patients respond to the MP combination, and the median remission is on the order of 2–2.5 years. Recently, combination regimens incorporating lenalidomide plus dexamethasone or the proteosome inhibitor bortezomib plus melphalan and prednisone have been shown to be more effective as first-line therapy.

In patients who are thought to be candidates for high-dose therapy with stem cell transplantation, melphalan and other alkylating agents are to be avoided, as prior therapy will affect the success of stem cell harvesting.

Thalidomide is now a well-established agent for treating refractory or relapsed disease, and about 30% of patients will achieve a response to this therapy. More recently, thalidomide has been used in combination with dexamethasone, and response rates on the order of 65% have been observed. Studies are now under way to directly compare VAD with the combination of thalidomide and dexamethasone. In some patients, especially those with poor performance status, single-agent pulse dexamethasone administered on a weekly basis can be effective in palliating symptoms. Bortezomib is approved for use in relapsing or refractory multiple myeloma. This agent is thought to exert its main cytotoxic effects through inhibition of the nuclear factor kappa B (NF-B) signaling pathway, and further efforts are focused on developing this agent in combination regimens.

Breast Cancer

Stage I & Stage II Disease

The management of primary breast cancer has undergone a remarkable evolution as a result of major efforts at early diagnosis (through encouragement of self-examination as well as through the use of cancer detection centers) and the implementation of combined modality approaches incorporating systemic chemotherapy as an adjuvant to surgery and radiation therapy. Women with stage I disease (small primaries and negative axillary lymph node dissections) are currently treated with surgery alone, and they have an 80% chance of cure.

Women with node-positive disease have a high risk of both local and systemic recurrence. Thus, lymph node status directly indicates the risk of occult distant micrometastasis. In this situation, postoperative use of systemic adjuvant chemotherapy with six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF protocol) or of fluorouracil, doxorubicin, and cyclophosphamide (FAC) has been shown to significantly reduce the relapse rate and prolong survival. Alternative regimens with equivalent clinical benefit include four cycles of doxorubicin and cyclophosphamide and six cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC). Each of these chemotherapy regimens has benefited women with stage II breast cancer with one to three involved lymph nodes. Women with four or more involved nodes have had limited benefit thus far from adjuvant chemotherapy. Long-term analysis has clearly shown improved survival rates in node-positive premenopausal women who have been treated aggressively with multiagent combination chemotherapy. The results from three randomized clinical trials clearly show that the addition of trastuzumab, a monoclonal antibody directed against the HER-2/neu receptor, to anthracycline- and taxane-containing adjuvant chemotherapy benefits women with HER-2-overexpressing breast cancer with respect to disease-free and overall survival.

Breast cancer was the first neoplasm shown to be responsive to hormonal manipulation. Tamoxifen is beneficial in postmenopausal women when used alone or when combined with cytotoxic chemotherapy. The present recommendation is to administer tamoxifen for 5 years of continuous therapy after surgical resection. Longer durations of tamoxifen therapy do not appear to add additional clinical benefit. Postmenopausal women who complete 5 years of tamoxifen therapy should be placed on an aromatase inhibitor such as anastrozole for at least 2.5 years, although the optimal duration is unknown. In women who have completed 2–3 years of tamoxifen therapy, treatment with an aromatase inhibitor for a total of 5 years of hormonal therapy is now recommended (see Chapter 40).

Results from several randomized trials for breast cancer have established that adjuvant chemotherapy for premenopausal women and adjuvant tamoxifen for postmenopausal women are of benefit to women with stage I (node-negative) breast cancer. While this group of patients has the lowest overall risk of recurrence after surgery alone (about 35–50% over 15 years), this risk can be further reduced with adjuvant therapy.

Stage III & Stage IV Disease

The approach to women with advanced breast cancer remains a major problem, as current treatment options are only palliative. Combination chemotherapy, endocrine therapy, or a combination of both results in overall response rates of 40–50%, but only a 10–20% complete response rate. Breast cancers expressing estrogen receptors (ER) or progesterone receptors (PR), retain the intrinsic hormonal sensitivities of the normal breast—including the growth-stimulatory response to ovarian, adrenal, and pituitary hormones. Patients who show improvement with hormonal ablative procedures also respond to the addition of tamoxifen. The aromatase inhibitors anastrozole and letrozole are now approved as first-line therapy in women with advanced breast cancer whose tumors are hormone-receptor positive. In addition, these agents and exemestane are approved as second-line therapy following treatment with tamoxifen.

Patients with significant visceral involvement of the lung, liver, or brain and those with rapidly progressive disease rarely benefit from hormonal maneuvers, and initial systemic chemotherapy is indicated in such cases. For the 25–30% of breast cancer patients whose tumors express the HER-2/neu cell surface receptor, the humanized monoclonal anti-HER-2/neu antibody, trastuzumab, is available for therapeutic use alone or in combination with cytotoxic chemotherapy.

Systemic Chemotherapy for Breast Cancer

About 50–60% of patients with metastatic disease respond to initial chemotherapy. A broad range of anticancer agents have activity in this disease, including the anthracyclines (doxorubicin, mitoxantrone, and epirubicin), the taxanes (docetaxel, paclitaxel, and albumin-bound paclitaxel) along with the microtubule inhibitor ixabepilone, navelbine, capecitabine, gemcitabine, cyclophosphamide, methotrexate, and cisplatin. Doxorubicin and the taxanes are the most active cytotoxic drugs. Combination chemotherapy has been found to induce higher and more durable remissions in up to 50–80% of patients, and anthracycline-containing regimens are now considered the standard of care in first-line therapy. With most combination regimens, partial remissions have a median duration of about 10 months and complete remissions have a duration of about 15 months. Unfortunately, only 10–20% of patients achieve complete remissions with any of these regimens, and as noted, complete remissions are usually not long-lasting. Recently, the anti-VEGF antibody bevacizumab was shown to confer benefit to paclitaxel chemotherapy in women with advanced breast cancer, and a growing number of studies show the beneficial effect of combining bevacizumab with other cytotoxic agents.

Prostate Cancer

Prostate cancer was the second cancer shown to be responsive to hormonal manipulation. The treatment of choice for patients with advanced prostate cancer is elimination of testosterone production by the testes through either surgical or chemical castration. Bilateral orchiectomy or estrogen therapy in the form of diethylstilbestrol was previously used as first-line therapy. Presently, the use of luteinizing hormone-releasing hormone (LHRH) agonists—including leuprolide and goserelin agonists, alone or in combination with an antiandrogen (eg, flutamide, bicalutamide, or nilutamide)—has become the preferred approach. There appears to be no survival advantage of total androgen blockade using a combination of LHRH agonist and antiandrogen agent compared with single-agent therapy. Hormonal treatment reduces symptoms—especially bone pain—in 70–80% of patients and may cause a significant reduction in the prostate-specific antigen (PSA) level, which is now widely accepted as a surrogate marker for response to treatment in prostate cancer. Although initial hormonal manipulation is able to control symptoms for up to 2 years, patients usually develop progressive disease. Second-line hormonal therapies include aminoglutethimide plus hydrocortisone, the antifungal agent ketoconazole plus hydrocortisone, or hydrocortisone alone.

Unfortunately, nearly all patients with advanced prostate cancer eventually become refractory to hormone therapy. A regimen of mitoxantrone and prednisone is approved in patients with hormone-refractory prostate cancer since it provides effective palliation in those who experience significant bone pain. Estramustine is an antimicrotubule agent that produces an almost 20% response rate as a single agent. However, when used in combination with either etoposide or a taxane such as docetaxel or paclitaxel, response rates are more than doubled to 40–50%. The combination of docetaxel and prednisone was recently shown to confer survival advantage when compared with the mitoxantrone-prednisone regimen, and this combination has now become the standard of care for hormone-refractory prostate cancer.

Gastrointestinal Cancers

Colorectal cancer (CRC) is the most common type of gastrointestinal malignancy. About 145,000 new cases are diagnosed each year in the USA; worldwide, nearly one million cases are diagnosed each year. At the time of initial presentation, only about 40–45% of cases are potentially curable with surgery. Patients presenting with high-risk stage II disease and stage III disease are candidates for adjuvant chemotherapy with an oxaliplatin-based regimen in combination with 5-FU plus leucovorin (FOLFOX or FLOX), or with oral capecitabine and are generally treated for up to 6–8 months following surgical resection. Treatment with this combination regimen reduces the recurrence rate after surgery by 35% in these patients and clearly improves overall patient survival compared with surgery alone.

Significant advances have been made over the past 10 years with respect to treatment of advanced, metastatic CRC. There are four active cytotoxic agents—5-FU, the oral fluoropyrimidine capecitabine, oxaliplatin, and irinotecan; and three active biologic agents—the anti-VEGF antibody bevacizumab and the anti-EGFR antibodies cetuximab and panitumumab. In general, a fluoropyrimidine with either intravenous 5-FU or oral capecitabine serves as the main pillar of combination regimens. Recent clinical studies have shown that FOLFOX/FOLFIRI regimens in combination with the anti-VEGF antibody bevacizumab or with the anti-EGFR antibody cetuximab result in significantly improved clinical efficacy with no worsening of the toxicities normally observed with chemotherapy. In order for patients to derive maximal benefit, they should be treated with each of these active agents in a continuum of care approach. Using this strategy, median survivals now are in the 24–26 month range, and in some cases, approach 3 years. With so many treatment options, one of the main challenges facing clinicians is to begin to identify which patients would benefit from these various cytotoxic and biologic agents as well as identify who might experience increased toxicity.

The incidence of gastric cancer, esophageal cancer, and pancreatic cancer is much lower than for colorectal cancer, but these malignancies tend to be more aggressive and result in greater tumor-related symptoms. In most cases, they cannot be completely resected surgically, as most patients present with either locally advanced or metastatic disease at the time of their initial diagnosis. 5-FU-based chemotherapy, using either intravenous 5-FU or oral capecitabine, is generally considered the main backbone for regimens targeting gastroesophageal cancers. In addition, cisplatin-based regimens in combination with either irinotecan or with one of the taxanes, paclitaxel or docetaxel, also exhibit clinical activity. Response rates in the 40–50% range are now being reported. In addition, neoadjuvant approaches with combination chemotherapy and radiation therapy prior to surgery appear to have promise in selected patients. Although gemcitabine is approved for use as a single agent in metastatic pancreatic cancer, the overall response rate is less than 10%, with no complete responses. Intense efforts continue to be placed on incorporating gemcitabine into various combination regimens and on identifying novel agents that target signal transduction pathways thought to be critical for the growth of pancreatic cancer. One such agent is the small molecule inhibitor erlotinib, which targets the EGFR-associated tyrosine kinase. This agent is now approved for use in combination with gemcitabine in locally advanced or metastatic pancreatic cancer although the improvement in clinical benefit demonstrated thus far is small.

Lung Cancer

Lung cancer is divided into two main histopathologic subtypes, non-small cell and small cell. Non-small cell lung cancer (NSCLC) makes up about 75–80% of all cases of lung cancer, and this group includes adenocarcinoma, squamous cell cancer, and large cell cancer, while small cell lung cancer (SCLC) makes up the remaining 20–25%. When NSCLC is diagnosed in an advanced stage with metastatic disease, the prognosis is extremely poor, with a median survival of about 8 months. It is clear that prevention (primarily through avoidance of cigarette smoking) and early detection remain the most important means of control. When diagnosed at an early stage, surgical resection can result in patient cure. Moreover, recent studies have shown that adjuvant platinum-based chemotherapy provides a survival benefit in patients with pathologic stage IB, II, and IIIA disease. However, in most cases, distant metastases have occurred at the time of diagnosis. In certain instances, radiation therapy can be offered for palliation of pain, airway obstruction, or bleeding and to treat patients whose performance status would not allow for more aggressive treatments.

In patients with advanced disease, palliative systemic chemotherapy is generally recommended. At this time, for patients with good performance status and those with nonsquamous histology, the combination of the anti-VEGF antibody bevacizumab with carboplatin and paclitaxel has become the treatment of choice. In patients who are deemed not to be candidates for bevacizumab therapy, a platinum-based chemotherapy regimen in combination with the anti-EGFR antibody cetuximab is a reasonable treatment option.

Small cell lung cancer is the most aggressive form of lung cancer, and it is extremely sensitive to platinum-based combination regimens, including cisplatin and etoposide or cisplatin and irinotecan. The topoisomerase I inhibitor topotecan is used as second-line monotherapy in patients who have failed a platinum-based regimen. When diagnosed at a limited stage, this disease is potentially curable with a combined modality approach using chemotherapy and radiation therapy.

Ovarian Cancer

In the majority of patients, this cancer remains occult and becomes symptomatic only after it has already metastasized to the peritoneal cavity. At this stage, it usually presents with malignantascites. It is important to accurately stage this cancer with laparoscopy, ultrasound, and CT scanning. Patients with stage I disease appear to benefit from whole-abdomen radiotherapy and may receive additional benefit from combination chemotherapy with cisplatin and cyclophosphamide.

Combination chemotherapy is the standard approach to stage III and stage IV disease. Randomized clinical studies have shown that the combination of paclitaxel and cisplatin provides survival benefit compared with the previous standard combination of cisplatin plus cyclophosphamide. More recently, carboplatin plus paclitaxel has become the treatment of choice. In patients who present with recurrent disease, the topoisomerase I inhibitor topotecan, the alkylating agent altretamine, and liposomal doxorubicin are used as single agent monotherapy.

Testicular Cancer

The introduction of platinum-based combination chemotherapy has made an impressive change in the treatment of patients with advanced testicular cancer. At present, chemotherapy is recommended for patients with stage IIC or stage III seminomas and nonseminomatous disease. Over 90% of patients respond to chemotherapy and, depending upon the extent and severity of disease, complete remissions are observed in up to 70–80% of patents. Over 50% of patients achieving complete remission are cured with chemotherapy. In patients with good risk features, three cycles of cisplatin, etoposide, and bleomycin (PEB protocol) or four cycles of cisplatin and etoposide yield virtually identical results. In patients with high-risk disease, the combination of cisplatin, etoposide, and ifosfamide can be used as well as etoposide and bleomycin with high-dose cisplatin.

Malignant Melanoma

Malignant melanoma is curable when it presents locally and is surgically resected. However, once it spreads to metastatic sites, it is one of the most difficult neoplasms to treat as it is a relatively drug-resistant tumor. While dacarbazine, temozolomide, and cisplatin are the most active cytotoxic agents for this disease, the overall response rates to these agents remains low. Biologic agents, including interferon-alfa and interleukin-2 (IL-2), have greater activity than traditional cytotoxic agents, and treatment with high-dose IL-2 has led to cures, albeit in a small subset of patients. Several clinical trials are actively investigating the combination of biologic therapy with combination chemotherapy in what has been labeled biochemotherapy regimens. To date, overall response rates as well as complete response rates appear to be much higher with biochemotherapy regimens compared with chemotherapy alone. Unfortunately, treatment toxicity also seems to be increased. This approach remains investigational, and further studies are required to determine whether this approach can lead to improved patient survival.

Brain Cancer

Chemotherapy has only limited efficacy in the treatment of malignant gliomas. In general, the nitrosoureas, because of their ability to cross the blood-brain barrier, are the most active agents in this disease. Carmustine (BCNU) can be used as a single agent, or lomustine (CCNU) can be used in combination with procarbazine and vincristine (PCV regimen). In addition, the newer alkylating agent temozolomide is active when combined with radiotherapy and used in patients with newly diagnosed glioblastoma multiforme (GBM) as well as in those with recurrent disease. The histopathologic subtype oligodendroglioma has been shown to be especially chemosensitive, and the PCV regimen is the treatment of choice for this disease. There is growing evidence that the anti-VEGF antibody alone or in combination with irinotecan has promising activity in adult GBM and small molecule inhibitors of VEGFR-TKs also are showing interesting clinical activity in adult brain tumors.

Secondary Malignancies & Cancer Chemotherapy

The development of secondary malignancies is a late complication of the alkylating agents and the epipodophyllotoxin etoposide. The most frequent secondary malignancy is acute myelogenous leukemia (AML), and it has been observed in up to 15% of patients with Hodgkin's lymphoma who have received radiotherapy plus MOPP chemotherapy and in patients with multiple myeloma, ovarian carcinoma, or breast carcinoma treated with melphalan. The increased risk of AML is observed as early as 2–4 years after the initiation of chemotherapy and typically peaks at 5 and 9 years. With improvements in the clinical efficacy of various combination chemotherapy regimens resulting in prolonged survival and in some cases actual cure of cancer, the issue of how second cancers may affect long-term survival assumes greater importance. There is already evidence that certain alkylating agents (eg, cyclophosphamide) may be less carcinogenic than others (eg, melphalan). Other secondary malignancies have been well-described, including non-Hodgkin's lymphoma and bladder cancer, the latter most typically associated with cyclophosphamide therapy.

Preparations Available

The reader is referred to the manufacturer's literature for the most recent information on preparations available.

References

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