Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

104. Cancer Treatment and Chemotherapy

Stacy S. Shord and Patrick J. Medina


 Images Carcinogenesis is a multistep process that includes initiation, promotion, conversion, and progression. The growth of normal and cancerous cells is genetically controlled by the balance or imbalance of oncogene and tumor suppressor gene protein products. Multiple genetic mutations are required to convert normal cells to cancerous cells. Apoptosis and cellular senescence (aging) are normal mechanisms for cell death.

 Images Several signaling pathways are dysregulated in many common cancers. Several agents have been developed to prevent signal transduction through these pathways. Monoclonal antibodies, which competitively bind to extracellular receptors or their natural ligands, and targeted drugs, which target a component of the intracellular signal transduction pathway, are available for several cancers.

 Images Tumors must develop new blood vessels through the process of angiogenesis in order to grow. This process, regulated by proangiogenic and antiangiogenic factors, becomes dysregulated in several cancers and can lead to tumor growth, invasion, and metastasis. New anticancer agents can target this process and decrease tumor growth.

 Images Because patients with clinically evident metastatic cancer can rarely be cured, early detection is critical. Screening programs are designed to detect cancers in asymptomatic people who are at risk of a specific cancer. Knowing the early warning signs of cancer is also important in early detection, when cancers are most likely to be localized.

 Images Treatment for cancer should not begin until the presence of cancer is confirmed by a tissue (e.g., histologic) diagnosis. Clinical cancer staging provides prognostic information, and in conjunction with the patient’s treatment goals, guides the selection of anticancer treatment. The goals include cure, prolongation of life, and palliation. Surgery and radiation provide the best chance of cure for patients with localized cancers, but systemic treatment methods are required for disseminated cancers.

 Images Adjuvant therapy is systemic therapy that is administered to treat any existing micrometastases remaining after surgical excision of localized disease. Because adjuvant therapy is given to patients with no remaining clinical evidence of cancer, the benefit of the treatment cannot be proven for an individual patient but only for patient populations. Treatment decisions are based largely on an assessment of the presence of risk factors in an individual patient and their estimated risk for cancer recurrence. The effectiveness of adjuvant therapy is measured by the relative and absolute reduction in the risk of recurrence.

 Images Traditional chemotherapy affects rapidly proliferating cells. Chemotherapy can be either “cell-cycle phase specific,” targeting one specific phase of the cell cycle, or “cell-cycle phase nonspecific,” targeting all proliferating cells regardless of their place in the cell cycle. Whereas cell-cycle phase-specific chemotherapies are generally given more frequently or as continuous infusions, cell-cycle phase-nonspecific chemotherapies are usually given as a single dose.

 Images Monoclonal antibodies recognize an antigen that is expressed preferentially on cancer cells or target growth factors responsible for cancer growth. These therapies can vary in the amount of foreign component that can be used to predict tolerability. Monoclonal antibodies that target cellular antigens induce cell death by a variety of mechanisms that involve the host immune system. These antibodies can also be used to deliver drugs, radioisotopes, or toxins to the antigen-expressing cells.

 Images Understanding the mechanism of toxicities can lead to more effective prevention and treatment of these toxicities. Prospective dose modification of some chemotherapy and targeted therapies are essential in patients with impaired organ function to reduce the risk of severe adverse events. Identification of genetic variations that affect activation and metabolism may permit the development of individualized therapy that optimize effectiveness and minimize toxicity.

 Images Myelosuppression is the acute dose-limiting toxicity for most nonspecific chemotherapy. Whereas anemia can cause fatigue in patients with cancer, the risk of infection in patients is related to the depth and duration of neutropenia. Unexplained fever in neutropenic patients requires prompt initiation of empiric antibiotic therapy. Colony-stimulating factors are available to improve fatigue in patients with anemia and reduce the risk of febrile neutropenia. Evidence-based clinical guidelines should direct the use of these supportive care measures.


Cancer is a group of more than 100 different diseases that are characterized by uncontrolled cellular growth, local tissue invasion, and distant metastases.1 It is now the leading cause of death in Americans younger than age 85 years. Nearly 1.7 million cases of cancer were projected for 2013 with an estimated 580,350 lives claimed in the United States.2 Figure 104-1 illustrates the estimated incidence of common cancers and cancer-related deaths. The four most common cancers are prostate, breast, lung, and colorectal cancer. The most common cause of cancer-related deaths in the United States is lung cancer, which accounts for about 160,000 deaths each year. These cancers are discussed in further detail in the chapters that follow.


FIGURE 104-1 Estimated 2013 cancer incidences (top) and deaths (bottom) in the United States for males and females. *Estimate are rounded to the nearest 10 and exclude basal cell and squamous cell skin cancers and in situ carcinoma except urinary bladder. (Reproduced with permission from Siegel et al.2)

The roles of healthcare providers in the management of patients with cancer can be very diverse. Thorough knowledge of the pharmacology and the pharmacokinetics of anticancer agents is essential to prevent and manage toxicities. Supportive care issues, such as nutritional support, pain management, infection, and nausea and vomiting, require application of clinical, pharmacologic, and economic principles. Provision of drug information to other healthcare providers and to patients and their families is another critical role. Experienced healthcare providers are able to fulfill these roles and make valuable contributions to patient care in the oncology setting.

This chapter introduces the basic concepts of carcinogenesis, tumor growth, and anticancer treatment; provides general information on the pharmacology and clinical use of anticancer agents; and presents an overview of supportive care issues.



Images The mechanisms by which cancers occur are incompletely understood. A cancer is thought to develop from a cell in which the normal mechanisms for control of growth and proliferation are altered. Current evidence supports the concept of carcinogenesis as a multistage process that is genetically regulated.36 The first step in this process is initiation, which requires exposure of normal cells to carcinogenic substances. These carcinogens produce genetic damage that, if not repaired, results in irreversible cellular mutations. This mutated cell has an altered response to its environment and a selective growth advantage, giving it the potential to develop into a clonal population of neoplastic cells. During the second phase, known as promotion, carcinogens or other factors alter the environment to favor growth of the mutated cell population over normal cells. The primary difference between initiation and promotion is that promotion is a reversible process. Because it is reversible, the promotion phase may be the target of future chemoprevention strategies, including changes in lifestyle and diet. At some point, however, the mutated cell becomes cancerous (conversion or transformation). Depending on the cancer, 5 to 20 years may elapse between the initiation and promotion and the development of a clinically detectable cancer. The final stage of neoplastic growth, called progression, involves further genetic changes leading to increased cell proliferation. The critical elements of this phase include tumor invasion into local tissues and the development of metastases.

Substances that may act as carcinogens or initiators include chemical, physical, and biologic agents.5 Exposure to chemicals may occur by virtue of occupational and environmental means, as well as lifestyle habits. The association of aniline dye exposure and bladder cancer is one such example. Benzene is known to cause leukemia. Some drugs and hormones used for therapeutic purposes are also classified as carcinogenic chemicals (Table 104-1). Physical agents that act as carcinogens include ionizing radiation and ultraviolet light; radiation induces mutations by forming free radicals that damage DNA (deoxyribonucleic acid) and other cellular components. Viruses are biologic agents that are associated with certain cancers. The Epstein-Barr virus (EBV) is believed to be an important factor in the initiation of Burkitt lymphoma. Likewise, infection with human papilloma virus (HPV) is known to be a major cause of cervical cancer and head and neck cancers. All of the previously mentioned carcinogens, as well as age, gender, diet, growth factors, and chronic irritation, are among the factors considered to be promoters of carcinogenesis.

TABLE 104-1 Selected Drugs and Hormones Known to Cause Cancer in Humans


Genetic and Molecular Basis of Cancer

Images In recent years, there has been marked progress in our understanding of the genetic changes that lead to the development of cancer, largely because of improvements in research techniques and new genomic information.3,57Two major classes of genes are involved in carcinogenesis: oncogenes and tumor suppressor genes. Figure 104-2 illustrates the acquired capabilities of cancer cells that differ from normal cellular function.8 Oncogenes develop from normal genes, called protooncogenes, and may have important roles in all phases of carcinogenesis. Protooncogenes are present in all cells and are essential regulators of normal cellular functions, including the cell cycle. Genetic alteration of the protooncogene through point mutation, chromosomal rearrangement, or gene amplification activates the oncogene. These genetic alterations may be caused by carcinogenic agents such as radiation, chemicals, or viruses (somatic mutations), or they may be inherited (germ-line mutations). After activation, the oncogene produces either excessive amounts of the normal gene product or an abnormal gene product. The result is dysregulation of normal cell growth and proliferation, which imparts a distinct growth advantage to the cell and increases the probability of neoplastic transformation. An example is the human epidermal growth factor receptor (HER) family of oncogenes. This family of receptor tyrosine kinases contains four members: epidermal growth factor receptor (EGFR), HER2, HER3, and HER4. When activated, these receptors mediate cell proliferation and differentiation of cells through activation of intracellular tyrosine kinase receptors and downstream signaling pathways. As an oncogene, the gene product is overexpressed or amplified, resulting in excessive cellular proliferation, metastasis, angiogenesis, and cell survival in several cancers. Table 104-2 lists examples of oncogenes by their cellular function.9


FIGURE 104-2 Functional capabilities acquired by cancer cells, including angiogenesis, self-proliferation, insensitivity to antigrowth signals and limitless growth potential, metastasis, and antiapoptotic effects. It is thought that most, if not all, cancer cells acquire these functions through a variety of mechanisms, including activation of oncogenes and mutations in tumor suppressor genes. (Reprinted from Cell, Vol 144(5), Hanahan D, Weinberg RA, The Hallmarks of Cancer: The Next Generation, Copyright © 2011, with permission from Elsevier.)

TABLE 104-2 Examples of Oncogenes and Tumor Suppressor Genes


In contrast, tumor suppressor genes regulate and inhibit inappropriate cellular growth and proliferation.3,6,7 Gene loss or mutation results in loss of control over normal cell growth. Two common examples of tumor suppressor genes are the retinoblastoma (Rb) and p53 genes. Mutation of p53 is one of the most common genetic changes associated with cancer, and it is estimated to occur in half of all cancers.7 The normal gene product of p53 is responsible for negative regulation of the cell cycle, allowing the cell cycle to halt for repairs, corrections, and responses to other external signals. Inactivation of p53 removes this checkpoint, allowing mutations to occur. Mutation of p53 is linked to a variety of cancers, including brain tumors (astrocytoma); carcinomas of the breast, colon, lung, cervix, and anus; and osteosarcoma. Another important function of p53 may be modulation of cytotoxic drug effects. Loss of p53 is associated with anticancer drug resistance.

Another group of genes important in carcinogenesis are the DNA repair genes. The normal function of these genes is to repair DNA that is damaged by environmental factors or errors in DNA that occur during replication.6 If not corrected, these errors can result in mutations that activate oncogenes or inactivate tumor suppressor genes. As more mutations in the genome occur, the risk for malignant transformation increases. The DNA repair genes have been classified as tumor suppressor genes, because a loss in their function results in an increased risk for carcinogenesis. Deficiencies in DNA repair genes have been discovered in familial colon cancer (hereditary nonpolyposis colon cancer) and breast cancer.

Images Oncogenes and tumor suppressor genes provide the stimulatory and inhibitory signals that ultimately regulate the cell cycle.3,7 These signals converge on a molecular system in the nucleus known as the cell-cycle clock. The function of the clock in normal tissue is to integrate the signal input and to determine if the cell cycle should proceed. The clock is composed of a series of interacting proteins, the most important of which are cyclins and cyclin-dependent kinases (CDKs). Cyclins (especially cyclin D1) and CDKs promote entry into the cell cycle and are overexpressed in several cancers, including breast cancer. CDK inhibitors have been identified as important negative regulators of the cell cycle.

The cell cycle proceeds from one cell division to the next. The cycle involves five phases: DNA replication (S phase), cell division (M phase), two resting phases (G1, G2), and a nondividing state (G0 phase). In the first resting phase G1, the cell grows in size and decides to commit to the cell cycle or remain in a resting state. If the cell is normal the cell will move into the S phase to synthesize its DNA. Next, the cell enters the second resting phase G2, in which the cell prepares to divide. In the M phase, the cell enters mitosis and yields two daughter cells. If the cell is not normal the cell can stop dividing and initiate apoptosis.

Four checkpoints exist within the cell cycle, one in each phase of the cell cycle, and serve as quality control checkpoints. The cell will not proceed to the next phase unless all requirements for the current phase are met. Complexes of cyclin and CDK regulate these checkpoints. These complexes lead to the activation of other proteins that are responsible for the specific events of each phase of the cell cycle. The first checkpoint is called the restriction site. The restriction site is controlled by Rb complexed to a transcription factor called E2F. The presence of this complex prevents cell-cycle progression. A cell can proceed beyond the G1 restriction site and continue into the S phase, when cyclin–CDK complexes phosphorylate Rb and target it for degradation. A cell may alternatively withdraw into the G0 phase in the presence of antimitogenic or the absence of mitogenic factors.10

Images When the normal regulatory mechanisms for cellular growth fail, backup defense systems may be activated. The secondary defenses include apoptosis (programmed cell death or suicide) and cellular senescence (aging). Apoptosis is a normal mechanism of cell death required for tissue homeostasis.3,7,11 This process is regulated by oncogenes and tumor suppressor genes and is also a mechanism of cellular death after exposure to cytotoxins. Overexpression of oncogenes responsible for apoptosis may produce an “immortal” cell, which has increased potential for malignancy. The bcl-2 oncogene is an example. The most common chromosomal abnormality found in lymphoid malignancies is the t(14;18) translocation. The bcl-2 protooncogene is normally located on chromosome 18. Translocation of this protooncogene to chromosome 14 in proximity to the immunoglobulin heavy chain gene leads to overexpression of bcl-2, which decreases apoptosis and confers a survival advantage to the cell. Studies show that p53 is also a regulator of apoptosis. Loss of p53 disrupts normal apoptotic pathways, imparting a survival advantage to the cell. Apoptosis may also play an important role as a mechanism of inherent resistance to chemotherapy.11

Cellular senescence is another important defense mechanism.6,7 Laboratory studies demonstrate that after a cell population has undergone a preset number of doublings, growth stops, and cells die. This is known as senescence, a process that is regulated by telomeres. Telomeres are the DNA segments or caps at the ends of chromosomes. They are responsible for protecting the end of the DNA from damage. With each replication, the length of the telomeres is shortened. After the telomeres are shortened to a critical length, senescence is triggered. In this way, telomeres tally and limit the number of cell doublings. In cancer cells, the function of telomeres is overcome by overexpression of an enzyme known as telomerase. Telomerase replaces the portion of the telomeres that is lost with each cell division, thereby avoiding senescence and permitting an infinite number of cell doublings. Telomerase is a target for anticancer agent development.

Images As information regarding the role of oncogenes and tumor suppressor genes accumulated, it became evident that a single mutation is probably insufficient to initiate cancer.47 Scientists postulate that combinations of mutations are required for carcinogenesis and that each mutation is inherited by the next generation of cells. Thus, several detectable genetic mutations may be present in an established tumor. Whereas early mutations are found in both premalignant lesions and established tumors, later mutations are found only in the established tumor. This theory of sequential genetic mutations resulting in cancer has been demonstrated in colon cancer. In colon cancer, the initial genetic mutation is believed to be loss of the adenomatous polyposis coli gene, which results in formation of a small benign polyp. Oncogenic mutation of the ras gene is often the next step, leading to enlargement of the polyp. Loss of function of DNA mismatch repair enzymes may occur at many points in the progression of malignant transformation. Loss of the p53 gene and another gene, believed to be the deleted in colorectal cancer (DCC) gene, completes the transformation into a malignant lesion. Loss of p53 is thought to be a late event in the development and progression of the malignancy.

Identification of genes and other proteins involved in carcinogenesis has several important clinical implications. They may be used in cancer screening to identify individuals at increased risk for cancer and are being used to design new anticancer agents and gene therapies, several of which have recently been approved for use. Specific genetic abnormalities are so commonly associated with some cancers that the presence of that abnormality may aid in the diagnosis of that cancer. If the presence of these genes (i.e., gene expression profile) can reliably predict the clinical course of a cancer or response to certain cancer therapies, then genetic analysis may also become an important prognostic and treatment decision tool. An example of this is overexpression of HER2 predicting response to trastuzumab.9

Oncogenes and Tumor Suppressor Genes

Recent advances in molecular biology have identified many oncogenes and tumor suppressor genes that contribute to the functional capabilities that are acquired by cancer cells. These activated oncogenes and mutated tumor suppressor genes can be segregated into families and identified by their interactions with specific intracellular signaling pathways. Monoclonal antibodies (MoABs) have been developed to target the extracellular receptors or their natural ligands and prevent ligand binding to the receptor. In addition, small molecular inhibitors that target intracellular tyrosine kinases receptors or signal transduction pathways are available. The net effect of both strategies is to prevent downstream activation of the signal transduction resulting in a decrease in cell proliferation (Fig. 104-3). Some common receptors and pathways targeted by available targeted drugs and MoABs include HER, vascular endothelial growth factor (VEGF), mitogen-activated protein kinase pathway (MAPK) and phosphatidylinositide 3-kinase (PI3K) pathway.


FIGURE 104-3 Common elements of intracellular signaling pathways and targeted strategies that inhibit these pathways, such as (1) monoclonal antibodies (MoABs) against the growth factor receptor, (2) MoABs against the growth factor itself, (3) molecules that target intracellular tyrosine kinases and prevent phosphorylation of tyrosine residues and subsequent activation of downstream signals, and (4) targeting downstream signals. All targeted therapies have the same goal of decreasing cell proliferation and increasing cell death of cancer cells. (MAPK, mitogen-activated protein kinase.)

Human Epidermal Growth Factor Receptors

Images Targeting the HER pathway is currently used to treat a variety of solid tumors. The HER family of receptors contains four known members, which upon binding to growth factor ligands result in intracellular phosphorylation of transcription factors and cell proliferation (Fig. 104-4).9,12,13 EGFR and HER2 are known to be overexpressed in several cancers, including breast, lung, gastric, and colon cancers. Activation of these receptors leads to uncontrolled cellular growth and proliferation, tumor metastasis, and the prevention of apoptosis in cancer cells.12 The roles of HER3 and HER4 in cancer growth and proliferation are still under investigation. All members of this family contain a transmembrane glycoprotein extracellular ligand binding site, a transmembrane domain, and a cytosolic tyrosine kinase tail. Members of the HER family are inactive by themselves and must form a dimer (a molecule composed of two subunits) either with a member of the same family (homodimer) or with a member of a different HER family (heterodimer).22 Dimerization of the receptor leads to tyrosine kinase phosphorylation and subsequent activation of downstream pathways required to activate signal transduction and cell growth.


FIGURE 104-4 The human epidermal growth factor receptor (HER) family of growth factor receptors. All members of the HER family contain a transmembrane glycoprotein, an extracellular ligand binding site, and a hydrophobic intracellular portion with a tyrosine kinase domain. HER1 (or more commonly called EGFR [epidermal growth factor receptor]) has several known ligands, and HER2 has no known ligands, but the significance of ligands for HER3 and HER4 is unknown at this time. After the molecule binds to another member of the HER family, the tyrosine kinase domain is phosphorylated, and genes regulating proliferation, antiapoptosis, and cell transformation are turned on. (TGF, transforming growth factor.)

Vascular Endothelial Growth Factor

Images Vascular endothelial growth factor (VEGF) is a protein that stimulates angiogenesis, which is the development of new blood vessels. Angiogenesis is a process important for normal physiologic processes, but becomes unregulated in several malignancies and can lead to tumor growth, invasion, and metastasis. This process is regulated by pro- and antiangiogenic growth factors, which are released in response to hypoxia and other stresses to the cell.14 Proangiogenic growth factors include VEGF, fibroblast growth factors, platelet-derived growth factor (PDGF), tumor necrosis factor-α (TNF-α), and keratinocyte growth factor. Antiangiogenic growth factors include interleukin-12 (IL-12), interferons (IFNs), platelet factor 4, and tissue inhibitors of metalloproteinase.15

The best studied proangiogenic factor is VEGF, whose elevated levels have been associated with a poor prognosis and an increased risk of metastases in a variety of malignancies, including acute myelogenous leukemia (AML), breast cancer, hepatocellular carcinoma, non–small cell lung cancer (NSCLC), ovarian cancer, and colon cancer.15 Similar to other growth factors, VEGF binds to specific receptors located on the extracellular domain of growth factor receptors. Three known receptors of VEGF have been identified: VEGFR-1, -2, and -3.15 The VEGFR-1 and VEGFR-2 receptors are expressed primarily in endothelial cells and in some cancer cells and mediate the biologic effects of VEGF. Each of the receptors induces a different signal transduction pathway. These pathways eventually result in the generation of proteases that are necessary for the breakdown of the extracellular matrix, the first step of angiogenesis. Interference with their ability to develop new blood vessels by means of antiangiogenic agents can limit or prevent tumor growth.15

Intracellular Signaling Pathways

Well-described intracellular signaling pathways include PI3K, JAK-STAT (Janus kinase–signal transducers and activators of transcription), and MAPK pathways; when activated, they promote cell proliferation and survival. These pathways consist of a chain of proteins that ultimately communicate a signal to the DNA found in the nucleus from a cell surface receptor (e.g., EGFR). A protein within a signaling pathway communicates by adding a phosphate group to its neighboring protein; the phosphate groups act as “on” or “off” switch for the pathway. In cancer, a mutated protein permits the pathway to remain in the “on” or “off” position. The downstream effectors of these pathways also initiate cell cycle progression by promoting the expression of cyclins and repressing the expression of CDK inhibitors.

The MAPK signaling pathways regulates many fundamental cellular processes, including cell differentiation, proliferation, and senescence. These pathways relay the intracellular signals through a series of Ras, Raf, MEK (MAPK/ERK) and ERK (extracellular signaling receptor kinase) proteins that subsequently phosphorylate and regulate nuclear and cytoplasmic structures. Some of these proteins are commonly mutated in pancreatic, melanoma, colorectal, hepatocellular, and other solid tumors.16

The PI3K signaling pathway also regulates cell proliferation, growth, survival, and mobility. PI3K becomes activated in response to growth hormones, and it ultimately activates AKT, a serine–threonine kinase that serves as a master switch for the cell cycle progression. Fully activated AKT translocates to the nucleus, where it can inhibit proapoptotic signals and activate antiapoptotic substrates. It can also phosphorylate mammalian target of rapamycin (mTOR). After being activated, mTOR stimulates protein synthesis by phosphorylating translation regulators. mTOR also contributes to protein degradation and angiogenesis.17 Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene that blocks intracellular signaling through this pathway and is frequently inactivated in several solid tumors.18,19

The JAK-STAT signaling pathway helps regulate the immune system. This pathway contains three main components: extracellular receptors, JAKs, and STAT. The pathway is initiated when cytokines or growth factors bind to the receptor, activate JAK, and subsequently recruit STAT. The STAT proteins then translocate to the nucleus and modify gene expression. Altered JAK signaling has been associated with JAK mutations in patients with myelofibrosis.20


Epigenetics refers to changes in gene expression that occur without altering the DNA sequence.21 The two most common mechanisms of epigenetic regulation include methylation and histone modification. DNA methylation commonly occurs at CpG dinucleotides (or islands) and is catalyzed by DNA methyltransferases (DNMT). Histones are basic proteins associated with DNA in the nucleosome. These proteins may be modified by acetylation, methylation, or phosphorylation on their N-terminal tail. These modifications play a role in transcriptional regulation. For example, whereas histone deacetylases (HDACs) repress transcription, histone acetylases activate transcription. Epigenetic changes may be involved in the development of cancer by either priming the cell and making it susceptible to genetic changes associated with the development of cancer or initiating malignant transformation. As an example, hypermethylation at CpG dinucleotides found near tumor suppressor genes can switch these genes off and promote the development of cancer. Anticancer agents, identified as inhibitors of DNMT or HDAC, target these modifications. Figure 104-5 shows the effects of these inhibitors on methylation, chromatin formation, and transcription.


FIGURE 104-5 Epigenetic regulation of gene expression in cancer cells. CpG islands within the promoter and enhancer regions of the gene are methylated, resulting in the complexes with histone deacetylase (HDAC) activity. Chromatin is in a condensed conformation that inhibits transcription (upper figure). Inhibitors of DNMT in combination with inhibitors of HDAC confer a chromatin structure that allows transcription (lower figure). (From Longo DL. Cancer Cell Biology and Angiogenesis. In: Longo DL, Fauci AS, Kasper DL, et al. eds. Harrison’s Principles of Internal Medicine, 18th ed. New York, NY: McGraw-Hill, 2012.)


Tumor Origin

Tumors may arise from any of four basic tissue types: epithelial tissue, connective tissue (i.e., muscle, bone, and cartilage), lymphoid tissue, and nerve tissue. Most cancer cells retain enough traits to identify their basic tissue type; therefore, tumors are typically named based on the tissue of origin. For example, benign tumors are named for their cell or tissue of origin followed the suffix -omaTable 104-3 lists common tumor nomenclature by tissue type.6

TABLE 104-3 Tumor Classification by Tissue Type


Some cancers are preceded by cellular changes that are abnormal but not yet malignant. Correcting these early changes could potentially prevent the occurrence of a cancer. These precancerous lesions may be described as consisting of either hyperplastic or dysplastic cells. Hyperplasia is an increase in the number of cells in a particular tissue or organ, which results in an increased size of the organ. It should not be confused with hypertrophy, which is an increase in the size of the individual cells. Hyperplasia occurs in response to a stimulus and reverses when the stimulus is removed. Dysplasia is defined as an abnormal change in the size, shape, or organization of cells or tissues. Hyperplasia and dysplasia may precede the appearance of a cancer by several months or years.

Cancer cells are divided into those of epithelial origin or the other tissue types. Carcinomas are malignant growths arising from epithelial cells and sarcomas are malignant growths of muscle or connective tissue. Carcinoma in situ is a preinvasive stage of malignancy in which the cancer is limited to the epithelial cells or origin. Malignancies of hematologic origin, such as leukemias and lymphomas, are classified separately. Leukemias and lymphomas are discussed in later chapters.

Tumor Characteristics

Tumors may be either benign or malignant. Benign tumors are noncancerous growths that are often encapsulated, localized, and indolent. The cells of benign tumors resemble the cells from which they developed. These masses seldom metastasize, and after being removed, they rarely recur. In contrast, malignant tumors invade and destroy the surrounding tissue. The cells of malignant tumors are genetically unstable, and loss of normal cell architecture results in cells that are atypical of their tissue or cell of origin. These cells lose the ability to perform their usual functions. This loss of structure and function is called anaplasia. Malignant tumors tend to metastasize, and consequently, recurrences are common after removal or destruction of the primary tumor.

Invasion and Metastasis

Images Metastasis is the spread of cancer cells from the primary tumor site to distant sites.5,22 Despite advances in diagnostic techniques and screening for cancer, many patients have metastatic disease at diagnosis. When distant metastases are clinically evident, cancers are seldom curable. Newly diagnosed cancer patients may also have microscopic cancer metastases (i.e., micrometastases). Although clinically undetectable, these microscopic metastases must be present because many patients subsequently relapse at distant sites despite removal or destruction of the primary tumor. However, some patients with micro-metastatic disease may be cured with systemic therapy.

The two primary pathways of metastasis are hematogenous and lymphatic. Other less common modes of disease spread include dissemination via cerebrospinal fluid and transabdominal spread within the peritoneal cavity. Tumors constantly shed neoplastic cells into the systemic circulation or surrounding lymphatics. The onset and time course for the development of metastasis depends largely on the tumor biology. Breast cancer, for example, tends to metastasize very early. Not all of the shed cancer cells result in a metastatic lesion; the cells must first find an environment suitable for growth.22 This process is illustrated in the diverse patterns of metastasis observed for different cancers. As an example, prostate cancer commonly metastasizes to bone but rarely to the brain.

The process of invasion and metastasis involves several essential steps. After transformation, the cancer cells and surrounding host tissue secrete substances that stimulate angiogenesis.23 Cancer cells must then detach from the primary mass and invade surrounding blood and lymph vessels. The cancer cells or cell aggregates detach and embolize through these vessels, but most do not survive circulation. The disseminated cells must then attach to the vascular endothelium. The cells may proliferate within the lumen of the vessel but most commonly extravasate into the surrounding tissue. The local microenvironment may provide growth factors that can serve as “fertilizer” to potentiate the proliferation of the metastasis. At every step, the potential metastatic cell must fight the host immune system. Finally, the metastasis must again initiate angiogenesis to ensure continued growth and proliferation. Because angiogenesis has been recognized as a critical element in primary tumor growth as well as metastasis, it has become a target for development of new anticancer agents, which are described later in the chapter.



Because cancers are most curable before they have metastasized, early detection and treatment have obvious potential benefits. Cancer screening programs are designed to detect signs of cancer in people who have not yet developed symptoms from cancer. Lack of effective screening methods and inaccessible anatomic sites limit the availability of screening methods for some cancers. Other limitations of screening methods include false-negative test results (related to the sensitivity of the test), false-positive test result (related to the specificity), and overdiagnosis (true positives that will not become clinically significant). For example, most abnormal test results identified by a screening mammography are false-positive results, although the specificity of this screening method exceeds 90%. Public education on the early warning signs of common cancers is extremely important for facilitating early detection. Effective screening procedures exist for some cancers. The Papanicolaou (Pap) smear test, for example, is an effective tool to detect cervical cancer in its early stages. The American Cancer Society publishes yearly guidelines for routine screening examinations (Table 104-4).24

TABLE 104-4 Screening Guidelines for Early Detection of Cancer in Average-Risk, Asymptomatic People



The presenting signs and symptoms of cancer vary widely and depend on the cancer. The presentation in adults may include any of cancer’s seven warning signs (Table 104-5), pain, or loss of appetite.25 The warning signs of cancer in pediatrics are different and reflect the tumors more common in this population (Table 104-6).25 Even with increased public awareness, the fear of a cancer diagnosis can deter people from seeking medical attention. The definitive diagnosis of cancer relies on the procurement of a sample of the tissue or cells suspected of malignancy and pathologic assessment of this sample. This sample can be obtained by numerous methods, including biopsy, exfoliative cytology, or fine-needle aspiration. A tissue diagnosis is essential, because many benign conditions can masquerade as cancer. Definitive treatment should not begin without a pathologic diagnosis.

TABLE 104-5 Cancer’s Seven Warning Signs


TABLE 104-6 Cancer’s Warning Signs in Children


Staging and Workup

Images In addition to tissue diagnosis, tumors should be staged to determine the extent of disease before any definitive treatment is initiated. The process is dictated by knowledge of the biology of the tumor and by the signs and symptoms elicited in the history and physical examination. Staging provides information on prognosis and guides treatment selection. A staging workup may involve radiographs, computed tomography scans, magnetic resonance imaging, positron emission tomography scans, ultrasonograms, bone marrow biopsies, bone scans, lumbar puncture, and a variety of laboratory tests (including appropriate tumor markers). After treatment is implemented, the staging workup is usually repeated to evaluate the effectiveness of the treatment. Some cancers produce antigens or other substances; these tumor markers are often nonspecific and may be elevated in many different cancers or in patients with nonmalignant diseases. As a result, tumor markers are generally more useful for monitoring response and detecting recurrence than as diagnostic tools. Examples are human chorionic gonadotropin and alfa-fetoprotein in patients with testicular cancer or prostate-specific antigen in prostate cancer.6

The most commonly applied staging system for solid tumors is the TNM classification, where T = tumor, N = node, and M = metastases. A numerical value is assigned to each letter to indicate the size or extent of disease. The designated rating for a tumor describes the size of the primary mass and ranges from T1 to T4. Carcinoma in situ is designated as Tis. Nodes are described in terms of the extent of the spread of regional lymph nodal involvement (N0to N3). Metastases are generally scored depending on their presence or absence (M0 or M1). To simplify the staging process, most cancers are classified according to the extent of disease by a numerical system involving stages I through IV. Stage I usually indicates localized tumor, stages II and III represent local and regional spread of disease, and stage IV denotes the presence of distant metastases. The assigned TNM rating translates into a particular stage classification. For example, T3 N1 M0 describes a moderate- to large-sized primary mass, with regional lymph node involvement and no distant metastases and for most cancers is stage III. The criteria for classifying disease extent are quite specific for each different cancer.26 For some tumors, such as prostate cancer, alternative alphabetical systems (stage A, B, C, or D) are used in clinical practice. Leukemias and lymphomas follow alternate staging systems that are discussed in subsequent chapters.


Modalities of Cancer

Five primary modalities are used to treat cancer: surgery, radiation, traditional chemotherapy, targeted drug therapy, and biologic therapy. The oldest treatment modality is surgery, which plays a major role in the diagnosis and treatment of cancer. Surgery remains the treatment of choice for most solid tumors diagnosed in the early stages. Radiation therapy was first used for cancer treatment in the late 1800s and remains a mainstay in the management of cancer. Although very effective for treating many cancers, surgery and radiation are local treatments. These modalities are likely to produce a cure in patients with truly localized disease. Because most patients with cancer have micrometastatic or metastatic disease at diagnosis, localized anticancer treatment often fail to completely eliminate the cancer. In addition, systemic diseases such as leukemia cannot be treated with a localized modality. Chemotherapy, targeted drug therapies, and biologic therapies all access the systemic circulation and can theoretically treat the primary tumor or metastatic disease. Biologic therapies are made from a living organism or its products and include antibodies, vaccines, growth factors, and cytokines.

Images Many solid tumors or lymphomas appear to be eliminated by surgery or radiation. However, the high incidence of disease recurrence implies that the primary tumor metastasized before it was removed. Adjuvant therapy is the use of systemic therapy to eradicate micrometastatic disease after localized modalities, such as surgery or radiation. The goal of adjuvant therapy is to reduce recurrence rates and prolong long-term survival. Thus, adjuvant therapy is given to patients with potentially curable malignancies who have no clinically detectable disease after surgery or radiation. Because adjuvant therapy is given at a time when the cancer is undetectable (i.e., no measurable disease), its effectiveness is evaluated by recurrence rates and survival. The value of adjuvant therapy is best established in colorectal and breast cancers. Systemic therapy may also be given in the neoadjuvant or preoperative setting. The goals in these instances are to make other treatment modalities more effective by reducing tumor burden and destroying micrometastases. For example, in breast cancer, it is often used to reduce the size of the primary tumor and allow for a less invasive surgical procedure.

These modalities may be used alone, but are typically used in combination. Early-stage breast cancer is a good example of the use of a combined-modality approach. The primary tumor is removed surgically, and radiation therapy is delivered to the remaining breast (after lumpectomy) or to the axilla (if there is marked lymph node involvement). Adjuvant therapy, including chemotherapy and biologic therapy, is then administered to eradicate any micrometastatic disease. Neoadjuvant therapy may sometimes be administered before definitive surgery to increase the likelihood of a tumor resection compared with a mastectomy.

The management of hematologic malignancies also involves the use of combined modalities, but the terminology is different. Chemotherapy that is administered to eradicate the cancer cells is called induction therapy. When a complete remission (the disappearance of all signs of the cancer) is documented, postremission or consolidation therapy is administered. These therapies are designed to eradicate any remaining disease, similar to adjuvant therapy for solid tumors, and can include systemic therapy, a hematopoietic stem cell transplant, or radiation therapy. Maintenance therapy is sometimes administered after consolidation therapy. This therapy is given to prevent the cancer from recurring and may include combination chemotherapy.

When an anticancer agent is administered to patients with local or regional disease, the treatment is often administered to cure the patient and may be labeled curative therapy. However, when the cancer has metastasized to distant sites, cure is usually not possible. Anticancer agents can be administered to patients with metastatic disease to slow the progression of cancer and prolong survival by months to years. Anticancer agents administered to patients with terminal cancer with the goal of reducing symptoms is called palliative therapy.

The era of modern cancer chemotherapy was born in 1941 when Goodman and Gilman first administered nitrogen mustard to patients with lymphoma.27 Since then, numerous anticancer agents have been developed, and a variety of treatment regimens have been investigated in every cancer. Table 104-7 lists tumors and their responsiveness to chemotherapy.6,28 Chemotherapy may be indicated as a curative or palliative. Treatment with chemotherapy is the primary curative modality for a few diseases, including leukemias, lymphomas, choriocarcinomas, and testicular cancer. Most solid tumors are not curable with chemotherapy alone, either because of the biology of the tumor or because of advanced disease at presentation. Chemotherapy in this setting is often initiated for palliative purposes. It is often possible to decrease tumor size or to retard growth enough to reduce untoward symptoms caused by the tumor.

TABLE 104-7 The Role of Chemotherapy in the Treatment of Cancer



Principles of Tumor Growth

The study of tumor growth forms the foundation for many of the basic principles of modern cancer chemotherapy. The growth of most tumors is illustrated by the gompertzian tumor growth curve (Fig. 104-5).6,28,29 Gompertz was an insurance actuary who described the relationship between age and expected death. This mathematical model also approximates tumor cell proliferation. In the early stages, tumor growth is exponential, which means that the tumor takes a constant amount of time to double its size. During this early phase, most cancer cells are actively dividing. This population of cells is called the growth fraction. The doubling time, or time required for the tumor to double in size, is very short. Because most anticancer agents have greater effect on rapidly dividing cells, tumors are most sensitive to their effects when the tumor is small and the growth fraction is high. However, as the tumor grows, the doubling time is slowed.28,29 The growth fraction is decreased, probably owing to the tumor’s outgrowing its blood and nutrient supply or the inability of blood and nutrients to diffuse throughout the tumor mass. Wide variability exists in measured doubling times for different cancers. The doubling time of most solid tumors is about 2 to 3 months. However, some tumors have doubling times of only days (e.g., aggressive non-Hodgkin lymphomas [NHLs]), and others have even longer doubling times (e.g., some salivary gland tumors).6

Figure 104-6 also illustrates the impact of tumor burden. It takes about 109 cancer cells (1-g mass, 1 cm in diameter) for a tumor to be clinically detectable by palpation or radiography. Such a tumor has undergone about 30 doublings in cell number. It only takes 10 additional doublings for this 1-g mass to reach 1 kg in size. A tumor possessing 1012 cells (1-kg mass) is considered lethal. Thus, a tumor is clinically undetectable for most of its life span. Tumor burden also impacts response to treatment. The cell kill hypothesis states that a certain percentage of cells (not a certain number of cells) will be killed with each treatment course. For example, if a tumor consists of 1,000 cells and the treatment kills 90% of the cells, then 10% or 100 cells remain. The second treatment course kills another 90% of cells, and again only 10% or 10 cells remain. According to this hypothesis, the tumor burden will never reach zero. Tumors consisting of less than 104 cells are believed to be small enough for elimination by host factors, including immunologic mechanisms, and these factors must be in place for a cure to be possible. The limitations of this theory are that it assumes all cancers are equally responsive and that resistance to anticancer agents and metastases do not occur.1,6,28,29


FIGURE 104-6 Gompertzian kinetics tumor-growth curve: relationship to symptoms, diagnosis, and various treatment regimens. (Reproduced with permission from Buick RN. Cellular basis of chemotherapy. In: Dorr RT, Von Hoff DD, eds. Cancer Chemotherapy Handbook, 2nd ed. New York: Appleton & Lange/McGraw-Hill, 1994:3–14.)

Tumor Proliferation

Both cancer cells and normal cells reproduce in a series of steps known as the cell cycle as described earlier in the chapter. Figure 104-7 depicts the cell cycle and the phases of activity for some traditional chemotherapies.28,29


FIGURE 104-7 Cell-cycle activity for anticancer drugs. Cell-cycle phase-specific chemotherapies appear to be most active during a particular phase but may also be active in another phase. Cell-cycle phase-nonspecific chemotherapies may have greater activity in one phase than another but not to the degree of cell-cycle phase-specific chemotherapies. In many cases, it is likely that chemotherapy cytotoxicity involves multiple intracellular sites of action and may not be linked to specific cell-cycle events.

Images All cancer cells do not proliferate faster than normal cells; some cancer cells reproduce more rapidly, but others are more indolent. Many chemotherapies target rapidly proliferating cells (both normal and cancerous cells), and these therapies might act at selective or multiple sites of the cell cycle. Chemotherapy that demonstrates major activity in a particular phase of the cell cycle are known as cell-cycle phase-specific chemotherapies. For example, antimetabolites exert their major effect during the S phase. Cell-cycle phase-specific therapies may also be active to a lesser extent in other phases of the cycle. Cell-cycle phase-nonspecific chemotherapy are those with significant activity in multiple phases. Alkylating agents, such as nitrogen mustards, are examples of a cell-cycle nonspecific agent. In many cases, the cytotoxic effects of an agent may result from interactions with other intracellular activities and are not related to specific cell-cycle events. Endocrine therapies and targeted drugs are examples of these anticancer agents.

Knowledge of cell-cycle specificity has been use to optimize the scheduling of chemotherapy. By definition, cell-cycle phase-specific chemotherapies exert their major activity when cells are in a particular phase of the cell cycle. At any given time, the heterogeneous cell populations within a tumor are at various phases in the cell cycle. By giving cell-cycle phase-specific chemotherapies as a continuous infusion or in multiple repeated fractions, healthcare providers can theoretically target more cells as they progress into the sensitive phase. Thus, cell-cycle phase-specific chemotherapies are also termed schedule dependent. In contrast, cell-cycle phase-nonspecific chemotherapies are active in many phases and consequently are not schedule dependent. The activity of these chemotherapies depends on the dose and these chemotherapies are termed dose dependent.

Biologic therapies and targeted drugs interfere with cancer cell proliferation in a different manner compared with traditional chemotherapy. These therapies stop cancer progression by blocking aberrant intracellular signaling pathways that govern cell responses, movement, and division. Some of these agents can cause cancer cell death by inducing apoptosis or stimulating the immune system to destroy the cancer cells. Some targeted drug therapies and biologic therapies are used in combination with traditional chemotherapy.

Molecular Biology

Because many anticancer agents interfere with the cellular synthesis of DNA, RNA, and proteins, it is important to review the basic principles of molecular biology.3 Each normal human cell contains 46 chromosomes, which are composed of DNA. DNA carries hereditary information in units called genes. A single chromosome can contain 20,000 or more genes. Genes code for specific proteins that regulate cellular activity and inherited traits (some of which affect carcinogenesis and cancer growth, as well as the efficacy and metabolism of anticancer agents). The genetic information is encoded in DNA by precise sequencing of subunits known as nucleotides. Each nucleotide consists of a sugar (deoxyribose), phosphoric acid, and a base. Four bases exist in DNA: adenine, thymine, guanine, and cytosine. Adenine and guanine are purines, and thymine and cytosine are pyrimidines (Fig. 104-8). These nucleotides are connected linearly to form a chain. Each DNA molecule is made up of two chains of nucleotides, which wind around each other to form a double helix. The two strands are held together by chemical bonding between the bases. The bonding process is very specific—adenine binds only with thymine, and guanine binds only with cytosine. This is known as complementary base pairing. RNA is important in the DNA-directed synthesis of proteins or enzymes. RNA differs from DNA in that it is composed of a single strand of nucleotides, the sugar is ribose, and the base uracil is substituted for thymine. There are three known types of RNA: messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA).


FIGURE 104-8 Structures of DNA bases.

DNA Synthesis

During the DNA synthesis phase (S phase cell cycle), which takes place in the cell nucleus, the DNA unwinds and exposes its nucleotides. When DNA unwinds for replication or protein synthesis, only the portion of the molecule containing the needed nucleotides needs to be exposed. Rather than unwinding the entire strand, topoisomerase I and II enzymes cleave the DNA strands to facilitate unwinding of the section that is needed. The enzyme DNA polymerase matches free complementary nucleotides from the environment to the exposed nucleotides of the DNA. The newly created strands rewind, resulting in two complete double helices. The topoisomerase enzymes are also responsible for resealing the cleaved DNA strands. Most traditional chemotherapies interfere with DNA synthesis.

Protein Synthesis

The synthesis of proteins is a more complex process. Proteins consist of chains of amino acids in very specific sequences. As in DNA synthesis, the double helix must unwind. However, in protein synthesis, only the portion of the DNA molecule that codes for the desired protein is exposed. The enzyme RNA polymerase matches free complementary RNA nucleotides to the exposed DNA nucleotides, and the resultant chain of nucleotides is called mRNA. This process is called transcription. The mRNA travels to ribosomes in the cytoplasm, where protein synthesis occurs. Each three nucleotides of the mRNA chain compose a codon, whose sequence is specific for a particular amino acid. The codon is recognized by tRNA, which then carries the amino acid to the ribosome, where it is added to the growing peptide chain. This process is known as translation. The completed protein is then ready for its intended use as an enzyme or as a structural component. Targeted therapies, such as targeted drugs and MoABs, typically affect protein synthesis, including aberrant growth factor receptors, dysregulated intracellular signaling pathways, and defective apoptosis and angiogenesis. Whereas MoABs affect cell surface receptors, targeted drugs tend to inhibit intracellular signaling. Other anticancer agents that affect proteins include asparaginase and chemotherapy that interfere with microtubules.


Anticancer agents are commonly categorized by their mechanism of action or by their origin. Akylators exert their effects on DNA and protein synthesis by binding to DNA and preventing the unwinding of the DNA molecule. Antimetabolites resemble naturally occurring nuclear structural components (“metabolites”), such as the nucleotide bases, or inhibit enzymes involved in the synthesis of DNA and proteins. Antitumor antibiotics derive their name from their source; they are fermentation products of Streptomyces species. Figure 104-9 shows the sites of action of common categories of anticancer agents, including traditional chemotherapy, biologic therapies, and targeted drugs. The following sections address these classes of chemotherapies used in the treatment of cancer. The clinical uses, mechanisms, adverse events, and practical patient management for commonly used chemotherapies in each class are detailed. Table 104-8 summarizes dose modifications of individual chemotherapies.


FIGURE 104-9 Mechanisms of action of commonly used anticancer agents. (ATRA, all-trans-retinoic acid.) (From Chabner BA. General Principles of Chemotherapy. In: Brunton LL, Chabner BA, Knollman BC (eds). Goodman & Gilman’s The Pharmacologic Basis of Therapeutics, 12th ed. New York: McGraw-Hill, 2010.)

TABLE 104-8 Monitoring of Anticancer Drugs—a











Antimetabolites are similar to the nucleotides that make up DNA and RNA. The body mistakes these anticancer agents for the naturally occurring nucleotide bases and metabolizes these agents as the natural nucleotides. These anticancer agents ultimately disrupt replication and cell division by interfering with the production of nucleic acids, DNA, and RNA. Unfortunately, these compounds are not selective for cancer cells, and rapidly dividing normal cells may be poisoned. The most common adverse events associated with the antimetabolites are secondary to a direct cytotoxic effect on rapidly dividing normal cells, such as the bone marrow cells. The three major classes of antimetabolites include pyrimidines, purines, and folate antagonists.

Fluorinated Pyrimidines

5-Fluorouracil 5-Fluorouracil (5-FU) is a fluorinated analog of uracil that was originally synthesized in the late 1950s. It is a prodrug and undergoes sequential phosphorylation to a mono-, di-, and triphsophate similar to natural nucleotide bases to become an active anticancer agent. In the presence of folates, the monophosphate binds tightly to and interferes with the function of thymidylate synthase. This enzyme is required for synthesis of thymidine. The triphosphate metabolite is incorporated into RNA as a false base and interferes with its function. Interference with both thymidine formation and RNA function is important in producing the cytotoxic effects of 5-FU. Although 5-FU nucleotides can also be incorporated directly into DNA and affect its stability, the contribution to cell damage remains unclear. The method of administration influences the mechanism of action, with thymidylate synthesis inhibition playing a greater role in continuous-infusion regimens and incorporation into RNA being more important for intermittent bolus schedules.30

Several pharmacologic strategies have been attempted to increase the cytotoxicity of 5-FU against cancer cells and decrease its toxicity to normal cells. The most common strategy combines 5-FU with the reduced folate leucovorin. Folates increase the stability of the monophosphate-thymidylate synthase complex, thereby increasing the cytotoxicity and clinical activity of 5-FU.30 Dihydropyrimidine dehydrogenase (DPD) catabolize 5-FU and reduced expression of this enzyme has been associated with severe adverse events.31

Capecitabine Capecitabine is an oral pyrimidine uracil analog and is a prodrug of 5-FU. Because capecitabine is enzymatically converted to 5-FU, it shares the same mechanisms of action. It generates higher levels of 5-FU selectively within some tumors as compared with normal tissues. Because chronic twice-daily oral dosing of capecitabine produces sustained 5-FU levels similar to continuous IV infusions of 5-FU, the toxicity pattern is similar to that of a continuous infusion of 5-FU.30,32

The most common toxicities of fluoropyrimidines include neutropenia, thrombocytopenia, and anemia when administered as an IV bolus administration and hand-foot syndrome and diarrhea when administered as a continuous IV infusion.30,32

Cytidine Analogs

Cytarabine Cytarabine (ara-C) is an arabinose analog of cytosine. It is phosphorylated to its active triphosphate within cancer cells and inhibits DNA polymerase, an enzyme responsible for strand elongation. It is also incorporated directly into DNA, where it inhibits the replication of DNA and acts as a chain terminator to prevent DNA elongation. Deaminase enzymes, particularly cytidine deaminase, degrades ara-C.30,33

Cytidine deaminase levels are very low in the central nervous system (CNS). Therefore, cytotoxic concentrations of ara-C are maintained in the CNS for several hours after intrathecal administration of traditional cytarabine formulations and for more than 2 weeks after administration of a depot formulation.

The toxicity of cytarabine is dose dependent. The most characteristic toxicity associated with high-dose ara-C (>1 g/m2 per dose) is a cerebellar syndrome that manifests as dysarthria, nystagmus, and ataxia. The risk of CNS toxicity is strongly correlated with advanced age and renal dysfunction. Renal dysfunction permits accumulation of high levels of the triphosphate, which is believed to be neurotoxic. Hepatic dysfunction, high cumulative doses, and bolus dosing may also increase the risks of neurotoxicity.30,33

Gemcitabine Gemcitabine is a fluorine-substituted deoxycytidine analog that is related structurally to cytarabine. Its activation and mechanism of action are similar to those of cytarabine. Gemcitabine is incorporated into DNA, where it inhibits DNA polymerase activity. It also inhibits ribonucleotide reductase, which is the enzyme required to convert ribonucleotides into the deoxyribonucleotides that are needed for both DNA synthesis and repair. Compared with cytarabine, gemcitabine achieves intracellular concentrations about 20 times higher, secondary to increased penetration of cell membranes and greater affinity for the activating enzyme deoxycytidine kinase. Gemcitabine that is incorporated into DNA has a prolonged intracellular half-life. Its stereoconfiguration causes another normal base pair to be added next to the fraudulent gemcitabine base pair in the DNA strand. This “masked chain termination” protects the gemcitabine from excision and elimination.30,33

Purines and Purine Antimetabolites

Mercaptopurine and Thioguanine 6-Mercaptopurine (6-MP) and its analog thioguanine are rapidly converted to ribonucleotides that inhibit purine biosynthesis. They also undergo purine interconversion reactions needed to supply purine precursors for synthesis of nucleic acids. Clinical cross-resistance is generally observed.30 Both anticancer agents are metabolized by thiopurine methyltransferase (TPMT) and hypoxanthine phosphoribosyl transferase to produce multiple metabolites responsible for the efficacy, hepatic toxicity, and myelosuppression. Genetic polymorphisms of TPMT are associated with reduced enzyme activity and decreased tolerance of standard doses of 6-MP.

6-MP depends on xanthine oxidase for an initial oxidation step. Its metabolism is markedly decreased by concomitant administration of the xanthine oxidase inhibitor allopurinol, and serious toxicity may result. Oral 6-MP doses must be reduced when allopurinol is administered together with 6-MP.30

Fludarabine Monophosphate Fludarabine monophosphate is an analog of the purine adenine. Similar to cytarabine, fludarabine interferes with DNA polymerase, causing chain termination. Fludarabine also incorporates into RNA, resulting in inhibited transcription. The usual dose-limiting toxicity is myelosuppression. Fludarabine is also immunosuppressive, with associated opportunistic infections resulting from its effect on T cells and a subsequent decrease in CD4 counts; prophylactic antibiotics and antiviral medications are recommended and should continue until CD4 counts normalize.30,34

Cladribine and Pentostatin Cladribine and pentostatin are purine nucleoside analogs with slightly different mechanisms of action. Cladribine is resistant to inactivation by adenosine deaminase and triphosphorylated to an active form that is incorporated into DNA, resulting in inhibition of DNA synthesis and early chain termination. Its antitumor activity is unusual for an antimetabolite in that it affects both actively dividing and resting cancer cells. Pentostatin is a potent inhibitor of adenosine deaminase. Adenosine deaminase is an enzyme critical in purine base metabolism and is found in high concentrations in lymphatic tissue. Similar to fludarabine, these chemotherapies have immunosuppressive effects that place patients at risk for serious opportunistic infections.30,33


Folate vitamins are essential cofactors in DNA synthesis. These vitamins carry one-carbon groups in transfer reactions that are required for purine and thymidylic acid synthesis. Natural folates circulating in the blood have a single glutamic acid group, but natural folates within cells are converted to polyglutamates, which are more efficient cofactors and preferentially retained inside cells.35

Dietary folates must be chemically reduced to their tetrahydrofolate forms to be active. The enzyme responsible for this reduction is dihydrofolate reductase (DHFR). Antifolates are associated with neutropenia and thrombocytopenia, mucositis, and nausea and vomiting.

Methotrexate Methotrexate (MTX) inhibits DHFR, which results in the depletion of intracellular pools of reduced folates (tetrahydrofolates) essential for thymidylate and purine synthesis. Lack of either thymidine or purines prevents synthesis of DNA. The DHFR-mediated effects of antifolates on normal and tumor cells may be neutralized by supplying reduced folates exogenously. The reduced folate used clinically for “rescue” is leucovorin (folinic acid), which bypasses the metabolic block induced by DHFR inhibitors.35

Amplification of DHFR can lead to tumor cell resistance. Other potential causes of resistance are slow rates of thymidylate synthesis, decreased affinity for DHFR, lack of polyglutamation within cancer cells and saturated transport. In high doses, passive diffusion may overcome tumor cell resistance caused by saturated active transport systems. Malignant cells may achieve greater MTX polyglutamate levels than normal cells, which may, in part, explain the selective effects of MTX on malignant versus normal cells.35

Accurate and readily available assays for serum MTX levels have made therapeutic drug monitoring of MTX a valuable clinical tool. The threshold for cytotoxic effects of MTX is about 0.02 mg/L (50 nmol/L). Toxicity and efficacy relates not only to peak concentrations, but more importantly to time that concentrations remain above this threshold level. For MTX doses requiring leucovorin rescue (generally doses greater than 1,000 mg/m2), leucovorin must be administered until levels fall below 0.02 mg/L (50 nmol/L). Therapeutic drug monitoring is also an effective means of increasing the likelihood of therapeutic success by individualizing doses based on target levels.35 Renal tubular necrosis is seen with high-doses of MTX and vigorous hydration with or without alkalinization of the urine necessary to decrease risk of renal failure.

Glucarpidase has been approved for the treatment of toxic plasma MTX concentrations in patients with delayed MTX clearance because of impaired renal function. It is important to note that MTX concentrations within 48 hours after glucarpidase administration can only be reliably measured by chromatographic methods. Immunoassays can overestimate MTX concentration because of interference from metabolites.36

Pralatrexate Pralatrexate is an antifolate drug approved for patients with relapsed or refractory peripheral T-cell leukemias. It competitively inhibits DHFR. It is also a competitive inhibitor for polyglutamylation by the enzyme folylpolyglutamyl synthetase. This inhibition results in the depletion of thymidine and other synthesis of biological molecules that depends on single carbon transfer.37

Pemetrexed Pemetrexed is a multitargeted antifolate that inhibits at least three biosynthetic pathways in thymidine and purine synthesis. In addition to inhibiting DHFR, it also inhibits thymidine synthase and glycinamide ribonucleotide formyltransferase, decreasing the risk of the development of drug resistance. Severe hematologic toxicity and deaths associated with neutropenic sepsis have been reported in clinical trials. Elevated baseline cystathionine or homocysteine concentrations correlated with this unexpected toxicity. Routine supplementation of folic acid and vitamin B12 lowers levels of these substances and lowers the risk of mortality related to neutropenic sepsis. The approved labeling of pemetrexed requires administration of folic acid and vitamin B12 throughout the duration of treatment.27

Microtubule-Targeting Drugs

Vinca Alkaloids

Vincristine, vinblastine, and vinorelbine are natural alkaloids derived from the periwinkle (vinca) plant. They act as mitotic inhibitors, or “spindle poisons.” Although the alkaloids are very similar structurally, they have different activities and patterns of toxicity. Whereas vinorelbine and vinblastine are associated with dose-limiting myelosuppression, vincristine causes mild myelosuppressive effects but is more neurotoxic.

Vinca alkaloids bind to tubulin, the structural protein that polymerizes to form microtubules. These hollow tubes make up the mitotic spindle and are important in nerve conduction and neurotransmission. Vinca alkaloids disrupt the normal balance between polymerization and depolymerization of microtubules, inhibiting assembly of microtubules and disrupting microtubule dynamics. This interferes with formation of the mitotic spindle and causes cells to accumulate in mitosis. They also disturb a variety of microtubule-related processes in cells and induce apoptosis. Resistance to the vinca alkaloids develops primarily from P-glycoprotein (Pgp)-mediated multidrug resistance, which decreases drug accumulation and retention within cancer cells.38


Paclitaxel and docetaxel are taxane plant alkaloids with antimitotic activity. Paclitaxel was isolated from the bark of the Pacific yew tree, Taxus brevifolia, but is now produced semisynthetically from the needles of the European yew, Taxus baccata. Docetaxel is a semisynthetic taxoid extracted from 10-deacetyl baccatin III, a noncytotoxic precursor found in the renewable needle biomass of yew plants.38

Paclitaxel and docetaxel both act by binding to tubulin, but unlike the vinca alkaloids, they do not interfere with tubulin assembly. Instead, the taxanes promote microtubule assembly and therefore interfere with microtubule disassembly. They induce tubulin polymerization, resulting in formation of inappropriately stable, nonfunctional microtubules. The stability of the microtubules damages cells by disrupting the dynamics of microtubule-dependent structures required for mitosis and other cellular functions. Taxanes also have some nonmitotic actions that can promote cancer cell death, such as inhibition of angiogenesis. Resistance to the antitumor effects of the taxanes is attributable to alterations in tubulin or tubulin binding sites or to Pgp multidrug resistance. Although paclitaxel and docetaxel have very similar mechanisms of action, cross-resistance between the two chemotherapies is incomplete.38Myelosuppression is common with both taxanes, but other adverse events can differ. While increased fluid retention is seen with docetaxel, increased neurotoxicity and hypersensitivity reactions are seen with paclitaxel.27,38 Both require premedications with corticosteroids; paclitaxel also requires antihistamines to decrease the likelihood of hypersensitivity reactions.

To circumvent the hypersensitivity reactions with paclitaxel and to possibly increase its efficacy, paclitaxel was formulated to be bound to albumin (nab-paclitaxel). This new dosage form is devoid of the Cremophor excipient that is believed to mediate the hypersensitivity reactions and exacerbate myelosuppression with the conventional formulation. This formulation appears to be selectively activated by cancer cells to the active paclitaxel compound.39 In clinical trials, nab-paclitaxel has shown comparable activity to the conventional formulation of paclitaxel with a lower incidence of hypersensitivity reactions. Peripheral neuropathies remain a common adverse event with this formulation.

Cabazitaxel is a new semisynthetic derivative of docetaxel that has been demonstrated to elicit an antitumor response in tumors resistant to paclitaxel and docetaxel despite having the same mechanism of action. This is partially because of its lack of affinity for Pgp mentioned earlier that allows cabazitaxel to remain inside the cancer cells. Adverse events and premedications are similar to traditional taxanes.40


Similar to the taxanes, the epothilones work in the M phase of the cell cycle. Epothilone binding to microtubules is distinct from taxanes with activity demonstrated in paclitaxel-resistant cell lines.41Epothilones appear to be poor substrates for Pgp and their cytotoxicity is not affected by its overexpression. Natural epothilones are macrolide derivatives that have stability and pharmacokinetic problems. Synthetic anticancer agents have been developed with the epothilone, ixabepilone, approved for the treatment of metastatic breast cancer. Toxicities are similar to those of the taxanes; premedication with antihistamines are required, although no corticosteroid is administered unless the patient experiences a hypersensitivity reaction to a previous dose.


Eribulin is a nontaxane antimicrotuble analogue of the macrolide halichondrin B. It was originally isolated from the marine sponge Halichondria okadai but is now fully synthetic. Similar to the vinca alkaloids, eribulin inhibits tubulin polymerization by inhibiting microtubule growth; however, in contrast, it does not shorten or promote depolymerization of microtubules.42 Additionally, eribulin only binds to the β-tubulin subunit and has demonstrated the ability to overcome taxane resistance conferred by β-tubulin mutations.42 Adverse events are similar to those of vinblastine (e.g., neutropenia), with a decreased incidence of neuropathy compared with vincristine and taxanes.


Estramustine is an unusual drug, because it structurally combines the alkylating agent nor-nitrogen mustard with estradiol.27 It was designed with the intent that the estradiol portion of the molecule would facilitate uptake of the alkylating agent into hormone-sensitive prostate cancer cells. Despite the inclusion of an alkylator, estramustine does not function in vivo as an alkylating agent. The estradiol is released after its administration and is responsible for most of the toxicity associated with estramustine, but it is not believed to contribute to its cytotoxic effect. In the mid 1980s, estramustine was redefined as an antimicrotubule agent. It binds covalently to microtubule-associated proteins that are part of the structural support for microtubules. The binding causes the separation of microtubule-associated proteins from the microtubules, inhibiting microtubule assembly and eventually causing their disassembly.27

Topoisomerase Inhibitors

Topoisomerases are essential enzymes involved in maintaining DNA topologic structure during replication and transcription. DNA topoisomerase enzymes relieve torsional strain during DNA unwinding by producing strand breaks. They cleave DNA strands and form intermediates with the strands, producing a gap through which DNA strands can pass, and then reseal the strand breaks. Topoisomerase I produces single-strand breaks; topoisomerase II produces double-strand breaks.43 Several important anticancer agents interact with topoisomerase enzymes: camptothecins, anthracyclines, and the epipodophyllotoxins.

Camptothecin Derivatives

The camptothecin analogs irinotecan and topotecan were synthesized to reduce toxicity and improve therapeutic effects of camptothecin, a plant alkaloid derived from Camptotheca acuminata. Topotecan and irinotecan, through its active metabolite SN-38, inhibit topoisomerase I enzyme activity. Topoisomerase I enzymes stabilize DNA single-strand breaks and inhibit strand resealing.43,44 Irinotecan undergoes metabolism to SN-38 by the polymorphic enzyme uridine diphosphate glucosyltransferase, and variant tandem repeats in the promoter of this gene are associated with a higher risk of diarrhea and neutropenia.

Etoposide and Teniposide

Etoposide and teniposide are semisynthetic podophyllotoxin derivatives that bind to tubulin and interfere with microtubule formation. Etoposide and teniposide also damage cancer cells by causing strand breakage through inhibition of topoisomerase II.43 Resistance may be caused by differences in topoisomerase II levels, increased cell ability to repair strand breaks, or increased levels of Pgp. Etoposide and teniposide are usually clinically cross-resistant. They are cell-cycle phase specific and arrest cells in the S or early G2 phase. As a result, activity is much greater when they are administered in divided doses over several days rather than in large single doses.

Anthracene Derivatives

The most widely used and best understood anthracene derivative is doxorubicin (Adriamycin or “Adria”). Other members of the anthracene group include daunorubicin (daunomycin), idarubicin, epirubicin, and mitoxantrone. All of these derivatives, except mitoxantrone, are anthracyclines and share a common, four-membered anthracene ring complex with an attached aglycone or sugar portion. The ring complex is a chromophore and accounts for the intense colors of these derivatives.43,45

Doxorubicin, Daunorubicin, Idarubicin, and Epirubicin Anthracyclines are classified as antitumor antibiotics, but they have multiple mechanisms of action. Although anthracyclines can intercalate into DNA and cause structural changes that interfere with DNA and RNA synthesis, this is not their primary mechanism of cytotoxicity. Intercalating anticancer agents insert or stack between base pairs of DNA. However, anthracyclines primarily inhibit topoisomerase II, producing double-strand DNA breaks.27,43,45

The anthracyclines also undergo electron reductions to reactive compounds that can damage DNA and cell membranes. Free radicals formed from reduction of the anthracyclines first donate electrons to oxygen to make superoxide, which can react with itself to make hydrogen peroxide. Cleavage of hydrogen peroxide produces the highly reactive and destructive hydroxyl radical. This last step requires iron, and anthracyclines are potent iron binders. Iron-anthracycline complexes can then bind to DNA and react rapidly with hydrogen peroxide to produce the hydroxyl radicals that actually cleave DNA. Human cells have natural defenses against oxygen radical damage, in the form of enzymes that can convert the radicals to less reactive compounds, or that can repair DNA damage. Differences in distribution of these defensive enzymes may account for the cumulative dose limiting cardiotoxicity associated with anthracyclines. For example, cardiac muscle has low levels of defensive enzymes and high levels of enzymes that activate anthracyclines. Oxygen free-radical formation is firmly established as a cause of cardiac damage and extravasation injury but is not a major mechanism of tumor-cell killing. Resistance to anthracyclines is usually secondary to Pgp-dependent multidrug resistance. Altered topoisomerase II activity may contribute to the development of resistance.27,45

Mitoxantrone Mitoxantrone was synthesized in an attempt to develop a chemotherapy with comparable antitumor activity to doxorubicin but with an improved safety profile. Similar to the anthracyclines, mitoxantrone is an intercalating topoisomerase II inhibitor, but its potential for free-radical formation is much less than that of the anthracyclines. This decreased tendency for free-radical formation may explain the reduced risks of cardiac toxicity and ulceration after extravasation.27,45

Alkylating Agents

The alkylating agents are among the oldest and most useful classes of anticancer agents. Their clinical use evolved from the observation of bone marrow suppression and lymph node shrinkage in soldiers exposed to sulfur mustard gas warfare during World War I.27 In an effort to develop similar agents that might be useful in treating cancerous overgrowths of lymphoid tissues, less reactive derivatives were synthesized. Their effectiveness as anticancer agents was confirmed by clinical trials in the mid-1940s.

All alkylating agents work by covalently bonding to highly reactive alkyl groups or substituted alkyl groups with nucleophilic groups of proteins and nucleic acids. Some agents react directly with biologic molecules, but others form an intermediate compound that reacts with these molecules. The most common binding site for alkylating agents is the seven-nitrogen group of the DNA base guanine. These covalent interactions result in cross-linking between two DNA strands or between two bases in the same strand of DNA. Reactions between DNA and RNA and between drug and proteins may also occur, but the main insult that results in cell death is inhibition of DNA replication because the interlinked strands do not separate as required. Because the alkylating agents can damage DNA during any phase of the cell cycle, they are not cell-cycle phase specific. However, their greatest effect is seen in rapidly dividing cells.

As a class, alkylators are cytotoxic, mutagenic, teratogenic, carcinogenic, and myelosuppressive. Resistance to these chemotherapies can occur from increased DNA repair capabilities, decreased entry into or accelerated exit from cells, increased inactivation inside cells, or lack of cellular mechanisms to result in cell death after DNA damage. They react with water and are inactivated by hydrolysis, making spontaneous degradation an important component of their elimination.46

Nitrogen Mustards

Cyclophosphamide and Ifosfamide Cyclophosphamide and ifosfamide are nitrogen mustard derivatives and are widely used in the treatment of solid tumors and hematologic malignancies. These mustards are closely related in structure, clinical use, and toxicity. Neither agent is active in its parent form and must be activated by cytochrome P450 (CYP) enzymes. One of the active metabolites of cyclophosphamide is phosphoramide mustard and of ifosfamide is ifosfamide mustard. The CYP-mediated metabolites 4-hydroxy-cyclophosphamide and 4-hydroxyifosfamide are also cytotoxic compounds. Acrolein, a metabolite of both cyclophosphamide and ifosfamide, has little antitumor activity, but is responsible for the hemorrhagic cystitis associated with ifosfamide and sometimes high-dose cyclophosphamide.46 Encephalopathy after ifosfamide can occur within 48 to 72 hours after the infusion and is reversible. The increased production of dechloroethylated metabolites after administration of ifosfamide compared with cyclophosphamide may explain the increased risk of CNS toxicity associated with ifosfamide.47

Bendamustine Bendamustine is an alkylating agent (nitrogen mustard derivative) with a benzimidazole ring (purine analog) that demonstrates only partial cross-resistance (in vitro) with other alkylating agents.48 It leads to cell death via single- and double-strand DNA cross-linking, and it is active against quiescent and dividing cells. The primary cytotoxic activity is due to bendamustine rather than its metabolites. It is used primarily to treat lymphoid malignancies, such as chronic lymphocytic leukemia (CLL) and NHL.


The nitrosoureas are alkylating agents characterized by lipophilicity and ability to cross the blood-brain barrier. Carmustine or bischloroethylnitrosourea (BCNU) and lomustine (CCNU) are commercially available. BCNU is available as an IV preparation and as a drug-impregnated biodegradable wafer (Gliadel) for direct application to residual tumor tissue after surgical resection of brain tumors. The nitrosoureas decompose to reactive alkylating metabolites and to isocyanate compounds that have several effects on reproducing cells.46

Nonclassic Alkylating Agents

Several other cytotoxic chemotherapies appear to act as alkylators, although their structures do not include the classic alkylating groups. They are capable of binding covalently to cellular components and include procarbazine, dacarbazine, temozolomide, and the heavy metal compounds.46

Dacarbazine and Temozolomide Dacarbazine and temozolomide are nonclassic alkylating agents. Both compounds undergo demethylation to the same active intermediate (monomethyl triazeno-imidazole-carboxamide [MTIC]) that interrupts DNA replication by causing methylation of guanine. Unlike dacarbazine, temozolomide does not require the liver for activation and is chemically degraded to MTIC at physiologic pH. Both agents inhibit DNA, RNA, and protein synthesis.27,46

Important pharmacokinetic differences exist between these two agents. Dacarbazine is poorly absorbed and must be administered by IV infusion. Temozolomide is rapidly absorbed after oral administration and is nearly 100% bioavailable when given on a completely empty stomach. Dacarbazine penetrates the CNS poorly, but temozolomide readily crosses the blood-brain barrier, achieving therapeutically active concentrations in cerebrospinal fluid and brain tumor tissues.27,46

Cisplatin, Carboplatin, and Oxaliplatin The platinum derivatives—cisplatin, carboplatin, and oxaliplatin—are anticancer agents with remarkable usefulness in cancer treatment. Recognition of cisplatin’s cytotoxic activity was the result of a serendipitous observation that bacterial growth in culture was altered when an electric current was delivered to the media through platinum electrodes. The growth change was noted to be similar to that produced by alkylating agents and radiation. It was found that a platinum-chloride complex, now known as cisplatin, generated by the current was responsible for the changes. Carboplatin is a structural analog of cisplatin in which the chloride groups of the parent compound are replaced by a carboxycyclobutane moiety. It shares a similar spectrum of clinical activity with cisplatin, and cross-resistance is common. Oxaliplatin is an organoplatinum compound in which the platinum is complexed with an oxalate ligand as the leaving group and to diaminocyclohexane. Its spectrum of activity differs substantially from the other platinum compounds and includes notable activity against colorectal cancers.27,46

The cytotoxicity of the platinum derivatives depends on platinum binding to DNA and the formation of intrastrand cross-links or adducts between neighboring guanines. These intrastrand links cause a major bending of the DNA. They may cause cellular damage by distorting the normal DNA conformation and preventing bases that are normally paired from lining up with each other. Interstrand cross-links also occur.27,46

The cytotoxic form of cisplatin is the aquated species in which hydroxyl groups or water molecules replace the two chloride groups. This reaction occurs readily in low concentrations of chloride, such as the concentrations present within cells, and produces a positively charged compound that can react with DNA. The aquated species is responsible for both the efficacy and toxicity of cisplatin. Carboplatin also undergoes aquation but at a slower rate. Oxaliplatin becomes active when the oxalate ligand is displaced in physiologic solutions.27,46

Resistance to the therapeutic effects of platinum compounds may occur through several mechanisms. The ability to repair platinum-induced DNA damage may be increased, or the compounds may be inactivated by increased levels of intracellular glutathione, metallothioneins, or other thiol-containing proteins. Altered uptake into cells may also affect sensitivity to platinum compounds.27,46

Cisplatin is a highly toxic anticancer agent that can cause serious nephrotoxicity, ototoxicity, peripheral neuropathy, emesis, and anemia. The significant efficacy of cisplatin against many tumors makes it a valuable agent despite these toxicities, most of which can be prevented or managed with aggressive supportive care measures.27 In contrast, carboplatin administration is limited by hematologic toxicity. Patients with compromised renal function require dose reductions to limit myelosuppressive toxicity.27,46 The most widely used dosage schema, the Calvert formula (Table 104-9), uses a target area under the curve and renal function parameters to estimate the carboplatin dose. Carboplatin’s potential to cause renal damage, peripheral neuropathy, ototoxicity, and nausea and vomiting is much less than that of comparable cisplatin doses.46 Oxaliplatin is not nephrotoxic or ototoxic and is moderately emetogenic, but it can cause peripheral neuropathies and unique cold-induced neuropathies.49 All of the platinum derivatives have potential to cause hypersensitivity reactions, including anaphylaxis, after a threshold exposure is reached.

TABLE 104-9 Dosing Formulas for Chemotherapy


Endocrine Therapies

Perhaps the earliest successful approach to target the growth processes of cancer cells was the use of endocrine therapies. Endocrine manipulation is an option for management of cancers from tissues whose growth is under gonadal hormonal control, especially breast, prostate, and endometrial cancers. These cancers may regress if the “feeding” hormone is eliminated or antagonized. Major organ system toxicity is uncommon from endocrine therapies, making it the least toxic of systemic anticancer agents. Specific anticancer agents such as the selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) have increased the utility of hormonal therapies in the treatment of cancer.5052 These therapies are discussed in detail in Chapters 105 and 108 (Table 104-8).

Corticosteroids are also useful anticancer agents because of their lymphotoxic effects. Their primary use is in management of hematologic malignancies, especially lymphoid malignancies such as lymphomas, lymphocytic leukemias, and multiple myeloma. In addition to their cytotoxic effects, corticosteroids have many other applications as supportive care. Corticosteroids have diverse toxicities in chronic or high-dose use, but are generally well tolerated in the short-term therapies usually used in cancer patient care.53

Miscellaneous Agents


Bleomycin is an antitumor antibiotic. It is a mixture of peptides from fungal Streptomyces species and its strength is expressed in units of drug activity.27 One unit is roughly equal to 1 mg of polypeptide protein. The predominant peptide is bleomycin A2, which makes up about 70% of the commercial drug product. Its cytotoxicity is secondary to DNA strand breakage, or scission, which it produces via free-radical formation. Cytotoxicity depends on binding of the bleomycin-iron complex to DNA. The bleomycin-iron complex then reduces molecular oxygen to free oxygen radicals that cause primarily single-strand breaks in DNA. Bleomycin has greatest effect on cells in the G2 and M phases of the cell cycle.27

Bleomycin is inactivated within cells by the enzyme aminohydrolase. This enzyme is widely distributed but is present in only low concentrations in the skin and the lungs, explaining the predominant toxicities of bleomycin to those sites. Baseline pulmonary function tests and monitoring for pulmonary toxicity are necessary during bleomycin therapy. The presence of hydrolase enzymes in cancer cells is the primary mechanism of resistance to bleomycin. Cells can also become resistant by repairing the DNA breaks produced by bleomycin.27


Hydroxyurea is a unique drug that inhibits ribonucleotide reductase. Cells accumulate in the S phase, because DNA synthesis is inhibited and only abnormally short DNA strands are produced.30 This drug is often used to cause a rapid decline in a patient’s white blood cells (WBCs) before more potent chemotherapy is initiated.

Arsenic Trioxide

Arsenic is an organic element and a well-known poison that is an effective treatment for acute promyelocytic leukemia.54 As an anticancer agent, arsenic trioxide acts as a differentiating agent, inducing the growth progression of cancerous cells into mature, more normal cells. It also induces programmed cell death or apoptosis. This chemotherapy is discussed in more detail in Chapter 111.


Vitamin A and its metabolites, collectively referred to as the retinoids, play important roles in numerous biologic processes, including normal cellular differentiation. Because cancerous growth is characterized by abnormal cellular differentiation, retinoids may play important therapeutic roles in the treatment and perhaps in the prevention of cancers. Tretinoin (all-trans-retinoic acid) is a naturally occurring derivative of vitamin A (retinol). Other retinoids indicated for treatment of cancers include alitretinoin (9-cis-retinoic acid), available in gel form for topical management of Kaposi’s sarcoma lesions, and bexarotene (Targretin®) gel or capsules for treatment of cutaneous T-cell lymphoma.27,55

Retinoids are classed as morphogens, small molecules released from one type of cell that can affect the growth and differentiation of neighboring cells. Their normal roles in the human body are to induce differentiation of some cells, stop the differentiation of others, and both suppress and induce apoptosis in different cell types. Their diverse actions come from the diversity of their receptors. The two classes of retinoid receptors are retinoid X receptors (RXRs) and retinoic acid receptors (RARs), each with αβ, and γ subclasses. RXRs are versatile; they bind to RARs and to other nuclear receptors, such as thyroid hormone receptors. After being activated, the receptors act as transcription factors that in turn regulate the expression of genes that control cellular growth and differentiation.27,55

Tretinoin binds primarily to the RAR-α receptors. Alitretinoin is considered a panagonist, which means that it binds to all known retinoid receptors, producing diverse regulatory effects. Bexarotene is synthetic and is classed as a rexinoid. It is the first RXR-selective retinoid agonist. The exact mechanism of action of alitretinoin and bexarotene as anticancer agents is unknown.27,55

Mitomycin C

Mitomycin C is a natural product that is sometimes classified as an antitumor antibiotic.46,56 It has similarities to nitrogen mustard compounds and may function as an alkylating agent, although its toxicity pattern differs from conventional alkylating agents.

Omacetaxine Mepesuccinate

Omacetaxine mepesuccinate (previously referred to as homoharringtonine) is a plant alkaloid that inhibits protein translation, thus preventing the initial elongation step of protein synthesis. It appears to decreases cancer stem cells; proliferation proteins; and cell survival proteins, such as c-MYC, in chronic myeloid leukemia (CML) cells in vitro. Omacetaxine was approved for the treatment of patients with CML who have failed two or more approved targeted drugs for this disease. Additionally, synergy with these inhibitors has been demonstrated in a few clinical studies. and additional combination trials are ongoing.57


BCR-ABL Inhibitors


Imatinib is a selective inhibitor of the tyrosine kinase activity of BCR-ABL fusion gene, the product of the Philadelphia chromosome.58 The Philadelphia chromosome is the hallmark finding of CML and is a translocation of genetic material between chromosomes 9 and 22. Imatinib binds to the kinase binding site of the BCR-ABL gene, competitively blocking access to adenosine triphosphate (ATP). This prevents tyrosine-kinase phosphorylation of the gene and downstream activation of cellular proliferation.59 Imatinib also causes apoptosis or arrest of growth in cells expressing BCR-ABL. An additional effect of imatinib is its ability in blocking the tyrosine kinase activity of c-KIT (stem-cell factor receptor) and platelet-derived growth factor receptor (PDGFR).58,60

Imatinib is a standard treatment option for newly diagnosed Philadelphia chromosome-positive (Ph+) CML and for c-KIT-positive gastrointestinal stromal tumors (GIST). A major advantage of imatinib is that it can eliminate the Philadelphia chromosome, resulting in cytogenetic responses (elimination of the genetic defect). Imatinib and the other BCR-ABL inhibitors are further discussed in Chapter 112. Imatinib is also approved for the treatment of (Ph+) acute lymphoblastic leukemia (ALL) and other rare diseases.

Adverse events observed with imatinib are usually mild to moderate in severity. Severe fluid retention (pleural effusion, pericardial effusion, and ascites) occurs in fewer than 10% of patients taking imatinib. Patients should be monitored regularly for early signs and symptoms of fluid retention (leg swelling, shoes no longer fitting, and shortness of breath) and instructed to call their healthcare providers when symptoms first develop. Additional adverse events include mild or moderate superficial edema, elevation of liver enzymes, nausea, muscle cramps, headache, and rash.61 A rash may require early intervention because rare cases of Stevens-Johnson’s syndrome have been reported with imatinib and may require permanent discontinuation of imatinib.61

Dasatinib, Nilotinib, and Bosutinib

These targeted drugs are next-generation tyrosine kinase inhibitors (TKIs) that share the same binding site on the BCR-ABL tyrosine kinase ATP-binding domain with imatinib.62,63 These inhibitors maintain clinical activity in patients with CML with some mutations in the BCR-ABL binding site that confer imatinib resistance with the exception of one polymorphism (T351I) in which all four inhibitors appear resistant. Nilotinib and dasatinib are approved for the treatment of patients with CML resistant or intolerant to imatinib in addition to approval for first-line treatment of newly diagnosed CML. These two inhibitors are also approved for the treatment of (Ph+) ALL. Bosutinib is approved for the treatment of patients resistant or intolerant to the other inhibitors. Both bosutinib and dasatinb also inhibit a family of tyrosine kinases called SRC kinases that are believed to mediate cellular differentiation, proliferation, and survival; SRC kinases have been implicated in modulating multiple oncogenic signal transduction pathways.59,63

Overall, these targeted drugs have a toxicity profile similar to that of imatinib with myelosuppression, nausea and vomiting, headache, and fluid retention being commonly reported, although bosutinib does not inhibit the c-KIT or PDGFR, which may account for its reported decrease in myelosuppression.63 Similar to other TKIs, these anticancer agents could interact with substrates, inducers, or inhibitors of multiple CYP enzymes.


As mentioned earlier, the T351I mutation, often referred to as the gatekeeper mutation, confers resistance to the above TKIs of BCR-ABL. Ponatinib was developed using a computational chemistry-based approach to inhibit this mutated conformation of BCR-ABL as well as nonmutated forms providing an effective treatment for this traditional resistant tumor.64 Ponatinib is also approved for patients with (Ph+) ALL that is resistant or intolerant to prior therapy. The more common adverse events reported are similar to other TKIs, such as hypertension, rash, headache, constipation, fever, and nausea. Arterial thrombosis and hepatic toxicity have been observed.

Histone Deacteylase Inhibitors

Vorinostat and romidepsin both inhibit HDAC; these inhibitors likely inhibit class I and II HDAC enzymes. As described in the section on epigenetics, HDAC catalyzes the removal of acetyl groups from the lysine residues of proteins, including histones and transcription factors.21,65 By inhibiting HDAC activity, these inhibitors cause the accumulation of acetylated histones and induce cell-cycle arrest and apoptosis of tumor cells. Romidepsin is approved for the treatment of patients with cutaneous T-cell lymphoma who have received at least one prior therapy, and vorinostat is approved for the treatment of patients with cutaneous T-cell lymphoma who have received at least two prior therapies. Adverse events observed with romidepsin include nausea, vomiting, arrhythmias, and infection. Adverse events reported with vorinostat include pulmonary embolism and deep vein thrombosis along with dose-related thrombocytopenia and anemia; other adverse events that have been reported are nausea, diarrhea, hypertriglyceridemia, and hyperuricemia, hypoglycemia, hypokalemia, hyponatremia, hyperkalemia, hypercholesterolemia, hypophos-phatemia, and proteinuria.

DNA Methyltransferase Inhibitors

Azacytidine and decitabine are approved for the treatment of patients with myelodysplastic syndrome, a disorder of hematopoietic cell maturation that can progress to AML (see Chap. 114). These agents are nucleoside analogs that demonstrate dose-dependent effects. At lower doses, these analogs exert their effects by directly incorporating into DNA and inhibiting DNMT, which leads to cellular differentiation and apoptosis.24 At higher doses, these agents might cause the formation of covalent adducts between DNMT and active drug being incorporated into DNA, particularly in cells actively dividing. Hypomethylation also appears to normalize the function of genes that control cell differentiation and proliferation, promoting normal cell maturation.66

These inhibitors have demonstrated efficacy in slowing the progression of myelodysplastic syndrome to AML, reducing transfusion requirements, and allowing for the improvement of normal hematopoiesis over time. The primary toxicity is myelosuppression, particularly during early phases of treatment as the malignant clone driving the myelodysplastic syndrome is cleared from the bone marrow and normal hematopoiesis is slowly restored. As a result, infectious complications occur frequently.

mTOR Pathway Inhibitors


Temsirolimus binds to the intracellular protein FKBP-12, and this protein-drug complex inhibits mTOR by blocking its kinase activity.26 mTOR inhibition suppresses the production of proteins that regulate progression through the cell cycle and angiogenesis as described earlier in this chapter. Temsirolimus is approved for metastatic renal cell carcinoma.

The most common adverse reactions with temsirolimus are rash, fatigue, mucositis, nausea, edema, and loss of appetite. The most common laboratory abnormalities are increases in serum creatinine and liver function test results, thrombocytopenia, and neutropenia. Additionally, hyperglycemia and hyperlipidemia that require monitoring of glucose and lipid profiles should be expected.26 Rare but potentially serious adverse events include interstitial lung disease, immunosuppression (and infection), and renal failure. Temsirolimus is metabolized by CYP3A4, and possible drug interactions requiring dosage adjustments may be necessary.


Everolimus is an oral mTOR inhibitor that is approved for the treatment of patients with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib, postmenopausal women with breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole, adult and pediatric patients with subependymal giant cell astrocytoma with tubular sclerosis complex (TSC), patients with renal angiomyolipoma and TSC, and patients with pancreatic neuroendocrine tumors.26 It is available as traditional oral tablets and tablets for oral suspension. Adverse reactions and potential drug interactions are similar to those of temsirolimus. Drug interactions with inducers or inhibitors of CYP3A4 and inhibitors of Pgp might warrant discontinuation of the concomitant drug or a reduced dose of everolimus.

Epidermal Growth Factor Receptor Pathway Inhibitors


Erlotinib is an oral selective EGFR TKI. By competing with ATP for its binding site on the EGFR tyrosine kinase cytosolic domain, it blocks the intracellular downstream signaling and ultimately interferes with the proliferation and growth of cancer cells.67,68

Erlotinib is indicated for the treatment of patients with locally advanced or metastatic NSCLC as a second-line agent.68 It appears effective in patients with or without EGFR-activating mutations, but it appears to be more effective in patients with EGFR-activating mutations.69 Erlotinib is also approved for use in pancreatic cancer in combination with gemcitabine. Erlotinib has also demonstrated activity in a variety of other tumors, such as head and neck and brain tumors.

Rash and diarrhea are the most common adverse events reported with erlotinib. Some studies suggest that the development of a rash may be predictive of a response to therapy and correlates with clinical benefit.70 Interstitial lung disease is a rare adverse event reported in patients taking erlotinib. Possible drug interactions include warfarin and CYP3A4 inhibitors or inducers.


Lapatinib is a 4-anilinoquinazoline kinase inhibitor that inhibits the intracellular kinase domains of both EGFR and HER2.71 It has demonstrated clinical activity in combination with capecitabine in patients with breast cancer who overexpress HER2 and who have previously received therapy with trastuzumab, an anthracycline, and a taxane.71 Toxicity for lapatinib was notable for an increased incidence of diarrhea, hepatotoxicity, rash, and QT interval prolongation. Lapatinib has significant CYP-mediated interactions. A specific mutation observed in the HLA-DQA gene has been associated with an increased risk of hepatotoxicity.72

Multikinase Inhibitors

Sunitinib, Sorafenib, Pazopanib, and Axitinib

Sunitinib and sorafenib inhibit multiple growth factor receptors (VEGFR-2 and PDGFR), cell surface proteins (c-KIT), and cytokine receptors (FLT3) and thus disrupt multiple aberrant intracellular signaling pathways. In addition, sorafenib inhibits Raf, which is part of the MAPK signaling pathway as described earlier.73 Sunitinib is approved for GIST and pancreatic neuroendocrine tumors and, sorafenib is approved for metastatic hepatocellular cancers.

Pazopanib and axitinib are second-generation inhibitors. Pazopanib inhibits VEGFR-1, -2, and -3 with additional activity against c-KIT and PDGFR, and axitinib has enhanced potency and selectivity to all VEGFR tyrosine kinases (VEGFR-1, -2, and -3) with minor activity against PDGFR and c-KIT.74,75 These drugs are approved for the treatment of advanced renal cell cancers. Ponatinib is also approved from sarcomas.

Gastrointestinal adverse events such as diarrhea are common with these drugs, as are rash, fatigue, and hypertension (Table 104-8).


Regorafenib is an oral multikinase inhibitor that blocks the activity of several protein kinases, including those involved in the regulation of tumor angiogenesis (VEGFR-1, -2, and -3), oncogenes and downstream targets (c-KIT, RET, RAF1, and BRAF), as well as PDGFR and fibroblast growth factor receptor (FGFR).76 Because many of these targets are important in colon cancer, regorafenib has demonstrated activity and is approved for the treatment of patients with metastatic colorectal cancer. Serious adverse events reported with regorafenib include hepatotoxicity, hemorrhage, and gastrointestinal perforation.


Vandetanib is a small molecule inhibitor of RET, VEGFR-2 and -3, and EGFR.77 Because most medullary thyroid cancers express mutated RET, vandetanib has demonstrated activity in this tumor. It is approved for the treatment of metastatic medullary thyroid cancer. Observed adverse events include diarrhea, hypertension, rash, and QT interval prolongation.


Cabozantinib is a small molecule inhibitor of numerous receptor kinases, most importantly the RET, VEGFR-2, and the MET membrane receptor.78 MET is required for several important processes during embryogenesis (e.g., angiogenesis) but leads to abnormal growth and proliferation of several tumors. Because medullary thyroid cancers express mutated RET as well as VEGFR-2 and MET, cabozanitinib has demonstrated activity in this tumor. Cabozantinib is approved for the treatment of patients with metastatic medullary thyroid cancers. Its clinical activity in prostate cancer and other tumors is currently being evaluated. Adverse events reported in clinical trials included diarrhea, hand-foot syndrome, lymphopenia, hypocalcemia, hypertension, transaminitis, and stomatitis.

Proteasome Inhibitors

The proteasome is an enzyme complex that is responsible for degrading proteins that control the cell cycle. Some of the proteins degraded by proteosomes regulate critical functions for cancer growth, such as regulation of the cell cycle, transcription factors, apoptosis, angiogenesis, and cell adhesion.14


Bortezomib has very specific affinity for the catalytic portion of the 26S proteasome. It is a specific inhibitor of this proteasome, which results in accumulation of IκB, an inhibitor of the major transcription factor nuclear factor κB (NF-κB). NF-κB induces transcription of genes that block cell death pathways and promote cell proliferation. Its activity depends on its release from its inhibitory partner protein, IκB, in the cytoplasm and its move to the nucleus. When IκB fails to degrade, through the actions of bortezomib, NF-κB remains in the cytoplasm, preventing it from transcribing the genes that promote cancer growth. Bortezomib is approved for the treatment of multiple myeloma and mantle cell lymphoma.14

The most commonly reported adverse events are asthenia (fatigue, malaise, and weakness), nausea, and diarrhea, occurring in more than 50% of patients. Additional adverse events include decreased appetite, nausea, constipation, myelosuppression, peripheral neuropathies, and fever.14 Most of these adverse events are mild to moderate and managed with supportive care measures. Of these common adverse events, severe adverse events were limited to thrombocytopenia, neutropenia, asthenia, and peripheral neuropathies. Bortezomib is administered every 72 hours to minimize cumulative toxicity by permitting the restoration of proteasome function between doses.


Carfilzomib is a second-generation proteasome inhibitor approved for relapsed or refractory multiple myeloma. Whereas it irreversibly and rapidly binds to the proteolytic core particle within the 26S proteasome, bortezomib exhibits reversible inhibition of multiple proteasome targets.79 This decreases the systemic exposure to the drug while maintaining efficacy. Carfilzomib has been demonstrated to overcome bortezomib resistance in cell lines.


Thalidomide, Lenalidomide, and Pomalidomide

Thalidomide, the infamous drug that caused severe limb deformities (phocomelia or “seal limbs”) when used by pregnant women as a nonprescription sedative in the 1960s, is approved for treatment of leprosy and multiple myeloma. Thalidomide is a glutamic acid derivative and is broadly classified as an immunomodulatory drug. Lenalidomide and pomalidomide are analogs of thalidomide with similar therapeutic activity but different adverse event profiles.80 Lenalidomide has been approved for multiple myeloma in patients who have received prior therapy and in patients with transfusion-dependent anemia caused by myelodysplastic syndrome with a specific mutation. Pomalidomide has been approved for the treatment of patients with multiple myeloma with disease progression after prior therapy. These drugs have many potential mechanisms of action, with the main hypothesis thought to be through angiogenesis inhibition, an action also linked to its teratogenic effects. Other possible mechanisms include direct inhibition of cancer cells, free radical oxidative damage to DNA, interfering with adhesion of cancer cells, inhibiting TNF-α production, or altering secretion of cytokines that affect the growth of cancer cells.80

The most common adverse events for thalidomide include somnolence, constipation, dizziness, orthostatic hypotension, rash, and peripheral neuropathies. Neutropenia is extremely rare. In contrast, lenalidomide is associated with much less somnolence and neuropathies compared with thalidomide.80 Neutropenia, thrombocytopenia, and thrombotic issues are prevalent with both lenalidomide and pomalidomide. Because these drugs are teratogenic, these drugs are only available under a special restricted distribution programs.


Crizotinib binds to the ATP intracellular domain of activated anaplastic lymphoma kinase (ALK), thereby inhibiting phosphorylation and subsequent downstream signaling, similar to other targeted drugs. ALK rearrangements were first identified in large cell lymphomas and later in NSCLC (and a variety of other tumors). In NSCLC, the most common rearrangement involves inversion of chromosome 2p that is primarily fused to the echinoderm microtubule-like protein 4 (EML4), which forms the ALK-EML4 oncogene fusion protein. This rearrangement leads to the activation of downstream signaling pathways (through the Ras pathway) and inhibition of apoptosis.81 Crizotinib also inhibits the c-MET tyrosine kinase. Crizotinib is approved for the treatment of patients with locally advanced or metastatic NSCLC that is ALK positive as detected by an approved test.


Vemurafenib is approved for the treatment of patients with previously untreated metastatic or unresectable melanoma with the BRAF V600E mutation as detected by an approved test, and it is in various stages of clinical trials in additional solid tumors (e.g., colon and thyroid cancers). The BRAF gene is mutated in a variety of solid tumors with most mutations occurring at codon 600. This codon is in the activation loop of BRAF and increases kinase activity and downstream proliferation of cancer cells. The V600E mutation (replacing valine with glutamic acid) is the most common V600 mutation and is seen in about 50% of all melanomas. Vemurafenib inhibits BRAF V600E and blocks downstream phosphorylation in BRAF-mutated cells. Cutaneous squamous cell carcinomas have been reported in patients treated with vemurafenib.82


Vismodegib is an oral small molecule inhibitor of the Hedgehog signaling pathway that it is abnormally activated in a variety of solid tumors, including basal cell carcinoma, medulloblastoma, and ovarian cancers. This pathway is essential for early embryogenesis; therefore, both men and women must use highly effective contraception for up to at least 2 months after their last dose. Vismodegib binds to smoothened receptor (SMO), which prevents downstream signaling and activation of the Hedgehog pathway and inhibits tumor growth.83 It is currently approved for metastatic basal cell cancer but is actively being investigated in a variety of solid tumors.


Ruxolitinib is an oral inhibitor of JAK1 and JAK2 of the JAK-STAT signaling pathway; these kinases are involved in the regulation of blood and immunologic functioning. It is approved for the treatment of myelofibrosis. The most common adverse events include thrombocytopenia, anemia, dyspnea, headache, diarrhea, and nausea.84


Biologic therapies include cytokines, MoABs, growth factors, and vaccines. MoABs are designed to target pathways critical for the survival and growth of cancer cells. These therapies are designed to improve outcomes while minimizing adverse events. MoABs can bind to either the extracellular receptor or to its natural ligand and prevent the activation of the downstream intracellular signaling. Several biologic therapies are available to treat both solid and hematologic malignancies.

Images MoABs consist of immunoglobulin sequences that are known to recognize a specific antigen or protein on the surface of cells. There are five classes of immunoglobulins (IgA, IgD, IgE, IgG, and IgM), with IgG the most commonly used therapeutically. The fundamental structure of all antibodies is identical and consists of two heavy and two light chains joined to form a molecule that resembles the letter Y. The variable region (Fab fragment) of antibodies differs greatly and is composed of three complementary determining regions. The Fab portion is composed of heavy (VH) and light chains (VL) that are responsible for binding to antigens. The constant region (Fc fragment) determines the effector function of the antibody.85

Two main classes of MoABs are used in the treatment of cancer, the most common of which are unconjugated or naked MoABs. The other class is immunoconjugates, in which MoABs are conjugated to a toxin (immunotoxin), chemotherapy (antibody drug conjugate), or radioactive particle (radioimmunoconjugate). MoABs may also be divided into agents that target cell surface antigens and those that target growth factor receptors or ligands.85

Standardized nomenclature exists for naming MoABs.86 The suffix -mab is used for all MoABs and fragments and is always preceded by the identification of the animal source of the product. The letters ouxi, and zu before the -mab suffix indicate a murine, human, chimeric, and humanized, respectively. The general disease state the MoABs is treating precedes the source and is identified using a code. Currently, most approved MoABs used in cancer have the code syllabus -tu(m) that designates it for use against miscellaneous tumors. If the product is conjugated, a separate word is added for to identify the toxin, chemotherapy, or radioactive particle.

Images The first MoABs used in humans were murine, but most of the MoABs used today are chimeric, humanized or human. These agents differ in the amount of foreign component. Hypersensitivity and infusion-related reactions, with or without the development of antiproduct antibodies (APAs), are generally greatest with murine antibodies and least with humanized antibodies.85,60 The severity of these reactions can range from mild (e.g., fever, chills, nausea, and rash) to severe, life-threatening anaphylaxis with cardiopulmonary collapse. Patients with a hypersensitivity or infusion-related reaction may also experience chest or back pain during the infusion. Patients with circulating cancer cells in the bloodstream are at highest risk for more severe reactions. Patients must be monitored closely during infusion. The reactions tend to be more severe with the initial infusion, and subside with subsequent treatments. Some MoABs require premedication with antihistamines and acetaminophen to minimize hypersensitivity reactions. Recommended infusion rates are usually lower for the initial dose, with incremental increases as tolerated by the patient. For patients experiencing signs or symptoms of infusion-related reactions, the infusion should be interrupted and prompt treatment with antihistamines, corticosteroids, and other supportive measures should be initiated. Pulmonary toxicity may occur as part of the infusion-related reaction or may occur as a distinct entity.60,85,87

The development of APAs can also increase the clearance of the MoAB from the body and subsequently decrease the half-life of the MoAB. These antibodies could also decrease the ability of the MoAB to bind to its target antigen and potentially decrease its efficacy over time.

Additionally, the toxicities of the MoABs will be determined by the selectivity of the target antigen. Antibodies against antigens found on normal and cancer cells will have increased toxicity compared with tumor-specific antigens found only on tumor tissues.

Unconjugated MoABs that target antigens on the cell surface of cancer cells may induce death of cancer cells by several mechanisms. These MoABs could directly mediate cell killing through complement activation (complement-dependent cytotoxicity [CDC]), antibody-dependent cellular toxicity (ADCC), or inhibiting intracellular signaling.60,85,88 CDC occurs when the Fc portion of the MoAB activates the complement system, leading to tumor cell lysis, and ADCC occurs when effector cells that contain Fc receptors bind to the Fc portion of the MoAB and either lyses or phagocytosizes the antibody-containing cell. Natural killer cells, monocytes, and macrophages are all capable of mediating ADCC. Finally, antibody binding may result in the transmission of signals that induce apoptosis, or programmed cell death in the targeted cell.

Antibody conjugates deliver chemotherapy, toxins, or radioactive particles to a cell targeted by the antibody. After being bound to target antigens, the conjugated drug, toxin, or radioparticle is internalized by the target cell and kills cancer cells through traditional mechanisms of action.89 In addition to killing the target cell, these conjugates are capable of killing antigen-negative cancer cells sometimes termed the “bystander” effect. Theoretically, immunoconjugates deliver therapy to specific sites of disease while limiting systemic exposure to the chemotherapy or radiation or toxin. The antibody might also contribute to the observed anticancer effects.

Monoclonal Antibodies and Immunoconjugates that Target Cell Surface Glycoproteins

Monoclonal Antibodies and Immunoconjugates that Target CD20

Rituximab Rituximab is a chimeric MoAB directed against the CD20 antigen found on the surface of normal and cancerous B cells.52 The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes and the Fc domain recruits immune effector functions to mediate B-cell lysis.90 Possible explanations for its anticancer effect include CDC- and ADCC-mediated killing of malignant B cells along with a direct apoptotic effect.90

Rituximab is approved for the treatment of relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL and as first-line therapy for patients with aggressive and indolent NHL in combination with chemotherapy. It is also approved for use in patients with other malignancies with CD20-antigen expression (e.g., CLL) in combination with standard chemotherapy.90,91 Rituximab is also approved for the treatment of refractory rheumatoid arthritis and has an evolving role in a variety of immune-mediated diseases, such as Waldenström macroglobulinemia and aplastic anemia.

Most of the adverse events of rituximab occur during the first infusion and are components of an infusion-related complex secondary to the amount of circulating B cells. After the first infusion, the incidence and the severity of these reactions decrease dramatically.90,91 The most common events in the infusion-related complex are transient fever, chills, nausea, asthenia, and headache.

Ofatumumab Ofatumumab is a human antibody that also targets the CD20 antigen. Its mechanism of action is similar to that of rituximab; however, ofatumumab targets a different epitope then rituximab, has greater affinity for the antigen, and dissociates from the epitope slower than rituximab.92 In particular, ofatumumab binds to two regions of the CD20 antigen, the small extracellular loop and the N-terminal region of the large extracellular loop. This allows it to demonstrate anticancer activity in patients who have progressed on rituximab in a variety of B-cell cancers.92 Adverse reactions are similar to rituximab with fewer infusion-related reactions and a higher rate of infectious complications (Table 104-8).

Ibritumomab Tiuxetan Ibritumomab tiuxetan is an radioimmunoconjugate that consists of the murine anti-CD20 MoAB ibritumomab and tiuxetan, a linker chelator, that allows the attachment of indium-111 (used for imaging and dosimetry) and yttrium-90 (active radiotherapy).93 The therapeutic regimen consists of two steps.93,94 Y-90-ibritumomab is the therapeutic radiation isotope and selectively delivers radiation to B cells that express the CD20 antigen.

The radiation-induced cytotoxicity delivered by Y-90-ibritumomab not only affects the cancer cells it binds but also other cells that are within the path length of the radioisotope’s emissions (bystander effect).88,93,94 Consequently, Y-90-ibritumomab can induce cell death in CD-20-positive and -negative tumors and eradicate a large number of cancer cells. Ibritumomab tiuxetan also induces ADCC, CDC, and apoptosis.89,93,94

Ibritumomab tiuxetan is indicated for the treatment of relapsed or refractory, low-grade or follicular, or transformed B-cell NHL, including rituximab-refractory NHL. Because ibritumomab is derived from murine sources, only one course of therapy is recommended to prevent the development of human antimouse antibody (HAMA) reactions.

Adverse reactions include severe infusion-related reactions, such as anaphylaxis.89,93,94 Myelosuppression is common with ibritumomab as a consequence of the radioisotope.89,93 Ibritumomab tiuxetan results in prolonged thrombocytopenia and neutropenia, and dose modifications are necessary based on baseline neutrophil and platelet blood counts.93 The median durations of thrombocytopenia and neutropenia were 24 and 22 days, respectively, and monitoring and management of cytopenias, along with their complications (e.g., febrile neutropenia, bleeding) is necessary for up to 3 months after the completion of treatment.93,94

Tositumomab Tositumomab is another murine anti-CD20 radio-immunoconjugate similar to ibritumomab. One important difference is that tositumomab is combined with the radioisotope iodine I-131, which has therapeutic and safety implications. The tositumomab regimen also consists of two steps.89 The mechanisms of cell death are similar to ibritumomab as is the indication for refractory NHL.

Most adverse events are similar to ibritumomab with infusion-related reactions requiring appropriate premedications along with prolonged myelosuppression, primarily neutropenia and thrombocytopenia. Complete blood counts should be obtained weekly for 10 to 12 weeks to assess recovery of normal blood counts. To prevent iodine uptake by the thyroid gland, and subsequent delivery of ionizing radiation to the thyroid gland, thyroid protective agents, such as saturated solution of potassium iodide, should be initiated before the start of the tositumomab regimen and continued for 14 days after the therapeutic dose.89,95

Monoclonal Antibodies and Immunoconjugates that Target Other Cell Surface Receptors

Alemtuzumab Alemtuzumab is a recombinant humanized MoAB that is directed against CD52. CD52 is expressed on the surface of B and T lymphocytes, natural killer cells, monocytes, and macrophages.96Its anticancer activity comes from binding to the CD52 antigen present on leukemic lymphocytes and inducing cell lysis and death.96

Alemtuzumab is indicated for the treatment of B-cell CLL in patients who have been treated with alkylating agents and who have failed fludarabine. It is also being investigated as part of conditioning regimens for hematopoietic stem cell transplants, treatment of autoimmune hematologic disorders, indolent NHL, and treatment of graft-versus-host disease.94,96

Alemtuzumab is associated with severe infusion-related reactions, hematologic toxicity, and opportunistic infections that are severe enough to warrant a box warning in the product labeling.85,96 Hematologic toxicity consisting of severe prolonged neutropenia and thrombocytopenia occur in most patients. Healthcare providers should monitor blood counts prior to alemtuzumab administration to determine if the dose needs to be delayed or reduced.84,93,95

Because CD52 is expressed on lymphocytes, alemtuzumab can induce profound lymphopenia including a decrease in CD4 and CD8 counts.85,94,96 Patients should receive prophylaxis for Pneumocystis jirovecipneumonia and herpes virus, which should be continued for up to 6 months after alemtuzumab therapy or until recovery of CD4 counts to prevent complications.85,96

Brentuximab Vedotin Brentuximab vedotin is the first new agent approved for Hodgkin lymphoma in more than 30 years. Brentuximab vedotin is an antibody-drug conjugate that targets the CD30 antigen found on cancer cells. Upon binding to the CD30 antigen, brentuximab vedotin is internalized by endocytosis, and the dipeptide bond that links the naked MoAB to the chemotherapy monomethylauristatin E (MMAE) is cleaved.97 MMAE then binds to microtubules and acts as an inhibitor of microtubule polymerization. It may also induce apoptosis by inhibiting NF-κB. Brentuximab vedotin is indicated for Hodgkin lymphoma after failure of autologous hematopoietic stem cell transplant (or in patients who are not transplant candidates) and relapsed anaplastic large cell lymphoma.

Monoclonal Antibodies that Target Growth Factor Receptors and Ligands

Epidermal Growth Factor Receptor Signaling Pathway Inhibitors

Cetuximab and Panitumumab Cetuximab is a chimeric MoAB that binds specifically to the extracellular domain of EGFR60,85,98 on both normal and cancer cells and competitively inhibits the binding of epidermal growth factor and other ligands, such as transforming growth factor-α.60,98 Binding of cetuximab to the EGFR inhibits cell growth, induces apoptosis, and inhibits VEGF production. Cetuximab is given as monotherapy or in combination with other anti-cancer agents in the treatment of metastatic colorectal cancer.98,99 Cetuximab is also approved for use in head and neck cancer either alone or in combination with radiation.100 The most serious adverse events associated with cetuximab are infusion-related reactions and development of an acne-like rash.85,99,101 Skin reactions occur in most patients receiving cetuximab and can be severe. This reaction is similar between all EGFR inhibitors and appears to be related to the function of EGFR in skin follicles.70 These reactions are characterized by multiple follicular or pustular appearing lesions that generally appear within the first 2 weeks of therapy. Although the reactions usually resolve after cessation of treatment, resolution can be slow, continuing beyond 28 days in nearly half of cases. In patients who develop a severe rash, dose modifications may be necessary. Interestingly, a trend for improved responses with increasing severity of skin reactions has been reported and requires further follow-up to assess the clinical importance of these reactions.70,99 Other common adverse events with cetuximab include fatigue, gastrointestinal complaints (nausea, vomiting, diarrhea, and constipation), and abdominal pain.99

Panitumumab is a MoAB that also binds to the cell surface EGFR. It is an IgG2 antibody and the first fully human MoAB approved to treat cancer.102 Panitumumab is approved as a single agent in refractory metastatic colon cancer. Adverse reactions are similar to cetuximab, although severe reactions appear to be rare because it does not have a murine component.102

Both antibodies appear to be more effective in patients with tumors that are KRAS wild type, then patients with tumors that are KRAS mutation positive; therefore, patients with metastatic colorectal cancer should not receive anti-EGFR antibody therapy if a KRAS mutation is detected.103 Genetic testing in patients with colorectal cancer is discussed in further detail in the Chapter 107.

Trastuzumab Trastuzumab is a humanized MoAB that selectively binds to HER2.91,95 HER2 is overexpressed in about 33% of breast cancers, in about 22% of gastroesophageal junction and gastric cancers, and to varying degrees in other malignancies (e.g., ovarian, lung, prostate).9,91,104 Trastuzumab inhibits cell cycle progression by decreasing cells entering the S phase of the cell cycle, which leads to downregulation of HER2 receptors on cancer cells and decreased cell proliferation.103 Trastuzumab also leads to ADCC and CDC and directly induces apoptosis in cells overexpressing HER2.105 In addition, synergy between trastuzumab and traditional chemotherapy has been demonstrated, resulting in trastuzumab often being used in combination with chemotherapy.

Trastuzumab is approved for the treatment of metastatic breast cancer as a single agent or in combination with paclitaxel. It is also approved for adjuvant treatment as part of a combination chemotherapy regimen or as a single agent after multimodality anthracycline-based chemotherapy. It is not recommended to administer trastuzumab concomitantly with an anthracycline because of concerns of additive cardiotoxicity. Trastuzumab is also approved in combination with chemotherapy for the treatment of patients with HER2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma. The tumors should overexpress HER2 as measured by diagnostic tests that can qualify gene amplification or protein expression.

Trastuzumab is administered as a loading dose followed by weekly infusions.105 Trastuzumab has been administered every 3 weeks in combination with chemotherapy to simplify the treatment regimen.106

The most serious adverse reactions caused by trastuzumab include cardiomyopathy, infusion-related reactions, hypersensitivity reactions (including anaphylaxis), and increased myelosuppression. An evaluation of cardiac function should be performed before administration and extreme caution should be exercised in patients with preexisting cardiac dysfunction and in those who have received prior anthracyclines. In patients who develop a clinically significant decrease in left ventricular function (ejection fraction <50% or greater than 10% decrease), discontinuation of therapy should be considered. Similar to most MoABs, the symptoms associated with a hypersensitivity reaction are most common with the initial infusions of trastuzumab and occur infrequently thereafter. Myelosuppression is infrequent after the administration of trastuzumab as a single agent, but the incidence of neutropenia and febrile neutropenia is higher when trastuzumab is given with myelosuppressive chemotherapy as compared with giving the chemotherapy alone.105

Pertuzumab Pertuzumab is a humanized MoAB that targets the HER2 receptor. It is synergistic with trastuzumab and is effective in tumors that have developed resistance to trastuzumab. Pertuzumab binds to extracellular domain II of HER2, a site distinct from trastuzumab, and inhibits ligand-dependent HER2-HER3 dimerization, which subsequently decreases tumor proliferation and resistance pathways.107 Dual targeting of the HER2 receptor allows for increased efficacy against variant forms of the HER2 receptor, including truncated HER2 receptors. Similar to trastuzumab it appears to induce ADCC in cancer cells. Pertuzumab is currently approved in combination with trastuzumab and docetaxel for the treatment of HER2 overexpressed refractory metastatic breast cancer.

Ado-Trastuzumab Ematansine Ado-trastuzumab ematansine is indicated for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane. It is an antibody-drug conjugate that consists of the humanized anti-HER2 monoclonal antibody trastuzumab covalently linked to the microtubule-targeting inhibitor DM1.108

Vascular Endothelial Growth Factor Signaling Pathway Inhibitors

Bevacizumab Bevacizumab is a humanized MoAB directed against circulating VEGF.24 It binds to all biologically active circulating isoforms of VEGF and prevents the activation and promotion of angiogenesis.24

Bevacizumab is approved, in combination with chemotherapy, for the initial treatment of metastatic colorectal cancer109 and in combination with chemotherapy, for first-line treatment of patients with advanced nonsquamous NSCLC. Additional uses approved by the Food and Drug Administration (FDA) include metastatic renal cell carcinoma and progressive glioblastoma with off-label use in other cancers.

Several serious adverse events have been associated with bevacizumab, including hypertension, bleeding, and thrombotic events.109,110 Hypertension is more common in patients with a history of hypertension and responds to oral antihypertensive medications. Although the most common bleeding episodes are transient nosebleeds, fatal CNS and gastrointestinal hemorrhages have been reported. The product labeling includes a box warning regarding the risk of gastrointestinal perforation, wound dehiscence, and fatal hemoptysis.110 Bevacizumab is not recommended for use within 28 days of major surgery and patients should be instructed to report abdominal pain (an initial sign of gastrointestinal hemorrhage) to their healthcare providers immediately. Paradoxically, bevacizumab also has been associated with thrombotic events, including deep vein thrombosis, pulmonary embolism, and myocardial infarction, especially in elderly patients with a history of cardiac events. Another potentially serious adverse event associated with bevacizumab is proteinuria, and patients should be monitored for the development or worsening of proteinuria with serial urine dipsticks. Patients with a 2+ or greater urine dipstick should undergo further assessment.

Miscellaneous Monoclonal Antibodies


Ipilimumab is a human MoAB that blocks cytotoxic T-lymphocyte antigen (CTLA-4) that is approved for the treatment of metastatic melanoma. CTLA-4 acts a negative regulator of T-cell function, decreasing the ability of the immune system to mount an antitumor response. By binding to CTLA-4, ipilimumab allows for enhanced T-cell stimulation, proliferation, and antitumor activity.111 It can take 3 months or longer to demonstrate a response in patients with melanoma. Based on its enhanced immune response, several severe and fatal immune-mediated adverse reactions have been observed, including enterocolitis, hepatitis, dermatitis, neuropathy, and endocrinopathy (Table 104-8).



L-Asparaginase is unique among anticancer agents in its unusual mechanism of action, patterns of toxicity, and source. It is an enzyme produced by Escherichia coli or Erwinia chrysanthemi. L-Asparagine is a nonessential amino acid that can be synthesized by most mammalian cells except for those of certain lymphoid human malignancies, which lack or have very low levels of the synthetase enzyme required for L-asparagine formation.27 L-Asparagine is degraded by the enzyme L-asparaginase, which depletes existing supplies and inhibits protein synthesis. Increased L-asparagine synthetase activity within cancer cells causes resistance to L-asparaginase treatment.27 L-Asparaginase is a component of multiagent chemotherapy regimen used for the treatment of ALL and multiple products are available as listed in Table 104-8.



Interferons are a family of proteins produced by nucleated cells or recombinant DNA technology with antiviral, antiproliferative, and immunoregulatory activities. These proteins are classified as αβ, or γIFNs based on antigenic, biologic, and pharmacologic properties. IFN alfa has been approved for hairy cell leukemia, melanoma, Kaposi’s sarcoma, and CML. A pegylated INF-alfa has been approved for adjuvant treatment of metastatic melanoma.

The mechanisms by which IFNs exert their anticancer effects is unknown, but IFNs likely exert their effect by binding to specific membrane receptors and initiating various intracellular signaling pathways. IFNs can prolong the cell cycle, inhibit angiogenesis, and cause cytostasis and apoptosis. They can increase the expression of antigens on tumor cell surfaces, making the cancerous cells more easily recognized by immune effector cells. IFNs also inhibit certain oncogenes that can direct the unregulated cell growth that is characteristic of cancerous cells. Alterations in gene expression may change the levels of receptors for other cytokines or the concentration of regulatory proteins on immune cells or may activate enzymes that alter cellular growth and function.59

The most frequent adverse events are flu-like symptoms and elevated transaminases. Potentially serious adverse events include neuropsychiatric, autoimmune, ischemic, and infectious disorders.

Interleukin-2 (Aldesleukin)

Interleukin-2 is a cytokine produced by recombinant DNA technology that promotes B- and T-cell proliferation and differentiation and initiates a cytokine cascade with multiple interacting immunologic effects. The IL-2 receptor is expressed in increased amounts on activated T cells and mediates most of the effects of aldesleukin. Anticancer activity depends on proliferation of cytotoxic immune cells that can recognize and destroy cancer cells without damaging normal cells. Some of these cytotoxic cells are natural killer cells, lymphokine-activated killer (LAK) cells, and tumor-infiltrating lymphocytes.112Aldesleukin has been approved for the treatment of metastatic renal cell carcinoma and melanoma.

The toxicity of aldesleukin is related to dose, route, and duration of therapy, but aldesleukin is toxic therapy that requires vigorous supportive care. The most common dose-limiting toxicities are hypotension, fluid retention, and renal dysfunction. Aldesleukin decreases peripheral vascular resistance, producing peripheral vasodilation, tachycardia, and hypotension. A characteristic vascular or capillary leak syndrome produces fluid retention, which in turn can cause respiratory compromise. These toxicities require administration of vasopressors in most patients, judicious use of fluid support and diuretics, and supplemental oxygen. Patients with underlying cardiovascular or renal abnormalities are more susceptible to these adverse events, making careful patient selection important.112 Most patients treated with aldesleukin experience thrombocytopenia, anemia, eosinophilia, reversible cholestasis, and skin erythema with burning and pruritus, and some have neuropsychiatric changes, hypothyroidism, and bacterial infections.112 In general, the toxicities from aldesleukin reverse quickly after therapy is stopped and can be managed or prevented by careful prospective monitoring and supportive care.

Fusion Proteins

Denileukin Diftitox

Denileukin diftitox is a recombinant fusion protein that combines the active sections of both IL-2 and diphtheria toxin. Unconjugated diphtheria toxin is much too toxic to administer to humans. As the “payload” of the fusion protein, however, its cytotoxic effects are directed toward cells that express the high-affinity form of the IL-2 receptor, such as cancer cells of some patients with cutaneous T-cell lymphoma. When denileukin diftitox interacts with IL-2 receptors, the toxin inhibits protein synthesis in the cancer cells and causes cell death.113 It has been approved for the treatment of cutaneous T-cell lymphomas.

Although denileukin diftitox is directed therapy, its targeting of cells that express high-affinity IL-2 receptors is not specific because these receptors are expressed on cells other than cancer cells. Denileukin diftitox produces acute hypersensitivity reactions, flu-like symptoms, diarrhea, visual impairment, and vascular leak syndrome. It differs from the vascular leak syndrome produced by high-dose aldesleukin in that it occurs in fewer patients, is delayed in onset, is usually self-limited, and does not consistently recur on retreatment.112,113 Patients with an albumin concentration less than 3 g/dL (30 g/L) are at increased risk for vascular leak syndrome, and use in these patients is not recommended.


Ziv-aflibercept is a soluble recombinant fusion protein that was designed to block multiple signals that stimulate the angiogenic process. It was developed by fusing sections of the VEGFR-1 and VEGFR-2 immunoglobulin domains to the Fc portion of human IgG1. Ziv-aflibercept blocks VEGF-A, VEGF-B, and PIGF by “trapping” the ligands before they get to the native transmembrane receptors and thus decreasing proangiogenic signaling and tumor growth. It is approved in combination with chemotherapy in patients with resistant or progressive metastatic colorectal cancer and has adverse events similar to other anti-VEGF therapies.114


The response to anticancer agents and other treatment modalities could be described as a cure, complete response (CR), partial response (PR), stable disease, or progression.115 A cure implies that the patient is entirely free of disease and has the same life expectancy as a cancer-free individual. Because of our inability to detect small numbers of cancer cells we can never be absolutely certain that an individual patient is cured. Cancers that are curable with treatment are characterized by a stable plateau in the survival curve where the risk of relapse is very low. For most curable cancers, the survival curve has plateaued by about 5 years. Therefore, patients with a curable cancer who are alive 5 years from the time of diagnosis without disease recurrence are often considered “cured.” However, patients with some malignancies, such as breast cancer and melanoma, are still at significant risk for relapse after 5 years.

In an attempt to simply and unify response definitions in both clinical practice and published reports, the RECIST (Response Evaluation Criteria in Solid Tumors) criteria were developed in 2000 and revised in 2009.115 A complete response means complete disappearance of all cancer without evidence of new disease for at least 1 month after treatment. The terms cure and CR are not synonymous. Although an individual must have a CR to be cured, many individuals who achieve a CR will eventually relapse. A partial response is defined as a 30% or greater decrease in the tumor size or other objective disease markers and no evidence of any new disease for at least 1 month. Overall objective response rates for a given treatment are calculated by adding the CR and PR rates. Progressive disease is defined as a 20% increase in the tumor size or the development of any new lesions while receiving treatment. A patient whose tumor size neither grows nor shrinks by the above criteria is termed to have stable disease. Some patients may experience subjective improvement in the symptoms caused by their cancer without a defined response. Although clinically important, this does not indicate an objective response. The term clinical benefit response was recently developed to document these subjective responses; it refers to patients who have clinical benefit as measured by decreases in pain or analgesic consumption or improved quality of life or performance status.

These response definitions are applicable to solid tumors because leukemias and multiple myeloma are not characterized by discrete, measurable masses. Responses in these cancers are measured by elimination of abnormal cells (e.g., return to normal hematology parameters and normal bone marrow in leukemia), return of tumor markers to normal levels (e.g., normal serum protein electrophoresis in multiple myeloma), or improved function of affected organs (e.g., improved renal function after obstructive uropathy). Cytogenetic markers and molecular techniques have an increasingly important role in determining whether all cancer has been truly eliminated. For example, in CML, the Philadelphia chromosome can be detected by polymerase chain reaction (PCR) techniques even when no leukemia is evident in the bone marrow or bloodstream. Patients without evidence of the Philadelphia chromosome are classified as having a complete cytogenetic response. Measuring cytogenetic responses is increasingly common in patients with known cytogenetic abnormalities, and the absence of complete cytogenetic responses may predict disease relapse.

The FDA publishes guidance for industry to facilitate the drug development process.116 New therapies must demonstrate a favorable risk-to-benefit ratio in adequate and well-controlled clinical trials. Overall survival and symptom improvement is considered an appropriate measure of effectiveness. Accelerated approval promulgated in 1992 supported the approval of therapies intended to treat life-threatening or serious illnesses in which the new therapy demonstrated improvement compared to current therapies or provided therapy in the absence of current therapy based on surrogate end points that are likely to predict clinical benefit. Possible surrogate end points include disease-free survival, progression-free survival, objective response rates, and CR rates; overall response rate is the most common surrogate end point used to support accelerated approval. A clinical trial after accelerated approval must be conducted with due diligence and demonstrate clinical benefit, or the product may be removed from the market. In the period from 1990 to 2003, 75% of the new therapies for cancer were approved based on end points other than survival.116

Factors Affecting Response to Therapy

Factors affecting response include tumor burden, cancer cell heterogeneity, drug resistance, dose intensity, and patient-specific factors. The significance of tumor burden was discussed earlier in the Principles of Tumor Growth section. Tumors consist of a heterogeneous population of cells. Because of the genetic instability of cancer cells compared with normal cells, mutations commonly occur during cell division; thus, large tumors have undergone many cell divisions and express multiple mutations, resulting in genetically varied populations.6,28 In 1979, Goldie and Coldman proposed that these cytogenetic changes were not completely random and were highly associated with the development of the ability of tumors to develop drug resistance.1,6,28 The probability of developing resistant cell populations increases as tumor size increases. It is believed that a small percentage of resistant cancer cells may survive initial therapy. Resistant populations later proliferate and eventually become the dominant population, which could explain the common pattern of an initial response to therapy followed by progressive tumor regrowth despite continuing the same treatment.

Drug resistance may be either an acquired or inherited. Mechanisms of drug resistance include altered drug transport systems, metabolism, and target enzymes; inability to repair drug-induced damage; and insensitivity to drug-induced apoptosis.6,11,28 For example, multidrug resistance has been observed with natural chemotherapies (i.e., anthracyclines, vinca alkaloids, epipodophyllotoxins, and taxanes), and it occurs when some cancer cells are exposed to increasing concentrations of a specific chemotherapy.28,117 Surprisingly, these same cells also become resistant to other structurally unrelated chemotherapies and are therefore considered multidrug resistant. The resistant cancer cells possess the transporter Pgp, which enhances the export of these chemotherapies. Other potential mechanisms of drug resistance include inactivation of chemotherapy by glutathione metabolism, upregulation of drug targets, alternative intracellular signaling pathways, and decreased apoptosis. The last mechanism can be mediated by bcl-2oncogene overexpression or loss of the p53 gene, as discussed in the oncogene section.

The relationship between dose and response has been extensively explored for traditional chemotherapies1 because dose is believed to be a critical factor in determining response for many cancers. Dose intensity is defined as the dose delivered to the patient over a specified period of time. The three main variables that determine delivered dose intensity are the dose per course, the interval between doses, and the total cumulative dose. Dose density refers to shortening of the usual interval between doses (e.g., every 2 weeks instead of every 3 weeks) and is designed to maximize the effects of therapy on tumor growth kinetics. This strategy has been most extensively studied in breast cancer, with positive results from adjuvant therapy given to patients with high-risk node-positive disease. The delivery of optimal dose intensity is often compromised by the toxicities of the anticancer agent. Treatment cycles are commonly delayed because of inadequate recovery from toxicity, especially myelosuppression. Subsequent doses of the anticancer agents are often reduced to prevent or reduce the severity of these toxicities. The impact on patient outcome has been proven in studies showing reduced rates of response and survival in individuals receiving less-than-optimal doses.1 Understanding the pathophysiology of toxicities has led to the development of more effective agents to prevent and manage these toxicities. The development of agent- and toxicity-specific chemoprotective agents has facilitated application of dose-intensity principles.1 For example, the colony-stimulating factors avert neutropenia and permit delivery of dose-intensive or dose-dense regimens that are myelosuppressive. The issue of dose intensity is particularly important in the setting of high-dose chemotherapy with autologous hematopoietic stem cell support. Although lethal myelosuppression is avoided by administering hematopoietic stem cells, other severe end-organ toxicities emerge as doses of the anticancer agents are increased.

Patient-specific factors create unpredictable variability in response to anticancer therapy. For example, interindividual variations in absorption, distribution, elimination, or metabolism could lead to sub- or supratherapeutic levels of anticancer agents and their metabolites. The genetic mutations that resulted in the cancer can also affect response. For example, breast cancers that overexpress HER2 are often sensitive to anthracycline-based regimens.105 As a result, both efficacy and tolerability can be affected. Until recently, healthcare providers in oncology have modified dose based on variations in body size, blood counts, and organ function. Prospective dose modifications based on these parameters are still very important to optimize the effectiveness of therapy and minimize toxicity. But more specific tools are becoming available as we learn how to identify and apply differences in the genetic makeup of the patient and cancer to their anticancer therapy. Pharmacogenomics is the study of the role of inheritance in individual variation in drug response.118 In oncology, several clinically relevant genetic polymorphisms or variations have been identified that can affect pharmacokinetics and pharmacodynamics. Examples include polymorphisms in genes responsible for the activity of the enzymes DPD (responsible for 5-FU metabolism), TPMT (responsible for thiopurine metabolism), and UGT1A1 (responsible for irinotecan metabolism).118 Patients with deficiencies in these enzymes can experience significant, and possibly life-threatening, toxicity. Identifying these genetic variants could permit individualization of regimens containing these agents to avoid toxicity. Monitoring of anticancer agents concentrations could also improve the therapeutic index. For example, pharmacokinetic and pharmacodynamic modeling is associated with improved responses and decreased toxicity in children with ALL.

The presence of other disease states (e.g., comorbidities) may also affect response to treatment by limiting treatment options. The overall functional status of a patient may be assessed using performance status scales, such as the Karnofsky and Eastern Cooperative Oncology Group scales (Table 104-10).119 These scales can be used to predict patient tolerance of anticancer therapy and to assess the effects of therapy on the patient’s level of activity and quality of life. For many cancers, performance status at diagnosis is the most important prognostic indicator.

TABLE 104-10 Performance Status Scales


Today’s oncology health professionals have a wealth of information to consider when designing a personalized treatment approach. Patient-specific factors (e.g., performance status, comorbidities, organ function, and pharmacogenomics), tumor-specific factors (e.g., pathology, stage and molecular profile), and treatment goals (e.g., palliation and cure) are all considered when determining the best treatment option. Treatment cost can also be an important consideration.


Although single agents are sometimes used, the more common approach to anticancer therapy involves administration of multiple agents to overcome factors for decreased patient response noted previously.1,27,119 Initially, this approach was based on the Goldie-Coldman hypothesis, which addresses the issue of tumor cell heterogeneity and the inevitable development of drug resistance. Combination therapy is given to inhibit the many different cancer cells. The individual agents selected for combination therapy considers drug-specific factors, such as mechanism of action, cancer activity, and toxicity. Drugs that possess minimally overlapping mechanisms of action and toxicities are combined when possible. For example, myelosuppressive agents are typically combined with nonmyelosuppressive agents to minimize bone marrow suppression while gaining additive anticancer effects. The selected agents should each have significant activity against the cancer. If a synergistic reaction is known to exist for two agents, they may be combined in various treatment regimens.

With the availability of new targeted therapies, one area of research is to determine the optimal ways to combine these therapies, both with traditional chemotherapy and other targeted therapies. In theory, these therapies make ideal combination agents because they target the underlying cancer biology while usually avoiding the common adverse events associated with traditional chemotherapy. Healthcare providers must be careful when combining agents based on clinical data that demonstrate additive or synergistic benefit. Combinations of chemotherapy and targeted therapies have proven successful in breast and colon cancer. Predictive markers might be available to identify which patients may benefit from combinations of chemotherapy and targeted therapies for patients with breast and colon cancers.


Dosing and Administration

Healthcare providers should monitor several clinical and laboratory values before the administration of myelosuppressive agents. In general, a WBC count of 3,000 cells/mm3 (3 × 109/L) or above or an absolute neutrophil count (ANC) of 1,500 cells/mm3 (≥1.5 × 109/L) or above and a platelet count of 100,000 cells/mm3 (≥100 × 109/L) or above are usually required before administering myelosuppressive agents. In addition, a chemistry panel is drawn to assess organ function, especially for agents eliminated via those routes. Table 104-8 lists agents that require dosing adjustments and require specific laboratory tests before administration; failure to do so may result in overdosing and excessive toxicity.

Anticancer agents might be dosed based on body weight or body surface area (BSA) or as a fixed dose. Chemotherapy is generally dosed based on BSA.120 BSA is commonly used as an estimate of cardiac output and subsequent distribution to the liver and kidneys, the primary determinants of drug elimination. The most common methods used to determine BSA are the Mosteller and DuBois formulas, which are listed in Table 104-9. Body-sized dosing is also commonly used for MoABs and other therapeutic proteins, but the effect of body size on interpatient variability should be explored to determine optimal dosing approach. In contrast, most oral targeted agents are dosed as a fixed dose based on available tablet or capsule strengths.

Clinical Controversy…

The use of actual versus ideal body weight for calculating BSA is a source of debate in oncology. Although actual body weight is most often used, some healthcare providers prefer to use an adjusted body weight in obese patients. Healthcare providers need to clearly state the weight used in the BSA calculation. New methods of dosing using individual patient- and tumor-specific factors are an area of active research.

New dosing methods are being developed to improve the accuracy of chemotherapy dosing and prevent both over- and underdosing. For example, carboplatin is now commonly dosed based on the patient’s estimated glomerular filtration rate. This method, listed in Table 104-9, is known as the Calvert formula and has been demonstrated to achieve adequate levels of carboplatin without excessive toxicity.121Therapy might also be dosed based on drug levels (i.e., MTX), and healthcare providers should be proficient in these calculations before dosing and administering any chemotherapy. The health care provider should also be aware of diagnostic tests warranted before administering targeted agents, such as tamoxifen, AIs, trastuzumab, vemurafenib, and crizotinib. Additional methods using pharmacogenomic testing are being studied to individualize doses.

Safety and Handling Issues

All anticancer agents regardless of the route of administrations should be handled with care to avoid inadvertent exposure of healthcare providers.122 Consequently, all healthcare facilities should have written procedures for handling these drugs safely, and all personnel should be oriented to these procedures. Additionally, pharmacists should provide information about safe handling and disposal to patients and their families when a patient is prescribed oral anticancer agents. Safe handling includes avoiding skin contact and inhalation, but guidelines regarding safe handling of oral anticancer agents have not been developed.123

The United States Pharmacopeia Chapter 797 regulates the preparation of extemporaneously compounded sterile preparations and should be used by providers that prepare IV chemotherapy.122 The most common avenue of exposure is via inhalation of aerosolized drug. Individuals preparing IV chemotherapy should work in a class II biologic safety cabinet and wear gowns and powder-free disposable latex gloves. The gowns should be made of lint-free, low-permeability fabric with a solid front, long sleeves, and tight-fitting elastic cuffs. Negative-pressure techniques should be used in drug preparation to minimize aerosolization. Healthcare providers administering chemotherapy should take similar precautions to avoid exposure. Kits for cleaning up chemotherapy spills should be located in all areas where chemotherapy is handled. Cytotoxic waste should be disposed of properly, and patients should be informed of proper methods of disposing of potentially contaminated body excreta and cytotoxic waste.


Images The treatment of cancer with most anticancer agents is complicated by the risk of multiple serious adverse events, many of which are life threatening. Adverse events are commonly graded on a scale from no toxicity to death; a common scale used in clinical trials is the common terminology criteria for adverse events developed by the National Cancer Institute, and the standard adverse event reporting classification system used in the United States for all drugs is the Medical Dictionary for Regulatory Activities. Specific adverse events, such as doxorubicin-induced cardiotoxicity and bleomycin-related pulmonary toxicity, were summarized earlier. Several adverse events are common to many anticancer agents. For example, nausea and vomiting, myelosuppression, mucositis, alopecia, infertility, and carcinogenesis have been observed with traditional chemotherapy. With the addition of targeted therapies, new adverse events now need to be addressed by healthcare providers. The events observed with targeted therapies appear to depend on the intracellular signaling pathways that are inhibited. For example, rash has been observed with agents that affect the EGFR signaling pathway, and hemorrhage and thrombosis have been observed with agents that affect the VEGFR signaling pathway. Nutritional support and pain management are also important supportive care issues. The management of chemotherapy-induced nausea and vomiting and the basic principles of nutritional support and pain management are discussed in detail in other chapters.

Because many traditional chemotherapies affect DNA synthesis, all rapidly proliferating cells are more sensitive to the toxic effects. Normal tissues, such as the bone marrow, intestinal mucosa, and hair follicles, are tissues in which chemotherapy’s effects are manifested.


Images Although not seen with all anticancer agents, myelosuppression is the most common dose-limiting adverse event observed with chemotherapy. Myelosuppression is increased when chemotherapy is administered concurrently with radiation to the chest or pelvic region. Bone marrow suppression does not usually occur immediately after chemotherapy administration because blood components that have already been produced must be consumed before the effect is evident. WBCs, especially neutrophil precursors, are most significantly affected because of their rapid proliferation and short life span (6-12 hours). Platelets (5- to 10-day life span) are also affected but to a much less degree than neutrophils. Erythrocytes, with a 120-day life span, are affected the least. Usual nadirs, or lowest blood cell counts, occur at 10 to 14 days after chemotherapy administration, with recovery by 3 to 4 weeks. There are some exceptions to this general rule. The nitrosoureas, mitomycin C, and radiolabeled antibodies exhibit a delayed nadir (4-6 weeks) and recovery (6-8 weeks). Chemotherapy should be delayed until the suggested blood counts for a patient to safely receive myelosuppressive chemotherapy as listed in the previous section are achieved. Patients with leukemia or receiving a hematopoietic stem cell transplant may have a more rapid nadir of about 5 to 7 days.

Neutropenia, particularly with fever, is an undesirable adverse event during chemotherapy for most cancers. If significant neutropenia has occurred with prior courses, the doses of the offending chemotherapy in subsequent courses may be reduced. The magnitude of dose reduction is dictated by the degree of myelosuppression incurred and the incidence and severity of infection or bleeding. Empiric dose reductions may be made for the first chemotherapy treatment if the patient has a low baseline WBC or platelet count, has diminished bone marrow reserve, has impaired drug elimination, or is to receive a combination of several myelosuppressive agents. Patients who have received multiple prior courses of other myelosuppressive chemotherapy or extensive radiation therapy, especially to the pelvis or chest, may have a decreased bone marrow reserve. Therefore, these patients are more sensitive to the myelosuppressive effects of chemotherapy, and normal doses may produce profound bone marrow toxicity. Patients with impaired organ function may have compromised elimination of the chemotherapy and are at increased risk for severe bone marrow suppression if the dose is not appropriately adjusted (Table 104-8).

However, in some tumors (e.g., breast cancer, lymphoma), dosage reduction may compromise response, leading to worse patient outcomes.1 In patients who are responding well to treatment, some degree of myelosuppression is accepted by most healthcare providers if it is not compromising the patient’s quality of life and the cancer is responding to therapy. In these patients, empiric use of hematopoietic growth factors provides an alternative to dose reduction.


Although usually not life threatening, anemia is the most common hematologic complication of chemotherapy.124 The incidence of anemia depends on several factors, including the type and duration of therapy and the type and stage of the underlying malignancy. For example, carboplatin is more commonly associated with anemia than other chemotherapies. Multiple conditions are known to cause anemia in cancer patients, including chronic gastrointestinal blood loss, nutrient deficiency (e.g., iron and folate), chemotherapy and radiation therapy, bone marrow invasion, hemolysis, renal dysfunction, and anemia of chronic disease. Of all the signs and symptoms of anemia, fatigue is most common in patients with cancer.124 In fact, fatigue is the most commonly reported symptom overall in patients undergoing chemotherapy. The presence of fatigue is correlated with the severity of anemia; treatment of anemia may result in improvement in fatigue and quality of life. Anemia is only one of many possible causes of fatigue in patients with cancer. Other common causes of fatigue include insomnia, depression, unrelieved pain, and the underlying malignancy.

The treatments for chemotherapy-related anemia include red blood cell transfusions and human erythropoietic products (epoetin alfa and darbepoetin alfa).124 Both epoetin alfa and darbepoetin alfa can increase hemoglobin and hematocrit and decrease transfusion requirements. One difference between the products is that darbepoetin has longer half-life, which allows for less frequent administration of darbepoetin.125

Clinical practice guidelines for the treatment of cancer- and chemotherapy-related anemia are available.124 The first step is to evaluate the underlying cause of the anemia and initiate specific therapy as indicated. Red blood cell transfusions are the mainstay of treatment, but erythropoiesis-stimulating agents could be considered for patients with underlying kidney disease and for patients receiving palliative treatment. These agents must be prescribed and used under a risk management program. The presence of functional iron deficiency should be determined before administering these products.

Serious adverse events related to erythropoiesis-stimulating agents include thrombosis and pure red cell aplasia, which may result in an increased mortality rate from use. These events have generally occurred when the target hemoglobin of 12 g/dL (120 g/L; 7.45 mmol/L) is exceeded or the hemoglobin rises too quickly.124 Other rare and generally mild adverse events include pain at injection site, rash, flulike symptoms, seizures, and hypertension.


When the ANC falls below 500 cells/mm3 (0.5 × 109/L), the risk of infection increases.126 The ANC may be calculated by multiplying the percentage of neutrophils (segmented plus banded neutrophils) by the total WBC count. The risk of infection is also directly proportional to the duration of neutropenia. Other risk factors for infection include alteration in the integrity of physical defense barriers and the functional integrity of the WBCs. The underlying cancer, chemotherapy, and radiation can affect neutrophil function. The diagnosis of infection in the neutropenic patient is complicated by the lack of WBCs. Usual signs and symptoms of infection, such as pus, abscesses, and infiltrates on chest radiography, are often absent as a result of the lack of WBCs. Subsequently, healthcare providers must rely on fever as an indication of infection in these patients. Definitive culture results may take days, and a septic neutropenic cancer patient can die within hours if not treated. Therefore, empiric antibiotics are promptly initiated based on reliable coverage of the most likely organisms, antibiotic sensitivities at the institution, the patient’s signs and symptoms (if present), side effect profiles, and cost.126 The most common source of infection in these patients is self-infection with body flora, which includes both gram-positive and gram-negative bacteria. Specific treatment of infections in immunocompromised hosts is discussed in Chapter 100.

Numerous methods have been explored to prevent infections in patients with cancer. Colony-stimulating factors (CSFs) are commonly used for this purpose.126 These factors are naturally occurring proteins that are essential for the normal growth and maturation of blood cell components (Fig. 104-10). CSFs have the ability to enhance the production and the function of their target cells. Two recombinant products, G-CSF (granulocyte colony-stimulating factor) and GM-CSF (granulocyte-macrophage colony-stimulating factor), are commercially available in the United States. G-CSF (filgrastim) specifically stimulates the production of neutrophilic granulocytes, and GM-CSF (sargramostim) promotes the proliferation of granulocytes (neutrophils and eosinophils) and monocytes and macrophages.127 Although GM-CSF stimulates megakaryocytes, no consistent effect on platelet production has been observed in clinical trials. Both factors initially enhance demargination and mobilization of mature cells from the marrow and then provide constant stimulation of stem cell progenitors. Pegfilgrastim is a long-acting CSF created by adding a polyethylene glycol molecule to G-CSF.128 Clinical trials have demonstrated that a single dose of pegfilgrastim provides equivalent effects to 10 to 11 days of daily G-CSF, with similar adverse events.


FIGURE 104-10 Sites of action of hematopoietic growth factors in the differentiation and maturation of marrow cell lines. A selfsustaining pool of marrow stem cells differentiates under the influence of specific hematopoietic growth factors to form a variety of hematopoietic and lymphopoietic cells. Stem cell factor (SCF), FTL-3 ligand (FL), interleukin-3 (IL-3), and granulocyte-macrophage colony-stimulating factor (GM-CSF), together with cell–cell interactions in the bone marrow, stimulate stem cells to form a series of burst-forming units (BFU) and colony-forming units (CFUs): CFU-GEMM, CFU-GM, CFU-Meg, BFU-E, and CFU-E (GEMM, granulocyte, erythrocyte, monocyte, and megakaryocytes; GM, granulocyte and macrophage; Meg, megakaryocyte; E, erythrocyte). After considerable proliferation, further differentiation is stimulated by synergistic interactions with growth factors for each of the major cell lines—granulocyte colony-stimulating factor (G-CSF), monocyte/macrophage-stimulating factor (M-CSF), thrombopoietin, and erythropoietin. Each of these factors also influences the proliferation; maturation; and, in some cases, the function of the derivative cell line. (NK, natural killer.) (From Kaushansky K, Kipps TJ. Hematopoietic agents: Growth factors, minerals and vitamins. In: Brunton LL, Chabner BA, Knollman BC (eds). Goodman & Gilman’s The Pharmacologic Basis of Therapeutics, 12th ed. New York: McGraw-Hill, 2010.)

These growth factors may be used as primary or secondary prophylaxis of neutropenia. Primary prophylaxis refers to the use of CSFs to prevent neutropenia with the first cycle of chemotherapy. Recently, the American Society of Clinical Oncology stated that this strategy is clinically and economically appropriate for patients who are receiving a chemotherapy regimen with a 20% or higher risk of febrile neutropenia.129 Secondary prophylaxis refers to the use of growth factors to prevent recurrent neutropenia in patients who had experienced neutropenia with the prior cycle of chemotherapy. It is recommended that secondary prophylaxis be reserved for patients with chemosensitive cancers when dose reduction may affect disease-free or overall survival.130

The role of these factors in the treatment of established neutropenia is less well defined. Most studies suggest no or only minimal clinical benefit from use of CSFs in treating neutropenia; therefore, CSFs should not be routinely used in patients with established neutropenia regardless of the presence of fever. However, certain high-risk patients with fever and neutropenia may benefit from CSFs, including those with neutropenia for more than 10 days, ANC below 100 cells/mm3 (>0.1 × 109/L), age younger than 65 years, and infectious complications (pneumonia, sepsis, or invasive fungal infections) as well as those who are hospitalized at the time of the development of neutropenic fever.126,130

Both G-CSF and GM-CSF have also proven effective in accelerating hematopoietic engraftment and in treating graft failure after hematopoietic stem cell transplantation. Other uses for the CSFs include peripheral blood stem cell mobilization, neutropenia in patients with acquired immune deficiency syndrome, myelodysplastic syndromes, congenital neutropenia, and aplastic anemia. Growth factors should not be used in patients receiving concomitant chemotherapy and radiotherapy, especially if the radiation involves the mediastinum. These patients appear to experience more significant thrombocytopenia when administered CSFs.

At currently recommended doses, the CSFs are well tolerated. Adverse events are more commonly seen with GM-CSF and may be related to its ability to enhance binding of neutrophils to endothelial cells or to activation of monocytes or macrophages, which may stimulate the release of cytokines such as IL-1 and TNF-α.127 The most common adverse event with CSFs is bone pain (20%-25% of patients), which can be treated with acetaminophen. Other adverse events of G-CSF include an increase in lactate dehydrogenase, alkaline phosphatase, and uric acid levels. Additional adverse events of GM-CSF include constitutional symptoms, such as low-grade fever, myalgia, arthralgia, lethargy, and mild headache. GM-CSF may also produce an elevation in liver transaminases. At higher doses of GM-CSF, pleural and pericardial effusions, capillary leak syndrome, and thrombus formation may occur. Both G-CSF and GM-CSF may produce mild erythema at subcutaneous injection sites, as well as a generalized maculopapular rash with either subcutaneous or IV administration. The adverse events observed with pegfilgrastim are similar to those of G-CSF and are treated the same.128

The dosing and administration of CSFs approved for prophylaxis of chemotherapy-induced neutropenia after standard dose chemotherapy is as follows: G-CSF 5 mcg/kg until the ANC reaches 10,000 cells/mm3 (10 × 109/L) (or clinically safe) or pegfilgrastim 6 mg as a single dose. Both factors should be started between 24 and 72 hours after chemotherapy; G-CSF can be stopped the day before chemotherapy, but pegfilgrastim needs to be stopped within 14 days of the next dose because of its long half-life. The dose for other uses varies, such as the dose of 10 mcg/kg per day usually used in the setting of peripheral blood stem cell mobilization. The recommended dose of GM-CSF is 250 mcg/m2 per day. Pharmacokinetic data favor subcutaneous injection as the most effective route. However, in patients in whom subcutaneous injections are not feasible (e.g., anasarca), G-CSF and GM-CSF may be given IV. Pegfilgrastim should not be given IV. Because of the high cost associated with CSF use, alternative dosing regimens have been explored. These regimens attempt to decrease the total amount of CSF used by delaying the start, decreasing the dose, or decreasing the duration of therapy. Standardized doses of 300 mcg or 480 mcg of G-CSF and 500 mcg of GM-CSF, based on product vial sizes, are often used to minimize waste. Specifically, the posttreatment target ANC of 10,000 cells/mm3 (10 × 109/L) recommended by product information is often reduced in clinical practice to 5,000 cells/mm3 (5 × 109/L) or lower. For patients receiving pegfilgrastim, it is important that additional CSFs not be administered for the 10 days after administration because additional benefit is not realized.128


Chemotherapy-induced thrombocytopenia puts the patient at risk for significant bleeding. To date, platelet transfusions remain the mainstay of management. At most centers, platelet transfusions are reserved for patients with a platelet count of less than 10,000 cells/mm3 (<10 × 109/L) unless they are actively bleeding, must undergo a surgical procedure, or have documented infections or fever. For patients with nonmyeloid malignancies who experience significant thrombocytopenia with chemotherapy, oprelvekin (IL-11) may be considered as secondary prophylaxis in subsequent cycles.131 When used after chemotherapy associated with a high risk of thrombocytopenia, oprelvekin decreased the need for platelet transfusions, as well as the numbers of platelets required for transfusion. Unfortunately, oprelvekin is associated with some significant adverse events, mostly related to fluid retention (e.g., edema, dilutional anemia, dyspnea, and pleural effusions). Cardiac toxicity, especially tachycardia, and atrial fibrillation and flutter also have been observed. Prophylactic oprelvekin also is significantly more expensive than platelet transfusions.132 Considering the modest clinical benefit, the adverse events, and the high cost, oprelvekin use should be reserved for patients who are at high risk for severe thrombocytopenia from chemotherapy when dose reduction is known to compromise disease response.


The gastrointestinal mucosa is a common site of chemotherapy-anticancer agent induced toxicity.133 The subsequent inflammation, or mucositis, can lead to painful ulcerations; local infection; and an inability to eat, drink, or swallow. Disruption of the gastrointestinal mucosal barrier may also provide an avenue for systemic microbial invasion. Anticancer agents most commonly associated with mucositis include 5-FU, doxorubicin, MTX, multikinase inhibitors, and mTOR inhibitors. Currently, the most effective means of preventing mucositis is through good oral hygiene. Patients who are at high risk for this toxicity (those with poor dentition, high-dose chemotherapy, or radiation therapy involving the oropharynx) should be evaluated by a dentist before starting therapy and should be instructed to rinse their mouths frequently with baking soda and salt water or plain saline rinses during and during therapy. Clinical practice guidelines for the prevention and treatment of anticancer therapy-induced mucositis were recently published.133

A better understanding of the pathophysiology of mucositis has resulted in identification of promising new agents to better prevent mucositis. The keratinocyte growth factor palifermin is approved for use in patients receiving high-dose chemoradiotherapy before hematopoietic stem cell transplantation. Palifermin is given IV at a dose of 60 mcg/kg/day for 3 consecutive days immediately before the initiation of conditioning therapy and then again for 3 days after hematopoietic stem cell transplantation.134 The effect of palifermin on solid tumor growth is unknown, and its use in nonhematologic cancers is not recommended.

After mucositis has developed, treatment is mainly supportive, including use of topical or systemic analgesics and oral hygiene (including the rinses described).133 Viscous lidocaine, diphenhydramine liquid, and dyclonine are commonly used topical anesthetics. Severe cases of mucositis may lead to dehydration and require IV hydration and pain medications, including patient-controlled analgesia pumps. Local infections caused by Candida species and reactivation of herpes simplex viruses are common in these patients. Suspicious lesions should be cultured, and appropriate antifungal, or antiviral treatment should then be instituted. Antifungal therapy may be delivered topically for mild infections (thrush) with clotrimazole troches or nystatin oral suspension. For more severe oral or esophageal fungal infections, systemic treatment with oral fluconazole or IV antifungals is indicated.

Mucosal damage can occur at any point along the entire length of the gastrointestinal tract. In the lower portion of the gastrointestinal tract, this damage is usually manifested as diarrhea (mild to life threatening in nature) and abdominal pain. Support with IV fluids and electrolyte supplementation should be initiated promptly in severe cases. After infectious causes have been ruled out, diarrhea can safely be treated with antispasmodics, such as Lomotil or loperamide. The somatostatin analog octreotide has also been used successfully to treat severe cases of chemotherapy-induced diarrhea; guidelines exist to assist healthcare providers in treating diarrhea.133,135

Cutaneous Reactions

Chemotherapy-induced cutaneous reactions are generally reversible and self-limiting upon dose reductions or delays. Common reactions include localized rash, photosensitivity, skin hyperpigmentation, nail changes, and hand-foot syndrome. Hand-foot syndrome reactions can be uncomfortable and interfere with daily activities. Emollients, cooling procedures, and over-the-counter pain relievers can minimize discomfort. Common chemotherapies associated with cutaneous reactions include cytarabine, 5-FU, capecitabine, doxorubicin, and bleomycin.

Cutaneous reactions, such as rash and hand-foot syndrome, have also been observed with some targeted therapies; for example, rash is often the most common adverse event associated with therapy that inhibits EGFR signaling pathways and requires prompt recognition by healthcare providers to prevent drug discontinuation. Some studies suggest that the rash may be a surrogate marker of response to these agents, perhaps indicating a genetic predisposition to response with EGFR-targeted agents. Rash occurs in up to two-thirds of patients taking EGFR inhibitors, most commonly in the first month of treatment with the typical site of presentation being the face and upper torso. Although no clear guidelines exist for the treatment of this rash, patients should be supported based on their presentation.70 Anecdotal reports indicate that emollients help if patients complain of dry skin, topical and systemic antibiotics may help if the rash becomes infected, and steroids may help prevent itching and inflammation.70 Hand-foot syndrome has been reported with several multikinase inhibitors, including sorafenib and sunitinib. The management is the same as for the development of hand-foot syndrome with chemotherapy.


Many patients find alopecia the most distressing adverse event. Alopecia from chemotherapy is usually temporary, and the degree of hair loss varies widely.136 Hair loss is not limited to the scalp; any area of the body may be affected. Patients receiving a taxane as part of their chemotherapy regimen are especially prone to total body alopecia. Hair loss usually begins 1 to 2 weeks after chemotherapy, and regrowth may begin before the chemotherapy courses are completed. Cryotherapy (local application of ice) and scalp tourniquets have both been investigated as methods of preventing alopecia. Both techniques produce vasoconstriction, resulting in decreased exposure of hair follicles to the chemotherapy. These techniques are not uniformly effective and are contraindicated in patients with cancers that may metastasize to the scalp, such as leukemia and lymphoma.


Vesicants are agents that may cause severe tissue damage if they escape from the vasculature.129 These agents include the anthracyclines, actinomycin D, the vinca alkaloids, mitomycin C, nitrogen mustard, and the taxanes. The anthracyclines are the most notorious agents and the most extensively investigated. The tissue damage may result in prolonged pain, tissue sloughing, infection, and loss of mobility. Prompt initiation of the appropriate interventions is important to minimize morbidity. Unfortunately, most information on extravasation management is anecdotal; few controlled clinical trials have been conducted to determine optimal intervention strategies. Consequently, prevention is the focus of extravasation management. The most important method of prevention is good administration technique, but extravasations may occur despite good administration technique.129 The vein selected for administration should be on the distal portion of the arm. The large veins of the forearm are desirable because if a drug does extravasate, there is adequate soft tissue coverage to protect crucial structures such as nerves and tendons, and joint function is not put at risk. Peripherally administered vesicants should be given slowly via IV injection (IV push) through the side arm of a running IV line. The person administering the vesicant should verify needle stability and adequate blood return after each 1 to 2 mL of drug is injected. Vesicants should not be administered by IV infusion unless the patient has a central venous catheter. For extravasation of vesicants, one of the most important interventions is the application of ice packs to the affected area. One exception to this rule is the vinca alkaloids, which are better managed with application of heat. Only a few antidotes to vesicant agents are used clinically. Sodium thiosulfate is used to neutralize nitrogen mustard extravasations, and hyaluronidase (if available) can improve the outcome after extravasation of vinca alkaloids, etoposide, and taxanes. Topical application of dimethyl sulfoxide (DMSO) may be an effective method for managing anthracycline and mitomycin C extravasations.129 Dexrazoxane, marketed as Totect, has been approved to treat anthracycline extravasation and is given as an IV infusion.137


Advances in the treatment of some cancers, such as Hodgkin lymphoma and testicular cancer, have produced long-term survivors and the opportunity to examine the late consequences of chemotherapy. Infertility and secondary cancers have emerged as important late effects. The gonadal toxicities of chemotherapy have not received much attention in the past because they are not life threatening. High rates of fertility deficits and sexual dysfunction have been noted for both men and women.138 In men, chemotherapy can produce severe oligospermia or azoospermia, as well as infertility. Serum testosterone levels are rarely altered. The recovery of spermatogenesis after completing therapy is unpredictable. Men receiving combination chemotherapy appear to sustain more long-lasting adverse events on fertility than do men receiving single-agent chemotherapy. Age, total dose, duration of therapy, and the chemotherapy mechanism are other important variables. In women, toxic effects on the ovaries result clinically in amenorrhea, vaginal epithelial atrophy, and menopausal symptoms. These effects are related to dose and age. Younger patients are more resistant to the effects on the ovaries. As with men, the recovery of fertility is unpredictable, but women younger than 25 years of age appear to have the best outcomes. The effects of the alkylating agents on fertility have been extensively studied. These agents exert profound and consistently detrimental effects on reproductive function.138 The impact of this drug-induced amenorrhea on patient survival has been less clear with some trials demonstrating a benefit to patients who achieve chemotherapy-induced amenorrhea. Trial results have been mixed, though, and conclusive statements cannot be made at this time. Less is known about commonly used agents such as doxorubicin, taxanes, and platinum compounds. The risk of infertility should be discussed with all patients before they receive anticancer agents, and they should be informed about options for fertility preservation.

Secondary Malignancies

Secondary cancers induced by chemotherapy and radiation are serious long-term complications.139 Although many solid tumors have been reported as chemotherapy-induced malignancies, AML and myelodysplastic syndromes are the most common secondary cancers. AML and myelodysplastic syndrome have been reported after successful treatment of Hodgkin lymphoma and NHL, acute leukemias, multiple myeloma, breast cancer, and advanced ovarian cancer. For curable cancers, the relatively small risk for occurrence of secondary malignancies is far outweighed by the benefits of survival in large numbers of patients. However, for cancers such as ovarian cancer, the risk of leukemia is not offset by improved survival in patients treated with chemotherapy. The issue of secondary malignancies is of particular concern in patients receiving adjuvant chemotherapy. As with the late complication of infertility, the anticancer agents primarily associated with secondary cancers are the alkylating agents. Etoposide, teniposide, radionucleotides, and the anthracyclines also are linked to secondary leukemias. Solid tumors as secondary malignancies occur more commonly after treatment with radiation than with chemotherapy.






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