Principles and Pharmacology of Chemotherapy

Kenneth R. Hande

PRINCIPLES OF CHEMOTHERAPY

To optimally treat cancer patients, clinicians should understand the principles of cancer chemotherapy as well as the pharmacology of the drugs they are administering. The first section of this chapter reviews our understanding of (a) cancer biology, (b) mechanisms of antineoplastic drug action, (c) mechanisms of drug resistance, (d) drug toxicities, (e) pharmacologic principles (common and unique), and (f) potentials and limitations of therapy for individual patients. Specific drugs used to treat hematologic malignancies, their mechanism of action, and their toxicities are summarized in the second section of this chapter.

Cancer Biology

Most cancers are detected when there are 10⁴ to 10¹¹ neoplastic cells present.¹ The large number of cells present at diagnosis usually requires multiple courses of treatment or a long duration of therapy to result in a cure. Even if a drug, or a combination of drugs, is quite effective in killing cancer cells, such that it kills 999 of every 1,000 cells present (99.9% cell kill), one treatment will reduce a tumor population from 10¹¹ to 10⁸ cells. At least four treatments are therefore necessary to eliminate the final cancer cell, assuming there is no tumor cell growth during the treatment period. In fact, because of toxicity to normal tissues and the time needed for normal tissue recovery, cancer chemotherapy must be spaced out in treatment cycles. During the period between cycles, tumor regrowth occurs. Thus, most curative treatment regimens require prolonged therapy, often using multiple courses of chemotherapy, with the number of courses depending on the tumor mass at the time of diagnosis and the sensitivity of the tumor to the drugs. The fraction cell kill (e.g., 90%, 99%, 99.99% cell kill) depends on the sensitivity of cells to the antineoplastic drug and the dose of drug administered. Rapidly dividing cells are generally more sensitive to antineoplastic agents while nondividing cells are generally resistant.

Most cancers do not grow at a fixed rate throughout their course. Initial growth rates may be exponential. Gompertzian growth is sigmoid. In the Gompertzian model, the growth fraction of the tumor reduces as the tumor enlarges.² Because a significant proportion of cells in a large tumor mass are often in a resting or dormant phase, presumably as a result of lack of adequate nutrients or oxygen, they may not be affected by chemotherapy. The best opportunity for cell kill by chemotherapy is in the early portion of the growth curve, when all cells are dividing.

Recurrence of cancer after “complete remission” (disappearance of all detectable disease) can be explained by the inability of current staging methods to detect fewer than 10³ to 10⁴ tumor cells in the body even by the most sensitive means. Chemotherapy that kills several logs of tumor cells (e.g., from 10¹¹ to 10⁴) eliminates all visible evidence of cancer and prolongs survival, but the malignancy will recur at a later time. Examples of possible clinical courses associated with cancer chemotherapy are illustrated in Figure 68.1.

The growth fraction of a cancer represents the percentage of cells progressing actively through the cell cycle. A cell cycle is marked by two observable events. In S-phase (synthesis), DNA replication occurs; during M-phase (mitosis), cellular division into two daughter cells is noted.¹ G₁ (gap) is the time between the end of mitosis and the start of the next S-phase. G₂ is the time between the completion of S-phase and the start of M-phase. Cells that have ceased to proliferate for prolonged periods have entered a G₀ phase (or resting phase) of the cell cycle (Fig. 68.2). Some drugs are cytotoxic when exposed to cancer cells in any phase of the cell cycle. Other drugs are phase-specific; that is, they are cytotoxic to cells only in a particular phase of the cell cycle. Cytarabine, for example, is an S-phase-specific agent, whereas vincristine is M-phase-specific. For cells to be killed by cytarabine, the drug must be present when the cell is synthesizing DNA.

Mechanisms of Antineoplastic Drug Action

Antineoplastic agents have been discovered by many methods. Exposing cancer cells in culture to natural or synthetic compounds to screen for materials with antineoplastic activity has identified a number of active antineoplastic agents (drugs such as paclitaxel). Since DNA is important in cell division, compounds blocking DNA synthesis have been developed. Over the past 20 years, genes and their protein products that regulate cell division have been identified. The molecular pathways by which these oncogenes cause cellular proliferation have been determined.³ Knowledge of molecular pathways critical to the growth of cancer cells has led to the targeted development of molecules altering specific pathways (e.g., tyrosine kinase inhibitors, angiogenesis inhibitors). During the past two decades, the development of cancer drugs has shifted from a screening process where active agents are identified and their mechanism of action later defined, to first identifying a targetable pathway, finding a compound to block that pathway, and then testing for antineoplastic activity.

No matter how an antineoplastic has been developed, these drugs interfere with an essential step required for cell growth or division. The initial target of antineoplastic drugs varies widely, from direct attack on the DNA molecule to inhibition of signal transduction molecules. However, all antineoplastic agents cause a disruption in a cellular process so significant to the cancer cell that it requires the cell to either quickly repair the damage or to initiate the process of apoptosis (programmed cell death). Essentially, all antineoplastic agents result in cancer cell death through initiation of apoptosis.⁴ Apoptosis is the normal physiologic process of cellular suicide, which occurs in all living organisms to eliminate unwanted, functionally abnormal, or harmful cells. In apoptosis, in contrast to cellular necrosis, the cell shrinks and condenses, fragmenting into multiple membrane-bound bodies (apoptotic bodies) that are engulfed by surrounding cells without inflammation or damage to the surrounding tissues. Biochemically, apoptosis is characterized by fragmentation of nuclear DNA, demonstrated by a typical ladder pattern on agarose gel electrophoresis.

To understand how cytotoxic agents initiate apoptosis, an understanding of the events that occur during the normal cell cycle is important. As previously mentioned, DNA synthesis is not continuous from one mitosis to the next but takes place in only a specific period of the cell cycle, the S-phase. Similarly, mitosis or the M-phase takes up only a small part of the cell cycle.¹ In most, if not all cells, the cell cycle is temporarily halted during the G₁-S-phase checkpoint and at the G₂-M-phase checkpoint. At these times, cells determine whether to continue into the S-phase, initiate the process of apoptosis, or undergo DNA repair. Passage into a new phase of the cell cycle requires activation of a series of enzymes called cyclin-dependent kinases, which activate another group of enzymes (the cyclins).⁵ If cells are damaged by chemotherapeutic agents and are unable to repair the damage, apoptosis is initiated at the G₁-S or G₂-M checkpoint, provided the mechanisms for apoptosis are in place. Several critical factors are needed for apoptosis to occur such as p53, p63, and p21. P53 is a nuclear phosphoprotein capable of binding to specific DNA sequences and activating selected target genes triggering apoptosis. Cells with a mutated P53 gene have a relative resistance to cancer chemotherapeutic agents and are unable to initiate apoptosis properly.⁶ P21 is a protein induced by p53 that binds to and inactivates the cyclins required for progression of cells into the S-phase. Other factors are known to affect the apoptotic pathway. A protein originally found in B cell lymphomas, bcl-2, blocks apoptosis. Caspases are the key machinery causing the breakdown of DNA and proteins. Caspases are specialized proteases existing as proenzymes, which can be rapidly activated by a number of factors. The Fas ligand and tumor necrosis factor stimulate the protease cascade. It is clear that antineoplastic agents provide the initial trigger for beginning the pathway to programmed cell death (Fig. 68.3). However, the presence, or absence, of apoptotic proteins is as important as the initial interaction between a cytotoxic drug and its effecter in determining whether tumor cell kill occurs.⁴

FIGURE 68.1. Schematic representation of clinical course of two patients with Hodgkin disease. Both patients A and B are diagnosed with a clinically detected tumor mass (10¹¹ cells). Both patients are treated with ABVD (doxorubicin, bleomycin, vincristine, and DTIC) every 2 weeks. One course of therapy for patient A results in a 2-log tumor cell kill. Patient B’s therapy results in only a 1-log tumor cell kill. Some tumor growth occurs while waiting for normal tissue recovery before initiation of the next treatment. Three months into therapy, neither patient A nor B has clinically detectable disease. Treatment is stopped after 6 months of therapy. Patient A is cured, whereas disease recurs in patient B 3 months after stopping therapy.

FIGURE 68.2. The cell cycle. The cell cycle is marked by two observable events. During S-phase (synthesis), DNA replication occurs; and during M-phase (mitosis), cells divide. G₁ and G₂ (gap) are times between completion of M-phase and start of S-phase and between completion of S-phase and start of M-phase, respectively. During G₁ and G₂, the cell prepares for the S- and M-phases of the cell cycle. Cells may temporarily cease to divide and enter a resting or G₀ phase of the cell cycle. The G₁-S checkpoint is a critical phase in the cell cycle, when directions for entering S-phase or committing to apoptosis (programmed cell death) are given.

FIGURE 68.3. Potential pathways involved in cytotoxicity induced by chemotherapy. Chemotherapeutic drugs or growth factor deprivation damages cells. Cells are arrested at the G₁-S checkpoint. If the damage is sublethal, it may be repaired and the cell proceeds to S-phase. If significant DNA damage is present, the process of programmed cell death is initiated. Critical factors, such as p53 and p21 gene products, are required for the cell to undergo apoptosis.

Resistance to Anticancer Drugs

The presence of cancer cells that are resistant to chemotherapeutic agents is a common clinical occurrence. It has been postulated that by the time the number of cancer cells reaches 10³ to 10⁶, a resistant clone has developed.⁷ Unfortunately, there are many ways in which cells can become resistant to an antineoplastic agent. Steps in antineoplastic drug disposition within the cell are represented schematically in Figure 68.4. For an anticancer drug to be active, it must (a) be taken up into a cancer cell and (b) be converted into an active agent. It must then make its way within the cell to its target without being (c) metabolically inactivated, (d) chemically inactivated, or (e) excreted from the cell. Once it interacts with its cellular target, the cell must not be able to (f) alter the target or (g) repair the damage to the target. Finally, (h) mechanisms for apoptosis must be in place, as discussed in the preceding section. Examples of drug resistance at all of these steps have been described.⁸ Not only are there multiple potential mechanisms for drug resistance, but an individual tumor cell can become resistant to a particular drug in many ways. For example, resistance to methotrexate (MTX) has been described in some cell lines with altered folate transport that limits MTX uptake into cells.⁹ In other cell lines, MTX resistance results from the overexpression of the target enzyme, dihydrofolate reductase (DHFR).

Cancer cells may become simultaneously resistant to several types of chemotherapeutic drugs. Cells that express the multidrug resistance gene (MDR) produce a glycoprotein of 170-kDa weight known as p-glycoprotein or p170.⁸ Originally described in 1976, this protein is a drug transporter that sits in the cell wall of resistant tumor cells. P-glycoprotein transports a number of antineoplastic agents, most of which are hydrophobic, including vinca alkaloids, epipodophyllotoxins, anthracyclines, actinomycin, and taxanes. Cells in which the MDR gene is activated develop simultaneous resistance to these antineoplastic agents. The presence of p-glycoprotein on tumor cells has been correlated with poor prognosis in hematologic tumors.¹⁰ Efforts have been directed at inhibiting p-glycoprotein. However, MDR inhibitors often block either the hepatic or renal excretion of anticancer drugs, thereby increasing drug toxicity.¹¹ Clinical effectiveness of these MDR inhibitors has not been demonstrated. Cancer cell lines have been characterized that do not overexpress p-glycoprotein but do display a similar cross-resistance pattern. These lines have different types of transport proteins, such as MDR-related protein (MRP) or breast cancer resistance protein (BCRP). MRP and BCRP, like p-glycoprotein, are members of the adenosine triphosphate (ATP) binding cassette gene superfamily, but are structurally dissimilar to p-glycoprotein and with different inhibitors.¹², ¹³ In summary, tumor cells can develop resistance to antineoplastic drugs by numerous mechanisms. Resistance occurs as a result of random mutational changes in a population of cancer cells. Mutations to a drug-resistant cell line are estimated to occur at a population size of 10⁴ to 10⁶ tumor cells, a size smaller than is clinically detectable. Therefore, drug-resistant cancer cell populations will be present in the majority of tumors at diagnosis. The early presence of resistant tumor cells leads to the rationale for (a) early treatment of cancers to avoid multiple resistant populations and (b) use of multiple agents with differing mechanisms of action.

FIGURE 68.4. Potential pathways for antineoplastic drug disposition in tumor cells. For a drug to be effective, the drug, or its active metabolite, must reach its target site within the cell. Possible steps required for a drug to reach its receptor or to be inactivated include: (1) uptake into a cell through a particular transport protein; (2) enzymatic conversion of the drug to an inactive metabolite; (3) enzymatic conversion of the drug to its active metabolite; (4) binding of an active metabolite by a cellular protein or thiol, thereby inactivating drug; (5) excretion of the drug from the cell via an efflux transport pump; (6) alteration in the genetic makeup of the cell, changing the drug receptor site or number; and (7) changes in the ability of a cell to repair damage of a drug at its receptor.

Drug Toxicity

As opposed to many other classes of drugs, the therapeutic window for chemotherapeutic agents is narrow (Fig. 68.5). The dose of drug needed to achieve adequate tumor cell kill often causes toxicity to normal tissues. For many antineoplastic agents, a sigmoidal curve defining the relationship between toxicity and the dose of drug administered (or the area under the plasma drug concentration [AUC] versus time curve) has been demonstrated. At low drug concentrations, no cytotoxicity is observed. With increasing concentration, cell kill is proportional to dose. At higher concentrations, the effect plateaus. Similar relationships correlating the dose of drug and the antitumor response have also been demonstrated.¹⁴ A positive relationship between the drug dose administered and the tumor response rate has been found for many tumors, including the lymphomas. Higher response rates and an increased chance for cure are achieved with higher doses of selected agents.¹⁵, ¹⁶ For this reason, clinicians generally try to push doses of agents to toxicity to maximize the chance for cure. The optimal dose or AUC for an individual patient with a particular cancer is unknown.

Chemotherapeutic agents cause a wide variety of toxicities (Table 68.1). Myelosuppression and nausea are seen, to some degree, with many anticancer drugs. Nausea and vomiting, although generally self-limited and not life-threatening, are very distressing to patients. The emetogenic potential of antineoplastic agents varies from drug to drug and is dose-dependent¹⁷ (Table 68.2). Serotonin receptors, located within the vagal and splanchnic nerves of the gastrointestinal system and in the brain, are critical in the initiation of nausea by chemotherapeutic agents. The development of specific type 3 serotonin (5-hydroxytryptamine or 5HT₃) receptor blockers, such as ondansetron, dolasetron, and granisetron, and NK-1 inhibitors, such as aprepitant, has resulted in major improvement in control of chemotherapy-induced emesis.¹⁷, ¹⁸

FIGURE 68.5. Schematic representation curves relating drug concentrations to response. Antibacterial agents (A) have a wide therapeutic window, with a significant difference in the dose that produces bacterial cell kill and the dose that causes toxicity to normal tissues. For antineoplastic drugs (B), the therapeutic window is narrow (e.g., doses adequate to produce tumor cell kill usually produce toxicity to normal tissues). For a few cancers, such as ovarian (C), the shape of the dose-response curve has been defined.¹⁴ For most tumors, however, a specific dose-response (or AUC-response curve) has not been defined.

Myelosuppression is the most common dose-limiting antineoplastic agent toxicity. The suppression of hematopoietic cell lines is determined by the kinetics of the specific cell line in the peripheral compartment. Anemia occurs as a late effect because of the long half-life of red blood cells (120 days). Thrombocytopenia occurs in an intermediate time frame (platelet half-life 5 to 7 days), whereas granulocyte suppression occurs earliest. Granulocytopenia is a more frequent occurrence than thrombocytopenia or anemia. The white blood cell count usually drops 5 to 14 days after drug administration, with recovery by 7 to 21 days. Several exceptions are recognized, such as a predominant thrombocytopenia seen with carboplatin and delayed myelosuppression with busulfan and the nitrosoureas (occurring 4 to 5 weeks posttherapy). The degree and duration of bone marrow suppression are related directly to the dose of drug administered. High-dose chemotherapy regimens, used with stem cell transplantation, generally result in 10 to 25 days with neutrophils <500/mm³ and thrombocytopenia lasting for a more extended period. The length of cytopenias depend upon the stem cell source with peripheral blood shorter (10 to 14 days) than bone marrow (20 to 25 days). An increased risk of infectious complications occurs that is related directly to the degree and duration of granulocytopenia.¹⁹ The development of recombinant hematopoietic colony-stimulating factors (CSFs), such as erythropoietin, thrombopoietin, granulocyte-macrophage CSF, and granulocyte-CSF, has shortened the duration of bone marrow suppression but not eliminated it. CSFs are now commonly used prophylactically with regimens expected to produce an incidence of febrile neutropenia >20%. Guidelines for the use of these important, yet expensive, factors are available and should be followed.²⁰

The range of toxicities associated with antineoplastic agents is too great to review in detail in this chapter. Readers are referred to reviews on endocrine,²¹ oral,²² renal,²³ neurologic,²⁴ hepatic,²⁵ pulmonary,²⁶ cardiac,²⁷ and cutaneous²⁸ toxicities of antineoplastic agents. Physicians must also remember that most antineoplastic agents have teratogenic and mutagenic potential. Alkylating agents are the most damaging to testicular and ovarian function. Damage is dependent on drug dose, the age of the patient (older patients are more likely to experience toxicity), and sex (males more than females).²⁹ Second malignancies (primarily acute leukemia) have been associated with alkylating agents, epipodophyllotoxins, nitrosoureas, and anthracyclines.³⁰ Concomitant radiation therapy increases the risk of second malignancies (such as sarcomas or breast cancer) 5 to 20 years following therapy.

General Pharmacologic Principles

Antitumor activity of an antineoplastic agent is best correlated with the concentration of drug that reaches the site of drug action within the cancer cell (Fig. 68.5A). Several factors may affect what happens to a drug following administration until it reaches its site of action (Fig. 68.6). Pharmacokinetics describes what happens to a drug following administration (what the body does to the drug). Pharmacokinetics represents an attempt to predict quantitatively how a patient will handle a given dose of drug.³¹ Important pharmacokinetic parameters include (a) bioavailability or absorption, (b) volume of distribution, (c) clearance or drug elimination, and (d) drug half-life (Fig. 68.7). Pharmacodynamics describes what effect the drug has on a particular tissue (what the drug does to the body).

TABLE 68.1 ANTINEOPLASTIC DRUG TOXICITY

Nausea/Vomiting	Bone Marrow	Mucositis	Alopecia	Neurologic	Diarrhea	Hepatic	Vesicant	Pulmonary	Renal	Cardiac	Hypersensitivity
Actinomycin	Actinomycin^a	Actinomycin^a	Actinomycin	Ara-C^a	Arsenic trioxide	Asparaginase	Daunorubicin	Arsenic trioxide	5-Azacytidine	Arsenic trioxide	Asparaginase^a
Asparaginase	Alemtuzumab	Ara-C	Amsacrine	Asparaginase	Asparaginase	Azathioprine	Doxorubicin	ATRA^a	Bevacizumab	Cyclophosphamide	Bleomycin
Arsenic trioxide	Alkylating agents	Busulfan	Ara-C	Bortezomib^a	Ara-C	Ara-C	DTIC	Ara-C^a	Carboplatin	Desatinib	Denileukin diftitox^a
Ara-C	Asparaginase	Bleomycin	Bleomycin	Busultan	Denileuken diftitox	BCNU	Epirubicin	Azathioprine	Cisplatin	Daunorubicin	Docetaxel
Azacytidine	Ara-C^a	Capcitibine	Busulfan	Carboplatin	Dasatinib	Busulfan	Idarubicin^a	Bleomycin^a	Cladribine	Doxorubicin	Etoposide
Bortezomib	Azacytidine	Cyclophosphamide	Cyclophosphamide	Cisplatin^a	Doxorubicin	Clofarabine	Mechlorethamine	Busulfan	Fludarabine^a	Epirubicin	Monoclonal antibodies
Carboplatin	Bendamustine	Daunorubicin^a	Cytarabine	Cladribine	Fludarabine	Cytarabine	Mitomycin^a	Chlorambucil	Gemcitabine	Fluorouracil	HMM
Carmustine^a	Bortezamib	Docetaxel	Daunorubicin	Fludarabine	Fluorouracil^a	Dactinomycin	Mitoxantrone^a	Cyclophosphamide	Ifosfamide^a	Idarubicin^a	Paclitaxel
Cisplatin^a	Busulfan^a	Doxorubicin^a	Docetaxel	Fluorouracil^a	HMM	DTIC	Vinblastine^a	Dasatinib	Interferon	Mitoxantrone	Teniposide
Cyclophosphamide^a	Carboplatin^a	Epirubicin	DTIC	Gemcitabine	Idarubicin	Gemcitabine	Vincristine^a	Etoposide	Methotrexate	Trastuzumab
Daunorubicin^a	Chlorambucil^a	Etoposide	Doxorubicin	HMM	Imatinib	Interferon	Vinorelbine^a	Fludarabine	Mitomycin
Decitibine	Cladribine	Fludarabine^a	Etoposide	Ifosfamide^a	Irinotecan^a	Interleukin-2		Gemcitabine	Nitrosoureas
Denileuken- diftitox	Clotarabine	Hydroxyurea	Fluorouracil	Interferon	Methotrexate	L-Asparaginase^a		Ifosfamide	Pentostatin
Doxorubicin^a	Cyclophosphamide^a	Fluorouracil	Hydroxyurea	L-Asparaginase^a	Thioguanine	Imatinib		Irinotecan	Sorafenib
DTIC^a	Daunorubicin^a	Idarubicin	Idarubicin	Lenalidomide	Topotecan^a	Interferon^a		Lenalidomide	Streptozocin^a
Epirubicin	Decitibine	Ifosfamide	Ifosfamide	Methotrexate		Mercaptopurine		Mercaptopurine	Sunitinib
Etoposide	Docetaxel^a	Methotrexate^a	Irinotecan	Nitrosoureas		Methotrexate^a		Methotrexate^a	Carboplatin
Fludarabine	Doxorubicin^a	Mercaptopurine	Methotrexate	Nelarabine		Paclitaxel		Melphalan	Cisplatin
Fluorouracil	DTIC^a	Mitomycin	Mitoxantrone	Oxaliplatin^a		Mitomycin		Mitomycin^a	Cladribine
Gemcitabine	Etoposide^a	Mitoxantrone	Mustard	Paclitaxel^a		Nitrosoureas		Nitrosoureas^a	Fludarabine^a
HMM^a	Fludarabine^a	Nitrosoureas	Nitrosoureas	Pentostatin		Sunitinib		Oxaliplatin	Gemcitabine
Imatinib mesylate	Hydroxyurea^a	Paclitaxel	Paclitaxel	Procarbazine		Thioguanine		Procarbazine
Hydroxyurea	Ibitumomab	Procarbazine	Procarbazine	Rituzimab		Tretinoin		Paclitaxel
Idarubicin	Idarubicin^a	Taxotere	Vinblastine	Thalidomide^a				Thalidomide
Ifosfamide	Ifosfamide^a	Thioguanine	Vincristine	Tretinoin				Vinca alkaloids
Interferon	Interferon	Thiotepa (high-dose)	Vinorelbine	Vinblastine^a
Irinotecan	Irinotecan	Vinblastine		Vincristine^a
Mechlorethamine^a	Lenalidomide	Vincristine		Vinorelbine^a
Methotrexate	L-PAM^a
Mitomycin	Methotrexate
Mitoxantrone	Mercapto purine^a
Mustard^a	Mitomycin^a
Nitrosoureas	Mitoxantrone^a
Irinotecan	Mustard^a
Pentostatin	Nelarabine
Procarbazine	Nitrosoureas^a
Romidespin	Paclitaxel^a
Streptozocin^a	Pentostatin
Thioguanine	Procarbazine
Thiotepa	Romidespin
Topotecan	Teniposide^a
Vorinostat	Thioguanine
	Thiotepa
	Tositumomab
	Vinblastine
	Vinorelbine
	Vorinostat
Ara-C, cytosine arabinoside; ATRA, all-trans retinoic acid; DTIC, decarbazine; HMM, hexamethylmelamine; l-PAM, L-phenylalanine mustard.
^aMajor toxicity.

TABLE 68.2 EMETIC POTENTIAL OF SELECTED ANTINEOPLASTIC AGENTS

High (>90% risk)
Carmustine	Dactinomycin
Cisplatin	Mechlorethamine
Cyclophosphamide (>1.5 mg/m²)	Streptozocin
Dacarbazine
Moderate (30-90% risk)
Alemtuzumab	Doxorubicin
Azacytidine	Epirubicin
Bendamustine	Idarubicin
Carbazitaxel	Ifosfamide
Carboplatin	Irinotecan
Clofaribine	Methrotrexate (>250 mg/m²)
Cyclophosphamide (>1.5 g/m²)	Oxaliplatin
Cytarabine (>1 g/m²)	Pralatrexate
Daunorubicin	Temozolomide
Low (10-30% risk)
Bortezomib	Mitomycin
Cytarabine (<1 g/m²)	Mitoxantrone
Docetaxel	Paclitaxel
Eribulin	Panitumumab
Etoposide	Pegylated liposomal doxorubicin
5 Fluorouracil	Pemetrexed
Chlorambucil	Romidesin
Gemcitabine	Temsirolimus
Ixabepilone	Topotecan
Hydroxyurea	Trastuzumab
Melphalan	Vorinostat
Methotrexate (<250 mg/m²)
Minimal (<10% risk)
Bevacizumab	2-Chlorodeoxyadenosine
Bleomycin	Fludarabine
Busultan	Rituximab
Cetuximab	Vinca alkaloids

Bioavailability, the percentage of a dose of drug that reaches the plasma compartment, defines drug absorption (Fig. 68.7). Drugs given intravenously have, by definition, 100% bioavailability. Factors that decrease the bioavailability of orally administered drugs include poor solubility in aqueous solutions or metabolism of the drug by the intestine or liver before entry into the systemic circulation (first-pass effect). Bioavailability of poorly soluble drugs, such as etoposide, decreases at high oral drug doses.³² Bioavailability of orally administered 6-mercaptopurine (6-MP) and 5-fluorouracil is low because of extensive first-pass hepatic drug metabolism.³³, ³⁴ With poor or widely variable bioavailability of a particular agent, an intravenous route of administration is preferred. The most important factor regarding bioavailability is the variation from patient to patient in the amount of oral drug absorbed (coefficient of variation). If bioavailability of an oral anticancer drug were 50% in all patients, simply doubling the drug dose would produce an equivalent response to intravenously administered drug. However, the variation from patient to patient in the AUC achieved is usually greater with oral than with intravenously administered drug.³⁵ Therefore, variation in toxicity is also greater.

After a drug reaches the bloodstream, it is distributed into tissues. Figure 68.8 illustrates a plasma concentration-versustime curve for a drug with a typical two-phase (distribution and elimination) decline in plasma concentration. Distribution may be affected by drug binding to plasma proteins (usually albumin or α₁-acid glycoprotein). Only free drug is biologically active. Decreasing the amount of bound drug by having a low serum albumin concentration or displacing drug from its binding site may increase toxicity (as seen with etoposide).³⁶ Distribution of drug into a “third space,” such as ascites or a pleural effusion, may slow clearance and increase toxicity, as is noted with MTX.³⁷

Clearance is expressed as the volume of biologic fluid (usually plasma) from which a drug can be removed per unit of time. Clearance of most drugs is constant over a range of plasma concentrations, which means that the mechanism for elimination is not saturated. However, some drugs, such as paclitaxel, demonstrate saturable elimination at high plasma concentrations.³⁸ This means that a greater proportional drug effect is noted when high drug doses are employed. Clearance measurements allow physicians to maintain a particular plasma concentration because the dosage rate = clearance × desired plasma concentration.

Removal of drugs from the circulation occurs primarily by metabolism, renal elimination, or hepatic excretion. If urinary excretion is an important route of elimination, renal failure results in slower removal of the drug from the body. Administration of the usual dosage of a drug cleared by the kidney to a patient with renal insufficiency leads to greater drug accumulation and an increased likelihood of toxicity. In such cases, drug dosage needs to be modified to prevent excess toxicity. Using available data on drug clearance, the appropriate dose in renal insufficiency may be calculated as follows: Dose in renal insufficiency = normal dose × (clearance in renal insufficiency ÷ normal clearance)

In contrast to a predictable decline in renal drug clearance when glomerular filtration is reduced, it is not possible to make a general prediction of the effect of liver disease on hepatic biotransformation of drugs. Even in advanced hepatocellular disease, the magnitude of impairment in drug clearance usually is only two- to fivefold. The extent of such changes cannot be predicted by common tests of liver function. Consequently, even when it is suspected that drug elimination is altered in liver disease, there is no quantitative base on which to adjust the dosage regimen other than assessment of clinical response. Antineoplastic drugs for which dose modifications are indicated for renal or hepatic insufficiency are listed in Table 68.3.

The hepatic metabolism of drugs may be altered by genetic deficiency of a metabolizing enzyme or by inhibition of metabolism by another drug. Pharmacogenomics is the study of how a particular patient’s genetic makeup affects drug metabolism. It is now recognized that some patients inherit a mutated gene which produces an inactive or much less active enzyme important in clearing a drug from the body.³⁹ Such patients have a markedly lower drug clearance and a higher incidence of toxicity. Examples include the inherited deficiencies of dihydropyrimidine dehydrogenase, the enzyme that degrades 5-fluorouracil⁴⁰; UGT1A1, the enzyme that inactivates irinotecan⁴¹; and thiopurine methyltransferase, the enzyme that degrades azathioprine and 6-MP.⁴²

FIGURE 68.6. Schematic representation of drug disposition in the body. For a drug to function, it must be taken into the body (1) and the drug must avoid being cleared from the body by metabolism (2) or excretion (5). It must reach its site of action in active form (3), without being inactivated by protein binding (4).

Certain antineoplastic drugs are metabolized by the hepatic P-450 microsomal enzyme system (vincas, epipodophyllotoxins, cyclophosphamide, tyrosine kinase inhibitors, and the taxanes). The activity of the microsomal enzyme systems may be increased with concomitant use of phenobarbital, phenytoin, or other drugs. Use of anticonvulsants has been shown to increase the catabolism of teniposide, a drug eliminated from the body through hepatic microsomal metabolism.⁴³ Clearance of drugs metabolized by the hepatic P-450 enzyme system, such as paclitaxel or Taxotere, can be decreased with concomitant use of P-450 inhibitors, such as ketoconazole or selected antiretroviral agents.

It is important to recognize the unpredictable variation in the way chemotherapeutic drugs are handled by the body. Mean values for bioavailability, clearance, and volume of distribution of anticancer agents have standard deviations of 20%, 50%, and 30%, respectively. This means that target drug concentrations may vary widely from patient to patient, even those whose renal and hepatic function appears similar. This is particularly important for drugs with a low therapeutic index and necessitates that all patients receiving chemotherapy must be carefully monitored.

FIGURE 68.7. Pathway of a drug administered to a patient. Pharmacokinetics describes what the patient’s body does to a drug. Pharmacodynamics describes what the drug does to the patient’s tissues or cancer cells.

Approach to the Patient with Cancer

Before initiating cancer chemotherapy, a physician should (a) verify the accuracy of the diagnosis, (b) understand the natural history of the illness, and (c) identify, with the patient, the goals of therapy. Verification of the diagnosis, in nearly every case, requires histologic documentation of cancer. Once the diagnosis is established, the physician and patient must decide whether cure is possible or palliation is the optimal goal. If cure is the goal, the patient and physician may be willing to tolerate more severe toxicity. The patient must be a partner in such decisions. In many cases, several options may be reasonable and an informed patient can direct the physician as to whether intensive, potentially toxic therapy should be tried for a relatively small chance of cure.⁴⁴, ⁴⁵ Fortunately, curative therapy, even for disseminated disease, is available for many hematologic malignancies, including Hodgkin and non-Hodgkin lymphomas, and acute and chronic leukemia. In some illnesses, such as chronic lymphocytic leukemia and low-grade lymphomas, curative therapy may not be available, but the disease is often indolent. A discussion of these illnesses and their natural histories can reassure patients and help them understand why chemotherapy is not being immediately initiated. If high-dose, aggressive curative chemotherapy is planned, patients and their families need to be aware of anticipated and potential toxicities.

FIGURE 68.8. Plasma concentrations of a typical drug at various times following intravenous administration. Following an early distribution phase, drug concentrations decrease in a log-linear manner. Cp0 is the hypothetical drug plasma concentration at time zero if equilibrium were achieved instantaneously. The drug’s half-life is the time required for its concentration to decrease by half.

TABLE 68.3 DRUGS REQUIRING DOSE ALTERATIONS FOR ORGAN TOXICITY

Nephrotoxicity	Hepatic Toxicity
Arsenic trioxide	Bortezomib
Bleomycin	Cytarabine
Capecitabine	Daunorubicin^a
Carboplatin^a	Doxorubicin^a
Cisplatin^a	Docetaxel^a
Cladribine	Epirubicin^a
Cyclophosphamide (if CrCl < 20 ml/min)	Etoposide
Daunorubicin^a	Everolimus
Deoxycoformycin	5 Fluorouracil
Etoposide	Idarubicin
Fludarabine	Imatinib
Hydroxyurea	Irinotecan^a
Ifosfamide	Ixabepilone
Irinotecan	Nilotinib
Lenalidomide	Paclitaxel^a
Methotrexate^a	Procarbazine
Mithramycin	Temsirolimus
Mitomycin^a	Vinblastine^a
Nitrosoureas^a	Vincristine^a
Oxaliplatin (if CrCl < 20 ml/min)	Vinorelbine^a
Pemetrexede
Pentostatin
Sorafenib
Streptozocin
Topotecan^a
Vandetanib
^aMajor dose adjustment.

The use of chemotherapy for treatment of an individual requires a detailed knowledge of the patient, including his or her medical and psychological status, specific knowledge of the drugs to be used, and the availability of appropriate laboratory and hospital support services. Combination chemotherapy (use of several drugs simultaneously) is usually employed and multiple cycles of drugs administered to achieve adequate tumor cell kill without life-threatening toxicity or the development of tumor cell resistance. Certain patient selection factors are important in planning treatment. Age alone is seldom a reason to exclude patients from chemotherapy.⁴⁶ However, age-related changes in organ function, including reduced marrow reserve, abnormal liver function tests, and decreased renal function, are commonly seen and may increase the risk of toxicity. The performance status of a patient (either Karnofsky or American Joint Committee on Cancer scale) usually correlates with response and tolerance to chemotherapy (Table 68.4).

The nutritional state of a patient is important. Malnourished patients with hypoalbuminemia may have increased toxicity when highly protein-bound drugs are used.³⁶

Guidelines for dosing of chemotherapy drugs in obese patients have been developed.⁴⁷ Doses based on actual body weight are generally recommended, as myelosuppression is the same or less pronounced in the obese than the non-obese cancer patient given full-weight-based doses. Fixed dosing of carboplatin, vincristine, and bleomycin is appropriate. Altered organ function may eliminate the opportunity to use certain drugs (e.g., doxorubicin in patients with heart failure or bleomycin in patients with severe pulmonary toxicity). Drug doses may require modification for decreases in blood counts (Table 68.5) and also for changes in renal and hepatic function (see General Pharmacologic Principles).

It is common to re-evaluate patients after two to four cycles of chemotherapy to determine treatment effectiveness. If a response is seen, therapy is usually continued for a set number of courses or two cycles past a complete response. If tumor progression is noted, therapy should generally be discontinued. For patients with stable disease, an assessment of drug toxicity is important. If therapy is tolerable, a decision to continue treatment is reasonable, with the understanding that disease progression will eventually occur. Physicians administering potentially toxic chemotherapy must make certain that they have appropriate monitoring and support facilities available for their patients in the event of untoward toxicity.

DRUGS USED TO TREAT CANCER

A comprehensive review of the pharmacology of all chemotherapeutic agents is beyond the scope of this chapter. This section focuses on those agents most commonly used in the therapy of hematologic malignancies. Important information necessary for the optimal use of these drugs requires knowledge of their (a) mechanism of action; (b) pharmacology, including bioavailability, routes of elimination, and important drug interactions; and (c) toxicities. Table 68.6 summarizes this information for the majority of antineoplastic agents. A more detailed review of the agents commonly used to treat hematologic malignancies follows.

TABLE 68.4 KARNOFSKY AND AMERICAN JOINT COMMITTEE ON CANCER (AJCC) PERFORMANCE STATUS SCALES

Karnofsky Description	Karnofsky Scale (%)	AJCC Scale	AJCC or ECOG Description
Normal; no complaints; no evidence of disease	100	0	Normal activity
Able to carry on normal activity; minor signs or symptoms of disease	90
Normal activity with effort; some signs or symptoms of disease	80	1	Symptomatic and ambulatory; cares for self
Cares for self; unable to carry on normal activity or to do active work	70
Requires occasional assistance but is able to care for most of own needs	60	2	Ambulatory >50% of time; occasionally needs assistance
Requires considerable assistance and frequent medical care	50	3	Ambulatory 50% or less of time; nursing care needed less of time
Disabled; requires special care and assistance	40
Severely disabled; hospitalization indicated although death not imminent	30
Very sick; hospitalization necessary; active supportive treatment necessary	20	4	Bedridden; may need hospitalization
Moribund, fatal processes progressing rapidly	10
Dead	0

Alkylating Agents (Actinomycin-D, Bendamustine, Busulfan, Chlorambucil, Cyclophosphamide, Dacarbazine, Hexamethylmelamine, Ifosfamide, Melphalan, Mechlorethamine, Mitomycin C, Nitrosoureas (BCNU, CCNU), Procarbazine, Streptozocin, Temozolomide, Thiotepa)

Mechanism of Action

Alkylating agents covalently bind alkyl groups (one or more saturated carbon atoms) to cellular molecules, including DNA, RNA, and proteins. Alkylating agents form reactive carbonyl groups in plasma and within tissues. Attack at electron-rich sites on adenine or guanine (S_N 1 agents) in DNA is the primary mechanism for cytotoxicity.⁴⁸ The pattern of DNA lesions generated by an alkylating agent depends on the number of reactive sites within the alkylating agent, its particular reactivity, the type of alkyl group addition (methyl or chloroethyl) and the DNA substrate (double- or single-strand). Many alkylating agents (bendamustine, chlorambucil, cyclophosphamide, ifosfamide, mustard, melphalan) contain two reactive nitrochlorethyl groups, which allow them to react with both strands of DNA, forming cross-linkage (Fig. 68.9). Other agents (procarbazine, dacarbazine, temozolomide) produce single-strand alkylation. Most alkylators preferentially attack the N⁷ position of guanine. Nitrosoureas, procarbazine, and dacarbazine (DTIC) attack the O⁶ position. Depending on the site of DNA binding, the base adducts produced by alkylating agents block DNA replication and transcription, leading to cell death. However, alkylating agents may also compromise genome integrity, inducing mutagenesis. Alkylating agents are cell cycle-nonspecific.

TABLE 68.5 GENERALIZED DOSE ADJUSTMENT GUIDELINES FOR HEMATOLOGIC TOXICITY^a

	100% Dose	75% Dose	50% Dose	Omit
Granulocyte	>2,000	1,500-1,999	1,000-1,499	<1,000
White blood cell	>3,500	3,000-3,500	2,500-2,999	<2,500
Platelet	>100,000	75,000-100,000	50,000-75,000	<50,000
^aIn selected circumstances, such as the treatment of leukemia, these guidelines do not apply. Specific guidelines accompanying individual protocols should be sought.

There are multiple enzymes that have been identified that can repair the genomic damage caused by alkylating agents.⁴⁸ An example is the repair of alkylation sites on DNA by O⁶ methyl transferase; the overexpression of this enzyme in a cancer cell produces resistance to nitrosoureas but not to nitrogen mustard or cyclophosphamide.⁴⁹ An imbalance of any one repair enzyme can increase or decrease the alkylation sensitivity of a cell. Inhibitors of DNA-repair enzymes (such as Poly ADP ribose polymerase or PARP) may increase cell sensitivity to alkylating agents.

The most widely used alkylating agents in hematology are the nitrogen mustards: mechlorethamine, cyclophosphamide, ifosfamide, melphalan, and chlorambucil. Thiotepa is an aziridine that is closely related to the mustards. Busulfan is an alkyl sulfonate that has a poorly understood selective toxicity for myeloid precursors. Procarbazine and DTIC are metabolized to reactive intermediates that decompose to produce methyl diazonium, which covalently binds DNA. The basis of cytotoxicity of these nonfunctional alkylating agents is probably the formation of DNA strand breaks and inhibition of DNA polymerase.⁵⁰ Bendamustine, a recently FDA-approved alkylating agent for treatment of chronic lymphocytic leukemia and lymphomas, regulates different genes compared to other alkylating agents.⁵¹ It is not cross resistant with other alkylators and is effective against both quiescent and dividing cells. It produces more durable and extensive DNA double-stand breaks than do cyclophosphamide or melphalan.

Cellular thiols can provide nucleophilic targets, which bind alkylating agents before they reach their DNA target. Increasing or decreasing the concentration of thiols can decrease or increase antineoplastic drug activity and/or toxicity. Buthione sulfonamide (BSO) decreases glutathione synthesis (a naturally occurring thiol) and increases alkylating agent cytotoxicity.⁵² Amifostine (WR2721) provides an exogenous nucleophilic thiol that can decrease alkylating agent toxicity.⁵³

TABLE 68.6 CHEMOTHERAPEUTIC AGENTS (EXCLUDING HORMONAL AGENTS)

Name (Synonym)	Drug Class	Action	Clearance Route^a	Major Toxicity
Alemtuzumab (Campath^®)	Radioactive monoclonal antibody	Binds to CD₅₂ to target radioactivity	Radioactive extinction	Myelosuppression Hypersensitivity reaction Infection
Altretamine (Hexalen^®, hexamethylmelamine)	Nonclassical alkylating agent	Unknown, may alkylate DNA	Hepatic metabolism	Hypersensitivity reaction, deficient synthesis of key proteins (clotting factors, insulin), CNS depression, pancreatitis
Anagrelide (Agrylin^®)	Phospholipase inhibitor	Prevents megakaryocytes from maturing	Metabolism via CYP/A2	Palpitations, headache, nausea, abdominal pain, dizziness
Arsenic trioxide (Trisenox^®, ATO)	Targeted drug	Degrades PML-RAR fusion protein	Hepatic metabolism	APL differentiation syndrome, Q-T prolongation, nausea, fatigue
Asparaginase (Elspar^®, Oncaspar^®, pegasparaginase)	Enzyme	Breaks down the amino acid asparagine; sensitive lymphocytes lack ability to synthesize asparagine	Hepatic metabolism	N&V, neurotoxicity, myelosuppression, diarrhea, diabetes, anticoagulation
Azacitidine (Vidaza^®)	Hypomethylating agent	Inhibitor of DNA methylation	Hepatic metabolism	Myelosuppression
Bexarotene (Targretin^®)	Retinoid	Binds to the retinoid X receptor to induce cellular differentiation	Oxidative hepatic metabolism	Hepatotoxicity, hyperlipidemia, hypothyroidism, photosensitivity, teratogenicity
Bendamustine (Trenda^®)	Alkylating agent	Forms DNA cross-links	Hydrolysis in plasma to inactive metabolites	Nausea, fatigue, myelosuppression, fever
Bevacizumab (Avastin^®)	Monoclonal antibody to VEGF	Decreases angiogenesis	Protein degradation	Hypertension, headache, bleeding, thrombosis, proteinurea
Bleomycin (Blenoxane^®)	Antibiotic	Single-strand DNA breaks	Renal	Hypersensitivity reaction, pulmonary fibrosis, skin and mucocutaneous reactions, fevers
Bortezomib (Velcade^®)	Proteosome inhibitor (targeted agent)	Inhibits protein destruction blocking NFK-β	Oxidative hepatic metabolism	Nausea, fatigue, diarrhea, peripheral neuropathy, thrombocytopenia
Brentuximab vedotin	Monoclonal antibody	Binds with CD30 antigen with toxin then internalized	Hepatic	Hypersensitivity reaction, neuropathy, fatigue, fever, diarrhea, neutropenia
Busulfan (Myleran^®, Busulfex^®)	Alkylating agent	Forms DNA cross-links.	Metabolism	Myelosuppression, hepatotoxicity (venoocclusive disease), pulmonary fibrosis
Capecitibine (Xeloda^®)	Antimetabolite	A 5-FU prodrug	Hepatic metabolism	Diarrhea, myelosuppession, palmar-plantar erythrodysethesia
Carboplatin (CBDCA, Paraplatin^®)	Platinum complex	Produces DNA cross-links	Renal	Thrombocytopenia, leukopenia, nephrotoxicity, ototoxicity, neuropathy, N&V
Carmustine (BCNU)	Nitrosourea	Alkylates DNA at O⁶ position of guanine	Hepatic metabolism	Delayed (4-6 wk) myelosuppression, pulmonary toxicity, hepatotoxicity
Cetuximab (Erbitux^®)	Monoclonal antibody	Binds to the epidermal growth factor receptor	Binding of antibody to receptor	Anaphylactic reaction, skin rash, fevers
Chlorambucil (Leukeran)	Alkylating agent	Cross-links DNA	Metabolism	Myelosuppression, pulmonary toxicity, hepatotoxicity
Cisplatin (CDDP) (Platinol^®)	Platinum complex	Produces DNA cross-links	Protein binding	Nephrotoxicity, N&V, ototoxicity, alopecia, neuropathy
Cladribine (Leustatin^TM) (2-chlorodeoxy adenosine)	Antimetabolite (purine analog)	Incorporation into DNA; NAD consumption	Renal	Myelosuppression, fever, renal toxicity (high-dose)
Clofarabine (Clolar^®)	Antimetabolite	Incorporates into DNA; inhibits DNA polymerase	Renal	Nausea, hepatotoxicity, palmar-plantar erythrodysesthesia
Cyclophosphamide (Cytoxan^®, Neosar^®)	Alkylating agent	Cross-links DNA strands	Hepatic metabolism (renal)	Myelosuppression, N&V, cystitis, cardiac (high-dose)
Cytarabine (Cytosar^®, ara-C, cytosine arabinoside, DepoCyt^TM)	Antimetabolite (pyrmidine analog)	Incorporates into DNA; inhibits DNA polymerase	Hepatic metabolism	Myelosuppression, N&V, mucositis, ocular, hepatic
Dacarbazine (DTIC)	Nonclassical alkylating agent	DNA methylation	Renal (hepatic metabolism)	Vesicant, myelosuppression, N&V, hepatic
Dactinomycin (Cosmegen^®) (actinomycin-D)	Antibiotic	DNA intercalation	Biliary	Myelosuppression, N&V, vesicant, mucositis
Dasatinib (Sprycel^TM)	Targeted agent, signal transduction inhibitor	Inhibits the tyrosine kinase of several growth factor receptors including bcr-abl	Hepatic metabolism (CYP 3A4) and biliary excretion	Fluid retention, N&V, diarrhea, myelosuppression, hypothyroidism
Daunorubicin (Cerubidine^®, Dauno Xome^®)	Antibiotic (anthracycline)	Topoisomerase inhibition, DNA intercalation, free-radical formation	Biliary excretion, hepatic metabolism	Myelosuppression, N&V, cardiomyopathy, vesicant, red urine, mucositis
Decitabine (Dacogen^®)	Hypomethylating agent	Allows activation of tumor suppressor genes	Hepatic deamination	Myelosuppression, fatigue, nausea, teratogen
Denileukin diftitox (Ontak^®)	Toxin-fusion protein	Binds to the IL-2 receptor, where the diphtheria toxin is internalized	Proteolytic degradation	Infusion reactions (fever, hypotension, myalgias), skin rash, transaminitis, vascular leak syndrome, hypothyroidism
Docetaxel (Taxotere^®)	Tubulin binder	Mitotic spindle inhibitor	Hepatic metabolism, biliary excretion	Myelosuppression, hypersensitivity (steroids needed), fluid retention, neuropathy
Doxorubicin (Adriamycin^®, Rubex^®, Myocet^TM, Doxil^®)	Topoisomerase inhibitor (Anthracycline)	Topoisomerase inhibition, free-radical formation	Biliary excretion, hepatic metabolism	Myelosuppression, N&V, cardiomyopathy, vesicant, red urine, mucositis
Epirubicin (Ellence^TM)	Topoisomerase inhibitor (Anthracycline)	Inhibits topoisomerase II	Hepatic metabolism and excretion	Nausea, vomiting, myelosuppression, cardiac toxicity
Erlotinib (Tarceva^®)	Targeted agent	Inhibits the tyrosine kinase of the epidermal growth factor receptor	Hepatic oxidative metabolism	Skin rash, diarrhea
Etoposide (VePesid^®, VP-16, Etopophos^®, Toposar^®, etoposide phosphate)	Topoisomerase inhibitor	Inhibits topoisomerase II	Renal (hepatic metabolism)	Myelosuppression, mucositis, hypersensitivity reaction
Everolimus (Affinitor^®)	Targeted therapy	Blocks oncogenic pathway through m-TOR inhibition	Hepatic metabolism through CYP3A4	Edema, rash, stomatitis, diarrhea, myelosuppression, infection
Fludarabine (fludarabine phosphate, Fludara^®)	Antimetabolite (purine analog)	Inhibits DNA polymerase, incorporation into DNA and RNA, NAD depletion	Renal	Myelosuppression, mucositis, hypersensitivity reaction, neurologic
Fluorouracil (5-FU, Adrucil^®, FUDR^®)	Antimetabolite (pyrimidine analog)	Inhibits thymidylate synthetase, incorporated into DNA and RNA	Hepatic metabolism	Myelosuppression (more with bolus), diarrhea & mucositis (more with continuous infusion), stomatitis, cardiac ischemia, CNS (cerebellar ataxia)
Gefitinib (Iressa^®)	Targeted therapy	Block the tyrosine kinase of EGFR	Hepatic metabolism via CYP3A4	Rash, diarrhea
Gemcitabine (Gemzar^®)	Antimetabolite	Inhibits ribonucleotide reductase, incorporated into DNA as false nucleotide	Metabolism	Myelosuppression, nausea, diarrhea, hepatic, fever
Hydroxyurea (Hydrea^®, Droxia^TM, Mylocel^TM)	Antimetabolite	Inhibits ribonucleotide reductase	Hepatic metabolism, renal	Myelosuppression, mucositis
Idarubicin (Idamycin^®)	Topoisomerase inhibitor (anthracycline)	Similar to doxorubicin	Hepatic	Similar to doxorubicin
Ifosfamide (Ifex^®)	Alkylating agent	Cross-links DNA strands through alkyl groups	Hepatic metabolism, renal excretion.	Myelosuppression, N&V, neurologic, alopecia, cystitis (must be given with MESNA)
Imatinib mesylate (Gleevec^TM, STI-575)	Targeted agent	Inhibits the tyrosine kinase of the bcr-abl and c-kit oncogenes	Hepatic metabolism	Nausea, diarrhea, fluid retention, abnormal LFTs, hypothyroidism
Interferon-α (INF-α, Intron A^®, Roferon^®)	Biologic	Degradation of messenger RNAs, modulation of oncogene expression, increase in NK cells and other immunoregulatory elements	Renal metabolism	Fever, chills, myalgias, headache, fatigue, anorexia, myelosuppression, hepatic, CNS, depression
Ibritumomab (Zevalin^TM)	Monoclonal antibody	Antibody to CD20 coupled to Y⁹⁰	Radioactive decay	Myelosuppression, allergic reactions, hypothyroidism
Irinotecan (Camptosar^®, CPT-11)	Topoisomerase I inhibitor	Inhibits topoisomerase I	Metabolism, biliary excretion	Myelosuppression, diarrhea, pneumonitis, stomatitis
Lenalidomide (Revlimid^®)	Immunomodulator	Uncertain—possible TNF-α inhibitor; inhibits angiogenesis	Renal	Teratogenicity, myelosuppression, DVTs, diarrhea, fatigue
Lomustine (CeeNU^®, CCNU)	Alkylating nitrosourea	Same as carmustine	Same as carmustine	Same as carmustine
Mechlorethamine (nitrogen mustard, Mustargen^®)	Alkylating agent	Cross-links DNA via alkylation	Tissue binding	Vesicant, ototoxicity, myelosuppression, N&V
Melphelan (Alkeran^®, L-PAM, phenylalanine mustard)	Alkylating agent	Cross-links DNA strands via alkylation	Spontaneous degradation, protein binding	Myelosuppression, pulmonary fibrosis (rare), N&V (high-dose)
Mercaptopurine (6-MP, Purinethol^®)	Antimetabolite (purine analog)	Incorporation into DNA	Hepatic metabolism	Myelosuppression, hepatotoxicity
Methotrexate (MTX)	Antimetabolite (folic acid analog)	Inhibits dihydrofolate reductase with decreased thymidylate and protein synthesis	Renal excretion	Myelosuppression, mucositis, hepatotoxicity (chronic low-dose), renal (high-dose), pulmonary
Mitomycin (Mutamycin^®)	Antibiotic	Cross-links DNA strands	Hepatic metabolism	Myelosuppression, N&V, vesicant, pulmonary, hepatic, renal
Mitoxantrone (Novantrone^®, DHAD)	Anthraquinone	Similar to doxorubicin	Hepatic metabolism	Similar to doxorubicin, blue-green urine
Nelarabine (Arranon^®)	Antimetabolite (purine analog)	Incorporated into DNA and blocks DNA replication	Hepatic demethylation	Neurotoxicity including somnolence, fatigue, dizziness, headache, myelosuppression
Nilotinib (Tasigna^®)	Targeted therapy	Inhibits the tyrosine kinase of BCR/ABL	Hepatic metabolism via CYP3A4	Myelosuppression, QT prolongation, N & V, hepatic toxicity, edema
Ofatumumab (Arzerra^®)	Monoclonal antibody	Binds to CD20	Proteolytic degradation	Infusion reaction, infection, myelosuppression, HBV reactivation
Oxaliplatin (Eloxatin^®)	Platinum complex	Produces DNA cross-links	Renal and tissue binding	Hypersensitivity reaction, neuropathy, hepatitis, pulmonary fibrosis
Paclitaxel (Taxol^®, Abraxane^®)	Plant alkaloid	Mitotic spindle inhibitor, stabilizes microtubulin.	Hepatic metabolism, biliary excretion	Myelosuppression, hypersensitivity syndrome (use with steroids and antihistamines), mucositis, neuropathy, myalgia
Panitumumab (Vectibix^TM)	Monoclonal antibody	Binds to EGFR	Proteolytic degradation	Rash, infusion reaction, diarrhea
Pazopanib (Votrient^®)	Targeted agent	Inhibits the TKI of VEGF receptors	Hepatic metabolism via CYP3A4	Hypertension, hair color change, diarrhea, myelosuppression, QT prolongation, hepatotoxicity
Pemetrexed (Alimta^®)	Antimetabolite	An antifolate that inhibits dihydrofolate reductase, and thymidylate synthetase	Renal	Myelosuppression, fatigue, N&V
Pentostatin (Nipent^®, 2-deoxycoformycin)	Antimetabolite (purine analog)	Adenosine deaminase inhibitor.	Renal	Myelosuppression, fever, rash, hepatotoxicity, pulmonary, CNS
Prelatrexate (Folotyn^®)	Antimetabolite	Inhibits DHFR (see methotrexate)	Renal	Myelosuppression, mucositis
Procarbazine (Matulane)	Nonclassical alkylating agent	Alkylates DNA; DNA strand breaks	Hepatic metabolism	Myelosuppression, N&V, CNS (confusion, depression), MAO inhibition, hepatic, pulmonary
Rituximab (Rituxan^®)	Monoclonal antibody	Binds to CD20 on lymphocytes and initiates complementmediated cytotoxicity	Proteolytic degradation	Fevers, hypersensitivity reaction, Hepatitis B reactivation, infection
Sorafenib (Nexavar^®)	Targeted therapy	Inhibits the tyrosine kinase of VEGER, PDGFR, c-kit, and FLT-3	Heptic metabolism: Oxidation and glucuronidation	Fatigue, palmar-plantar erythrodysethesia, hypertension, hyperphosphatemia, rash proteinuria
Streptozocin (Zanosar^®)	Alkylating nitrosourea	Methylation of O⁶-guanine of DNA	Renal	Myelosuppression, N&V, renal, diabetes, vesicant
Sunitinib (Sutent^®)	Targeted therapy	Inhibits the tyrosine kinases of VEGFR, PDGFR, c-kit; inhibits angiogenesis	Hepatic oxidative metabolism	Hypertension, bleeding, diarrhea, mucositis, fatigue
Temozolomide (Temodar^®)	Atypical alkylating agent	Methylates DNA guanine resulting in strand breaks	Metabolism by hydrolysis	Myelosuppression, N & V, fatigue
Teniposide (VM-26, Vumon^®)	Microtubulin inhibitor	Binds to topoisomerase II, causing DNA strand breaks	Hepatic metabolism	Myelosuppression, hypersensitivity reactions
Temsirolimus (Torisel^®)	Targeted agent	Inhibits m-TOR	Hepatic metabolism and biliary excretion	Edema, hyperlipidemia, myelosuppression, hepatic toxicity, hyperglycemia
Thalidomide (Thalomid^®)	Immunomodulatory agent	Suppresses TNF, blocks angiogenesis, increases IL2 and interferon	Nonenzymatic hydrolysis	Birth defects, thrombosis, fatigue, somnolence, neuropathy
Thioguanine (6-thioguanine, 6-TG, Tabloid^®)	Antimetabolite (purine analog)	Incorporates into DNA as fraudulent nucleotide	Hepatic metabolism	Myelosuppression, hepatic venoocclusive disease
Thiotepa (Thioplex^®)	Alkylating agent	Trifunctional alkylating agent, cross-links DNA	Metabolism	Myelosuppression, stomatitis
Topotecan (Hycamtin^®)	Topoisomerase I inhibitor	Inhibits the enzyme topoisomerase I, causing DNA stand breaks	Renal	Myelosuppression, N&V
Tositumomab (Bexxar^®)	Monclonal antibody	Radioactive drug that binds to CD20	Proteolytic degradation	Myelosuppression, fever, nausea, hypersensitivity reaction
Trastuzumab (Herceptin^®)	Monoclonal antibody	Binds to the Her2^neu oncogene, resulting in apoptosis	Protein binding and proleotytic degradation	Hypersensitivity reaction, cardiomyopathy, fever, diarrhea
Tretinoin (ATRA, Vesanoid^®)	Targeted retinoid therapy	Induces maturation of promyelocytes	Hepatic oxidative metabolism and glucuronidation	Fever, dyspnea, pulmonary infiltrates (retinoic acid symdrome), headache, fever, neurologic, hepatic
Venmurafanib (Zelboraf^®)	Targeted agent	Inhibits the tyrosine kinase of the BRAF oncogene	Hepatic metabolism	Rash, erythema, squamous cell skin cancers, photosensitivity, abnormal LFTs, fatigue
Vinblastine (Velban^®, VLB)	Microtubulin inhibitor	Binds to tubulin, prevents formation of mitotic spindle	Hepatic	Myelosuppression, vesicant, neurotoxin
Vincristine (Oncovin^®, Vincasar^®, VCR)	Microtubulin inhibitor	Binds to tubulin, prevents formation of mitotic spindle	Hepatic	Neurotoxin, vesicant, CNS
Vinorelbine (Navelbine^®)	Microtubulin inhibitor	Binds to tubulin, prevents formation of mitotic spindle	Hepatic	Myelosuppression, vesicant, neuropathy
Vismodegib (Erivedge^®)	Targeted agent	Inhibits the Hedgehog signaling pathway	Hepatic metabolism and excretion	Teratogenic, fatigue, muscle spasms, diarrhea, alopecia
Vorinostat (Zolinza^®)	Histone deacytylase inhibitor	Inhibits histone deacytelase to unmask DNA methylation	Hepatic	Fatigue, diarrhea, N&V pulmonary emboli